Next Article in Journal
A Simple Method for the Prediction of Therapeutic Proteins (Monoclonal and Polyclonal Antibodies and Non-Antibody Proteins) for First-in-Pediatric Dose Selection: Application of Salisbury Rule
Next Article in Special Issue
Structural Investigation of Therapeutic Antibodies Using Hydroxyl Radical Protein Footprinting Methods
Previous Article in Journal
Integrating Single Domain Antibodies into Field-Deployable Rapid Assays
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Antibodies
Volume 11
Issue 4
10.3390/antib11040065
antibodies-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

IMGT® Nomenclature of Engineered IGHG Variants Involved in Antibody Effector Properties and Formats

by
Marie-Paule Lefranc
* and
Gérard Lefranc
*
IMGT®, The International ImMunoGeneTics Information System®, Laboratoire d’ImmunoGénétique Moléculaire (LIGM), Institut de Génétique Humaine (IGH), Centre National de la Recherche Scientifique (CNRS), Université de Montpellier (UM), UMR 9002 CNRS-UM, CEDEX 5, 34396 Montpellier, France
*
Authors to whom correspondence should be addressed.
Antibodies 2022, 11(4), 65; https://doi.org/10.3390/antib11040065
Submission received: 17 August 2022 / Revised: 10 October 2022 / Accepted: 12 October 2022 / Published: 18 October 2022
(This article belongs to the Special Issue Higher Order Structure Characterization of Therapeutic Antibodies-Second Volume)
Browse Figures
Versions Notes

Abstract

:
The constant region of the immunoglobulin (IG) or antibody heavy gamma chain is frequently engineered to modify the effector properties of the therapeutic monoclonal antibodies. These variants are classified in regards to their effects on effector functions, antibody-dependent cytotoxicity (ADCC), antibody-dependent phagocytosis (ADCP), complement-dependent cytotoxicity (CDC) enhancement or reduction, B cell inhibition by the coengagement of antigen and FcγR on the same cell, on half-life increase, and/or on structure such as prevention of IgG4 half-IG exchange, hexamerisation, knobs-into-holes and the heteropairing H-H of bispecific antibodies, absence of disulfide bridge inter H-L, absence of glycosylation site, and site-specific drug attachment engineered cysteine. The IMGT engineered variant identifier is comprised of the species and gene name (and eventually allele), the letter ‘v’ followed by a number (assigned chronologically), and for each concerned domain (e.g, CH1, h, CH2 and CH3), the novel AA (single letter abbreviation) and IMGT position according to the IMGT unique numbering for the C-domain and between parentheses, the Eu numbering. IMGT engineered variants are described with detailed amino acid changes, visualized in motifs based on the IMGT numbering bridging genes, sequences, and structures for higher order description.

1. Introduction

The adaptive immune response, acquired by jawed vertebrates (or gnathostomata) more than 450 million years ago and found in all extant jawed vertebrate species from fish to humans, is characterized by a remarkable immune specificity and memory, which are the properties of the B and T cells because of the extreme diversity of their antigen receptors [1]. The antigen receptors of the adaptive immune response [1,2] comprise the immunoglobulins (IG) or antibodies of the B cells and plasmocytes [3,4] and the T cell receptors (TR) of the T cells [5]. The IG recognizes antigens in their native (unprocessed) form, whereas the TR recognizes processed antigens, which are presented as peptides through its highly polymorphic major histocompatibility (MH, in humans HLA for human leucocyte antigens) proteins [6]. Immunoglobulins (IG) or antibodies serve a dual role in immunity. First, they both recognize antigens on the surface of foreign bodies such as bacteria and viruses, and second, they trigger elimination mechanisms such as cell lysis and phagocytosis to rid the body of these invading cells and particles [4]. IMGT®, the international ImMunoGeneTics information system® (https://www.imgt.org) (accessed on 11 October 2022) [1], was created in 1989 by Marie-Paule Lefranc in Montpellier, France, Laboratoire d’ImmunoGénétique Moléculaire (LIGM) des Prof G. and M-P. Lefranc (Université de Montpellier and CNRS) to manage the huge diversity of the IG and TR repertoires. For the first time, immunoglobulin (IG) or antibody and T cell receptor (TR) variable (V), diversity (D), joining (J) and constant (C) genes were officially recognized as ‘genes’ and conventional genes [1,3,5,7,8,9,10]. Through its creation, IMGT® marks the advent of a new science, immunoinformatics, which emerged at the interface between immunogenetics and bioinformatics [1]. As an ontology and system, IMGT® bridges genes, sequences and structures of the antigen receptors to better understand their functions. Focusing on the constant region of the IgG, a standardized definition of engineered variants of therapeutic antibodies is provided based on the IMGT concepts.

2. An Ontology and a System to Bridge Genes, Sequences and Structures to Functions

IMGT®, the international ImMunoGeneTics information system® (Figure 1) [1,11,12,13,14,15,16,17,18,19,20,21], is an integrated system for the genes, sequences and structures of the IG or antibodies, TR and MH of the adaptive immune responses of the jawed vertebrates, as well as other proteins of the IG superfamily (IgSF) [22] and MH superfamily (MhSF) of vertebrates and invertebrates [23].
Immunoinformatics [1] builds and organizes molecular immunogenetics knowledge to be managed and shared in IMGT®. IMGT® comprises seven databases [24,25,26,27,28,29,30], 17 tools [31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50] and more than 25,000 pages of web resources (Table 1). IMGT® dababases are specialized in sequences (i.e., IMGT/LIGM-DB [24,25]), genes and alleles (IMGT/GENE-DB [26]), two-dimensional (2D) structures (IMGT/2Dstructure-DB) and three-dimensional (3D) structures (IMGT/3Dstructure-DB) [27,28,29], whereas the IMGT/mAb-DB [30] interface allows the querying of therapeutic monoclonal antibodies (IG, mAb), fusion proteins for immunological applications (FPIA), composite proteins for clinical applications (CPCA) and related proteins (RPI) of therapeutic interest (with links to amino acid sequences in IMGT/2Dstructure-DB, and if available, to 3D structures in IMGT/3D structure-DB. The IMGT® tools include: (1) For nucleotide sequence analysis, IMGT/V-QUEST [31,32,33,34,35,36] and the integrated IMGT/JunctionAnalysis [37,38] and IMGT/Automat [39,40] tools, and for next generation sequencing, the high-throughput version IMGT/HighV-QUEST [36,41,42,43,44,45] and the downloadable IMGT/StatClonotype [46,47] package (which allows for statistical pairwise analysis of the diversity and expression of the IMGT clonotypes (AA) [43] and repertoire comparisons in adaptive immune responses); (2) for genomic analysis, IMGT/LIGMotif [48] (which allows for the identification and description of new genes in genomic sequences); (3) for amino acid sequence analysis per the domain, IMGT/DomainGapAlign [28,49,50]; and (4) for graphical representations of the domains, the IMGT/Collier-de-Perles tool [51] (e.g., IMGT Colliers de Perles of the variable (V), constant (C) and groove (G) domains). IMGT® Web resources (‘the IMGT Marie-Paule page’) comprise the IMGT Repertoire (IG and TR, MH and RPI), IMGT Scientific chart, IMGT Education (IMGT Lexique, Aide-mémoire (amino acid physicochemical properties [52], splicing sites) and tutorials, etc.).
The bridging of genes, structures and functions is based on the IMGT-ONTOLOGY axioms and concepts from which were generared the IMGT Scientific chart rules [78,79,80,81,82] (Table 2): CLASSIFICATION for theIMGT standardized gene and allele nomenclature [1,2,3,4,5,7,8,9,10,61,62,63], IDENTIFICATION for IMGT standardized keywords and keyword abbreviations (e.g., clonotype, paratope and epitope, variant, Fc receptor and FcR) [53,54], DESCRIPTION forIMGT standardized labels [55,56,57,58] (e.g., complementarity determining region (CDR)-IMGT (CDR1-IMGT to CDR3-IMGT) [57] and framework region (FR-IMGT) (FR1-IMGT to FR4-IMGT) [58]), NUMEROTATION for the IMGT unique numbering [64,65,66,67,68,69,70,71,72] and the IMGT Colliers de Perles [51,73,74,75,76,77]. IMGT positions per domain are used in Protein displays, Alignments of alleles, CDR-IMGT lengths, Allotypes [59,60] sections of the IMGT Repertoire, and to number amino acids involved in paratope/epitope (antigen receptor V-domains/target interactions [83]) (Table 1) and in effector properties (antigen receptor C-domain/effector binding proteins [6]).
IMGT standards have been used since 2006 in the description of the therapeutic antibodies published in the World Health Organization’s (WHO) International Nonproprietary Names (INN) programme [84,85,86]. Since 2003, IMGT® has been widely used in the analysis of therapeutical antibodies for humanization and/or engineering [4,11,13,87,88,89,90,91,92,93,94,95,96].

3. Immunoglobulin IgG Receptor, Chains, Domains and Amino Acids

The Homo sapien’s IgG1-kappa (Figure 2) is taken as an example (Table 3) because it is the most represented subclass in therapeutic antibodies.
In the IMGT system, the C-domain includes the C-DOMAIN of the IG and of the TR [1] and the C-LIKE-DOMAIN of the IgSF other than IG and TR [22]. The C-domain description of any receptor, any chain and any species is based on the IMGT unique numbering for the C-domain (C-DOMAIN and C-LIKE-DOMAIN) [68]. A C-domain (Figure 3) comprises about 90–100 amino acids and is made up of seven antiparallel beta strands (A, B, C, D, E, F and G), linked by beta turns (AB, DE and EF), a transversal strand (CD) and two loops (BC and FG), and forms a sandwich of two sheets [ABED] [GFC]. A C-domain has a topology and a three-dimensional structure that is similar to that of a V-domain [67], but without the C’ and C’’ strands and the C’C’’ loop, which is replaced by a transversal CD strand [68]. The lengths of the strands and loops (Table 4) are visualized in the IMGT Colliers de Perles on one layer and two layers (Figure 3).
There are six IMGT anchors in a C-domain (four of them identical to those of a V-domain): Positions 26 and 39 (anchors of the BC loop), 45 and 77 (by extension, anchors of the CD strand as there is no C’-C’’ loop in a C-domain [68]), and 104 and 118 (anchors of the FG loop). A C-domain has five characteristic amino acids at given positions (positions with bold (online red) letters in the IMGT Colliers de Perles). Four of them are highly conserved and hydrophobic [52] and are common to the V-domain: 23 (1st-CYS), 41 (CONSERVED-TRP), 89 (hydrophobic) and 104 (2nd-CYS). These amino acids contribute to the two major features shared by the V and C-domains: The disulfide bridge (between the two cysteines 23 and 104) and the internal hydrophobic core of the domain (with the side chains of tryptophan W41 and amino acid 89). The fifth position, 118, is diverse and is characterized as being an FG loop anchor. In the IMGT system, the C-domains (C-DOMAIN and C-LIKE-DOMAIN) are delimited considering the exon delimitation, whenever appropriate, allowing the integration of strands A and G, which do not have structural alignments.
The 20 usual amino acids (AA) have been classified in eleven IMGT physicochemical classes [52] (IMGT® https://www.imgt.org, IMGT Education > Aide-mémoire > Amino acids) (Figure 4).

4. IGHG, IGKC and IGLC2 Engineered Variants

One hundred and fourteen IGHG engineered variants have been defined by their IMGT gene nomenclature, the IMGT unique numbering for C-domain [68] and IMGT motifs in domain strands and/or loops (Table 4, Figure 3), with corresponding Eu positions [97] (IMGT https://www.imgt.org, IMGT Scientific chart > Correspondence between C numberings > Correspondence between the IMGT unique numbering for C-DOMAIN, the IMGT exon numbering, the EU and Kabat numberings: Human IGHG [97,98] https://www.imgt.org/IMGTScientificChart/Numbering/Hu_IGHGnber.html) (Supplementary Table S1). The IGKC and IGLC2 engineered variants involved in the structure have also been defined similarly by their IMGT gene nomenclature, the IMGT unique numbering for the C-domain [68] and IMGT motifs in the domain strands and/or loops (Table 4), with corresponding Eu positions [97] (IMGT https://www.imgt.org, IMGT Scientific chart > Correspondence between C numberings > Correspondence between the IMGT unique numbering for the C-DOMAIN, the IMGT exon numbering, the EU and Kabat numberings: Human IGKC [97,98].
The correspondence between the IMGT unique numbering and the Eu positions are provided here in a horizontal format for the IGHG1 CH1, hinge, CH2 and CH3-domains (Figure 5), and hinges of IGHG1, IGHG2, IGHG3 and IGHG4 (Figure 6), and by extension to the alignment of IGKC and IGLC2 with IGHG1 CH1 (Figure 7).
Standardized characterization has become a necessity, owing to the increasing number of engineered antibodies of effector properties [99,100] and/or various formats. Based on the IMGT Scientific chart rules, we propose a standardized IMGT nomenclature of engineered variants involved in effector properties (ADCC, ADCP and CDC), half-life and structure of therapeutical monoclonal antibodies. The standardized variant characterization comprises (1) the IMGT engineered Fc variant name (e.g. G1v1), (2) the IMGT variant definition (for each amino acid (AA) change: domain, AA in the one-letter abbreviation [52] and its position in the IMGT unique numbering for C domain [68], e.g. CH2 P1.4, (3) the IMGT amino acid changes on the IGHG CH domain with the Eu numbering between parentheses (e.g., CH2 E1.4 > P (233)), (4) the Eu numbering variant (e.g., E233P), (5) the IMGT motif positions according to the IMGT unique numbering [68], followed between parentheses, by the Eu numbering, motif with AA before and after the AA change in bold (e.g., IGHG1 CH2 1.6–3 (231–239) APELLGGPS > APPLLGGPS; underlined amino acids in the motif correspond to additional positions in the IMGT unique numbering for the C-domain [68,70,71,72], e.g., APELLG and APPLLG which correspond to 1.6, 1.5, 1.4, 1.3, 1.2 and 1.1), and (6) information from the literature regarding ‘property and function’.
These properties and functions have allowed to classify the IMGT engineered variants in 19 types (#1 to #19) corresponding to four categories. The first category ‘Effector’ refers to the variants that affect the effector properties: ADCC reduction #1 (Table 5), ADCC enhancement #2 (Table 6), ADCP and CDC enhancement #3 (Table 7), CDC enhancement #4 (Table 8), CDC reduction #5 (Table 9), ADCC and CDC reduction #6 (Table 10), B cell inhibition by the coengagement of antigen and FcγR on the same cell #7 (Table 11), knock out CH2 84.4 glycosylation #8 (Table 12), the second category ‘Half-life’ refers to the variants that affect (most of them increasing) the half-life #9 (Table 13), the third one ‘Protein A’ refers to the abrogation of binding to protein A #10 (Table 14), the fourth one ‘Structure’ refers to variants that affect the stability or structure of monospecific, bispecific or multispecific antibodies and include: formation of additional bridge stabilizing CH2 in the absence of N84.4 (297) glycosylation #11 (Table 15), prevention of IgG4 half-IG exchange #12 (Table 16), hexamerisation #13 (Table 17), knobs-into-holes and the enhancement of heteropairing H-H of bispecific antibodies #14 (Table 18), suppression of inter H-L and/or inter H-H disulfide bridges #15 (Table 19), site-specific drug attachment #16 (Table 20), enhancement of hetero pairing H-L of bispecific antibodies #17 (Table 21), control of half-IG exchange of bispecific IgG4 #18 (Table 22), reducing acid-induced aggregation #19 (Table 23).
In the tables, the different columns correspond to the items of the standardized variant characterization detailed above. Engineered amino acid changes are in bold in the IMGT variants (red before the change, green after the change. The motif is in yellow and shown before and after the AA change(s).
The variants involved in antibody-dependent cellular cytotoxicity (ADCC) reduction. include nine Homo sapiens IGHG1 variants, which comprise: G1v1 [1], G1v2 [1], G1v3 [1], G1v5 [6], G1v47 [37], G1v50 (the variant G1v50 is a variant combining the G1v1, G1v2, G1v3 and G1v47 amino acid changes), G1v52 ‘GRLR’, G1v66 and G1v67 (Table 5).
The variants involved in antibody-dependent cellular cytotoxicity (ADCC) enhancement include nine variants, of which six Homo sapiens IGHG1 variants: G1v6 [3], G1v7 ‘DE’ [4], G1v8 ‘DLE’ ‘3M’ [4] [25], G1v9 [14], G1v10 [15] and G1v11 [15]; one Homo sapiens IGHG2 variant: G2v1 [1]; one Homo sapiens IGHG4 variant: G4v1 [1]; and one Mus musculus IGHG2B variant: Musmus G2Bv1 [5] (Table 6).
The variants involved in antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) enhancement include three Homo sapiens IGHG1 variants: G1v12 ‘GASDALIE’ [26], G1v13 ‘GASDIE’ ‘ADE’ [16] and G1v45 ‘GAALIE’ (Table 7).
The variants involved in complement-dependent cytotoxicity (CDC) enhancement include 8 variants, of which seven Homo sapiens IGHG1 variants: G1v5 [6], G1v15 [6], G1v16 [6], G1v17 ‘EFT’ [18], G1v18 [19], G1v35 ‘SE’ [18,27] and the chimeric G1G3v1 [17], and one IGHG4 variant: G4v2 [8] (Table 8).
The variants involved in complement-dependent cytotoxicity (CDC) reduction include six variants, of which three Homo sapiens IGHG1 variants: G1v8 ‘DLE’ [4], G1v19 [2] and G1v20 [2,39]; and three Mus musculus IGHG2B variants: Musmus G2Bv2 [7], Musmus G2Bv3 [7] and Musmus G2Bv4 [7] (Table 9).
The variants involved in antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) reduction include 32 variants and four variant associations, of which 22 Homo sapiens IGHG1 variants: G1v4 [2], G1v14 ‘LALA’ [21,39], G1v14-1, G1v14-4, G1v14-48, G1v14-49 ‘LALAPG’ [40], G1v14-67, G1v23 [20], G1v38 [35], G1v39 ‘FES’ ‘TM’ [20,24], G1v40, G1v41 [20,24], G1v43, G1v48, G1v49 [40], G1v51, G1v53 ‘FQQ’, G1v59 [41], G1v60, G1v63, G1v65, G1v70 and one association G1v53-G1v21 ‘FQQ-YTE’ [38]; three Homo sapiens IGHG2 variants: G2v2 ‘IgG2m4′ [23], G2v3 ‘G2sigma’ [24] and the chimeric G2G4v1 [22]; five Homo sapiens IGHG4 variants: G4v3 ‘LE’ [20], G4v3-49 ‘LEPG’ [40], G4v4 ‘FALA’ [21], G4v7, G4v49 [40] and three associations G4v3-G4v5 ‘SPLE’ [12,20], G4v3-49-G4v5 ‘SPLEPG’ [40] [12] and G4v4-G4v5 ‘IgG4ProAlaAla’ [12,24] and two Canis lupus familiaris IGHG2 variants: CanlupfamG2v1 and CanlupfamG2v2 (Table 10).
The variants involved in B cell inhibition by coengagement of antigen and FcγR on the same cell include one Homo sapiens IGHG1 variant: G1v25 [33,34] (Table 11).
The variants involved in knock out CH2 84.4 glycosylation include five variants, of which three Homo sapiens IGHG1 variants: G1v29 [42], G1v30 [42], G1v36; one Homo sapiens IGHG4 variant: G4v36; and one Canis lupus familiaris IGHG2 variant: Canlupfam G2v29 (Table 12).
The variants involved in half-life increase or decrease include 13 variants, 12 of them increase half-life, of which five Homo sapiens IGHG1 variants: G1v21 ‘YTE’ [9,29,30,31,32], G1v22 [30], G1v24 [32], G1v42 [30] and G1v46; 3 Homo sapiens IGHG2 variants: G2v4 [10], G2v5 [10] and G2v6 [10]; one Homo sapiens IGHG3 variant: G3v1 [11]; three Homo sapiens IGHG4 variants: G4v21 ‘YTE’ [30], G4v22 [36] and G4v24. One variant G2v8-1 abrogates binding to FCGRT (FcRn) (Table 13).
The variants involved in abrogation of binding to Protein A include one Homo sapiens IGHG4 variant: G4v8 (Table 14).
The variants involved in formation of additional bridge stabilizing CH2 in the absence of N84.4 (Eu 297) glycosylation include four Homo sapiens IGHG1 variants: G1v54, G1v54-29, G1v54-30 and G1v54-36 (Table 15).
The variants involved in prevention of IgG4 half-IG exchange include two Homo sapiens IGHG4 variants: G4v5 [12] and G4v6 [13] (Table 16).
The variants involved in hexamerisation include one Homo sapiens IGHG1 variant: G1v34 (Table 17).
The variants involved in knobs-into-holes and enhancement of heteropairing H-H of bispecific antibodies include six Homo sapiens IGHG1 variants: G1v26 knob [28] and G1v31 hole [28], G1v32 knob and G1v33 hole, G1v68 and G1v69 (Table 18).
The variants involved in suppression of inter H-L and/or inter H-H disulfide bridges includes three Homo sapiens IGHG1 variants: G1v37, G1v61 and G1v62 (Table 19).
The variants involved in site-specific drug attachment include six Homo sapiens IGHG1 variants: G1v27, G1v28, G1v44, G1v55, G1v56 and G1v64 (Table 20).
The variants involved in enhancement of hetero pairing H-Linclude two Homo sapiens IGHG1 variants: G1v57 used in association with Homo sapiens IGKC variant: KCv57, and G1v58, used in association with Homo sapiens IGLC2 variant: LC2v58 (Table 21).
The variants involved in control of half-IG exchange of bispecific IgG4 antibodies include one Homo sapiens IGHG4 variant: G4v10 (Table 22).
The variants involved in reducing acid-induced aggregation include one Homo sapiens IGHG2 variant: G2v7 (Table 23).
Two variants have been assigned to two properties belonging to different types and are therefore found in two tables, G1v5 (Table 5 and Table 8) and G1v8 (Table 6 and Table 9).
Supplementary Table S2 provides the variants of Table 5, Table 6, Table 7, Table 8, Table 9, Table 10, Table 11, Table 12, Table 13, Table 14, Table 15, Table 16, Table 17, Table 18, Table 19, Table 20, Table 21, Table 22 and Table 23 in an alphanumeric order of the IMGT engineered variants involved in the effector properties (ADCC, ADCP and CDC), half-life and structure of the therapeutical monoclonal antibodies.

5. Conclusions

The therapeutic monoclonal antibody engineering field is the most promising in the medical field. A standardized analysis of IG genomic and expressed sequences, structures and interactions is crucial for a better molecular understanding and comparison of the mAb specificity, affinity, half-life, Fc effector properties and potential immunogenicity. IMGT has provided the concepts for the IG loci description of newly sequenced genomes [2], antibody structure/function characterization [4], antibody engineering (single chain Fragment variable (scFv), phage displays, combinatorial libraries) and antibody humanization (chimeric, humanized and human antibodies). IMGT® standardization allows the repertoire analysis and antibody humanization studies to move to novel, high-throughput methodologies with the same high-quality criteria. The CDR-IMGT lengths are now required for mAb INN applications and are included in the WHO-INN definitions (84–86). The characterization of the IGHG engineered variants for effector properties, half-life increase, and new structures of bi- and multi-specific antibodies brings a new level of standardized information in the comparative analysis of therapeutic antibodies.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/antib11040065/s1, Table S1: Correspondence between the IMGT unique numbering for C-DOMAIN, the IMGT exon numbering, the EU and Kabat numberings: Human IGHG [97,98] https://www.imgt.org/IMGTScientificChart/Numbering/Hu_IGHGnber.html; Table S2: IMGT nomenclature (alphanumeric order) of engineered variants involved in effector properties (ADCC, ADCP, CDC), half-life and structure of therapeutical monoclonal antibodies.

Author Contributions

Conceptualization, methodology, validation, investigation, data curation, writing, review and editing, visualization, ontology, M.-P.L. and G.L. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

Data is contained within the article or Supplementary material.

Acknowledgments

We thank Souphatta Sasorith, Mélissa Cambon and Karima Cherouali for their contribution in the early phase of this work.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Lefranc, M.-P. Immunoglobulin and T cell receptor genes: IMGT® and the birth and rise of immunoinformatics. Front Immunol. 2014, 5, 22. [Google Scholar] [CrossRef] [Green Version]
  2. Lefranc, M.-P.; Lefranc, G. IMGT® Homo sapiens IG and TR loci, gene order, CNV and haplotypes: New concepts as a paradigm for jawed vertebrates genome assemblies. Biomolecules 2022, 12, 381. [Google Scholar] [CrossRef] [PubMed]
  3. Lefranc, M.-P.; Lefranc, G. The Immunoglobulin FactsBook; Academic Press: London, UK, 2001; pp. 1–457. [Google Scholar]
  4. Lefranc, M.-P.; Lefranc, G. Immunoglobulins or Antibodies: IMGT® Bridging Genes, Structures and Functions. Biomedicines 2020, 8, 319. [Google Scholar] [CrossRef] [PubMed]
  5. Lefranc, M.-P.; Lefranc, G. The T Cell Receptor FactsBook; Academic Press: London, UK, 2001; pp. 1–397. [Google Scholar]
  6. Lefranc, M.-P.; Lefranc, G. Antibody sequence and structure analyses using IMGT®: 30 years of immunoinformatics. In Computer Aided Antibody Design: Methods and Protocols; Tsumoto, K., Kuroda, D., Eds.; Methods in Molecular Biology; Springer: New York, NY, USA, 2022; in press. [Google Scholar]
  7. Lefranc, M.-P. Nomenclature of the human immunoglobulin genes. In Current Protocols in Immunology; Coligan, J.E., Bierer, B.E., Margulies, D.E., Shevach, E.M., Strober, W., Eds.; John Wiley and Sons: Hoboken, NJ, USA, 2000; pp. A.1P.1–A.1P.37. [Google Scholar]
  8. Lefranc, M.-P. Nomenclature of the human T cell Receptor genes. In Current Protocols in Immunology; Coligan, J.E., Bierer, B.E., Margulies, D.E., Shevach, E.M., Strober, W., Eds.; John Wiley and Sons: Hoboken, NJ, USA, 2000; pp. A.1O.1–A.1O.23. [Google Scholar]
  9. Lefranc, M.-P. WHO-IUIS Nomenclature Subcommittee for Immunoglobulins and T cell receptors report. Immunogenetics 2007, 59, 899–902. [Google Scholar] [CrossRef] [PubMed]
  10. Lefranc, M.-P. WHO-IUIS Nomenclature Subcommittee for Immunoglobulins and T cell receptors report. Immunoglobulins and T cell receptors report August 2007, 13th International Congress of Immunology, Rio de Janeiro, Brazil. Dev. Comp. Immunol. 2008, 32, 461–463. [Google Scholar] [CrossRef] [PubMed]
  11. Lefranc, M.-P. IMGT, the international ImMunoGeneTics information system. In Immunoinformatics: Bioinformatic Strategies for Better Understanding of Immune Function; Bock, G., Goode, J., Eds.; Novartis Foundation Symposium; John Wiley and Sons: Chichester, UK, 2003; Volume 254, pp. 126, discussion 136–142, 216–222, 250–252. [Google Scholar]
  12. Lefranc, M.-P.; Giudicelli, V.; Ginestoux, C.; Chaume, D. IMGT, the international ImMunoGeneTics information system: The reference in immunoinformatics. Stud. Health Technol. Inform. 2003, 95, 74–79. [Google Scholar] [PubMed]
  13. Lefranc, M.-P. IMGT, the International ImMunoGenetics Information System®. In Antibody Engineering Methods and Protocols, 2nd ed.; Lo, B.K.C., Ed.; Methods in Molecular Biology; Humana Press: Totowa, NJ, USA, 2004; Volume 248, pp. 27–49. [Google Scholar]
  14. Lefranc, M.-P. IMGT, the international ImMunoGeneTics information system: A standardized approach for immunogenetics and immunoinformatics. Immunome Res. 2005, 1, 3. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Lefranc, M.-P. IMGT®, the international ImMunoGeneTics information system® for immunoinformatics. Methods for querying IMGT® databases, tools and Web resources in the context of immunoinformatics. In Immunoinformatics: Predicting Immunogenicity in Silico; Flower, D.R., Ed.; Methods in Molecular Biology; Humana Press: Totowa, NJ, USA, 2007; Chapter 2; Volume 409, pp. 19–42. [Google Scholar] [CrossRef]
  16. Lefranc, M.-P.; Giudicelli, V.; Regnier, L.; Duroux, P. IMGT, a system and an ontology that bridge biological and computational spheres in bioinformatics. Brief. Bioinform. 2008, 9, 263–275. [Google Scholar] [CrossRef] [PubMed]
  17. Lefranc, M.-P. IMGT®, the international ImMunoGeneTics information system® for immunoinformatics. Methods for querying IMGT® databases, tools and Web resources in the context of immunoinformatics. Mol. Biotechnol. 2008, 40, 101–111. [Google Scholar] [CrossRef]
  18. Lefranc, M.-P.; Giudicelli, V.; Ginestoux, C.; Jabado-Michaloud, J.; Folch, G.; Bellahcene, F.; Wu, Y.; Gemrot, E.; Brochet, X.; Lane, J.; et al. IMGT®, the International ImMunoGeneTics Information System®. Nucleic Acids Res. 2009, 37, D1006–D1012. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  19. Lefranc, M.-P. IMGT, the International ImMunoGeneTics Information System. Cold Spring Harb. Protoc. 2011, 6, 595–603. [Google Scholar] [CrossRef]
  20. Lefranc, M.-P. IMGT® information system. In Encyclopedia of Systems Biology; Dubitzky, W., Wolkenhauer, O., Cho, K.-H., Yokota, H., Eds.; Springer: New York, NY, USA, 2013; pp. 959–964. [Google Scholar] [CrossRef]
  21. Lefranc, M.-P.; Giudicelli, V.; Duroux, P.; Jabado-Michaloud, J.; Folch, G.; Aouinti, S.; Carillon, E.; Duvergey, H.; Houles, A.; Paysan-Lafosse, T.; et al. IMGT®, the International ImMunoGeneTics Information System® 25 Years on. Nucleic Acids Res. 2015, 43, D413–D422. [Google Scholar] [CrossRef] [Green Version]
  22. Lefranc, M.-P. Immunoglobulin superfamily (IgSF). In Encyclopedia of Systems Biology; Dubitzky, W., Wolkenhauer, O., Cho, K.-H., Yokota, H., Eds.; Springer: New York, NY, USA, 2013. [Google Scholar] [CrossRef]
  23. Lefranc, M.-P. MH Superfamily (MhSF). In Encyclopedia of Systems Biology; Dubitzky, W., Wolkenhauer, O., Cho, K.-H., Yokota, H., Eds.; Springer: New York, NY, USA, 2013. [Google Scholar] [CrossRef]
  24. Lefranc, M.-P.; Giudicelli, V.; Busin, C.; Malik, A.; Mougenot, I.; Déhais, P.; Chaume, D. LIGM-DB/IMGT: An integrated database of Ig and TcR, part of the Immunogenetics database. Ann. N. Y. Acad. Sci. 1995, 764, 47–49. [Google Scholar] [CrossRef]
  25. Giudicelli, V.; Duroux, P.; Ginestoux, C.; Folch, G.; Jabado-Michaloud, J.; Chaume, D.; Lefranc, M.-P. IMGT/LIGM-DB, the IMGT® comprehensive database of immunoglobulin and T cell receptor nucleotide sequences. Nucleic Acids Res. 2006, 34, D781–D784. [Google Scholar] [CrossRef] [Green Version]
  26. Giudicelli, V.; Chaume, D.; Lefranc, M.-P. IMGT/GENE-DB: A comprehensive database for human and mouse immunoglobulin and T cell receptor genes. Nucleic Acids Res. 2005, 33, D256–D261. [Google Scholar] [CrossRef] [Green Version]
  27. Kaas, Q.; Ruiz, M.; Lefranc, M.-P. IMGT/3Dstructure-DB and IMGT/StructuralQuery, a database and a tool for immunoglobulin, T cell receptor and MHC structural data. Nucleic Acids Res. 2004, 32, D208–D210. [Google Scholar] [CrossRef]
  28. Ehrenmann, F.; Kaas, Q.; Lefranc, M.-P. IMGT/3Dstructure-DB and IMGT/DomainGapAlign: A Database and a Tool for Immunoglobulins or Antibodies, T Cell Receptors, MHC, IgSF and MhcSF. Nucleic Acids Res. 2010, 38, D301–D307. [Google Scholar] [CrossRef]
  29. Ehrenmann, F.; Lefranc, M.-P. IMGT/3Dstructure-DB: Querying the IMGT Database for 3D Structures in Immunology and Immunoinformatics (IG or Antibodies, TR, MH, RPI, and FPIA). Cold Spring Harb. Protoc. 2011, 6, 750–761. [Google Scholar] [CrossRef]
  30. Poiron, C.; Wu, Y.; Ginestoux, C.; Ehrenmann, F.; Duroux, P.; Lefranc, M.-P. IMGT/mAb-DB: The IMGT® database for therapeutic monoclonal antibodies. In Proceedings of the 11èmes Journées Ouvertes de Biologie, Informatique et Mathématiques (JOBIM), Montpellier, France, 7–9 September 2010. [Google Scholar]
  31. Giudicelli, V.; Chaume, D.; Lefranc, M.-P. IMGT/V-QUEST, an Integrated Software for Immunoglobulin and T Cell Receptor V-J and V-D-J Rearrangement Analysis. Nucleic Acids Res. 2004, 32, W435–W440. [Google Scholar] [CrossRef] [Green Version]
  32. Giudicelli, V.; Lefranc, M.-P. Interactive IMGT on-line tools for the analysis of immunoglobulin and T cell receptor repertoires. In New Research on Immunology; Veskler, B.A., Ed.; Nova Science Publishers Inc.: New York, NY, USA, 2005; pp. 77–105. [Google Scholar]
  33. Brochet, X.; Lefranc, M.-P.; Giudicelli, V. IMGT/V-QUEST: The Highly Customized and Integrated System for IG and TR Standardized V-J and V-D-J Sequence Analysis. Nucleic Acids Res. 2008, 36, W503–W508. [Google Scholar] [CrossRef] [Green Version]
  34. Giudicelli, V.; Lefranc, M.-P. IMGT® standardized analysis of immunoglobulin rearranged sequences. In Immunoglobulin Gene Analysis in Chronic Lymphocytic Leukemia; Ghia, P., Rosenquist, R., Davi, F., Eds.; Wolters Kluwer Health Italy: Milano, Italy, 2008; Chapter 2; pp. 33–52. [Google Scholar]
  35. Giudicelli, V.; Brochet, X.; Lefranc, M.-P. IMGT/V-QUEST: IMGT standardized analysis of the immunoglobulin (IG) and T cell receptor (TR) nucleotide sequences. Cold Spring Harb. Protoc. 2011, 6, 695–715. [Google Scholar] [CrossRef]
  36. Alamyar, E.; Duroux, P.; Lefranc, M.-P.; Giudicelli, V. IMGT® tools for the nucleotide analysis of immunoglobulin (IG) and T cell receptor (TR) V-(D)-J repertoires, polymorphisms, and IG mutations: IMGT/V-QUEST and IMGT/HighV-QUEST for NGS. In Immunogenetics; Christiansen, F., Tait, B., Eds.; Methods in Molecular Biology; Humana Press: New York, NY, USA, 2012; Chapter 32; Volume 882, pp. 569–604. [Google Scholar] [CrossRef]
  37. Yousfi Monod, M.; Giudicelli, V.; Chaume, D.; Lefranc, M.-P. IMGT/JunctionAnalysis: The first tool for the analysis of the immunoglobulin and T cell receptor complex V-J and V-D-J JUNCTIONs. Bioinformatics 2004, 20, i379–i385. [Google Scholar] [CrossRef] [Green Version]
  38. Giudicelli, V.; Lefranc, M.-P. IMGT/JunctionAnalysis: IMGT standardized analysis of the V-J and V-D-J Junctions of the rearranged immunoglobulins (IG) and T cell receptors (TR). Cold Spring Harb. Protoc. 2011, 6, 716–725. [Google Scholar] [CrossRef]
  39. Giudicelli, V.; Protat, C.; Lefranc, M.-P. The IMGT strategy for the automatic annotation of IG and TR cDNA sequences: IMGT/Automat. In Proceedings of the European Conference on Computational Biology (ECCB 2003), Data and Knowledge Bases, Institut National de Recherche en Informatique et en Automatique, Poster DKB_31, ECCB 2003, Paris, France, 27–30 September 2003; pp. 103–104. [Google Scholar]
  40. Giudicelli, V.; Chaume, D.; Jabado-Michaloud, J.; Lefranc, M.-P. Immunogenetics sequence Annotation: The strategy of IMGT based on IMGT-ONTOLOGY. Stud. Health Technol. Inform. 2005, 116, 3–8. [Google Scholar]
  41. Alamyar, E.; Giudicelli, V.; Duroux, P.; Lefranc, M.-P. IMGT/HighV-QUEST: A high-throughput system and web portal for the analysis of rearranged nucleotide sequences of antigen receptors—High-throughput version of IMGT/V-QUEST. In Proceedings of the 11èmes Journées Ouvertes de Biologie, Informatique et Mathématiques (JOBIM), Montpellier, France, 7–9 September 2010. [Google Scholar]
  42. Alamyar, E.; Giudicelli, V.; Li, S.; Duroux, P.; Lefranc, M.-P. IMGT/HighV-QUEST: The IMGT® web portal for immunoglobulin (IG) or antibody and T cell receptor (TR) analysis from NGS high throughput and deep sequencing. Immunome Res. 2012, 8, 26. [Google Scholar]
  43. Li, S.; Lefranc, M.-P.; Miles, J.J.; Alamyar, E.; Giudicelli, V.; Duroux, P.; Freeman, J.D.; Corbin, V.; Scheerlinck, J.-P.; Frohman, M.A.; et al. IMGT/HighV-QUEST paradigm for T cell receptor IMGT clonotype diversity and next generation repertoire immunoprofiling. Nat. Commun. 2013, 4, 2333. [Google Scholar] [CrossRef] [Green Version]
  44. Giudicelli, V.; Duroux, P.; Lavoie, A.; Aouinti, S.; Lefranc, M.-P.; Kossida, S. From IMGT-ONTOLOGY to IMGT/HighV-QUEST for NGS immunoglobulin (IG) and T cell receptor (TR) repertoires in autoimmune and infectious diseases. Autoimmun. Infect. Dis. 2015, 1, 1–15. [Google Scholar]
  45. Giudicelli, V.; Duroux, P.; Kossida, S.; Lefranc, M.-P. IG and TR single chain Fragment variable (scFv) sequence analysis: A new advanced functionality of IMGT/V-QUEST and IMGT/HighV-QUEST. BMC Immunol. 2017, 18, 35. [Google Scholar] [CrossRef]
  46. Aouinti, S.; Malouche, D.; Giudicelli, V.; Kossida, S.; Lefranc, M.-P. IMGT/HighV-QUEST statistical significance of IMGT clonotype (AA) diversity per gene for standardized comparisons of next generation sequencing immunoprofiles of immunoglobulins and T cell receptors. PLoS ONE 2015, 10, e0142353, https://doi.org/10.1371/journal.pone.0142353. eCollection 2015. Correction: PLoS ONE 2016, 11, e0146702. [Google Scholar] [CrossRef] [Green Version]
  47. Aouinti, S.; Giudicelli, V.; Duroux, P.; Malouche, D.; Kossida, S.; Lefranc, M.-P. IMGT/StatClonotype for pairwise evaluation and visualization of NGS IG and TR IMGT clonotype (AA) diversity or expression from IMGT/HighV-QUEST. Front. Immunol. 2016, 7, 339. [Google Scholar] [CrossRef] [Green Version]
  48. Lane, J.; Duroux, P.; Lefranc, M.-P. From IMGT-ONTOLOGY to IMGT/LIGMotif: The IMGT® standardized approach for immunoglobulin and T cell receptor gene identification and description in large genomic sequences. BMC Bioinform. 2010, 11, 223. [Google Scholar] [CrossRef] [Green Version]
  49. Ehrenmann, F.; Lefranc, M.-P. IMGT/DomainGapAlign: IMGT standardized analysis of amino acid sequences of Variable, Constant, and Groove domains (IG, TR, MH, IgSF, MhSF). Cold Spring Harb. Protoc. 2011, 6, 737–749. [Google Scholar] [CrossRef]
  50. Ehrenmann, F.; Lefranc, M.-P. IMGT/DomainGapAlign: The IMGT® tool for the analysis of IG, TR, MHC, IgSF and MhcSF domain amino acid polymorphism. In Immunogenetics; Christiansen, F., Tait, B., Eds.; Methods in Molecular Biology; Humana Press: New York, NY, USA, 2012; Chapter 33; Volume 882, pp. 605–633. [Google Scholar] [CrossRef]
  51. Ehrenmann, F.; Giudicelli, V.; Duroux, P.; Lefranc, M.-P. IMGT/Collier de Perles: IMGT Standardized representation of Domains (IG, TR, and IgSF Variable and Constant Domains, MH and MhSF Groove Domains). Cold Spring Harb. Protoc. 2011, 6, 726–736. [Google Scholar] [CrossRef]
  52. Pommié, C.; Levadoux, S.; Sabatier, R.; Lefranc, G.; Lefranc, M.-P. IMGT standardized criteria for statistical analysis of immunoglobulin V-REGION amino acid properties. J. Mol. Recognit. 2004, 17, 17–32. [Google Scholar] [CrossRef]
  53. Lefranc, M.-P. From IMGT-ONTOLOGY IDENTIFICATION axiom to IMGT standardized keywords: For immunoglobulins (IG), T cell receptors (TR), and conventional genes. Cold Spring Harb. Protoc. 2011, 6, 604–613. [Google Scholar] [CrossRef]
  54. Lefranc, M.-P. IMGT-ONTOLOGY, IDENTIFICATION axiom. In Encyclopedia of Systems Biology; Dubitzky, W., Wolkenhauer, O., Cho, K.-H., Yokota, H., Eds.; Springer: New York, NY, USA, 2013. [Google Scholar] [CrossRef]
  55. Lefranc, M.-P. From IMGT-ONTOLOGY DESCRIPTION axiom to IMGT standardized labels: For immunoglobulin (IG) and T cell receptor (TR) sequences and structures. Cold Spring Harb. Protoc. 2011, 6, 614–626. [Google Scholar] [CrossRef]
  56. Lefranc, M.-P. IMGT-ONTOLOGY, DESCRIPTION axiom. In Encyclopedia of Systems Biology; Dubitzky, W., Wolkenhauer, O., Cho, K.-H., Yokota, H., Eds.; Springer: New York, NY, USA, 2013. [Google Scholar] [CrossRef]
  57. Lefranc, M.-P. Complementarity Determining Region (CDR-IMGT). In Encyclopedia of Systems Biology; Dubitzky, W., Wolkenhauer, O., Cho, K.-H., Yokota, H., Eds.; Springer: New York, NY, USA, 2013. [Google Scholar] [CrossRef]
  58. Lefranc, M.-P. Framework Region (FR-IMGT). In Encyclopedia of Systems Biology; Dubitzky, W., Wolkenhauer, O., Cho, K.-H., Yokota, H., Eds.; Springer: New York, NY, USA, 2013. [Google Scholar] [CrossRef]
  59. Jefferis, R.; Lefranc, M.-P. Human immunoglobulin allotypes: Possible implications for immunogenicity. mAbs 2009, 1, 332–338. [Google Scholar] [CrossRef] [Green Version]
  60. Lefranc, M.-P.; Lefranc, G. Human Gm, Km and Am allotypes and their molecular characterization: A remarkable demonstration of polymorphism. In Immunogenetics; Christiansen, F., Tait, B., Eds.; Humana Press: New York, NY, USA, 2012; Chapter 34; Volume 882, pp. 635–680. [Google Scholar] [CrossRef]
  61. Lefranc, M.-P. Nomenclature of the human immunoglobulin heavy (IGH) genes. Exp. Clin. Immunogenet. 2001, 18, 100–116. [Google Scholar] [CrossRef]
  62. Lefranc, M.-P. From IMGT-ONTOLOGY CLASSIFICATION axiom to IMGT standardized gene and allele nomenclature: For immunoglobulins (IG) and T cell receptors (TR). Cold Spring Harb. Protoc. 2011, 6, 627–632. [Google Scholar] [CrossRef]
  63. Lefranc, M.-P. IMGT-ONTOLOGY, CLASSIFICATION Axiom. In Encyclopedia of Systems Biology; Dubitzky, W., Wolkenhauer, O., Cho, K.-H., Yokota, H., Eds.; Springer: New York, NY, USA, 2013. [Google Scholar] [CrossRef]
  64. Lefranc, M.-P. IMGT-ONTOLOGY, NUMEROTATION axiom. In Encyclopedia of Systems Biology; Dubitzky, W., Wolkenhauer, O., Cho, K.-H., Yokota, H., Eds.; Springer: New York, NY, USA, 2013. [Google Scholar] [CrossRef]
  65. Lefranc, M.-P. Unique database numbering system for immunogenetic analysis. Immunol. Today 1997, 18, 509. [Google Scholar] [CrossRef]
  66. Lefranc, M.-P. The IMGT unique numbering for Immunoglobulins, T cell receptors and Ig-like domains. Immunology 1999, 7, 132–136. [Google Scholar]
  67. Lefranc, M.-P.; Pommié, C.; Ruiz, M.; Giudicelli, V.; Foulquier, E.; Truong, L.; Thouvenin-Contet, V.; Lefranc, G. IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains. Dev. Comp. Immunol. 2003, 27, 55–77. [Google Scholar] [CrossRef]
  68. Lefranc, M.-P.; Pommié, C.; Kaas, Q.; Duprat, E.; Bosc, N.; Guiraudou, D.; Jean, C.; Ruiz, M.; Da Piedade, I.; Rouard, M.; et al. IMGT unique numbering for immunoglobulin and T cell receptor constant domains and Ig superfamily C-like domains. Dev. Comp. Immunol. 2005, 29, 185–203. [Google Scholar] [CrossRef]
  69. Lefranc, M.-P.; Duprat, E.; Kaas, Q.; Tranne, M.; Thiriot, A.; Lefranc, G. IMGT unique numbering for MHC groove G-DOMAIN and MHC superfamily (MhcSF) G-LIKE-DOMAIN. Dev. Comp. Immunol. 2005, 29, 917–938. [Google Scholar] [CrossRef]
  70. Lefranc, M.-P. IMGT unique numbering for the Variable (V), Constant (C), and Groove (G) domains of IG, TR, MH, IgSF, and MhSF. Cold Spring Harb. Protoc. 2011, 6, 633–642. [Google Scholar] [CrossRef]
  71. Lefranc, M.-P. IMGT unique numbering. In Encyclopedia of Systems Biology; Dubitzky, W., Wolkenhauer, O., Cho, K.-H., Yokota, H., Eds.; Springer: New York, NY, USA, 2013; pp. 952–959. [Google Scholar] [CrossRef]
  72. Lefranc, M.-P. Immunoinformatics of the V, C, and G domains: IMGT® definitive system for IG, TR and IgSF, MH, and MhSF. In Immunoinformatics: From Biology to Informatics, 2nd ed.; De, R.K., Tomar, N., Eds.; Methods in Molecular Biology; Humana Press: New Yor, NY, USA, 2014; Volume 1184, pp. 59–107. [Google Scholar] [CrossRef]
  73. Ruiz, M.; Lefranc, M.-P. IMGT gene identification and Colliers de Perles of human immunoglobulins with known 3D structures. Immunogenetics 2002, 53, 857–883. [Google Scholar]
  74. Kaas, Q.; Lefranc, M.-P. IMGT Colliers de Perles: Standardized sequence-structure representations of the IgSF and MhcSF superfamily domains. Curr. Bioinform. 2007, 2, 21–30. [Google Scholar] [CrossRef] [Green Version]
  75. Kaas, Q.; Ehrenmann, F.; Lefranc, M.-P. IG, TR and IgSf, MHC and MhcSF: What do we learn from the IMGT Colliers de Perles? Brief. Funct. Genom. Proteom. 2007, 6, 253–264. [Google Scholar] [CrossRef] [Green Version]
  76. Lefranc, M.-P. IMGT Collier de Perles for the Variable (V), Constant (C), and Groove (G) domains of IG, TR, MH, IgSF, and MhSF. Cold Spring Harb. Protoc. 2011, 6, 643–651. [Google Scholar] [CrossRef]
  77. Lefranc, M.-P. IMGT Collier de Perles. In Encyclopedia of Systems Biology; Dubitzky, W., Wolkenhauer, O., Cho, K.-H., Yokota, H., Eds.; Springer: New York, NY, USA, 2013; pp. 944–952. [Google Scholar] [CrossRef]
  78. Giudicelli, V.; Lefranc, M.-P. Ontology for Immunogenetics: IMGT-ONTOLOGY. Bioinformatics 1999, 15, 1047–1054. [Google Scholar] [CrossRef] [Green Version]
  79. Lefranc, M.-P. IMGT-ONTOLOGY and IMGT databases, tools and web resources for immunogenetics and immunoinformatics. Mol. Immunol. 2004, 40, 647–660. [Google Scholar] [CrossRef] [PubMed]
  80. Lefranc, M.-P. IMGT-ONTOLOGY, IMGT® databases, tools and Web resources for Immunoinformatics. In Immunoinformatics; Schoenbach, C., Ranganathan, S., Brusic, V., Eds.; Immunomics Reviews, Series of Springer Science and Business Media LLC.; Springer: New York, NY, USA, 2008; Chapter 1; Volume 1, pp. 1–18. [Google Scholar]
  81. Giudicelli, V.; Lefranc, M.-P. IMGT-ONTOLOGY 2012. Frontiers in Bioinformatics and Computational Biology. Front. Genet. 2012, 3, 79. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  82. Giudicelli, V.; Lefranc, M.-P. IMGT-ONTOLOGY. In Encyclopedia of Systems Biology; Dubitzky, W., Wolkenhauer, O., Cho, K.-H., Yokota, H., Eds.; Springer: New York, NY, USA, 2013; pp. 964–972. [Google Scholar] [CrossRef]
  83. Lefranc, M.-P.; Lefranc, G. IMGT/3Dstructure-DB: T-cell Receptor TR Paratope and peptide/Major Histocompatibility pMH contact sites and epitope. Methods Mol. Biol. 2022, 2453, 533–570. [Google Scholar] [CrossRef]
  84. Lefranc, M.-P. Antibody nomenclature: From IMGT-ONTOLOGY to INN definition. mAbs 2011, 3, 1–2. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. World Health Organization. International Nonproprietary Names (INN) for Biological and Biotechnological Substances (a Review). WHO/EMP/RHT/TSN/2019.1. Available online: http://www.nihs.go.jp/dbcb/INN/BioReview2019.pdf (accessed on 14 August 2022).
  86. Guimaraes Koch, S.S.; Thorpe, R.; Kawasaki, N.; Lefranc, M.-P.; Malan, S.; Martin, A.C.R.; Mignot, G.; Plückthun, A.; Rizzi, M.; Shubat, S.; et al. International nonproprietary names for monoclonal antibodies: An evolving nomenclature system. mAbs 2022, 14, 2075078. [Google Scholar] [CrossRef]
  87. Lefranc, M.-P. Antibody databases and tools: The IMGT® experience. In Therapeutic Monoclonal Antibodies: From Bench to Clinic; An, Z., Ed.; John Wiley & Sons, Inc.: Hoboken, NJ, USA, 2009; Chapter 4; pp. 91–114. ISBN 978-0-470-11791-0. [Google Scholar]
  88. Lefranc, M.-P. Antibody databases: IMGT®, a French platform of world-wide interest. Bases de données anticorps: IMGT®, une plate-forme française d’intérêt mondial “Anticorps monoclonaux en thérapeutique”. Méd./Sci. 2009, 25, 1020–1023. [Google Scholar] [CrossRef] [Green Version]
  89. Lefranc, M.-P.; Ehrenmann, F.; Ginestoux, C.; Duroux, P.; Giudicelli, V. Use of IMGT® databases and tools for antibody engineering and humanization. In Antibody Engineering; Chames, P., Ed.; Methods in Molecular Biology; Humana Press: New York, NY, USA, 2012; Chapter 1; Volume 907, pp. 3–37. [Google Scholar]
  90. Lefranc, M.-P. How to use IMGT® for therapeutic antibody engineering. In Handbook of Therapeutic Antibodies, 2nd ed.; Dübel, S., Reichert, J., Eds.; Defining the Right Antibody Composition; Wiley: Hoboken, NJ, USA, 2014; Chapter 10; Volume 1, pp. 229–264. [Google Scholar]
  91. Lefranc, M.-P. IMGT® immunoglobulin repertoire analysis and antibody humanization. In Molecular Biology of B Cells, 2nd ed.; Alt, F.W., Honjo, T., Radbruch, A., Reth, M., Eds.; Academic Press: London, UK, 2014; Chapter 26; pp. 481–514. ISBN 978-0-12-397933-9. [Google Scholar]
  92. Shirai, H.; Prades, C.; Vita, R.; Marcatili, P.; Popovic, B.; Xu, J.; Overington, J.P.; Hirayama, K.; Soga, S.; Tsunoyama, K.; et al. Antibody informatics for drug discovery. Biochim. Biophys. Acta 2014, 1844, 2002–2015. [Google Scholar] [CrossRef] [PubMed]
  93. Alamyar, E.; Giudicelli, V.; Duroux, P.; Lefranc, M.-P. Antibody V and C domain sequence, structure and interaction analysis with special reference to IMGT®. In Monoclonal Antibodies: Methods and Protocols, 2nd ed.; Ossipow, V., Fischer, N., Eds.; Methods in Molecular Biology; Humana Press: New York, NY, USA, 2014; Volume 1131, pp. 337–381. [Google Scholar] [CrossRef]
  94. Lefranc, M.-P. Immunoglobulins: 25 years of Immunoinformatics and IMGT-ONTOLOGY. Biomolecules 2014, 4, 1102–1139. [Google Scholar] [CrossRef] [Green Version]
  95. Lefranc, M.-P. Antibody informatics: IMGT, the international ImMunoGeneTics information system. In Antibodies for Infectious Diseases; Crowe, J.E., Boraschi, D., Rappuoli, R., Eds.; ASM Press: Washington, DC, USA, 2015; pp. 363–379. [Google Scholar] [CrossRef]
  96. Lefranc, M.-P.; Lefranc, G. IMGT® and 30 years of Immunoinformatics insight in antibody V and C domain structure and function. Antibodies 2019, 8, 29. [Google Scholar] [CrossRef] [Green Version]
  97. Edelman, G.M.; Cunningham, B.A.; Gall, W.E.; Gottlieb, P.D.; Rutishauser, U.; Waxdal, M.J. The covalent structure of an entire gammaG immunoglobulin molecule. Proc. Natl. Acad. Sci. USA 1969, 63, 78–85. [Google Scholar] [CrossRef] [Green Version]
  98. Kabat, E.A.; Wu, T.T.; Reid-Miller, M.; Perry, H.M.; Gottesman, K.S. Sequences of Proteins of Immunological Interest, 5th ed.; NIH publication n° 91-3242; US Department of Health and Human Services: Washington, DC, USA, 1991; pp. 662, 680, 689.
  99. Booth, B.J.; Ramakrishnan, B.; Narayan, K.; Wollacott, A.M.; Babcock, G.J.; Shriver, Z.; Viswanathan, K. Extending human IgG half-life using structure-guided design. mAbs 2018, 10, 1098–1110. [Google Scholar] [CrossRef]
  100. Liu, R.; Oldham, R.J.; Teal, E.; Beers, S.A.; Cragg, M.S. Fc-Engineering for Modulated Effector Functions-Improving Antibodies for Cancer Treatment. Antibodies 2020, 9, 64. [Google Scholar] [CrossRef] [PubMed]
  101. Chappel, M.S.; Isenman, D.E.; Everett, M.; Xu, Y.Y.; Dorrington, K.J.; Klein, M.H. Identification of the Fc gamma receptor class I binding site in human IgG through the use of recombinant IgG1/IgG2 hybrid and point-mutated antibodies. Proc. Natl. Acad. Sci. USA 1991, 88, 9036–9040. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  102. Idusogie, E.E.; Wong, P.Y.; Presta, L.G.; Gazzano-Santoro, H.; Totpal, K.; Ultsch, M.; Mulkerrin, M.G. Engineered antibodies with increased activity to recruit complement. J. Immunol. 2001, 166, 2571–2575. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  103. Brinkhaus, M.; Douwes, R.G.J.; Bentlage, A.E.H.; Temming, A.R.; de Taeye, S.W.; Tammes Buirs, M.; Gerritsen, J.; Mok, J.Y.; Brasser, G.; Ligthart, P.C.; et al. . Glycine 236 in the lower hinge region of human IgG1 differentiates FcγR from Complement effector function. J. Immunol. 2020, 205, 3456–3467. [Google Scholar] [CrossRef]
  104. Shields, R.L.; Namenuk, A.K.; Hong, K.; Meng, Y.G.; Rae, J.; Briggs, J.; Xie, D.; Lai, J.; Stadlen, A.; Li, B.; et al. High resolution mapping of the binding site on human IgG1 for Fc gamma RI, Fc gamma RII, Fc gamma RIII, and FcRn and design of IgG1 variants with improved binding to the Fc gamma R. J. Biol. Chem. 2001, 276, 6591–6604. [Google Scholar] [CrossRef]
  105. Lazar, G.A.; Dang, W.; Karki, S.; Vafa, O.; Peng, J.S.; Hyun, L.; Chan, C.; Chung, H.S.; Eivazi, A.; Yoder, S.C.; et al. Engineered antibody Fc variants with enhanced effector function. Proc. Natl. Acad. Sci. USA 2006, 103, 4005–4010. [Google Scholar] [CrossRef] [Green Version]
  106. Oganesyan, V.; Damschroder, M.M.; Leach, W.; Wu, H.; Dall’Acqua, W.F. Structural characterization of a mutated, ADCC-enhanced human Fc fragment. Mol. Immunol. 2008, 45, 1872–1882. [Google Scholar] [CrossRef]
  107. Stavenhagen, J.B.; Gorlatov, S.; Tuaillon, N.; Rankin, C.T.; Li, H.; Burke, S.; Huang, L.; Vijh, S.; Johnson, S.; Bonvini, E.; et al. Fc optimization of therapeutic antibodies enhances their ability to kill tumor cells in vitro and controls tumor expansion in vivo via low-affinity activating Fcgamma receptors. Cancer Res. 2007, 67, 8882–8890. [Google Scholar] [CrossRef] [Green Version]
  108. Mimoto, F.; Igawa, T.; Kuramochi, T.; Katada, H.; Kadono, S.; Kamikawa, T.; Shida-Kawazoe, M.; Hattori, K. Novel asymmetrically engineered antibody Fc variant with superior FcγR binding affinity and specificity compared with afucosylated Fc variant. mAbs 2013, 5, 229–236. [Google Scholar] [CrossRef] [Green Version]
  109. Duncan, A.R.; Woof, J.M.; Partridge, L.J.; Burton, D.R.; Winter, G. Localization of the binding site for the human high-affinity Fc receptor on IgG. Nature 1988, 332, 563–564. [Google Scholar] [CrossRef] [PubMed]
  110. Ahmed, A.A.; Keremane, S.R.; Vielmetter, J.; Bjorkman, P.J. Structural characterization of GASDALIE Fc bound to the activating Fc receptor FcγRIIIa. J. Struct. Biol. 2016, 1, 78–89. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  111. Richards, J.O.; Karki, S.; Lazar, G.A.; Chen, H.; Dang, W.; Desjarlais, J.R. Optimization of antibody binding to FcgammaRIIa enhances macrophage phagocytosis of tumor cells. Mol. Cancer Ther. 2008, 7, 2517–2527. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  112. Moore, G.L.; Chen, H.; Karki, S.; Lazar, G.A. Engineered Fc variant antibodies with enhanced ability to recruit complement and mediate effector functions. mAbs 2010, 2, 181–189. [Google Scholar] [CrossRef] [Green Version]
  113. Diebolder, C.A.; Beurskens, F.J.; de Jong, R.N.; Koning, R.I.; Strumane, K.; Lindorfer, M.A.; Voorhorst, M.; Ugurlar, D.; Rosati, S.; Heck, A.J.; et al. Complement is activated by IgG hexamers assembled at the cell surface. Science 2014, 343, 1260–1263. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  114. Smith, P.; DiLillo, D.J.; Bournazos, S.; Li, F.; Ravetch, J.V. Mouse model recapitulating human Fcγ receptor structural and functional diversity. Proc. Natl. Acad. Sci. USA 2012, 109, 6181–6186. [Google Scholar] [CrossRef]
  115. Natsume, A.; In, M.; Takamura, H.; Nakagawa, T.; Shiz, Y.; Kitajima, K.; Wakitani, M.; Ohta, S.; Satoh, M.; Shitara, K.; et al. Engineered antibodies of IgG1/IgG3 mixed isotype with enhanced cytotoxic activities. Cancer Res. 2008, 68, 3863–3872. [Google Scholar] [CrossRef] [Green Version]
  116. Tao, M.H.; Smith, R.I.; Morrison, S.L. Structural features of human immunoglobulin G that determine isotype-specific differences in complement activation. J. Exp. Med. 1993, 178, 661–667. [Google Scholar] [CrossRef]
  117. Idusogie, E.E.; Presta, L.G.; Gazzano-Santoro, H.; Totpal, K.; Wong, P.Y.; Ultsch, M.; Meng, Y.G.; Mulkerrin, M.G. Mapping of the C1q binding site on rituxan, a chimeric antibody with a human IgG1 Fc. J. Immunol. 2000, 164, 4178–4184. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  118. Hezareh, M.; Hessell, A.J.; Jensen, R.C.; van de Winkel, J.G.; Parren, P.W. Effector function activities of a panel of mutants of a broadly neutralizing antibody against human immunodeficiency virus type 1. J. Virol. 2001, 75, 12161–12168. [Google Scholar] [CrossRef] [Green Version]
  119. Duncan, A.R.; Winter, G. The binding site for C1q on IgG. Nature 1988, 332, 738–740. [Google Scholar] [CrossRef] [PubMed]
  120. Xu, D.; Alegre, M.L.; Varga, S.S.; Rothermel, A.L.; Collins, A.M.; Pulito, V.L.; Hanna, L.S.; Dolan, K.P.; Parren, P.W.; Bluestone, J.A.; et al. In vitro characterization of five humanized OKT3 effector function variant antibodies. Cell Immunol. 2000, 200, 16–26. [Google Scholar] [CrossRef] [PubMed]
  121. Schlothauer, T.; Herter, S.; Koller, C.F.; Grau-Richards, S.; Steinhart, V.; Spick, C.; Kubbies, M.; Klein, C.; Umaña, P.; Mössner, E. Novel human IgG1 and IgG4 Fc-engineered antibodies with completely abolished immune effector functions. Protein Eng. Des. Sel. 2016, 29, 457–466. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  122. Alegre, M.L.; Collins, A.M.; Pulito, V.L.; Brosius, R.A.; Olson, W.C.; Zivin, R.A.; Knowles, R.; Thistlethwaite, J.R.; Jolliffe, L.K.; Bluestone, J.A. Effect of a single amino acid mutation on the activating and immunosuppressive properties of a “humanized” OKT3 monoclonal antibody. J. Immunol. 1992, 148, 3461–3468. [Google Scholar]
  123. Shang, L.; Daubeuf, B.; Triantafilou, M.; Olden, R.; Dépis, F.; Raby, A.C.; Herren, S.; Dos Santos, A.; Malinge, P.; Dunn-Siegrist, I.; et al. Selective antibody intervention of Toll-like receptor 4 activation through Fc γ receptor tethering. J. Biol. Chem. 2014, 289, 15309–15318. [Google Scholar] [CrossRef] [Green Version]
  124. Vafa, O.; Gilliland, G.L.; Brezski, R.J.; Strake, B.; Wilkinson, T.; Lacy, E.R.; Scallon, B.; Teplyakov, A.; Malia, T.J.; Strohl, W.R. An engineered Fc variant of an IgG eliminates all immune effector functions via structural perturbations. Methods 2014, 65, 114–126. [Google Scholar] [CrossRef]
  125. Borrok, M.J.; Mody, N.; Lu, X.; Kuhn, M.L.; Wu, H.; Dall’Acqua, W.F.; Tsui, P. An “Fc-Silenced” IgG1 format with extended half-life designed for improved stability. J. Pharm. Sci. 2017, 106, 1008–1017. [Google Scholar] [CrossRef]
  126. Wilkinson, I.; Anderson, S.; Fry, J.; Julien, L.A.; Neville, D.; Qureshi, O.; Watts, G.; Hale, G. Fc-engineered antibodies with immune effector functions completely abolished. PLoS ONE 2021, 16, e0260954. [Google Scholar] [CrossRef]
  127. An, Z.; Forrest, G.; Moore, R.; Cukan, M.; Haytko, P.; Huang, L.; Vitelli, S.; Zhao, J.Z.; Lu, P.; Hua, J.; et al. IgG2m4, an engineered antibody isotype with reduced Fc function. mAbs 2009, 1, 572–579. [Google Scholar] [CrossRef] [Green Version]
  128. Rother, R.P.; Rollins, S.A.; Mojcik, C.F.; Brodsky, R.A.; Bell, L. Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Nat. Biotechnol. 2007, 25, 1256–1264. [Google Scholar] [CrossRef]
  129. Labrijn, A.F.; Buijsse, A.O.; van den Bremer, E.T.; Verwilligen, A.Y.; Bleeker, W.K.; Thorpe, S.J.; Killestein, J.; Polman, C.H.; Aalberse, R.C.; Schuurman, J.; et al. Therapeutic IgG4 antibodies engage in Fab-arm exchange with endogenous human IgG4 in vivo. Nat. Biotechnol. 2009, 27, 767–771. [Google Scholar] [CrossRef] [PubMed]
  130. Chu, S.Y.; Vostiar, I.; Karki, S.; Moore, G.L.; Lazar, G.A.; Pong, E.; Joyce, P.F.; Szymkowski, D.E.; Desjarlais, J.R. Inhibition of B cell receptor-mediated activation of primary human B cells by coengagement of CD19 and FcgammaRIIb with Fc-engineered antibodies. Mol. Immunol. 2008, 45, 3926–3933. [Google Scholar] [CrossRef] [PubMed]
  131. Szili, D.; Cserhalmi, M.; Bankó, Z.; Nagy, G.; Szymkowski, D.E.; Sármay, G. Suppression of innate and adaptive B cell activation pathways by antibody coengagement of FcγRIIb and CD19. mAbs 2014, 6, 991–999. [Google Scholar] [CrossRef] [Green Version]
  132. Leabman, M.K.; Meng, Y.G.; Kelley, R.F.; DeForge, L.E.; Cowan, K.J.; Iyer, S. Effects of altered FcγR binding on antibody pharmacokinetics in cynomolgus monkeys. mAbs 2013, 5, 896–903. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  133. Robbie, G.J.; Criste, R.; Dall’acqua, W.F.; Jensen, K.; Patel, N.K.; Losonsky, G.A.; Griffin, M.P. A novel investigational Fc-modified humanized monoclonal antibody, motavizumab-YTE, has an extended half-life in healthy adults. Antimicrob. Agents Chemother. 2013, 57, 6147–6153. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  134. Dall’Acqua, W.F.; Woods, R.M.; Ward, E.S.; Palaszynski, S.R.; Patel, N.K.; Brewah, Y.A.; Wu, H.; Kiener, P.A.; Langermann, S. Increasing the affinity of a human IgG1 for the neonatal Fc receptor: Biological consequences. J. Immunol. 2002, 169, 5171–5180. [Google Scholar] [CrossRef] [Green Version]
  135. Zalevsky, J.; Chamberlain, A.K.; Horton, H.M.; Karki, S.; Leung, I.W.; Sproule, T.J.; Lazar, G.A.; Roopenian, D.C.; Desjarlais, J.R. Enhanced antibody half-life improves in vivo activity. Nat. Biotechnol. 2010, 28, 157–159. [Google Scholar] [CrossRef]
  136. Hinton, P.R.; Johlfs, M.G.; Xiong, J.M.; Hanestad, K.; Ong, K.C.; Bullock, C.; Keller, S.; Tang, M.T.; Tso, J.Y.; Vásquez, M.; et al. Engineered human IgG antibodies with longer serum half-lives in primates. J. Biol. Chem. 2004, 279, 6213–6216. [Google Scholar] [CrossRef] [Green Version]
  137. Oganesyan, V.; Damschroder, M.M.; Cook, K.E.; Li, Q.; Gao, C.; Wu, H.; Dall’Acqua, W.F. Structural insights into neonatal Fc receptor-based recycling mechanisms. J. Biol. Chem. 2014, 289, 7812–7824. [Google Scholar] [CrossRef] [Green Version]
  138. Stapleton, N.M.; Andersen, J.T.; Stemerding, A.M.; Bjarnarson, S.P.; Verheul, R.C.; Gerritsen, J.; Zhao, Y.; Kleijer, M.; Sandlie, I.; de Haas, M.; et al. Competition for FcRn-mediated transport gives rise to short half-life of human IgG3 and offers therapeutic potential. Nat. Commun. 2011, 2, 599. [Google Scholar] [CrossRef] [Green Version]
  139. Zhang, J.; Huang, Y.; Xi, G.; Zhang, F. HX008: A humanized PD-1 blocking antibody with potent antitumor activity and superior pharmacologic properties. mAbs 2020, 12, 1724751. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  140. Dall’Acqua, W.F.; Kiener, P.A.; Wu, H. Properties of human IgG1s engineered for enhanced binding to the neonatal Fc receptor (FcRn). J. Biol. Chem. 2006, 281, 23514–23524. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  141. Labrijn, A.F.; Rispens, T.; Meesters, J.; Rose, R.J.; den Bleker, T.H.; Loverix, S.; van den Bremer, E.T.; Neijssen, J.; Vink, T.; Lasters, I.; et al. Species-specific determinants in the IgG CH3 domain enable Fab-arm exchange by affecting the noncovalent CH3-CH3 interaction strength. J. Immunol. 2011, 187, 3238–3246. [Google Scholar] [CrossRef] [Green Version]
  142. Ridgway, J.B.; Presta, L.G.; Carter, P. ‘Knobs-into-holes’ engineering of antibody CH3 domains for heavy chain heterodimerization. Protein Eng. 1996, 9, 617–621. [Google Scholar] [CrossRef] [Green Version]
  143. Saito, S.; Namisaki, H.; Hiraishi, K.; Takahashi, N.; Iida, S. Engineering a human IgG2 antibody stable at low pH. Protein Sci. 2020, 29, 1186–1195. [Google Scholar] [CrossRef] [PubMed]
Antibodies 11 00065 g001 550
Figure 1. IMGT® is the international ImMunoGenetics information system® (https://www.imgt.org) [11,12,13,14,15,16,17,18,19,20,21]. The IMGT web resources (>25,000 pages, the IMGT Marie-Paule page) are not shown. IMGT/mAb-DB, the interface for therapeutic monoclonal antibodies and fusion proteins for immune applications (FPIA), has been available online since 4 December 2009 and IMGT/HighV-QUEST portal for the next generation sequencing (NGS) high-throughput sequence analysis since 22 November 2010 (with permission from M-P.Lefranc and G. Lefranc, LIGM, Founders of IMGT® from the international ImMunoGeneTics information system® (https://www.imgt.org)).
Figure 1. IMGT® is the international ImMunoGenetics information system® (https://www.imgt.org) [11,12,13,14,15,16,17,18,19,20,21]. The IMGT web resources (>25,000 pages, the IMGT Marie-Paule page) are not shown. IMGT/mAb-DB, the interface for therapeutic monoclonal antibodies and fusion proteins for immune applications (FPIA), has been available online since 4 December 2009 and IMGT/HighV-QUEST portal for the next generation sequencing (NGS) high-throughput sequence analysis since 22 November 2010 (with permission from M-P.Lefranc and G. Lefranc, LIGM, Founders of IMGT® from the international ImMunoGeneTics information system® (https://www.imgt.org)).
Antibodies 11 00065 g001
Antibodies 11 00065 g002 550
Figure 2. Immunoglobulin IgG1. The structure is that of the antibody b12, an IgG1-kappa, and so far is the only complete human IG crystallized (PDB code: 1hzh, from IMGT® https://www.imgt.org, IMGT/3Dstructure-DB). H-GAMMA-1 and L-KAPPA (usedfor the chains), VH, CH1, CH2, CH3, V-KAPPA and C-KAPPA (for the domains) are written in capital letters as they are IMGT standardized labels (DESCRIPTION) [1]. This first 3D-structure of a complete Homo sapiens IG shows the expected Y shape with the two Fragment antigen binding (Fab) arms (one L-KAPPA light chain (V-KAPPA-C-KAPPA) paired to the VH-CH1 of each H-GAMMA-1 heavy chain) and the Fragment crystallisable (Fc), made of the paired hinge-CH2-CH3 of the two H-GAMMA-1 heavy chains. The figure also shows the relative position, in space, of the L-KAPPA relative to the VH-CH1 in each Fab (in the front on the left hand side, and the back right hand side). The sequences of the two H-GAMMA1 chains (colored in purple and dark blue for a better visibility) are identical and the sequences of the two L-KAPPA chains (colored in orange and green for a better visibility) are identical (with permission from M-P. Lefranc and G. Lefranc, LIGM, Founders of IMGT®, the international ImMunoGeneTics information system®, https://www.imgt.org).
Figure 2. Immunoglobulin IgG1. The structure is that of the antibody b12, an IgG1-kappa, and so far is the only complete human IG crystallized (PDB code: 1hzh, from IMGT® https://www.imgt.org, IMGT/3Dstructure-DB). H-GAMMA-1 and L-KAPPA (usedfor the chains), VH, CH1, CH2, CH3, V-KAPPA and C-KAPPA (for the domains) are written in capital letters as they are IMGT standardized labels (DESCRIPTION) [1]. This first 3D-structure of a complete Homo sapiens IG shows the expected Y shape with the two Fragment antigen binding (Fab) arms (one L-KAPPA light chain (V-KAPPA-C-KAPPA) paired to the VH-CH1 of each H-GAMMA-1 heavy chain) and the Fragment crystallisable (Fc), made of the paired hinge-CH2-CH3 of the two H-GAMMA-1 heavy chains. The figure also shows the relative position, in space, of the L-KAPPA relative to the VH-CH1 in each Fab (in the front on the left hand side, and the back right hand side). The sequences of the two H-GAMMA1 chains (colored in purple and dark blue for a better visibility) are identical and the sequences of the two L-KAPPA chains (colored in orange and green for a better visibility) are identical (with permission from M-P. Lefranc and G. Lefranc, LIGM, Founders of IMGT®, the international ImMunoGeneTics information system®, https://www.imgt.org).
Antibodies 11 00065 g002
Antibodies 11 00065 g003 550
Figure 3. IG constant (C) domain. (A) 3D structure ribbon representation with the IMGT strand and loop delimitations. (B) IMGT Collier de Perles on two layers with hydrogen bonds. The IMGT Colliers de Perles on two layers show, in the forefront, the GFC strands, and in the back, the ABED strands (located at the interface CH1/CL of the IG), linked by the CD transversal strand. The IMGT Collier de Perles with hydrogen bonds (green lines online, only shown here for the GFC sheet) is generated by the IMGT/Collier de Perles tool [51] integrated in the IMGT/3Dstructure-DB, from experimental 3D structure data. (C) IMGT Collier de Perles on two layers from IMGT/DomainGapAlign [28,49,50]. (D) IMGT Colliers de Perles on one layer. Amino acids are shown in the one-letter abbreviation. All proline (P) are shown online in yellow. IMGT anchors are represented by squares. Hatched circles are IMGT gaps according to the IMGT unique numbering for the C-domain [68]. Positions with bold (online red) letters indicate the four conserved positions that are common to a V-domain and to a C-domain: 23 (1st-CYS), 41 (CONSERVED-TRP), 89 (hydrophobic), 104 (2nd-CYS), and position 118, which is only conserved in V-DOMAIN. The identifier of the chain to which the CH-domain belongs is 1n0x_H (from the Homo sapiens b12 Fab, in IMGT/3Dstructure-DB, https://www.imgt.org) [27,28,29]. The 3D ribbon representation was obtained using PyMOL and “IMGT numbering comparison” of 1n0x_H (CH1) from IMGT/3Dstructure-DB (https://www.imgt.org) [27,28,29].
Figure 3. IG constant (C) domain. (A) 3D structure ribbon representation with the IMGT strand and loop delimitations. (B) IMGT Collier de Perles on two layers with hydrogen bonds. The IMGT Colliers de Perles on two layers show, in the forefront, the GFC strands, and in the back, the ABED strands (located at the interface CH1/CL of the IG), linked by the CD transversal strand. The IMGT Collier de Perles with hydrogen bonds (green lines online, only shown here for the GFC sheet) is generated by the IMGT/Collier de Perles tool [51] integrated in the IMGT/3Dstructure-DB, from experimental 3D structure data. (C) IMGT Collier de Perles on two layers from IMGT/DomainGapAlign [28,49,50]. (D) IMGT Colliers de Perles on one layer. Amino acids are shown in the one-letter abbreviation. All proline (P) are shown online in yellow. IMGT anchors are represented by squares. Hatched circles are IMGT gaps according to the IMGT unique numbering for the C-domain [68]. Positions with bold (online red) letters indicate the four conserved positions that are common to a V-domain and to a C-domain: 23 (1st-CYS), 41 (CONSERVED-TRP), 89 (hydrophobic), 104 (2nd-CYS), and position 118, which is only conserved in V-DOMAIN. The identifier of the chain to which the CH-domain belongs is 1n0x_H (from the Homo sapiens b12 Fab, in IMGT/3Dstructure-DB, https://www.imgt.org) [27,28,29]. The 3D ribbon representation was obtained using PyMOL and “IMGT numbering comparison” of 1n0x_H (CH1) from IMGT/3Dstructure-DB (https://www.imgt.org) [27,28,29].
Antibodies 11 00065 g003
Antibodies 11 00065 g004 550
Figure 4. IMGT physicochemical classes of the 20 usual amino acids (AA) [52] (with permission from M-P. Lefranc and G. Lefranc, LIGM, Founders of IMGT®, the international ImMunoGeneTics information system®, https://www.imgt.org).
Figure 4. IMGT physicochemical classes of the 20 usual amino acids (AA) [52] (with permission from M-P. Lefranc and G. Lefranc, LIGM, Founders of IMGT®, the international ImMunoGeneTics information system®, https://www.imgt.org).
Antibodies 11 00065 g004
Antibodies 11 00065 g005 550
Figure 5. Correspondence between the Homo sapiens IGHG1 amino acid sequence, based on the IMGT unique numbering for the C-domain [68] and the Eu positions (shown vertically) from 118 to 445 [97]. (A) IGHG1 CH1, CH2 and CH3. The standardized presentation of the IMGT unique numbering on the top two lines [68] can be obtained using IMGT/DomainGapAlign [28,49,50], the IMGT reference tool for constant C-domain amino acid sequence analysis. The IMGT unique numbering for the CH1, CH2 and CH3 is shown on the first horizontal line with additional IMGT positions (by comparison to the V-domain IMGT unique numbering [67]) on line two. Amino acids at these additional positions are highlighted in bold. The Eu numbers are read vertically (on three lines top to down) at each position below the amino acid sequence. For example, the first amino acid of the Homsap IGHG1 CH1 is A1.4 (read G1, and going left, K1.1, T1.2, S1.3 and A1.4) and corresponds to Eu 118 (below A, read one top line, one second line and eight third line). The last amino acid of CH1 is a V, at position IMGT 121 (3 dots after 118), and corresponds to Eu 215 (below V, read two top line, one second line and five third line). The first amino acid of the Homsap IGHG1 CH2 A1.6 corresponds to Eu 231, whereas the last one, K, at position IMGT 125 (7 dots after 118), corresponds to Eu 340. The first amino acid of the Homsap IGHG1 CH3 G1.4 corresponds to Eu 341, whereas the last one, P, at position IMGT 125, corresponds to Eu 445. The first amino acid of the CH1, hinge, CH2 and CH3 results from the splicing. The four conserved amino acids of the C-DOMAIN C23, W41, hydrophobic 89 and C104 are highlighted in colors (C23 and C104 in pink, W41 and hydrophobic 89 (V, L) in blue). The four AA and IMGT positions C23, W41, hydrophobic 89 and C104 correspond, respectively, to Eu 144, 158, 186 and 200 in CH1, 261, 277, 306 and 321 in CH2, and 367, 381, 410 and 425 in CH3. The CH2 asparagine N84.4 of the N-glycosylation site corresponds to Eu 297 (colored in green). The amino acids of the C-domain BC-LOOP and FG-LOOP (Table 4) are highlighted in bold and brown color. (B) Homsap IGHG1 hinge. The hinge IMGT 1 to 15 corresponds to Eu 216 to 230. Cysteines (C) and prolines (P) with Eu positions are highlighted in pink and yellow, respectively. (Drawn by Marie-Paule Lefranc and Gérard Lefranc, LIGM, Founders and Authors of IMGT®, the international ImMunoGeneTics information system®, https://www.imgt.org, Copyright 2022.)
Figure 5. Correspondence between the Homo sapiens IGHG1 amino acid sequence, based on the IMGT unique numbering for the C-domain [68] and the Eu positions (shown vertically) from 118 to 445 [97]. (A) IGHG1 CH1, CH2 and CH3. The standardized presentation of the IMGT unique numbering on the top two lines [68] can be obtained using IMGT/DomainGapAlign [28,49,50], the IMGT reference tool for constant C-domain amino acid sequence analysis. The IMGT unique numbering for the CH1, CH2 and CH3 is shown on the first horizontal line with additional IMGT positions (by comparison to the V-domain IMGT unique numbering [67]) on line two. Amino acids at these additional positions are highlighted in bold. The Eu numbers are read vertically (on three lines top to down) at each position below the amino acid sequence. For example, the first amino acid of the Homsap IGHG1 CH1 is A1.4 (read G1, and going left, K1.1, T1.2, S1.3 and A1.4) and corresponds to Eu 118 (below A, read one top line, one second line and eight third line). The last amino acid of CH1 is a V, at position IMGT 121 (3 dots after 118), and corresponds to Eu 215 (below V, read two top line, one second line and five third line). The first amino acid of the Homsap IGHG1 CH2 A1.6 corresponds to Eu 231, whereas the last one, K, at position IMGT 125 (7 dots after 118), corresponds to Eu 340. The first amino acid of the Homsap IGHG1 CH3 G1.4 corresponds to Eu 341, whereas the last one, P, at position IMGT 125, corresponds to Eu 445. The first amino acid of the CH1, hinge, CH2 and CH3 results from the splicing. The four conserved amino acids of the C-DOMAIN C23, W41, hydrophobic 89 and C104 are highlighted in colors (C23 and C104 in pink, W41 and hydrophobic 89 (V, L) in blue). The four AA and IMGT positions C23, W41, hydrophobic 89 and C104 correspond, respectively, to Eu 144, 158, 186 and 200 in CH1, 261, 277, 306 and 321 in CH2, and 367, 381, 410 and 425 in CH3. The CH2 asparagine N84.4 of the N-glycosylation site corresponds to Eu 297 (colored in green). The amino acids of the C-domain BC-LOOP and FG-LOOP (Table 4) are highlighted in bold and brown color. (B) Homsap IGHG1 hinge. The hinge IMGT 1 to 15 corresponds to Eu 216 to 230. Cysteines (C) and prolines (P) with Eu positions are highlighted in pink and yellow, respectively. (Drawn by Marie-Paule Lefranc and Gérard Lefranc, LIGM, Founders and Authors of IMGT®, the international ImMunoGeneTics information system®, https://www.imgt.org, Copyright 2022.)
Antibodies 11 00065 g005
Antibodies 11 00065 g006 550
Figure 6. Correspondence between the Homo sapiens IGHG1, IGHG2, IGHG3 (4 exons) and IGHG4 IMGT numbering with the IGHG1 Eu positions. The top line indicates the IMGT numbering for the IGHG1, IGHG2 and IGHG4 hinges and for the four exons (H1 to H4) of the IGHG3 hinge. The Eu numbers are read vertically (on three lines top to down) at each position below the amino acid sequence. Dashes indicate the positions that are absent in the Eu numbering. Cysteines (C) and prolines (P) with Eu positions are highlighted in pink and yellow, respectively. (Drawn by Marie-Paule Lefranc and Gérard Lefranc, LIGM, Founders and Authors of IMGT®, the international ImMunoGeneTics information system®, https://www.imgt.org, Copyright 2022).
Figure 6. Correspondence between the Homo sapiens IGHG1, IGHG2, IGHG3 (4 exons) and IGHG4 IMGT numbering with the IGHG1 Eu positions. The top line indicates the IMGT numbering for the IGHG1, IGHG2 and IGHG4 hinges and for the four exons (H1 to H4) of the IGHG3 hinge. The Eu numbers are read vertically (on three lines top to down) at each position below the amino acid sequence. Dashes indicate the positions that are absent in the Eu numbering. Cysteines (C) and prolines (P) with Eu positions are highlighted in pink and yellow, respectively. (Drawn by Marie-Paule Lefranc and Gérard Lefranc, LIGM, Founders and Authors of IMGT®, the international ImMunoGeneTics information system®, https://www.imgt.org, Copyright 2022).
Antibodies 11 00065 g006
Antibodies 11 00065 g007 550
Figure 7. Correspondence between the Homo sapiens IGKC, IGLC2 and IGHG1 CH1 sequences, based on the IMGT unique numbering [68] and the Eu positions [97]. The first amino acid of each sequence results from the splicing. The IGHG1 CH1 chosen as the CH representative is from Figure 5A. The IMGT unique numbering is shown on the top horizontal line one with additional IMGT positions on line two. Amino acids at these additional positions (by comparison to the V-domain IMGT unique numbering [67]) are highlighted in bold in the Homsap IGKC, IGLC2 and IGHG1 CH1 sequences. The Eu numbers are read vertically (on three lines top to down) at each position below the amino acid sequences. For example, the first amino acid of IGKC R1.4 corresponds to Eu 108, that of IGLC2 G1.5 to Eu 107, and that of IGHG1 CH1 A1.4 to Eu 118, the last amino acid of IGKC C126 corresponds to Eu 214, that of IGLC2 S215 to ‘deduced Eu position 215′ and that of IGHG1 CH1 V at position IMGT 121 corresponds to Eu 215. The four conserved amino acids of the C-DOMAIN C23, W41, hydrophobic 89 and C104 are highlighted in colors (C23 and C104 in pink, W41 and hydrophobic 89 (L, V) in blue). The four AA and IMGT positions C23, W41, hydrophobic 89 and C104 correspond, respectively, to Eu 134, 148, 179, 194 for IGKC and IGLC2 and to Eu 144, 158, 186 and 200 in IGHG1 CH1. The amino acids of the C-domain BC-LOOP and FG-LOOP (Table 4) are highlighted in bold and brown color. (Drawn by Marie-Paule Lefranc and Gérard Lefranc, LIGM, Founders and Authors of IMGT®, the international ImMunoGeneTics information system®, https://www.imgt.org, Copyright 2022.)
Figure 7. Correspondence between the Homo sapiens IGKC, IGLC2 and IGHG1 CH1 sequences, based on the IMGT unique numbering [68] and the Eu positions [97]. The first amino acid of each sequence results from the splicing. The IGHG1 CH1 chosen as the CH representative is from Figure 5A. The IMGT unique numbering is shown on the top horizontal line one with additional IMGT positions on line two. Amino acids at these additional positions (by comparison to the V-domain IMGT unique numbering [67]) are highlighted in bold in the Homsap IGKC, IGLC2 and IGHG1 CH1 sequences. The Eu numbers are read vertically (on three lines top to down) at each position below the amino acid sequences. For example, the first amino acid of IGKC R1.4 corresponds to Eu 108, that of IGLC2 G1.5 to Eu 107, and that of IGHG1 CH1 A1.4 to Eu 118, the last amino acid of IGKC C126 corresponds to Eu 214, that of IGLC2 S215 to ‘deduced Eu position 215′ and that of IGHG1 CH1 V at position IMGT 121 corresponds to Eu 215. The four conserved amino acids of the C-DOMAIN C23, W41, hydrophobic 89 and C104 are highlighted in colors (C23 and C104 in pink, W41 and hydrophobic 89 (L, V) in blue). The four AA and IMGT positions C23, W41, hydrophobic 89 and C104 correspond, respectively, to Eu 134, 148, 179, 194 for IGKC and IGLC2 and to Eu 144, 158, 186 and 200 in IGHG1 CH1. The amino acids of the C-domain BC-LOOP and FG-LOOP (Table 4) are highlighted in bold and brown color. (Drawn by Marie-Paule Lefranc and Gérard Lefranc, LIGM, Founders and Authors of IMGT®, the international ImMunoGeneTics information system®, https://www.imgt.org, Copyright 2022.)
Antibodies 11 00065 g007
Table
Table 1. The IMGT databases, tools and web resources (‘The IMGT Marie-Paule Page’) for sequences, genes and structures.
Table 1. The IMGT databases, tools and web resources (‘The IMGT Marie-Paule Page’) for sequences, genes and structures.
IMGT DatabasesIMGT ToolsIMGT Web Resources
‘The IMGT Marie-Paule Page’
SequencesIMGT/LIGM-DB [24,25]
IMGT/PRIMER-DB
IMGT/CLL-DB		IMGT/V-QUEST [31,32,33,34,35,36] IMGT/JunctionAnalysis [37,38]
IMGT/Automat [39,40]
IMGT/HighV-QUEST [36,41,42,43,44,45]
IMGT/StatClonotype [46,47]
IMGT/PhyloGene
IMGT/Allele-Align		Standardized keywords and labels [53,54]
Standardized labels [55,56,57,58]
IMGT Repertoire (IG and TR, MH, RPI
Alignments of alleles
Protein displays
Tables of alleles
CDR-IMGT lengths
Allotypes [59,60]
Isotypes, etc.
GenesIMGT/GENE-DB [26]IMGT/LIGMotif [48]
IMGT/LocusView
IMGT/GeneView
IMGT/GeneSearch
IMGT/CloneSearch
IMGT/GeneInfo		Gene and allele nomenclature [1,2,3,4,5,7,8,9,10,61,62,63]
Chromosomal localizations
Locus representations
Locus description
Gene exon/intron splicing sites
Gene tables
Potential germline repertoires
Lists of genes
Correspondence between nomenclatures.
StructuresIMGT/2Dstructure-DB
IMGT/3Dstructure-DB [27,28,29]
IMGT/mAb-DB [30]		IMGT/DomainGapAlign [28,49,50]
IMGT/DomainDisplay
IMGT/StructuralQuery
IMGT/Collier-de-Perles [51]		IMGT unique numbering per domain [64,65,66,67,68,69,70,71,72]
2D Colliers de Perles (IG and TR, MH, RPI) [51,73,74,75,76,77]
IMGT classes for amino acid physicochemical properties [52]
IMGT Colliers de Perles reference profiles [52]
3D representations.
Table
Table 2. IMGT-ONTOLOGY axioms, concepts and IMGT Scientific chart rules.
Table 2. IMGT-ONTOLOGY axioms, concepts and IMGT Scientific chart rules.
IMGT-ONTOLOGY Axioms and ConceptsIMGT Scientific Chart Rules
IDENTIFICATION [54]Concepts of identification [53]Standardized keywords [53,54]
(e.g., clonotype, paratope, epitope, variant, Fc receptor, FcR) (1).
DESCRIPTION
[56]		Concepts of description [55]Standardized labels and annotations [55,56,57,58] (e.g., CDR-IMGT [57], FR-IMGT [58], antibody description [84])
CLASSIFICATION [63]Concepts of classification [62]Reference sequences
Standardized IG and TR gene nomenclature (group, subgroup, gene, allele) [1,2,3,4,5,7,8,9,10,61,62,63] (1).
NUMEROTATION [64]Concepts of numerotation [65,66,67,68,69,70,71,72]IMGT unique numbering for
V- and V-LIKE domains [65,66,67]
C- and C-LIKE domains [68]
G- and G-LIKE domains [69]
IMGT Colliers de Perles [73,74,75,76,77]
ORIENTATIONConcepts of orientationChromosome orientation
Locus orientation
Gene orientation
DNA strand orientation
Domain beta-strand orientation
OBTENTIONStandardized origin
Standardized methodology
Keyword use versus gene name nomenclature for defining a receptor: in this paper, this concerns the related proteins of immune interest (RPI) such as the Fc receptor’s gamma. Owing to the diversity and multiplicity of these receptors, and in the absence of standardized sequence characterization in functional analysis, these receptors are usually identified with keywords, for example for Homo sapiens, FcγR, FcγRI, FcγRII, FcγRIII and so on. However, it should be noted that, when there is no ambiguity as to the interactive chain involved, the HGNC gene name should be used (FCGR1A, FCGR2A, FCGR2B, FCRG2C, FCGR3A and FCGR3B). This rule is applied in this paper for the neonatal Fc receptor (FcRn), which is made of the interactive Fc gamma receptor and transporter (FCGRT) chain that is associated with B2M.
Table
Table 3. The immunoglobulin IgG1 receptor, chain and domain structure labels and correspondence with sequence labels. IMGT standardized labels are in capital letters. They are shown with the example Homo sapiens IgG1-kappa.
Table 3. The immunoglobulin IgG1 receptor, chain and domain structure labels and correspondence with sequence labels. IMGT standardized labels are in capital letters. They are shown with the example Homo sapiens IgG1-kappa.
IG Structure Labels
(IMGT/3Dstructure-DB [27,28,29])		Sequence Labels (IMGT/LIGM-DB [24,25])
Receptor ChainDomain TypeDomainRegion 1
IG-GAMMA-1_KAPPAH-GAMMA-1VVHV-D-J-REGION
CCH1C-REGION 2
CCH2
CCH3
L-KAPPAVV-KAPPAV-J-REGION
CC-KAPPAC-REGION
1. The VH-domain (or V-D-J-REGION) and the VL-domain (V-KAPPA or V-LAMBDA) (or V-J-REGION) are encoded by rearranged V-(D)-J genes, whereas the remainder of the chain is the C-REGION (encoded by a C gene). The C-REGION comprises one C-domain (C-KAPPA or C-LAMBDA) for the L chain, or several C-domains (CH) for the H chain. 2 The heavy chain C-REGION also includes the HINGE-REGION, and for membrane IG (mIG), the CONNECTING-REGION (CO), TRANSMEMBRANE-REGION (TM) and CYTOPLASMIC-REGION (CY); for secreted IG (sIG), the C-REGION includes CHS instead of CO, TM and CY.
Table
Table 4. C-domain strands, turns and loops, IMGT positions and lengths, based on the IMGT unique numbering for C-domain (C-DOMAIN and C-LIKE-DOMAIN) [68]. (With permission from M-P. Lefranc and G. Lefranc, LIGM, Founders of IMGT®, the international ImMunoGeneTics information system®, https://www.imgt.org).
Table 4. C-domain strands, turns and loops, IMGT positions and lengths, based on the IMGT unique numbering for C-domain (C-DOMAIN and C-LIKE-DOMAIN) [68]. (With permission from M-P. Lefranc and G. Lefranc, LIGM, Founders of IMGT®, the international ImMunoGeneTics information system®, https://www.imgt.org).
C Domain Strands, Turns and Loops aIMGT Position bLengths c Characteristic IMGT Residue@Position d
A-STRAND1–c1515 (14 if gap at 10)
AB-TURN 15.1–15.30-3
B-STRAND16–26111st-CYS 23
BC-LOOP27–31
34–38		10 (or less)
C-STRAND39–457CONSERVED-TRP 41
CD-STRAND45.1–45.90–9
D-STRAND77–848 (or 7 if gap at 82)
DE-TURN84.1–84.7
85.1–85.7		0–14
E-STRAND85–9612hydrophobic 89
EF-TURN96.1–96.20–2
F-STRAND97–10482nd-CYS 104
FG-LOOP105–11713 (or less, or more)
G-STRAND118–12811 (or less)
a IMGT labels (concepts of description) are written in capital letters (no plural) [55,56]. b based on the IMGT unique numbering for C-domain (C-DOMAIN and C-LIKE-DOMAIN) [68]. c in number of amino acids (or codons). d IMGT Residue@Position is a given residue (usually an amino acid) or a given conserved property amino acid class, at a given position in a domain, based on the IMGT unique numbering [68].
Table
Table 5. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in antibody-dependent cellular cytotoxicity (ADCC) reduction (Effector #1).
Table 5. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in antibody-dependent cellular cytotoxicity (ADCC) reduction (Effector #1).
IMGT Engineered Fc Variant NameIMGT Engineered Variant DefinitionIMGT Amino Acid Changes on IGHG CH Domain (Eu Numbering between Parentheses)Amino Acid Changes With the Eu PositionsMotif Identifiable in Gene and Domain with Positions According to the IMGT Unique Numbering and with Eu Positions between Parentheses1. Property and Function2. Property and Function
G1v1CH2
P1.4		CH2
E1.4 > P (233)
E233P		IGHG1 CH2
1.6–3 (231–239)
APELLGGPS >
APPLLGGPS		ADCC reduction.
Prevents FcγRI binding [101]
G1v2CH2
V1.3		CH2
L1.3 > V (234)
L234V		IGHG1 CH2
1.6–3 (231–239)
APELLGGPS >
APEVLGGPS		ADCC reduction
Decreases FcγRI binding [101]
G1v3CH2
A1.2		CH2
L1.2 > A (235)
L235A		IGHG1 CH2
1.6–3 (231–239)
APELLGGPS >
APELAGGPS		ADCC reduction.
Prevents FcγRI binding [101]
G1v5CH2
W109		CH2
K109 > W (326)
K326W		IGHG1 CH2 FG
105–117 (322–332)
KVSNKA..LPAPI >
KVSNWA..LPAPI		ADCC reduction [102]CDC enhancement.
Increases C1q binding [102]
G1v47CH2
delG1.1		CH2
G1.1 > del (326)
G236del		IGHG1 CH2
1.6–3 (231–239)
APELLGGPS >
APELLGPS		ADCC reduction.
Eliminates binding to FcγRI, FcγRIIA, FcγRIIIA [103]
G1v50CH2
P1.4
V1.3
A1.2
delG1.1		CH2
E1.4 > P (233),
L1.3 > V (234),
L1.2 > A (235),
G1.1 > del (236)
E233P,
L234V,
L235A,
G236del		IGHG1 CH2
1.6–3 (231–239)
APELLGGPS >
APPVA-GPS		ADCC reduction.
Decreases FcgammaR binding (G2-like motif). [Combines G1v1, v2, v3 and v47]
G1v52CH2
R1.1,
R113		CH2
G1.1 > R (231)
L113 > R (328)

G236R,
L328R
GRLR		IGHG1 CH2
1.6–3 (231–239)
APELLGGPS >
APELLRGPS
IGHG1 CH2
FG 105–117 (322–332)
KVSNKA..LPAPI >
KVSNKA..RPAPI		ADCC reduction.
Abrogates FcgammaR binding
G1v66CH2
A27		CH2
D27 > A
D265A		IGHG1 CH2
23–31 (261–269)
CVVVDVSHE >
CVVVAVSHE		ADCC reduction.
Reduces FcγR binding.
G1v67CH2
S27		CH2
D27 > S
D265S		IGHG1 CH2
23–31 (261–269)
CVVVDVSHE >
CVVVSVSHE		ADCC reduction.
Reduces FcγR binding.
Engineered amino acid changes are in bold in the IMGT variants (red before the change, green after the change. The motif is in yellow and shown before and after the AA change(s). Amino acids of the motifs at additional positions in the IMGT unique numbering for C-domain [68] (by comparison to the V-domain IMGT unique numbering [67]) are underlined. Alias variant names found in the literature are written in blue in column 4 ‘Amino Acid Changes with the Eu Positions’. The background color indicates a reduction (pink color) or an enhancement (green color) of the involved effector ‘Property and Function’. For other ‘Property and Function’, background colors refer to structure (yellow), half-life (pale blue color) or protein A (pale orange).
Table
Table 6. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in antibody-dependent cellular cytotoxicity (ADCC) enhancement (Effector #2).
Table 6. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in antibody-dependent cellular cytotoxicity (ADCC) enhancement (Effector #2).
IMGT Engineered Fc Variant Name IMGT Engineered Variant DefinitionIMGT Amino Acid Changes on IGHG CH Domain (Eu Numbering between Parentheses)Amino Acid Changes with the Eu PositionsMotif Identifiable in Gene and Domain with Positions According to the IMGT Unique Numbering and with Eu Positions between Parentheses1. Property and Function2. Property and Function3D
G1v6CH2
A85.4,
A118,
A119		CH2
S85.4 > A(298),
E118 > A (333),
K119 > A (334)
S298A,
E333A,
K334A		IGHG1 CH2
84.1–85.1 (294–301)
EQYNSTYR >
EQYNATYR
FG 105–117,118,119
(322–334)
KVSNKA..LPAPIEK >
KVSNKA..LPAPIAA		ADCC enhancement.
Increases FcγRIIIa binding [104]
G1v7CH2
D3,
E117		CH2
S3 > D (239),
I117 > E (332)

S239D,
I332E
DE		IGHG1 CH2
1.6–3 (231–239)
APELLGGPS >
APELLGGPD
FG 105–117 (322–332)
KVSNKA..LPAPI >
KVSNKA..LPAPE		ADCC enhancement.
Increases FcγRIIIA binding [105]
G1v8CH2
D3,
L115,
E117		CH2
S3> D (239),
A115 > L (330),
I117 > E (332)

S239D,
A330L,
I332E
DLE, 3M		IGHG1 CH2
1.6–3 (231–239)
APELLGGPS >
APELLGGPD
FG 105–117 (322–332)
KVSNKA..LPAPI >
KVSNKA..LPLPE		ADCC enhancement.
Increases FcRIIIA binding [105]		Decreases FcγRIIB binding [105]3D [106]
G1v9CH2
L7,
P83,
L85.2,
I88.
CH3
L83		CH2
F7 > L (243),
R83 > P (292),
Y85.2 > L (300),
V88 > I (305)
CH3
P83 > L (396)

F243L,
R292P,
Y300L,
V305I,

P396l
LPLIL		IGHG1 CH2
6–10 (242–246)
LFPPK >
LLPPK
83–88
(292–305)
REEQYNSTYRVVSV >
PEEQYNSTLRVVSI
CH3 83–84.4
(396–401)
PVLDSD >
IVLDSD		ADCC enhancement.
100% increase. [107]
G1v10CH2
Y1.3,
Q1.2,
W1.1,
M3,
D30,
E34,
A85.4		CH2
L1.3 > Y (234),
L1.2 > Q (235),
G1.1 > W (236),
S3 > M (239),
H30 > D (268),
D34 > E (270),
S85.4 > A (298)
L234Y,
L235Q,
G236W,
S239M,
H268D,
D270E,
S298A		IGHG1 CH2
1.6–3 (231–239)
APELLGGPS >
APEYQWGPM
27–31,34 (265–270)
DVSHED >
DVSDEE
84.1–85.1
(294–301)
EQYNSTYR >
EQYNATYR		ADCC enhancement.
Increases FcγIIIA binding [108] >2000-fold (F158), >1000-fold (V158) in the association of G1v10 and G1v11 [108]
G1v11CH2
E34,
D109,
M115,
E119		CH2
D34 > E (270),
K109 > D (326),
A115 > M (330)
K119 > E (334)
D270E,
K326D,
A330M,
K334E		 IGHG1 CH2
27–31,34 (265–270)
DVSHED >
DVSHEE
FG 105–117,118,119 (322–334) KVSNKA..LPAPIEK >
KVSNDA..LPMPIEE		ADCC enhancement.
Increases FcγIIIA binding [108] >2000-fold (F158), >1000-fold (V158) in the association of G1v10 and G1v11 [108]
G2v1CH2
L1.3,
L1.2,
G1.1		CH2
V1.2 > LL(234,235)
A1.1 > G(236)
V235LL,
A236G		IGHG2 CH2
1.6–3 (231–239)
AP.PVAGPS >
APPLLGGPS		ADCC enhancement.
Confers FcγRI binding (WT does not show any binding capacity) [101]
G4v1CH2
L1.3		CH2
F1.3 > L (234)
F234L		IGHG4 CH2
1.6–3 (231–239)
APEFLGGPS >
APELLGGPS		ADCC enhancement.
Increases FcγRI affinity [101]
Mus musculus
G2Bv1		CH2
L1.2		CH2
E1.2 > L (235)
E235L		IGHG2B CH2
1.6–3 (231–239)
APNLEGGPS >
APNLLGGPS		ADCC enhancement.
Increases FcγRI affinity [109]
Table
Table 7. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) enhancement (Effector #3).
Table 7. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) enhancement (Effector #3).
IMGT Engineered Fc Variant NameIMGT Engineered Variant DefinitionIMGT Amino Acid Changes on IGHG CH Domain (Eu Numbering between Parentheses)Amino Acid Changes with the Eu PositionsMotif Identifiable in Gene and Domain with Positions According to the IMGT Unique Numbering and with Eu Positions between Parentheses1. Property and Function2. Property and Function3D
G1v12CH2
A1.1,
D3,
L115,
E117 		CH2
G1.1 > A (236),
S3 > D (239),
A115 > L (330),
I117 > E (332)

G236A,
S239D,
A330L,
I332E
GASDALIE		IGHG1 CH2
1.6–3 (231–239)
APELLGGPS >
APELLAGPD
FG 105–117 (322–332)
KVSNKA..LPAPI >
KVSNKA..LPLPE		ADCC enhancement.
Increases FcγRIIIA binding [110]		ADCP enhancement.
NK cell activation.
Increases FcγRIIA binding [110]		5d4q,
5d6d
G1v13CH2
A1.1,
D3,
E117		CH2
G1.1 > A (236),
S3 > D (239),
I117 > E (332)


G236A,
S239D,
I332E
GASDIE, ADE		IGHG1 CH2
1.6–3 (231–239)
APELLGGPS >
APELLAGPD
FG 105–117 (322–332)
KVSNKA..LPAPI >
KVSNKA..LPAPE		ADCC enhancement.
Increases FcγIIIA binding [111]		ADCP enhancement.
NK cell activation.
Increases FcγRIIA binding (70>fold)Increases FcγRIIA/FcγRIIB binding ratio (15-fold) [111]
G1v45CH2
A1.1,
L115,
E117		CH2
G1.1 > A (236),
A115 > L (330),
I117 > E(332)

G236A,
A330L,
I332E
GAALIE		IGHG1 CH2
1.6–3 (231–239)
APELLGGPS >
APELLAGPS
FG 105–117 (322–332)
KVSNKA..LPAPI >
KVSNKA..LPLPE		ADCC enhancement
Increases FcγIIIA binding		ADCP enhancement
NK cell activation
Table
Table 8. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in complement-dependent cytotoxicity (CDC) enhancement (Effector #4).
Table 8. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in complement-dependent cytotoxicity (CDC) enhancement (Effector #4).
IMGT Engineered Variant NameIMGT Engineered Variant DefinitionIMGT Amino Acid Changes on IGHG CH Domain (Eu Numbering between Parentheses)Amino Acid Changes with the Eu PositionsMotif Identifiable in Gene and Domain with Positions According to the IMGT Unique Numbering and with Eu Positions between Parentheses1. Property and Function2. Property and Function
G1v5CH2
W109		CH2
K109 > W (326)
K326W		IGHG1 CH2
FG 105–117 (322–332)
KVSNKA..LPAPI >
KVSNWA..LPAPI		CDC enhancement.
Increases C1q binding [102]		ADCC reduction [102].
G1v15CH2
S118		CH2
E118 > S (333)
E333S		IGHG1 CH2
FG 105–117,118 (322–333)
KVSNKA..LPAPIE >
KVSNKA..LPAPIS		CDC enhancement.
Increases C1q binding [102]
G1v16CH2
W109,
S118		CH2
K109 > W (326),
E118 > S (333)
K326W,
E333S		IGHG1 CH2
FG 105–117,118 (322–333)
KVSNKA..LPAPIE >
KVSNWA..LPAPIS		CDC enhancement.
Increases C1q binding [102]
G1v17CH2
E29,
F30,
T107		CH2
S29 > E (267),
H30 > F(268),
S107 > T (324)

S267E,
H268F,
S324T
EFT		IGHG1 CH2
27–31 (265–269)
DVSHE >
DVEFE
FG 105–117 (322–332)
KVSNKA..LPAPI >
KVTNKA..LPAPI		CDC enhancement
Increases C1q binding [112]
G1v18CH3
R1,
G109,
Y120		CH3
E1 > R (345),
E109 > G (430),
S120 > Y (440)
E345R,
E430G,
S440Y		IGHG1 CH3
1.4–2 (341–346)
GQPREP >
GQPRRP
105–110 (426–431)
SVMHEA >
SVMHGA
118–125 (438–445)
QKSLSLSP >
QKYLSLSP		CDC enhancement.
Increases C1q binding [113]. The triple mutant IgG1-005-RGY (IGHG1v18) form IgG1 hexamers [113]		Favors IgG1 hexamerization.
G1v35CH2
E29		CH2
S29 > E (267)

S267E
SE		IGHG1 CH2
27–31 (265–269)
DVSHE >
DVEHE		CDC enhancement.
Increases C1q binding [112]		Binds to FCGRT and FcγRIIB,
but not to other FcγR in a mouse model [114].
G1G3v1CH2
Q38,
K40,
F85.2		CH2
K38 > Q (274),
N40 > K (276),
Y85.2 > F (300)



K274Q,
N276K,
Y300F
chimere
G1–G3
(1)		IGHG1 CH2
34–41 (270–277)
DPEVKFNW >
DPEVQFKW
84.1–85.1 (294–301)
EQYNSTYR >
EQYNSTFR		CDC enhancement.
Increases C1q binding [115].
G4v2CH2
P116		CH2
S116 > P(331)
S331P		IGHG4 CH2
FG 105–117 (322–332)
KVSNKG..LPSSI >
KVSNKG..LPSPI		CDC enhancement [116].
(G1-, G2-, G3-like).
(1) The chimeric chain is the IGHG1*01 CH1-hinge—IGHG3*01 CH2-CH3. Amino acids Q38, K40 (CH2) and F85.2 (CH3) are from IGHG3*01. The changes are shown in comparison to the IGHG1*01 amino acids at the same positions as K38, N40 (CH2) and Y85.2 (CH3).
Table
Table 9. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in complement-dependent cytotoxicity (CDC) reduction (Effector #5].
Table 9. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in complement-dependent cytotoxicity (CDC) reduction (Effector #5].
IMGT Engineered Variant Name IMGT Engineered Variant DefinitionIMGT Amino Acid Changes on IGHG CH Domain (Eu Numbering between Parentheses)Amino Acid Changes with the Eu PositionsMotif Identifiable in Gene and Domain with Positions According to the IMGT Unique Numbering and with Eu Positions between ParenthesesProperty and Function
G1v8CH2
D3,
L115,
E117		CH2
S3 > D (239),
A115 > L (330),
I117 > E (332)

S239D,
A330L,
I332E
DLE		IGHG1 CH2
1.6–3 (231–239)
APELLGGPS >
APELLGGPD
FG 105–117 (322–332)
KVSNKA..LPAPI >
KVSNKA..LPLPE		CDC reduction.
Ablates CDC [105]
G1v19CH2
A34		CH2
D34 > A (270)
D270A		IGHG1 CH2
34–41 (270–277)
DPEVKFNW >
APEVKFNW		CDC reduction. Reduces
C1q binding [117]
G1v20CH2
A105		CH2
K105 > A (322)
K322A
IGHG1 CH2
FG 105–117 (322–332)
KVSNKA..LPAPI >
AVSNKA..LPAPI		CDC reduction.
Reduces C1q binding [117,118]
Mus musculus G2Bv2CH2
A101		CH2
E101 > A(318)

E318A
(2)		IGHG2B CH2
100–110
KEFKCKVNNKD >
KAFKCKVNNKD		CDC reduction.
Reduces C1q binding [119]
Mus musculus G2Bv3CH2
A103		CH2
K103 > A(320)

K320A
(2)		IGHG2B CH2
100–110
KEFKCKVNNKD >
KEFACKVNNKD		CDC reduction.
Reduces C1q binding [119]
Mus musculus G2Bv4CH2
A105		CH2
K105 > A(322)

K322A
(2)		IGHG2B CH2
100–110
KEFKCKVNNKD >
KEFKCAVNNKD		CDC reduction.
Reduces C1q binding [119]
(2) Mus musculus IGHG2B CH2 E101, K103 and K105 form a common core in the interactions of IgG and C1q [119].
Table
Table 10. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) reduction (Effector #6).
Table 10. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) reduction (Effector #6).
IMGT Engineered Fc Variant Name IMGT Engineered Variant DefinitionIMGT Amino Acid Changes on IGHG CH Domain (Eu Numbering between Parentheses)Amino Acid Changes with the Eu PositionsMotif Identifiable in Gene and Domain with Positions According to the IMGT Unique Numbering and with Eu Positions between Parentheses1. Property and Function2. Property and Function3. 3D and Property and Function
G1v4CH2
A114		CH2
P114 > A (329)
P329A)		IGHG1 CH2
FG 105–117 (322–332) KVSNKA..LPAPI >
KVSNKA..LAAPI		ADCC reduction.
Reduces FcγR binding [117]		CDC reduction.
Reduces C1q binding [117]
G1v14CH2
A1.3,
A1.2		CH2
L1.3 > A (234),
L1.2 > A (235)

L234A,
L235A
LALA		IGHG1 CH2
1.6–3 (231–239)
APELLGGPS >
APEAAGGPS		ADCC reduction.
Reduces FcγR binding [118,120]		CDC reduction.
Reduces C1q binding [118,120]
G1v14-1CH2
A1.3,
A1.2,
A1		CH2
L1.3 > A (234),
L1.2 > A (235),
G1 > A (237)
L234A,
L235A,
G237A		IGHG1 CH2
1.6–3 (231–239)
APELLGGPS >
APEAAGAPS		ADCC reduction.
Reduces FcγR binding.		CDC reduction.
Reduces C1q binding.
G1v14-4CH2
A1.3,
A1.2,
A114		CH2
L1.3 > A (234),
L1.2 > A (235),
P114 > A (329)
L234A,
L235A,
P329A		IGHG1 CH2
1.6–3 (231–239)
APELLGGPS >
APEAAGGPS
FG 105–117 (322–332)
KVSNKA..LPAPI >
KVSNKA..LAAPI		ADCC reduction.
Reduces FcγR binding.		CDC reduction.
Reduces C1q binding.
G1v14-48CH2
A1.3,
A1.2, 
R113 		CH2
L1.3 > A (234),
L1.2 > A (235),
L113 > R (328)
L234A,
L235A,
L328R		IGHG1 CH2
1.6–3 (231–239)
APELLGGPS >
APEAAGGPS
FG 105–117 (322–332)
KVSNKA..LPAPI >
KVSNKA..RPAPI		ADCC reduction.
Reduces FcγR binding.		CDC reduction.
Reduces C1q binding.
G1v14-49CH2
A1.3,
A1.2,
G114		CH2
L1.3 > A (234),
L1.2 > A (235),
P114 > G (329)

L234A,
L235A,
P329G
LALAPG		IGHG1 CH2
1.6–3 (231–239)
APELLGGPS >
APEAAGGPS
FG 105–117 (322–332) KVSNKA..LPAPI >
KVSNKA..LGAPI		ADCC reduction.
Reduces FcγR binding [121]		CDC reduction.
Reduces C1q binding [121]
G1v14-67CH2
A1.3,
A1.2,
S27		CH2
L1.3 > A (234),
L1.2 > A(235),
D27 > S (265)
L234A,
L235A,
D265S		IGHG1 CH2
1.6–3 (231–239)
APELLGGPS >
APEAAGGPS
23–31 (261–269)
CVVVDVSHE >
CVVVSVSHE		ADCC reduction.
Reduces FcγR binding [121].		CDC reduction.
Reduces C1q binding [121].		Combines Homsap G1v14 and G1v67 (G1 CH2 S27).
G1v23CH2
E1.2		CH2
L1.2 > E(235)
L235E		IGHG1 CH2
1.6–3 (231–239)
APELLGGPS >
APELEGGPS		ADCC reduction.
Reduces FcγR binding [122]		CDC reduction.
Reduces C1q binding [122]
G1v38CH2
S108,
F113		CH2
N108 > S (325),
L113 > F (328)
N325S,
L328F		IGHG1 CH2
FG 105–117 (322–332)
KVSNKA..LPAPI >
KVSSKA..FPAPI		ADCC reduction.
Abrogates FcγRIII binding, increases FcγRII binding, retains FcγRI high affinity binding [123]		CDC reduction.
Abrogates C1q binding.
G1v39CH2
F1.3,
E1.2,
S116		CH2
L1.3 > F (234),
L1.2 > E (235),
P116 > S (331)

L234F,
L235E,
P331S
FES, TM		IGHG1 CH2
1.6–3 (231–239)
APELLGGPS >
APEFEGGPS
FG 105–117 (322–332)
KVSNKA..LPAPI >
KVSNKA..LPASI		ADCC reduction
Reduces FcγR effector properties [124] (2)		CDC reduction.
Reduces C1q binding [122]		3D
3c2s
G1v40CH2
A1.3,
A1.2,
S116		CH2
L1.3 > A (234),
L1.2 > A (235),
P116 > S (331)
L234A,
L235A,
P331S		IGHG1 CH2
1.6–3 (231–239)
APELLGGPS >
APEAAGGPS
FG 105–117 (322–332)
KVSNKA..LPAPI >
KVSNKA..LPASI		ADCC reduction.
Reduces FcγR binding.		CDC reduction.
Reduces C1q binding.
G1v41CH2
F1.3,
E1.2		CH2
L1.3 > F (234),
L1.2 > E (235)

L234F,
L235E
FE		IGHG1 CH2
1.6–3 (231–239)
APELLGGPS >
APEFEGGPS		ADCC reduction.
Reduces FcγR binding [124]		CDC reduction.
Reduces C1q binding [122]
G1v43CH2
A1.3,
E1.2,
A1 		CH2
L1.3 > A (234),
L1.2 > E (235),
G1 > A (237)
L234A,
L235E,
G237A		IGHG1 CH2
1.6–3 (231–239)
APELLGGPS >
APEAEGAPS		ADCC reduction.
Reduces FcγR binding		CDC reduction.
Reduces C1q binding
G1v48CH2
R113		CH2
L113 > R (328)
L328R		IGHG1 CH2
FG 105–117 (322–332)
KVSNKA..LPAPI >
KVSNKA..RPAPI		ADCC reduction.
Reduces FcγR binding		CDC reduction.
Reduces C1q binding
G1v49CH2
G114		CH2
P114 > G (329)

P329G		IGHG1 CH2
FG 105–117 (322–332)
KVSNKA..LPAPI >
KVSNKA..LGAPI		ADCC reduction.
Reduces FcγR binding [121]		CDC reduction.
Reduces C1q binding [121]
G1v51CH2
K29		CH2
S29 > K (267)
S267K		IGHG1 CH2
27–31 (265–269)
DVSHE >
DVKHE		ADCC reduction.
Reduces FcγR binding		CDC reduction.
Reduces C1q binding
G1v53CH2
F1.3,
Q1.2,
Q105
CH2
L1.3 > F (234)
L1.2 > Q (235)
K105 > Q (322)


L234F,
L235Q,
K322Q,
FQQ		IGHG1 CH2
1.6–3 (231–239)
APELLGGPS >
APEFQGGPS
FG 105–117 (322–332)
KVSNKA..LPAPI >
QVSNKA..LPAPI		ADCC reduction.
Reduces FcγR binding		CDC reduction.
Reduces C1q binding
G1v53, G1v21CH2
F1.3,
Q1.2,
Q105
Y15.1,
T16,
E18		CH2
L1.3 > F (234),
L1.2 > Q (235),
K105 > Q (322)
M15.1 > Y (252),
S16 > T (254),
T18 > E (256)

L234F,
L235Q,
K322Q,
M252Y,
S254T,
T256E
FQQ–YTE
IGHG1 CH2
1.6–3 (231–239)
APELLGGPS >
APEFQGGPS
15–18 (251–256)
LMI.SRT >
LYITRE
FG 105–117 (322–332)
KVSNKA..LPAPI >
QVSNKA..LPAPI		ADCC reduction.
Reduces FcγR binding [125] (G1v53)		CDC reduction.
Reduces C1q binding [125] (G1v53)		Extends
half-life [125] (G1v21).
G1v59CH2
S1.3
T1.2
R1.1		CH2
L1.3 > S(234)
L1.2 > T (235)
G1.1 > R (236)
L234S
L235T
G236R		IGHG1 CH2
1.6–3 (231–239)
APELLGGPS >
APESTRGPS		ADCC undetectable.
Abrogates FcγR binding [126]		CDC undetectable.
Abrogates C1q binding [126]
G1v60CH2
S115,
S116		CH2
A115 > S(330)
P116 > S (331)
A330S
P331S		FG 105–117 (322–332)
KVSNKA..LPAPI >
QVSNKA..LPSSI		ADCC reduction.
Reduces FcγR binding.		CDC reduction.
Reduces C1q binding.
G1v63CH2
S2		CH2
P2 > S
P238S		IGHG1 CH2
1.6–3 (231–239)
APELLGGPS >
APELLGGSS		ADCC reduction.
Reduces FcγR binding.		CDC reduction.
Reduces C1q binding.
G1v65CH2
delE1.4,
delL1.3,
delL1.2		CH2
E1.4 > del,
L1.3 > del,
L1.2 > del
E233del,
L234del,
L235del		IGHG1 CH2
1.6–3 (231–239)
APELLGGPS >
AP- - -GGPS		ADCC reduction.
Reduces FcγR binding.		CDC reduction.
Reduces C1q binding.
G1v70h
S5,
S11,
S14,
CH2
S2		h
C5 > S(220),
C11 > S (226)
C14 > S(226)
CH2
P2 > S
C220S
C226S
C229S

P238S		IGHG1 h
1–15 (216–230)
EPKSCDKTHTCPPCP >
EPKSSDKTHTSPPSP
IGHG1 CH2
1.6–3 (231–239)
APELLGGPS >
APELLGGSS		ADCC reduction.
Reduces FcγR binding.		CDC reduction.
Reduces C1q binding.		Combines G1v63 with G1v37 (no H-L), G1v61 (no H-H h11) and G1v62 (no H-H h14).
G2v2CH2
Q30,
L92,
S115,
S116		CH2
H30 > Q(268),
V92 > L(309),
A115 > S(330),
P116 > S(331)

H268Q,
V309L,
A330S,
P331S
IgG2m4 		IGHG2 CH2
27–38 (265–274)
DVSHEDPEVQ >
DVSQEDPEVQ
89–96 (306–313)
LTVVHQDW >
LTVLHQDW
FG 105–117 (322–332)
KVSNKG..LPAPI >
KVSNKA..LPSSI		ADCC reduction.
Reduces FcγR binding [127]		CDC reduction.
Reduces C1q binding [127]
G2v3CH2
A1.2,
A1,
S2,
A30,
L92,
S115,
S116		CH2
V1.2 > A (235),
G1 > A (237),
P2 > S(238),
H30 > A(268),
V92 > L(309),
A115 > S(330),
P116 > S(331)

V235A,
G237A,
P238S,
H268A,
V309L,
A330S,
P331S
G2sigma		IGHG2 CH2
1.6–3 (231–239)
AP.PVAGPS >
AP.PAAASS
27–38 (265–274)
DVSHEDPEVQ >
DVSAEDPEVQ
89–96 (306–313)
LTVVHQDW >
LTVLHQDW
FG 105–117 (322–332)
KVSNKG..LPAPI >
KVSNKA..LPSSI		ADCC reduction.
Reduces FcγR binding [124]. Undetectable ADCC andV1 ADCP [124]		CDC reduction.
Reduces C1q binding [124]. Undetectable CDC [124]
G2G4v1
(1)		CH2
E1.4 > del
P1.3,
V1.2,
A1.1		CH2
E1.4 > del(233),
F1.3 > P(234),
L1.2 > V(235),
G1.1 > A(236)
E233del,
F234P,
L235V,
G236A		IGHG4 CH2
1.6–3 (231–239)
APEFLGGPS >
AP.PVAGPS 		ADCC reduction.
Reduces FcγR binding [128]		CDC reduction.
Reduces C1q binding [128]
G4v3CH2
E1.2
 CH2
L1.2 > E(235)


L235E
LE		IGHG4 CH2
1.6–3 (231–239)
APEFLGGPS >
APEFEGGPS		ADCC reduction.
Reduces FcγR binding [122]		CDC reduction.
Reduces C1q binding
[122]
G4v3
G4v5
h
P10,
CH2
E1.2
 h
S10 > P(228)
CH2
L1.2 > E(235)


S228P,

L235E
SPLE		IGHG4 h
1–12 (216–230)
ESKYGPPCPSCP >
ESKYGPPCPPCP
CH2
1.6–3 (231–239)
APEFLGGPS >
APEFEGGPS		ADCC reduction.
Reduces FcγR binding [122] (G4v3)		CDC reduction.
Reduces C1q binding [122] (G4v3)		Prevents IgG4
half-IG exchange
[129] (G4v5)
G4v3-49CH2
E1.2
G114
CH2
L1.2 > E(235)
P114 > G (329)


L235E
P329G
LEPG		IGHG4 CH2
1.6–3 (231–239)
APEFLGGPS >
APEFEGGPS
FG 105–117 (322–332)
KVSNKA..LPAPI >
KVSNKA..LGAPI		ADCC reduction.
Reduces FcγR binding [121]		CDC reduction.
Reduces C1q binding [121]
G4v3-49
G4v5		h
P10,
CH2
E1.2
G114
h
S10 > P(228)
CH2
L1.2 > E(235)
P114 > G (329)


S228P,

L235E
P329G
SPLEPG		IGHG4 h
1–12 (216–230)
ESKYGPPCPSCP
ESKYGPPCPPCP
CH2
1.6–3 (231–239)
APEFLGGPS >
APEFEGGPS
FG 105–117 (322–332)
KVSNKA..LPAPI >
KVSNKA..LGAPI		ADCC reduction.
Reduces FcγR binding [121] (G4v3-49)		CDC reduction.
Reduces C1q binding [121] (G4v3-49)		Prevents IgG4
half-IG exchange
[129] (G4v5).
G4v4CH2
A1.3,
A1.2		 CH2
F1.3 > A (234),
L1.2 > A (235)

F234A
L235A
FALA		IGHG4 CH2
1.6–3 (231–239)
APEFLGGPS >
APEAAGGPS		ADCC reduction.
Reduces FcγR binding [120].		CDC reduction.
Reduces C1q binding [120].
G4v4
G4v5		h
P10,
CH2
A1.3,
A1.2		h
S10 > P(228)
CH2
F1.3 > A (234)
L1.2 > A (235)


S228P,

F234A,
L235A
IgG4
ProAlaAla		IGHG4 h
1–12 (216–230)
ESKYGPPCPSCP >
ESKYGPPCPPCP
CH2
1.6–3 (231–239)
APEFLGGPS >
APEAAGGPS		ADCC reduction.
Reduces FcγR binding [124] (G4v4)		CDC reduction.
Reduces C1q binding [120] (G4v4)		Prevents IgG4
half-IG exchange [129] (G4v5).
G4v7CH2
delE1.4,
P1.3,
V1.2,
A1.1		CH2
E1.4 > del (233)
F1.3 > P (234),
L1.2 > V (235),
G1.1 > A (236),
E233del,
F234P,
L235V,
G236A		IGHG4 CH2
1.6–3 (231–239)
APEFLGGPS>
AP-PVAGPS
(G2-like)		ADCC reduction.
Reduces FcγR binding		CDC reduction.
Reduces C1q binding
G4v49CH2
G114		CH2
P114 > G (329)
P329G		IGHG4 CH2
FG 105–117 (322–332)
KVSNKA..LPAPI >
KVSNKA..LGAPI		ADCC reduction.
Reduces FcγR binding [121]		CDC reduction.
Reduces C1q binding [121]
Canis lupus familiaris
G2v1		CH2
A1.3,
A1.2,
A1		CH2
M1.3 > A (234),
L1.2 > A (235),
G1 > A (237).
M234A,
L235A,
G237A		IGHG2 CH2
1.6–3 (231–239)
APEMLGGPS >
APEAAGAPS		ADCC reduction.
Reduces FcγR binding		CDC reduction.
Reduces C1q binding
Canis lupus familiaris
G2v2		CH2
A1.3,
A1.2,
G114		CH2
M1.3 > A (234),
L1.2 > A(235)
P114 > G(329)
M234A,
L235A,
P329G		IGHG2 CH2
1.6–3 (231–239)
APEMLGGPS >
APEAAGGPS
IGHG1 CH2
FG 105–117 (322–332)
KVNNKA..LPSPI >
KVNNKA..LGSPI		ADCC reduction.
Reduces FcγR binding		CDC reduction.
Reduces C1q binding
(1) The monoclonal antibody is eculizumab. The heavy chain is the chimeric IGHG2*01 CH1-hinge—IGHG4*01 CH2-CH3. The CH2 and CH3 are from IGHG4*01, except for the CH2 positions 1.6-1.1 (AP.PVA) with del 1.4 and amino acids P1.3, V1.2 and A1.1 being from IGHG2*01. The changes are shown in comparison to the IGHG4*01 amino acids at the same positions as E1.4, F1.3, L1.2 and G1.1.
Table
Table 11. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in the B cell inhibition by the coengagement of antigen and FcγR on the same cell (Effector #7].
Table 11. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in the B cell inhibition by the coengagement of antigen and FcγR on the same cell (Effector #7].
IMGT Engineered Fc Variant NameIMGT Engineered Variant DefinitionIMGT Amino Acid Changes on IGHG CH Domain (Eu Numbering between Parentheses)Amino Acid Changes with the Eu PositionsMotif Identifiable in Gene and Domain with Positions According to the IMGT Unique Numbering and with Eu Positions between ParenthesesProperty and Function
G1v25CH2
E29,
F113		CH2
S29 > E (267),
L113 > F (328)
S267E,
L328F		IGHG1 CH2
27–31 (265–269)
DVSHE >
DVEHE
FG 105–117 (322–332)
KVSNKA..LPAPI >
KVSNKA..FPAPI		Increases FcγRIIB binding (400-fold) [130]
Inhibits by downstream ITIM signaling in B cells [131]
Table
Table 12. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in the knock out CH2 84.4 glycosylation (Effector #8).
Table 12. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in the knock out CH2 84.4 glycosylation (Effector #8).
IMGT Engineered Variant NameIMGT Engineered Variant DefinitionIMGT Amino Acid Changes on IGHG CH Domain (Eu Numbering between Parentheses)Amino Acid Changes with the Eu PositionsMotif Identifiable in Gene and Domain with Positions According to the IMGT Unique Numbering and with Eu Positions between ParenthesesProperty and Function
G1v29CH2
A84.4		CH2
N84.4 > A (297)
N297A		IGHG1 CH2
83–86
REEQYNSTYRVV >
REEQYASTYRVV		ADCC reduction. Reduces FcγR binding [132]
G1v30CH2
G84.4		CH2
N84.4 > G(297)
N297G		IGHG1 CH2
83–86
REEQYNSTYRVV >
REEQYGSTYRVV		ADCC reduction. Reduces FcγR binding [132]
G1v36CH2
Q84.4		CH2
N84.4 > Q (297)
N297Q		IGHG1 CH2
83–86
REEQYNSTYRVV >
REEQYQSTYRVV		ADCC reduction. Reduces FcγR binding
G4v36CH2
Q84.4		CH2
N84.4 > Q (297)
N297Q		IGHG4 CH2
83–86
REEQFNSTYRVV >
REEQFQSTYRVV		ADCC reduction. Reduces FcγR binding
Canis lupus familiaris
G2v29		CH2
A84.4		CH2
N84.4 > A (297)
N297A		IGHG1 CH2
83–86
REEQFNGTYRVV >
REEQFAGTYRVV		ADCC reduction. Reduces FcγR binding
Table
Table 13. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in half-life increase (Half-life #9).
Table 13. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in half-life increase (Half-life #9).
IMGT Engineered Variant NameIMGT Engineered Variant DefinitionIMGT Amino Acid Changes on IGHG CH Domain (Eu Numbering between Parentheses)Amino Acid Changes with the Eu PositionsMotif Identifiable in Gene and Domain with Positions According to the IMGT Unique Numbering and with Eu Positions between ParenthesesProperty and Function
G1v21CH2
Y15.1,
T16,
E18		CH2
M15.1 > Y (252),
S16 > T (254),
T18 > E (256)

M252Y,
S254T,
T256E
YTE		IGHG1 CH2 13–18 (249–256)
DTLMISRT >
DTLYITRE
Half-life increase
Enhances FCGRT binding at pH 6.0 [133,134] (1)
G1v22CH2
Y15.1,
T16,
E18,
CH3
K113,
F114,
H116		CH2
M15.1 > Y (252)
S16 > T (254)
T18 > E (256)
CH3
H113 > K (433)
N114 > F (434)
Y116 > H (436)
M252Y
S254T
T256E
H433K
N434F
Y436H		IGHG1 CH2 13–18 (249–256)
DTLMISRT >
DTLYITRE
CH3
FG 105–117 (426–437)
SVMHEA.LHNHYT >
SVMHEA.LKFHHT		Half-life increase
Enhances FCGRT binding at pH 6.0 [134]
G1v24CH3
L107,
S114		CH3
M107 > L (428),
N114 > S (434)
M428L,
N434S		GHG1 CH3-
FG 105–117 (426–437)
SVMHEA.LHNHYT >
SVLHEA.LHSHYT		Half-life increase
Enhances FCGRT binding at pH 6.0 (11-fold increase in affinity) [135] (2)
G1v42CH2
Q14,
CH3
L107		CH2
T14 > Q (250)
CH3
M107 > L (428)
T250Q
M428L		IGHG1 CH2
13–18 (249–256)
DTLMISRT >
DQLMISRT
CH3-
FG 105–117 (426–437)
SVMHEA.LHNHYT >
SVLHEA.LHNHYT		Half-life increase
Enhances FCGRT binding at pH 6.0 [134]
G1v46CH3
K113,
F114		CH3
H113 > K (433),
N114 > F(434)
H433K,
N434F		IGHG1 CH3-
FG 105–117 (426–437)
SVMHEA.LHNHYT >
SVMHEA.LKFHYT		Half-life increase
Enhances FCGRT
binding at pH 6.0.
G2v4CH2
Q14		CH2
T14 > Q (250)
T250Q		IGHG2 CH2
13–18 (249–256)
DTLMISRT >
DQLMISRT		Half-life increase
Enhances FCGRT binding at pH 6.0 [136]
G2v5CH3
L107		CH3
M107 > L (428)
M428L		IGHG2 CH3
FG 105–117 (426–437)
SVMHEA.LHNHYT >
SVLHEA.LHNHYT		Half-life increase
Enhances FCGRT binding at pH 6.0 [136]
G2v6CH2
Q14,
CH3
L107		CH2
T14 > Q (250)
CH3
M107 > L(428)
T250Q
M428L		IGHG2 CH2
13–18 (249–256)
DTLMISRT >
DQLMISRT
CH3
FG 105–117 (426–437)
SVMHEA.LHNHYT >
SVLHEA.LHNHYT		Half-life increase
Enhances FCGRT binding at pH 6.0 [136]
G2v8-1CH2
A93		CH2
H93 > A (310)
H310A		IGHG2 CH2
89–96 (306–313)
LTVVHQDW >
LTVVAQDW		Abrogates FCGRT binding at pH 6.0
(G2v8 any amino acid replacement of H93 except cystein) [137]. Number 1 of G2v8-1 is for A
G3v1CH3
H115		CH3
R115 > H(435)
R435H		IGHG3 CH3
FG 105–117 (426–437)
SVMHEA.LHNRFT >
SVMHEA.LHNHFT 		Half-life increase
Extends half-life [138]
G4v21CH2
Y15.1,
T16,
E18		CH2
M15.1 > Y (252),
S16 > T (254),
T18 > E (256)

M252Y,
S254T,
T256E
YTE		IGHG4 CH2
13–18 (249–256)
DTLMISRT >
DTLYITRE		Half-life increase
Enhances FCGRT binding at pH 6.0 [134]
G4v22CH2
T16,
P91,
CH3
A114		CH2
S16 > T(254),
V91 > P (308)
CH3
N114 > A (434)

S254T,
V308P

N434A		IGHG4 CH2
13–18 (249–256)
DTLMISRT >
DTLYITRE
CH3
FG 105–117 (426–437)
SVMHEA.LHNHYT >
SVMHEA.LHAHYT		Half-life increase
Enhances FCGRT binding at pH 6.0 [139]
G4v24CH3
L107
S114		CH3
M107 > L (428)
N114 > S(434)
M428L,
N434A		CH3
FG 105–117 (426–437)
SVMHEA.LHNHYT >
SVLHEA.LHSHYT		Half-life increase
Enhances FCGRT binding at pH 6.0
(1) Ten-fold increase at pH 6.0 [134] and four-fold increases half-life in a cynomolgus pK study [140]. The T18>E amino acid change provides two novel salt bridges between the Fc and ΒM2 of FCGRT IMGT/3Dstructure-DB: 4n0f, 4n0u [137]. A change of IGHG1 CH2 His H93 (310) into any other amino acid (excluding Cys) leads to an undetectable binding to FCGRT (FcRn) at pH 6.0 [137]. (2) An increased reduction in tumor burden in human FCGRT (FcRn) transgenic tumor-bearing mice treated with an anti-EGFR or an anti-VEGF antibody [135]. From the 3D structure, it is postulated that N114>S (434) allows for additional hydrogen bonds with FCGRT (FcRn) [137] IMGT/3Dstructure-DB: 4n0f, 4n0u.
Table
Table 14. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in the abrogation of binding to Protein A (Protein A #10).
Table 14. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in the abrogation of binding to Protein A (Protein A #10).
IMGT Engineered Variant Name IMGT Engineered Variant DefinitionIMGT Amino acid changes on IGHG CH domain (Eu numbering between parentheses)Amino acid changes with the Eu positionsMotif identifiable in gene and domain with positions according to the IMGT unique numbering and with Eu positions between parenthesesProperty and function
G4v8CH3
R115,
F116,
P125		CH3
H115 > R (435),
Y116 > F (436),
L125 > P (445)
H435R,
Y436F,
L445P		IGHG4 CH3-
FG 105–117 (426–437)
SVMHEA.LHNHYT >
SVMHEA.LHNRFT
118–125 (438–445)
QKSLSLSL >
QKSLSLSP		Abrogates binding to Protein A
Table
Table 15. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in the formation of additional bridge stabilizing CH2 in the absence of N84.4 (297) glycosylation (Structure #11).
Table 15. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in the formation of additional bridge stabilizing CH2 in the absence of N84.4 (297) glycosylation (Structure #11).
IMGT Engineered Variant NameIMGT Engineered Variant DefinitionIMGT Amino Acid Changes on IGHG CH Domain (Eu Numbering between Parentheses)Amino Acid Changes with the Eu PositionsMotif Identifiable in Gene and Domain with Positions According to the IMGT Unique Numbering and with Eu Positions between ParenthesesProperty and Function
G1v54CH2
C83,
C85		CH2
R83 > C (292),
V85 > C (302)
R292C,
V302C		IGHG1 CH2 83–86
REEQYNSTYRVV >
CEEQYASTYRCV (v29)
CEEQYGSTYRCV (v30)
CEEQYQSTYRCV (v36)		Stabilizes CH2 in the absence of N84.4 (297) glycosylation
G1v54-29CH2
C83,
A84.4,
C85		CH2
R83 > C (292),
N84.4 > A(297)
V85 > C (302)
R292C,
N297A
V302C		IGHG1 CH2 83–86
REEQYNSTYRVV >
CEEQYASTYRCV		Stabilizes CH2 in the absence of N84.4 (297) glycosylation
G1v54-30CH2
C83,
G84.4,
C85		CH2
R83 > C (292),
N84.4 > G (297)
V85 > C (302)
R292C,
N297G
V302C		IGHG1 CH2 83–86
REEQYNSTYRVV >
CEEQYGSTYRCV		Stabilizes CH2 in the absence of N84.4 (297) glycosylation
G1v54-36CH2
C83,
Q84.4,
C85		CH2
R83 > C (292),
N84.4 > Q (297)
V85 > C (302)
R292C,
N297Q
V302C		IGHG1 CH2 83–86
REEQYNSTYRVV >
CEEQYQSTYRCV		Stabilizes CH2 in the absence of N84.4 (297) glycosylation
Table
Table 16. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in the prevention of IgG4 half-IG exchange (Structure #12).
Table 16. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in the prevention of IgG4 half-IG exchange (Structure #12).
IMGT Engineered Variant NameIMGT Engineered Variant DefinitionIMGT Amino Acid Changes on IGHG CH Domain (Eu Numbering between Parentheses)Amino Acid Changes with the Eu PositionsMotif Identifiable in Gene and Domain with Positions According to the IMGT Unique Numbering and with Eu Positions between ParenthesesProperty and Function
G4v5
h
P10		h
S10 > P(228)
S228P		IGHG4 h
1–12 (216–230)
ESKYGPPCPSCP >
ESKYGPPCPPCP
(G1-like)		Prevents in vivo and in vitro IgG4 half-IG exchange
[129]
G4v6CH3
K88		CH3
R88 > K
R409K		IGHG1 CH3
85.4–89 (404–410)
GSFFLYSRL >
GSFFLYSKL		Reduces IgG4 half-IG exchange [141]
Table
Table 17. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in hexamerisation (Structure #13).
Table 17. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in hexamerisation (Structure #13).
IMGT Engineered Variant Name IMGT Engineered Variant DefinitionIMGT Amino Acid Changes on IGHG CH Domain (Eu Numbering between Parentheses)Amino Acid Changes with the Eu PositionsMotif Identifiable in Gene and Domain with Positions According to the IMGT Unique Numbering and with Eu Positions between ParenthesesProperty and Function
G1v34CH3
G109		CH3
E109 > G (430)
E430G		IGHG1 CH3-
FG 105–117 (426–437)
SVMHEA.LHNHYT >
SVMHGA.LHNHYT		Favors IgG1 hexamerisation by increased intermolecular Fc-Fc interactions after antigen binding on the cell surface
Table
Table 18. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in knobs-into-holes and the enhancement of heteropairing H-H of bispecific antibodies (Structure #14).
Table 18. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in knobs-into-holes and the enhancement of heteropairing H-H of bispecific antibodies (Structure #14).
IMGT Engineered Variant NameIMGT Engineered Variant DefinitionIMGT Amino Acid Changes on IGHG CH Domain (Eu Numbering between Parentheses)Amino Acid Changes with the Eu PositionsMotif Identifiable in Gene and Domain with Positions According to the IMGT Unique Numbering and with Eu Positions between ParenthesesProperty and Function
G1v26CH3
Y22		CH3
T22 > Y (366)
T366Y		IGHG1 CH3
20–26 (364–370)
SLTCLVK >
SLYCLVK		Knob of knobs-into-holes G1v26 knob/G1v31 hole interactions between the CH3 of the two different gamma1 chains [142]
G1v31CH3
T86		CH3
Y86 > T (407)
Y407T		IGHG1 CH3
85.4–89 (404–410)
GSFFLYSKL >
GSFFLTSKL		Hole of knobs-into-holes G1v26 knob/G1v31 hole interactions between the CH3 of the two different gamma1 chains [142] (G1v26 knob/G1v31 hole)
G1v32CH3
W22		CH3
T22 > W (366)
T366W		IGHG1 CH3
20–26 (364–370)
SLTCLVK >
SLWCLVK		Knob of knobs-into-holes G1v32 knob/G1v33 hole interactions between the CH3 of the two different gamma1 chains
G1v33CH3
S22,
A24,
V86		CH3
T22 > S (366),
L24 > A (368),
Y86 > V(407)
T366S,
L368A,
Y407V		IGHG1 CH3
20–26 (364–370)
SLTCLVK >
SLSCAVK
85.4–89 (404–410)
GSFFLYSKL>
GSFFLVSKL		Hole of knobs-into-holes G1v32 knob/G1v33 hole interactions between the CH3 of the two different gamma1 chains
G1v68CH3
V6,
L22,
L79,
W81		CH3
T6 > V (350)
T22 > L (366)
K79 > L (392)
T81 > W (394)
T350V
T366L
K392L
T394W		IGHG1 CH3
3–9 (347–353)
QVYTLPP >
QVYVLPP
20–26 (364–370)
SLTCLVK >
SLLCLVK
77–83 (390–396)
NYKTTPP >
NYLTWPP		Enhances, with G1v69, the heteropairing H-H of bispecific antibodies
G1v69CH3
V6,
Y7,
A85.1,
V86		CH3
T6 > V (350)
L7 > Y (351)
F85.1 > A (405)
Y86 > V (407)
T350V
L351Y
F405A
Y407V		IGHG1 CH3
3–9 (347–353)
QVYTLPP >
QVYVYPP
IGHG1 CH3
85.4–89 (404–410)
GSFFLYSKL >
GSFALVSKL		Enhances, with G1v68, the heteropairing H-H of bispecific antibodies
Table
Table 19. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in the suppression of inter H-L and/or inter H-H disulfide bridges (Structure #15).
Table 19. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in the suppression of inter H-L and/or inter H-H disulfide bridges (Structure #15).
IMGT Variant NameIMGT Variant DescriptionIMGT Amino Acid Changes on IGHG CH Domain with Eu Numbering between ParenthesesEu Numbering VariantMotif Identifiable in Gene and Domain with Positions According to the IMGT Unique NumberingProperty and Function
G1v37h
S5		h
C5 > S (220)
C220S		IGHG1 h 1–15
(216–230)
EPKSCDKTHTCPPCP >
EPKSSDKTHTCPPCP		No disulfide bridge inter H-L
G1v61h
S11		h
C11 > S (226)
C226S		IGHG1 h
1–15 (216–230)
EPKSCDKTHTCPPCP >
EPKSCDKTHTSPPCP		No disulfide bridge inter H-H h 11
G1v62h
S14		h
C14 > S (229)
C229S		IGHG1 h
1–15 (216–230)
EPKSCDKTHTCPPCP >
EPKSCDKTHTCPPSP		No disulfide bridge inter H-H h 14
Table
Table 20. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in site-specific drug attachment (Structure #16).
Table 20. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in site-specific drug attachment (Structure #16).
IMGT Variant NameIMGT Variant DescriptionIMGT Amino Acid Changes on IGHG CH Domain with Eu Numbering between ParenthesesEu Numbering VariantMotif Identifiable in Gene and Domain with Positions According to the IMGT Unique NumberingProperty and Function
G1v27CH2
C3		CH2
S3 > C(329)
S239C		IGHG1 CH2
1.6–4 (231–240)
APELLGGPSV >
APELLGGPCV		Site-specific drug attachment engineered cysteine
G1v28CH2
C(3^4)		CH2
(3^4)C(239^240)
C(239^240)		IGHG1 CH2
1.6–4 (231–240)
APELLGGPSV >
APELLGGPSCV		Site-specific drug attachment engineered cysteine
G1v44CH3
C122		CH3
S122 > C (442)
S442C		IGHG1 CH3
118–125 (438–445)
QKSLSLSP >
QKSLCLSP		Site-specific drug attachment engineered cysteine
G1v55CH3
C123		CH3
L123 > C (443)
L443C		IGHG1 CH3
118–125 (438–445)
QKSLSLSP >
QKSLSCSP		Site-specific drug attachment engineered cysteine
G1v56CH2
F85.2
CH3
F85.2		CH2
Y85.2 > F (pAMF)
CH3
F85.2 > F (pAMF)
Y300F

F404F		IGHG1 CH2
84.1–85.1 (294–301)
EQYNSTYR >
EQYNSTFR
CH3
84.1–85.1 (398–405)
LDSDGSFF
LDSDGSFF		Modified phenylalanine for conjugation (produced in Escherichia coli, non glycosylated)
G1v64CH2
C36		CH2
E36 > C
E272C		IGHG1 CH2
34–41 (270–277)
DPEVKFNW >
DPCVKFNW		Conjugation site-specific engineered cysteine
Table
Table 21. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in the enhancement of hetero pairing H-L of bispecific antibodies (Structure #17).
Table 21. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in the enhancement of hetero pairing H-L of bispecific antibodies (Structure #17).
IMGT Variant NameIMGT Variant DescriptionIMGT Amino Acid Changes on IGHG CH Domain with Eu Numbering between ParenthesesEu Numbering VariantMotif Identifiable in Gene and Domain with Positions According to the IMGT Unique NumberingProperty and Function
G1v57CH1
E26,
E119		CH1
K26 > E (147),
K119 > E(213)
K147E,
K213E		IGHG1 CH1
23–26 (144–147)
CLVK >
CLVE
118–121 (212–215)
DKKV >
DEKV		Enhances, with KCv57, the hetero pairing H-L of bispecific antibodies
KCv57IGKC
R12,
K13		IGKC
E12 > R,
Q13 > K
E123R,
Q124K		IGKC
10–15 (121–126)
SDEQLK >
SDRKLK		Enhances, with G1v57, the hetero pairing H-L of bispecific antibodies
G1v58CH1
C5,
h
V5		CH1
F5 > C (126),
h
C5 > V (220)
F126C,

C220V		IGHG1 CH1
1.4–15 (118–136)
ASTKGPSVFPLAPSSKSTS >
ASTKGPSVCPLAPSSKSTS
IGHG1 h
1–15 (216–230)
EPKSCDKTHTCPPCP >
EPKSVDKTHTCPPCP		Alternative interchain cysteine mutations to
enhance, with LC2v58, heteropairing of bispecific antibodies
LC2v58LC2
C10,
V126		IGLC
S10 > C (121),
C126 > V (214)
S121C,
C214V		IGLC2
1.5–15 (107A–126)
GQPKAAPSVTLFPPSSEELQ >
GQPKAAPSVTLFPPCSEELQ
IGLC2
118–127 (206–215)
EKTVAPTECS >
EKTVAPTEVS		Alternative interchain cysteine mutations to
enhance, with G1v58, heteropairing of bispecific antibodies
Table
Table 22. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in the control of half-IG exchange of bispecific IgG4 (Structure #18).
Table 22. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in the control of half-IG exchange of bispecific IgG4 (Structure #18).
IMGT Variant NameIMGT Variant DescriptionIMGT Amino Acid Changes on IGHG CH Domain with Eu Numbering between ParenthesesEu Numbering VariantMotif Identifiable in Gene and Domain with Positions According to the IMGT Unique NumberingProperty and Function
G4v10CH3
L85.1,
K88		CH3
F85.1 > L(405),
R88 > K (409)
F405L,
R409K		IGHG1 CH3
85.4–92 (402–413)
GSFFLYSRLTVD >
GSFLLYSKLTVD		Control of half-IG exchange of bispecific IgG4
Table
Table 23. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in reducing acid-induced aggregation (Structure #19).
Table 23. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in reducing acid-induced aggregation (Structure #19).
IMGT Engineered Fc Variant Name
IMGT Engineered Variant definitionIMGT Amino Acid Changes on IGHG CH Domain (Eu Numbering between Parentheses)Amino Acid Changes with the Eu PositionsMotif Identifiable in Gene and Domain with Positions According to the IMGT Unique Numbering and with Eu Positions between Parentheses1. Property and Function2. Property and Function3. Property and Function
G2v7CH2
Y85.2,
L92,
A339		CH2
F85.2 > Y(300)
V92 > L(309)
T339 > A(339)
F300Y
V309L
T339A		IGHG2 CH2
85.4–92 (300–309)
STFRVVSVLTVV >
STYRVVSVLTVL
118–125 (333–340)
EKTISKTK >
EKTISKAK		Reduces acid-induced aggregation [143]Low ADCC Low FcγR binding [143]Low CDC
Low C1q binding [143]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Lefranc, M.-P.; Lefranc, G. IMGT® Nomenclature of Engineered IGHG Variants Involved in Antibody Effector Properties and Formats. Antibodies 2022, 11, 65. https://doi.org/10.3390/antib11040065

AMA Style

Lefranc M-P, Lefranc G. IMGT® Nomenclature of Engineered IGHG Variants Involved in Antibody Effector Properties and Formats. Antibodies. 2022; 11(4):65. https://doi.org/10.3390/antib11040065

Chicago/Turabian Style

Lefranc, Marie-Paule, and Gérard Lefranc. 2022. "IMGT® Nomenclature of Engineered IGHG Variants Involved in Antibody Effector Properties and Formats" Antibodies 11, no. 4: 65. https://doi.org/10.3390/antib11040065

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop