Special Issue "Antibody-Drug Conjugate"

A special issue of Antibodies (ISSN 2073-4468).

Deadline for manuscript submissions: closed (30 November 2018)

Special Issue Editors

Guest Editor
Dr. Penelope M. Drake

Catalent Biologics (formerly Redwood Bioscience), 5703 Hollis Street, Emeryville, CA 94608, USA
Website | E-Mail
Interests: Antibody-Drug Conjugate
Guest Editor
Dr. Mary Jane Masson Hinrichs

Biologics Safety Assessment, MedImmune LLC, 1 MedImmune Way, Gaithersburg, MD 20892, USA
E-Mail

Special Issue Information

Dear Colleagues,

Antibody-drug conjugates (ADCs) represent a rapidly evolving area of drug development and research. Four ADCs are now approved for the treatment of various oncology indications, with additional promising molecules in late stage trials. At the same time, lessons from clinical failures fuel preclinical research that is often quickly translated back into the clinic. Research areas of study include identifying novel target antigens, developing new linker/payload combinations, and widening the therapeutic index. Approaches to the latter include limiting off-target toxicity through more selective tumor targeting, reducing ADC hydrophobicity through linker or conjugation site variation, modifying dosing regimens for greater tolerability, and exploring payloads across a range of potencies.

This Special Issue of Antibodies will present recent work selected from across the ADC field, showcasing the range of current thinking among investigators and drug developers. Topics will include novel target antigens, bispecific/biparatopic and alternate protein formats, pharmacokinetic/pharmacodynamic studies, combination therapies and checkpoint inhibitor synergies, new conjugation or linker technologies, new payloads, theoretical modeling, and ADCs for non-oncology indications. We welcome manuscripts describing your latest innovations and look forward to a thought-provoking issue.

Dr. Penelope M. Drake
Dr. Mary Jane Masson Hinrichs
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antibodies is an international peer-reviewed open access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 350 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Antibody-drug conjugate
  • Cytotoxic payload
  • Therapeutic index

Published Papers (5 papers)

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Research

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Open AccessArticle
Multiplex LC-MS/MS Assays for Clinical Bioanalysis of MEDI4276, an Antibody-Drug Conjugate of Tubulysin Analogue Attached via Cleavable Linker to a Biparatopic Humanized Antibody against HER-2
Antibodies 2019, 8(1), 11; https://doi.org/10.3390/antib8010011
Received: 19 October 2018 / Revised: 6 December 2018 / Accepted: 6 December 2018 / Published: 11 January 2019
Cited by 1 | PDF Full-text (1392 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Bioanalysis of complex biotherapeutics, such as antibody-drug conjugates (ADCs), is challenging and requires multiple assays to describe their pharmacokinetic (PK) profiles. To enable exposure-safety and exposure-efficacy analyses, as well as to understand the metabolism of ADC therapeutics, three bioanalytical methods are typically employed: [...] Read more.
Bioanalysis of complex biotherapeutics, such as antibody-drug conjugates (ADCs), is challenging and requires multiple assays to describe their pharmacokinetic (PK) profiles. To enable exposure-safety and exposure-efficacy analyses, as well as to understand the metabolism of ADC therapeutics, three bioanalytical methods are typically employed: Total Antibody, Antibody Conjugated Toxin or Total ADC and Unconjugated Toxin. MEDI4276 is an ADC comprised of biparatopic humanized antibody attached via a protease-cleavable peptide-based maleimidocaproyl linker to a tubulysin toxin (AZ13599185) with an approximate average drug-antibody ratio of 4. The conjugated payload of MEDI4276 can undergo ester hydrolysis to produce the conjugated payload AZ13687308, leading to the formation of MEDI1498 (de-acetylated MEDI4276). In this report, we describe the development, validation and application of three novel multiplex bioanalytical methods. The first ligand-binding liquid chromatography coupled with tandem mass spectrometry (LBA-LC-MS/MS) method was developed and validated for simultaneous measurement of total antibody and total ADC (antibody-conjugated AZ13599185) from MEDI4276. The second LBA-LC-MS/MS assay quantified total ADC (antibody-conjugated AZ13687308) from MEDI1498. The third multiplex LC-MS/MS assay was used for simultaneous quantification of unconjugated AZ13599185 and AZ13687308. Additional stability experiments confirmed that quantification of the released warhead in the presence of high concentrations of MEDI4276 was acceptable. Subsequently, the assays were employed in support of a first-in-human clinical trial (NCT02576548). Full article
(This article belongs to the Special Issue Antibody-Drug Conjugate)
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Open AccessArticle
A RAGE-Targeted Antibody-Drug Conjugate: Surface Plasmon Resonance as a Platform for Accelerating Effective ADC Design and Development
Antibodies 2019, 8(1), 7; https://doi.org/10.3390/antib8010007
Received: 25 November 2018 / Revised: 14 December 2018 / Accepted: 21 December 2018 / Published: 7 January 2019
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Abstract
Antibodies, antibody-like molecules, and therapeutics incorporating antibodies as a targeting moiety, such as antibody-drug conjugates, offer significant potential for the development of highly efficacious drugs against a wide range of disorders. Despite some success, truly harnessing the superior targeting properties of these molecules [...] Read more.
Antibodies, antibody-like molecules, and therapeutics incorporating antibodies as a targeting moiety, such as antibody-drug conjugates, offer significant potential for the development of highly efficacious drugs against a wide range of disorders. Despite some success, truly harnessing the superior targeting properties of these molecules requires a platform from which to effectively identify the best candidates for drug development. To streamline the development of antibody-drug conjugates targeting gynecological cancers within our laboratory, we incorporated surface plasmon resonance analysis (Biacore™ T200) into our development toolkit. Antibodies, selected based on positive ELISA screens as suitable for development as antibody-drug conjugates, were evaluated using surface plasmon resonance to determine a wide range of characteristics including specificity, kinetics/affinity, the effect of linker binding, the impact of the drug to antibody ratio, and the effect of endosomal pH on antibody-antigen binding. Analysis revealed important kinetics data and information regarding the effect of conjugation and endosomal pH on our antibody candidates that correlated with cell toxicity and antibody internalization data. As well as explaining observations from cell-based assays regarding antibody-drug conjugate efficacies, these data also provide important information regarding intelligent antibody selection and antibody-drug conjugate design. This study demonstrates the application of surface plasmon resonance technology as a platform, where detailed information can be obtained, supporting the requirements for rapid and high-throughput screening that will enable enhanced antibody-drug conjugate development. Full article
(This article belongs to the Special Issue Antibody-Drug Conjugate)
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Graphical abstract

Open AccessArticle
Systematic LC/MS/MS Investigations for the IND-Enabling Extended Characterization of Antibody–Drug Conjugate Modifications
Antibodies 2018, 7(4), 40; https://doi.org/10.3390/antib7040040
Received: 19 October 2018 / Revised: 12 November 2018 / Accepted: 13 November 2018 / Published: 16 November 2018
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Abstract
We hypothesized that systematic liquid chromatography-tandem mass spectrometry investigations of an antibody–drug conjugate (ADC), its small and large molecular components, and surrogate small-molecule conjugates might comprise a simple and efficient approach for the extended characterization of ADCs. Furthermore, we envisioned that results from [...] Read more.
We hypothesized that systematic liquid chromatography-tandem mass spectrometry investigations of an antibody–drug conjugate (ADC), its small and large molecular components, and surrogate small-molecule conjugates might comprise a simple and efficient approach for the extended characterization of ADCs. Furthermore, we envisioned that results from this work might allow us to assign specific composition changes in the ADC based on monoisotopic mass shifts of conjugatable modifications as detected in the surrogate small-molecule conjugates. We tested our hypothesis with a case study using an aldehyde-tag-based ADC conjugated to a noncleavable linker bearing a maytansine payload. Nearly quantitative bioconversion from cysteine to formylglycine was observed in the monoclonal antibody, and bioorthogonal conjugation was detected only on the formylglycine residues in the ADC. Using our method, both conjugatable and nonconjugatable modifications were discovered in the linker/payload; however, only conjugatable modifications were observed on the ADC. Based on these results, we anticipate that our approach to systematic mass spectrometric investigations can be successfully applied to other ADCs and therapeutic bioconjugates for investigational new drug (IND)-enabling extended characterization. Full article
(This article belongs to the Special Issue Antibody-Drug Conjugate)
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Review

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Open AccessReview
Pharmacologic Considerations in the Disposition of Antibodies and Antibody-Drug Conjugates in Preclinical Models and in Patients
Antibodies 2019, 8(1), 3; https://doi.org/10.3390/antib8010003
Received: 30 November 2018 / Revised: 21 December 2018 / Accepted: 22 December 2018 / Published: 1 January 2019
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Abstract
The rapid advancement in the development of therapeutic proteins, including monoclonal antibodies (mAbs) and antibody-drug conjugates (ADCs), has created a novel mechanism to selectively deliver highly potent cytotoxic agents in the treatment of cancer. These agents provide numerous benefits compared to traditional small [...] Read more.
The rapid advancement in the development of therapeutic proteins, including monoclonal antibodies (mAbs) and antibody-drug conjugates (ADCs), has created a novel mechanism to selectively deliver highly potent cytotoxic agents in the treatment of cancer. These agents provide numerous benefits compared to traditional small molecule drugs, though their clinical use still requires optimization. The pharmacology of mAbs/ADCs is complex and because ADCs are comprised of multiple components, individual agent characteristics and patient variables can affect their disposition. To further improve the clinical use and rational development of these agents, it is imperative to comprehend the complex mechanisms employed by antibody-based agents in traversing numerous biological barriers and how agent/patient factors affect tumor delivery, toxicities, efficacy, and ultimately, biodistribution. This review provides an updated summary of factors known to affect the disposition of mAbs/ADCs in development and in clinical use, as well as how these factors should be considered in the selection and design of preclinical studies of ADC agents in development. Full article
(This article belongs to the Special Issue Antibody-Drug Conjugate)
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Open AccessReview
ADME Considerations and Bioanalytical Strategies for Pharmacokinetic Assessments of Antibody-Drug Conjugates
Antibodies 2018, 7(4), 41; https://doi.org/10.3390/antib7040041
Received: 25 October 2018 / Revised: 21 November 2018 / Accepted: 26 November 2018 / Published: 30 November 2018
PDF Full-text (513 KB) | HTML Full-text | XML Full-text
Abstract
Antibody-drug conjugates (ADCs) are a unique class of biotherapeutics of inherent heterogeneity and correspondingly complex absorption, distribution, metabolism, and excretion (ADME) properties. Herein, we consider the contribution of various components of ADCs such as various classes of warheads, linkers, and conjugation strategies on [...] Read more.
Antibody-drug conjugates (ADCs) are a unique class of biotherapeutics of inherent heterogeneity and correspondingly complex absorption, distribution, metabolism, and excretion (ADME) properties. Herein, we consider the contribution of various components of ADCs such as various classes of warheads, linkers, and conjugation strategies on ADME of ADCs. Understanding the metabolism and disposition of ADCs and interpreting exposure-efficacy and exposure-safety relationships of ADCs in the context of their various catabolites is critical for design and subsequent development of a clinically successful ADCs. Sophisticated bioanalytical assays are required for the assessments of intact ADC, total antibody, released warhead and relevant metabolites. Both ligand-binding assays (LBA) and hybrid LBA-liquid chromatography coupled with tandem mass spectrometry (LBA-LC-MS/MS) methods have been employed to assess pharmacokinetics (PK) of ADCs. Future advances in bioanalytical techniques will need to address the rising complexity of this biotherapeutic modality as more innovative conjugation strategies, antibody scaffolds and novel classes of warheads are employed for the next generation of ADCs. This review reflects our considerations on ADME of ADCs and provides a perspective on the current bioanalytical strategies for pharmacokinetic assessments of ADCs. Full article
(This article belongs to the Special Issue Antibody-Drug Conjugate)
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