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18 October 2022

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

and
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
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Antibodies2022, 11(4), 65;https://doi.org/10.3390/antib11040065
This article belongs to the Special Issue Higher Order Structure Characterization of Therapeutic Antibodies-Second Volume
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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 []. The antigen receptors of the adaptive immune response [,] comprise the immunoglobulins (IG) or antibodies of the B cells and plasmocytes [,] and the T cell receptors (TR) of the T cells []. 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 []. 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 []. IMGT®, the international ImMunoGeneTics information system® (https://www.imgt.org) (accessed on 11 October 2022) [], 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 [,,,,,,]. Through its creation, IMGT® marks the advent of a new science, immunoinformatics, which emerged at the interface between immunogenetics and bioinformatics []. 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) [,,,,,,,,,,,], 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) [] and MH superfamily (MhSF) of vertebrates and invertebrates [].
Figure 1. IMGT® is the international ImMunoGenetics information system® (https://www.imgt.org) [,,,,,,,,,,]. 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)).
Immunoinformatics [] builds and organizes molecular immunogenetics knowledge to be managed and shared in IMGT®. IMGT® comprises seven databases [,,,,,,], 17 tools [,,,,,,,,,,,,,,,,,,,] and more than 25,000 pages of web resources (Table 1). IMGT® dababases are specialized in sequences (i.e., IMGT/LIGM-DB [,]), genes and alleles (IMGT/GENE-DB []), two-dimensional (2D) structures (IMGT/2Dstructure-DB) and three-dimensional (3D) structures (IMGT/3Dstructure-DB) [,,], whereas the IMGT/mAb-DB [] 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 [,,,,,] and the integrated IMGT/JunctionAnalysis [,] and IMGT/Automat [,] tools, and for next generation sequencing, the high-throughput version IMGT/HighV-QUEST [,,,,,] and the downloadable IMGT/StatClonotype [,] package (which allows for statistical pairwise analysis of the diversity and expression of the IMGT clonotypes (AA) [] and repertoire comparisons in adaptive immune responses); (2) for genomic analysis, IMGT/LIGMotif [] (which allows for the identification and description of new genes in genomic sequences); (3) for amino acid sequence analysis per the domain, IMGT/DomainGapAlign [,,]; and (4) for graphical representations of the domains, the IMGT/Collier-de-Perles tool [] (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 [], splicing sites) and tutorials, etc.).
Table 1. The IMGT databases, tools and web resources (‘The IMGT Marie-Paule Page’) for sequences, genes and structures.
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 [,,,,] (Table 2): CLASSIFICATION for theIMGT standardized gene and allele nomenclature [,,,,,,,,,,,], IDENTIFICATION for IMGT standardized keywords and keyword abbreviations (e.g., clonotype, paratope and epitope, variant, Fc receptor and FcR) [,], DESCRIPTION forIMGT standardized labels [,,,] (e.g., complementarity determining region (CDR)-IMGT (CDR1-IMGT to CDR3-IMGT) [] and framework region (FR-IMGT) (FR1-IMGT to FR4-IMGT) []), NUMEROTATION for the IMGT unique numbering [,,,,,,,,] and the IMGT Colliers de Perles [,,,,,]. IMGT positions per domain are used in Protein displays, Alignments of alleles, CDR-IMGT lengths, Allotypes [,] sections of the IMGT Repertoire, and to number amino acids involved in paratope/epitope (antigen receptor V-domains/target interactions []) (Table 1) and in effector properties (antigen receptor C-domain/effector binding proteins []).
Table 2. IMGT-ONTOLOGY axioms, concepts and IMGT Scientific chart rules.
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 [,,]. Since 2003, IMGT® has been widely used in the analysis of therapeutical antibodies for humanization and/or engineering [,,,,,,,,,,,,].

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.
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) []. 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).
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.
In the IMGT system, the C-domain includes the C-DOMAIN of the IG and of the TR [] and the C-LIKE-DOMAIN of the IgSF other than IG and TR []. 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) []. 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 [], but without the C’ and C’’ strands and the C’C’’ loop, which is replaced by a transversal CD strand []. 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).
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 [] integrated in the IMGT/3Dstructure-DB, from experimental 3D structure data. (C) IMGT Collier de Perles on two layers from IMGT/DomainGapAlign [,,]. (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 []. 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) [,,]. The 3D ribbon representation was obtained using PyMOL and “IMGT numbering comparison” of 1n0x_H (CH1) from IMGT/3Dstructure-DB (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) []. (With permission from M-P. Lefranc and G. Lefranc, LIGM, Founders of IMGT®, the international ImMunoGeneTics information system®, https://www.imgt.org).
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 []), 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 [] 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 [] (IMGT® https://www.imgt.org, IMGT Education > Aide-mémoire > Amino acids) (Figure 4).
Figure 4. IMGT physicochemical classes of the 20 usual amino acids (AA) [] (with permission from M-P. Lefranc and G. Lefranc, LIGM, Founders of IMGT®, the international ImMunoGeneTics information system®, https://www.imgt.org).

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 [] and IMGT motifs in domain strands and/or loops (Table 4, Figure 3), with corresponding Eu positions [] (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 [,] 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 [] and IMGT motifs in the domain strands and/or loops (Table 4), with corresponding Eu positions [] (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 [,].
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).
Figure 5. Correspondence between the Homo sapiens IGHG1 amino acid sequence, based on the IMGT unique numbering for the C-domain [] and the Eu positions (shown vertically) from 118 to 445 []. (A) IGHG1 CH1, CH2 and CH3. The standardized presentation of the IMGT unique numbering on the top two lines [] can be obtained using IMGT/DomainGapAlign [,,], 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 []) 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 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 7. Correspondence between the Homo sapiens IGKC, IGLC2 and IGHG1 CH1 sequences, based on the IMGT unique numbering [] and the Eu positions []. 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 []) 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.)
Standardized characterization has become a necessity, owing to the increasing number of engineered antibodies of effector properties [,] 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 [] and its position in the IMGT unique numbering for C domain [], 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 [], 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 [,,,], 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).
Table 5. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in antibody-dependent cellular cytotoxicity (ADCC) reduction (Effector #1).
Table 6. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in antibody-dependent cellular cytotoxicity (ADCC) enhancement (Effector #2).
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 8. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in complement-dependent cytotoxicity (CDC) enhancement (Effector #4).
Table 9. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in complement-dependent cytotoxicity (CDC) reduction (Effector #5].
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 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 12. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in the knock out CH2 84.4 glycosylation (Effector #8).
Table 13. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in half-life increase (Half-life #9).
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 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 16. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in the prevention of IgG4 half-IG exchange (Structure #12).
Table 17. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in hexamerisation (Structure #13).
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 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 20. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in site-specific drug attachment (Structure #16).
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 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 23. IMGT nomenclature, Eu positions and IMGT motif of engineered Fc variants involved in reducing acid-induced aggregation (Structure #19).
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 [], G1v2 [], G1v3 [], G1v5 [], G1v47 [], 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 [], G1v7 ‘DE’ [], G1v8 ‘DLE’ ‘3M’ [] [], G1v9 [], G1v10 [] and G1v11 []; one Homo sapiens IGHG2 variant: G2v1 []; one Homo sapiens IGHG4 variant: G4v1 []; and one Mus musculus IGHG2B variant: Musmus G2Bv1 [] (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’ [], G1v13 ‘GASDIE’ ‘ADE’ [] 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 [], G1v15 [], G1v16 [], G1v17 ‘EFT’ [], G1v18 [], G1v35 ‘SE’ [,] and the chimeric G1G3v1 [], and one IGHG4 variant: G4v2 [] (Table 8).
The variants involved in complement-dependent cytotoxicity (CDC) reduction include six variants, of which three Homo sapiens IGHG1 variants: G1v8 ‘DLE’ [], G1v19 [] and G1v20 [,]; and three Mus musculus IGHG2B variants: Musmus G2Bv2 [], Musmus G2Bv3 [] and Musmus G2Bv4 [] (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 [], G1v14 ‘LALA’ [,], G1v14-1, G1v14-4, G1v14-48, G1v14-49 ‘LALAPG’ [], G1v14-67, G1v23 [], G1v38 [], G1v39 ‘FES’ ‘TM’ [,], G1v40, G1v41 [,], G1v43, G1v48, G1v49 [], G1v51, G1v53 ‘FQQ’, G1v59 [], G1v60, G1v63, G1v65, G1v70 and one association G1v53-G1v21 ‘FQQ-YTE’ []; three Homo sapiens IGHG2 variants: G2v2 ‘IgG2m4′ [], G2v3 ‘G2sigma’ [] and the chimeric G2G4v1 []; five Homo sapiens IGHG4 variants: G4v3 ‘LE’ [], G4v3-49 ‘LEPG’ [], G4v4 ‘FALA’ [], G4v7, G4v49 [] and three associations G4v3-G4v5 ‘SPLE’ [,], G4v3-49-G4v5 ‘SPLEPG’ [] [] and G4v4-G4v5 ‘IgG4ProAlaAla’ [,] 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 [,] (Table 11).
The variants involved in knock out CH2 84.4 glycosylation include five variants, of which three Homo sapiens IGHG1 variants: G1v29 [], G1v30 [], 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’ [,,,,], G1v22 [], G1v24 [], G1v42 [] and G1v46; 3 Homo sapiens IGHG2 variants: G2v4 [], G2v5 [] and G2v6 []; one Homo sapiens IGHG3 variant: G3v1 []; three Homo sapiens IGHG4 variants: G4v21 ‘YTE’ [], G4v22 [] 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 [] and G4v6 [] (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 [] and G1v31 hole [], 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 [], antibody structure/function characterization [], 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 [,] 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.

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Integrating Single Domain Antibodies into Field-Deployable Rapid Assays
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