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Antibodies
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Antibody Drug Conjugates
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Antibody Drug Conjugates

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

Deadline for manuscript submissions: closed (15 December 2017) | Viewed by 83407

Special Issue Editor

Dr. R. James Christie

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Guest Editor
Department of Antibody Discovery and Protein Engineering, MedImmune, One MedImmune Way, Gaithersburg, MD 20878, USA
Interests: antibody discovery; protein engineering

Special Issue Information

Dear Colleagues,

Antibody drug conjugates (ADCs) are a promising class of biotherapeutics for treatment of diseases such as cancer.  Pairing potent drugs with antibodies through covalent attachment generates a unique therapeutic molecule, where the antibody provides cell-selectivity and extended serum half-life while the drug provides a potent inhibitor of metabolism. “Piggybacking” potent small molecule drugs onto large antibody carriers has allowed new drugs to be used for cancer treatment (such as auristatins, tubulysins, PBDs, and duocarmycins) that present challenges as small molecule therapies alone. Recently fueled by the clinical success of Kadcyla and Adcetris, research efforts continue to improve and refine the ADC platform through identification of new targets, control of drug load, optimizing the site of drug attachment and/or other changes in components that make up the ADC.

This Special Issue of Antibodies focuses on recent advances in ADC technology – including; drug-linker design, warhead selection, conjugation approaches, characterization, pharmacokinetics, biodistribution, antibody engineering, target selection, clinical manifestation and other aspects related to ADCs.

We look forward to receiving your submission to this Special Issue of Antibodies.

Best Wishes,

Dr. R. James (Jim) Christie  
Guest Editor


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 submissions that pass pre-check are 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 1800 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

  • drug-linker

  • drug delivery

  • conjugation

  • antibody engineering

  • personalized medicine

Published Papers (7 papers)

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Research

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13 pages, 2022 KiB  
Article
Hydrophilic Auristatin Glycoside Payload Enables Improved Antibody-Drug Conjugate Efficacy and Biocompatibility
by Tero Satomaa, Henna Pynnönen, Anja Vilkman, Titta Kotiranta, Virve Pitkänen, Annamari Heiskanen, Bram Herpers, Leo S. Price, Jari Helin and Juhani Saarinen
Antibodies 2018, 7(2), 15; https://doi.org/10.3390/antib7020015 - 22 Mar 2018
Cited by 29 | Viewed by 9903
Abstract
Antibody-drug conjugates (ADCs) offer a combination of antibody therapy and specific delivery of potent small-molecule payloads to target cells. The properties of the ADC molecule are determined by the balance of its components. The efficacy of the payload component increases with higher drug-to-antibody [...] Read more.
Antibody-drug conjugates (ADCs) offer a combination of antibody therapy and specific delivery of potent small-molecule payloads to target cells. The properties of the ADC molecule are determined by the balance of its components. The efficacy of the payload component increases with higher drug-to-antibody ratio (DAR), while homogeneous DAR = 8 ADCs are easily prepared by conjugation to the four accessible antibody hinge cystines. However, use of hydrophobic payloads has permitted only DAR = 2–4, due to poor pharmacokinetics and aggregation problems. Here, we describe generation and characterization of homogeneous DAR = 8 ADCs carrying a novel auristatin β-D-glucuronide, MMAU. The glycoside payload contributed to overall hydrophilicity of the ADC reducing aggregation. Compared to standard DAR = 2–4 ADCs, cytotoxicity of the homogeneous DAR = 8 ADCs was improved to low-picomolar IC50 values against cancer cells in vitro. Bystander efficacy was restored after ADC internalization and subsequent cleavage of the glycoside, although unconjugated MMAU was relatively non-toxic to cells. DAR = 8 MMAU ADCs were effective against target antigen-expressing xenograft tumors. The ADCs were also studied in 3D in vitro patient-derived xenograft (PDX) assays where they outperformed clinically used ADC. In conclusion, increased hydrophilicity of the payload contributed to the ADC’s hydrophilicity, stability and safety to non-target cells, while significantly improving cytotoxicity and enabling bystander efficacy. Full article
(This article belongs to the Special Issue Antibody Drug Conjugates)
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12 pages, 1800 KiB  
Article
A Polar Sulfamide Spacer Significantly Enhances the Manufacturability, Stability, and Therapeutic Index of Antibody–Drug Conjugates
by Jorge M. M. Verkade, Marloes A. Wijdeven, Remon Van Geel, Brian M. G. Janssen, Sander S. Van Berkel and Floris L. Van Delft
Antibodies 2018, 7(1), 12; https://doi.org/10.3390/antib7010012 - 20 Feb 2018
Cited by 22 | Viewed by 11442 | Correction
Abstract
Despite tremendous efforts in the field of targeted cancer therapy with antibody–drug conjugates (ADCs), attrition rates have been high. Historically, the priority in ADC development has been the selection of target, antibody, and toxin, with little focus on the nature of the linker. [...] Read more.
Despite tremendous efforts in the field of targeted cancer therapy with antibody–drug conjugates (ADCs), attrition rates have been high. Historically, the priority in ADC development has been the selection of target, antibody, and toxin, with little focus on the nature of the linker. We show here that a short and polar sulfamide spacer (HydraSpace™, Oss, The Netherlands) positively impacts ADC properties in various ways: (a) efficiency of conjugation; (b) stability; and (c) therapeutic index. Different ADC formats are explored in terms of drug-to-antibody ratios (DAR2, DAR4) and we describe the generation of a DAR4 ADC by site-specific attachment of a bivalent linker–payload construct to a single conjugation site in the antibody. A head-to-head comparison of HydraSpace™-containing DAR4 ADCs to marketed drugs, derived from the same antibody and toxic payload components, indicated a significant improvement in both the efficacy and safety of several vivo models, corroborated by in-depth pharmacokinetic analysis. Taken together, HydraSpace™ technology based on a polar sulfamide spacer provides significant improvement in manufacturability, stability, and ADC design, and is a powerful platform to enable next-generation ADCs with enhanced therapeutic index. Full article
(This article belongs to the Special Issue Antibody Drug Conjugates)
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17 pages, 6918 KiB  
Article
In-Depth Comparison of Lysine-Based Antibody-Drug Conjugates Prepared on Solid Support Versus in Solution
by Keith J. Arlotta, Aditya V. Gandhi, Hsiao-Nung Chen, Christine S. Nervig, John F. Carpenter and Shawn C. Owen
Antibodies 2018, 7(1), 6; https://doi.org/10.3390/antib7010006 - 07 Jan 2018
Cited by 15 | Viewed by 11659
Abstract
Antibody drug conjugates are a rapidly growing form of targeted chemotherapeutics. As companies and researchers move to develop new antibody–drug conjugate (ADC) candidates, high-throughput methods will become increasingly common. Here we use advanced characterization techniques to assess two trastuzumab-DM1 (T-DM1) ADCs; one produced [...] Read more.
Antibody drug conjugates are a rapidly growing form of targeted chemotherapeutics. As companies and researchers move to develop new antibody–drug conjugate (ADC) candidates, high-throughput methods will become increasingly common. Here we use advanced characterization techniques to assess two trastuzumab-DM1 (T-DM1) ADCs; one produced using Protein A immobilization and the other produced in solution. Following determination of payload site and distribution with liquid chromatography-mass spectrometry (LC/MS), thermal stability, heat-induced aggregation, tertiary structure, and binding affinity were characterized using differential scanning calorimetry (DSC), dynamic light scattering (DLS), Raman spectroscopy, and isothermal titration calorimetry (ITC), respectively. Small differences in the thermal stability of the CH2 domain of the antibody as well as aggregation onset temperatures were observed from DSC and DLS, respectively. However, no significant differences in secondary and tertiary structure were observed with Raman spectroscopy, or binding affinity as measured by ITC. Lysine-based ADC conjugation produces an innately heterogeneous population that can generate significant variability in the results of sensitive characterization techniques. Characterization of these ADCs indicated nominal differences in thermal stability but not in tertiary structure or binding affinity. Our results lead us to conclude that lysine-based ADCs synthesized following Protein A immobilization, common in small-scale conjugations, are highly similar to equivalent ADCs produced in larger scale, solution-based methods. Full article
(This article belongs to the Special Issue Antibody Drug Conjugates)
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3382 KiB  
Article
Pyrrolobenzodiazepine Antibody-Drug Conjugates Designed for Stable Thiol Conjugation
by R. James Christie, Arnaud C. Tiberghien, Qun Du, Binyam Bezabeh, Ryan Fleming, Amanda Shannon, Shenlan Mao, Shannon Breen, Jing Zhang, Haihong Zhong, Jay Harper, Herren Wu, Philip W. Howard and Changshou Gao
Antibodies 2017, 6(4), 20; https://doi.org/10.3390/antib6040020 - 28 Nov 2017
Cited by 13 | Viewed by 9780
Abstract
Thiosuccinimide-linked antibody-drug conjugates (ADCs) are susceptible to drug loss over time due to a retro-Michael reaction, which can be prevented by selecting stable conjugation positions or hydrolysis of the thiosuccinimide. Here, we investigate pyrrolobenzodiazepine (PBD) ADC drug-linkers equipped with N-phenyl maleimide functionality [...] Read more.
Thiosuccinimide-linked antibody-drug conjugates (ADCs) are susceptible to drug loss over time due to a retro-Michael reaction, which can be prevented by selecting stable conjugation positions or hydrolysis of the thiosuccinimide. Here, we investigate pyrrolobenzodiazepine (PBD) ADC drug-linkers equipped with N-phenyl maleimide functionality for stable thiol conjugation via thiosuccinimide hydrolysis. Two PBD drug-linker formats (enzyme-cleavable and non-cleavable) were evaluated following site-specific conjugation to an engineered cysteine incorporated at position T289, which is known to be unstable for N-alkyl maleimide conjugates. N-phenyl maleimide PBDs conjugated to antibodies with similar efficiencies as N-alkyl maleimide PBDs and enhanced thiosuccinimide hydrolysis for N-phenyl maleimide PBDs was confirmed by mass spectrometry, capillary isoelectric focusing, and a SYPRO Orange dye binding assay. All of the PBD ADCs were highly potent in vitro regardless of maleimide- or linker-type, exhibiting low pM EC50 values. Thiol conjugation to N-phenyl maleimide PBD minimized the retro-Michael reaction in both rat and mouse serum. However, cleavage of the valine-alanine dipeptide in mouse serum for ADCs containing cleavable drug-linker led to drug loss regardless of maleimide type, which impacted ADC potency in tumor growth inhibition studies that were conducted in mouse models. Therapeutic improvement in mouse tumor models was realized for ADCs prepared with non-cleavable PBD drug-linkers that were conjugated through N-phenyl maleimide, where a stronger tumor growth inhibition (TGI) response was achieved when compared to the analogous N-alkyl maleimide drug-linker ADC. Altogether, our findings highlight the stability and efficacy benefits of N-phenyl maleimide functionality for ADCs that are produced with thiol-maleimide conjugation chemistry. Full article
(This article belongs to the Special Issue Antibody Drug Conjugates)
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Review

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19 pages, 1022 KiB  
Review
Small-Format Drug Conjugates: A Viable Alternative to ADCs for Solid Tumours?
by Mahendra P. Deonarain, Gokhan Yahioglu, Ioanna Stamati, Anja Pomowski, James Clarke, Bryan M. Edwards, Soraya Diez-Posada and Ashleigh C. Stewart
Antibodies 2018, 7(2), 16; https://doi.org/10.3390/antib7020016 - 31 Mar 2018
Cited by 63 | Viewed by 15164
Abstract
Antibody–Drug Conjugates (ADCs) have been through multiple cycles of technological innovation since the concept was first practically demonstrated ~40 years ago. Current technology is focusing on large, whole immunoglobulin formats (of which there are approaching 100 in clinical development), many with site-specifically conjugated [...] Read more.
Antibody–Drug Conjugates (ADCs) have been through multiple cycles of technological innovation since the concept was first practically demonstrated ~40 years ago. Current technology is focusing on large, whole immunoglobulin formats (of which there are approaching 100 in clinical development), many with site-specifically conjugated payloads numbering 2 or 4. Despite the success of trastuzumab-emtansine in breast cancer, ADCs have generally failed to have an impact in solid tumours, leading many to explore alternative, smaller formats which have better penetrating properties as well as more rapid pharmacokinetics (PK). This review describes research and development progress over the last ~10 years obtained from the primary literature or conferences covering over a dozen different smaller format-drug conjugates from 80 kDa to around 1 kDa in total size. In general, these agents are potent in vitro, particularly more recent ones incorporating ultra-potent payloads such as auristatins or maytansinoids, but this potency profile changes when testing in vivo due to the more rapid clearance. Strategies to manipulate the PK properties, whilst retaining the more effective tumour penetrating properties could at last make small-format drug conjugates viable alternative therapeutics to the more established ADCs. Full article
(This article belongs to the Special Issue Antibody Drug Conjugates)
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12 pages, 638 KiB  
Review
Challenges in Optimising the Successful Construction of Antibody Drug Conjugates in Cancer Therapy
by Thomas Mehrling and Daniel Soltis
Antibodies 2018, 7(1), 11; https://doi.org/10.3390/antib7010011 - 13 Feb 2018
Cited by 12 | Viewed by 6859 | Correction
Abstract
Although considerable progress has been made in the field of cancer chemotherapy, there remains a significant unmet medical need, with a requirement to move away from traditional cytotoxics and explore novel, smarter chemotherapeutic approaches. One such example of the smart chemotherapy approach is [...] Read more.
Although considerable progress has been made in the field of cancer chemotherapy, there remains a significant unmet medical need, with a requirement to move away from traditional cytotoxics and explore novel, smarter chemotherapeutic approaches. One such example of the smart chemotherapy approach is antibody-drug conjugates (ADCs), which consist of an antibody that binds selectively to a cancer antigen linked to a cytotoxic agent. When developing an ADC, it may be necessary to produce a variety of constructs to fully assess the optimal configuration for the molecule. By testing ADCs prepared using a range of cytotoxic agents, linkers, or different antibodies, it is possible to fully assess the optimal approach for this treatment modality before advancing to the clinic. Since the development and approval of first-generation ADCs, significant improvements in development technology have occurred. Here, we consider the advances made within the field of ADCs, focusing on the development of EDO-B278 and EDO-B776, both of which have demonstrated efficacy in preclinical testing. Although some limitations remain in this field of development, the potential reduction in toxicity offered by ADCs justifies the investment in research to find workable solutions that could ultimately provide patients with superior outcomes. Full article
(This article belongs to the Special Issue Antibody Drug Conjugates)
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28 pages, 4861 KiB  
Review
Factors Affecting the Pharmacology of Antibody–Drug Conjugates
by Andrew T. Lucas, Lauren S. L. Price, Allison N. Schorzman, Mallory Storrie, Joseph A. Piscitelli, Juan Razo and William C. Zamboni
Antibodies 2018, 7(1), 10; https://doi.org/10.3390/antib7010010 - 07 Feb 2018
Cited by 75 | Viewed by 17208
Abstract
Major advances in therapeutic proteins, including antibody–drug conjugates (ADCs), have created revolutionary drug delivery systems in cancer over the past decade. While these immunoconjugate agents provide several advantages compared to their small-molecule counterparts, their clinical use is still in its infancy. The considerations [...] Read more.
Major advances in therapeutic proteins, including antibody–drug conjugates (ADCs), have created revolutionary drug delivery systems in cancer over the past decade. While these immunoconjugate agents provide several advantages compared to their small-molecule counterparts, their clinical use is still in its infancy. The considerations in their development and clinical use are complex, and consist of multiple components and variables that can affect the pharmacologic characteristics. It is critical to understand the mechanisms employed by ADCs in navigating biological barriers and how these factors affect their biodistribution, delivery to tumors, efficacy, and toxicity. Thus, future studies are warranted to better understand the complex pharmacology and interaction between ADC carriers and biological systems, such as the mononuclear phagocyte system (MPS) and tumor microenvironment. This review provides an overview of factors that affect the pharmacologic profiles of ADC therapies that are currently in clinical use and development. Full article
(This article belongs to the Special Issue Antibody Drug Conjugates)
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