Editorial pubs.acs.org/acsmedchemlett
Next-Generation Antibody-Drug Conjugates (ADCs) for Cancer Therapy
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efficient linker immolation and cell killing activity of disulfide linked PBD-based ADCs is reported. The utility of site-specific ADC conjugation technology was highlighted by engineering cysteine residues in the antibody.5 Subsequently, several other site-specific conjugation technologies were reported.6,7 This is an important development in the ADC therapeutic field, and four of the research articles in this issue further highlight the utility and applications of site-specific ADCs. Thomson et al. describe a straightforward glycoengineering approach to develop site-specific PBD-based ADCs. In the article by Kudrika et al., a novel, rapid and facile ligation technique to generate ADC with new architectures, which were not achievable with conventional ligation reactions, is described. Leverett et al. report on the design, synthesis, and cytotoxic evaluation of novel tubulysin analogues as ADC payload, representing a novel class of tubulin inhibitor payload for ADCs (tubulysin). In addition, a preliminary correlation between the hydrophobicity of an ADC compound and its susceptibility to metabolic enzymes was identified. Tumey et al. describe an elegant application of site-specific ADCs to design and develop optimized tubulysin analogues with reduced metabolic liabilities. We are currently witnessing one of the most significant paradigm changes in oncology drug development, with some of the new types of immuno-oncology (IO) compounds inducing unprecedented increases in survival in certain solid and liquid tumor indications.8 In this context, it is worth mentioning that many of the current classes of payloads employed for ADCs were previously reported to have very significant immunostimulatory activities when administered in the context of chemotherapy. The mechanisms by which these cytotoxic compounds stimulate the cancer immunity cycle include induction of immunogenic cell death (ICD) and direct activation of dendritic cell activation and maturation.9 The rapidly evolving IO combo trials in conjunction with next generation ADCs (for example, ADCs described in this issue or elsewhere) in oncology keep strong promises to further increasing the patient segments that benefit with durable responses, ultimately increasing patient survival. We are very grateful to the authors for their outstanding contributions to this special issue. We also thank the numerous reviewers of manuscripts for the special issue who have provided careful and insightful reviews of the submissions. Particular thanks go to Ms. Susan Uppena, Dr. Kristen N. Kindrachuk, Dr. Dennis C. Liotta (Editor-in-Chief), Editors and Associated Editors of the ACS Medicinal Chemistry Letters journal, and the editorial office staff for their continuous support of this project.
elcome to the special issue of the ACS Medicinal Chemistry Letters on “Antibody-Drug Conjugates and Bioconjugates”. This special issue highlights the application of linkers, cytotoxic payloads, and conjugation chemistries enabling the design of the next-generation antibody-drug conjugates (ADCs) and bioconjugates as they become an emerging and promising modality for the treatment of cancer. ADC drug discovery has its beginning in the observation that most function blocking, naked monoclonal antibodies lacked significant antitumor activities when administered as single agents to patients with solid tumors. In fact, most monoclonal antibodies that were approved during the past 20 years are currently administered in combination with standard of care (SOC) treatment, including chemotherapy. Thus, the primary objective to develop ADCs as a platform was to generate compounds that were “better than chemotherapy”, by targeting the cytotoxic payload selectively to tumors to improve efficacy while avoiding the off-target toxicities that frequently limited the use of chemotherapy during prolonged treatment periods.1−3 Currently, there are 59 ADCs4 in clinical development, which is reflective of the exponential growth of ADC drug development in the pharma/biotech industry for the past 10 years. Such increased activities in clinical development of ADCs can be attributed to three major factors: 1. Development of antibody technologies that result in humanized or human antibodies to reduce the immunogenicity of antibodies in patients; 2. Early proof of clinical concept by Mylotarg, the first approved ADC for the treatment of AML targeted therapy, which raised the level of interest in ADC drug development; 3. Recent ADC approvals of Adcetris and Kadcyla, which further emphasized the value and benefits that ADCs provide to cancer patients. The preclinical ADC development witnessed significant technology improvements over the past five years with respect to exploring novel ADC targets, linker design, payload diversity, and development of site-specific conjugation technologies. This special issue highlights such progress and features in the form of one Viewpoint article and six original research articles authored by groups working at the cutting edge of ADC drug development. In his Viewpoint article, Ravi Chari emphasizes the importance of expanding on the three most frequently employed classes of linker types, including the protease cleavable peptide linker, the reductively cleavable disulfide linkages, and thioether linkages. Ravi also summarizes the progress made in protein engineering of the mAb portion of ADCs and the increased focus around linker chemistry and new payload development. The addition of the pyrrolobenzodiazepine (PBD) class of minor-groove binding DNA damaging warhead to the ADC payload family brought an excitement into the ADC development. Tiberghien et al. describe the design and synthesis of teserine, a clinical ADC PBD-dimer payload. In the article by Zhang et al., a positive relationship between © 2016 American Chemical Society
Special Issue: Antibody-Drug Conjugates and Bioconjugates Published: November 10, 2016 972
DOI: 10.1021/acsmedchemlett.6b00421 ACS Med. Chem. Lett. 2016, 7, 972−973
ACS Medicinal Chemistry Letters
Editorial
Jagath Reddy Junutula, Guest Editor Vice President, Antibody Discovery & Development, Cellerant Therapeutics, Inc.
Hans-Peter Gerber, Guest Editor
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CSO and Vice President, Targeted Therapeutics Discovery, Oncology Research Unit, Pfizer Worldwide Research and Development
AUTHOR INFORMATION
Notes
Views expressed in this editorial are those of the authors and not necessarily the views of the ACS.
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REFERENCES
(1) Sievers, E. L.; Senter, P. D. Antibody-Drug Conjugates in Cancer Therapy. Annu. Rev. Med. 2013, 64, 15−29. (2) Gerber, H. P.; Koehn, F. E.; Abraham, R. T. The antibody-drug conjugate: an enabling modality for natural product-based cancer therapeutics. Nat. Prod. Rep. 2013, 30, 625−639. (3) Donaghy, H. Effects of antibody, drug and linker on the preclinical and clinical toxicities of antibody-drug conjugates. mAbs 2016, 8, 659−671. (4) https://clinicaltrials.gov. (5) Junutula, J. R.; Raab, H.; Clark, S.; Bhakta, S.; Leipold, D. D.; Weir, S.; Chen, Y.; Simpson, M.; Tsai, S. P.; Dennis, M. S.; Lu, Y.; Meng, Y. G.; Ng, C.; Yang, J.; Lee, C. C.; Duenas, E.; Gorrell, J.; Katta, V.; Kim, A.; McDorman, K.; Flagella, K.; Ross, S.; Venook, R.; Spencer, S. D.; Wong, W. L.; Lowman, H. B.; Vandlen, R.; Slikowski, M. X.; Scheller, R. H.; Polakis, P.; Malllet, W. Site-specific conjugation of cytotoxic drugs to antibodies substantially improves the therapeutic index. Nat. Biotechnol. 2008, 26, 925−932. (6) Panowski, S.; Bhakta, S.; Raab, H.; Polakis, P.; Junutula, J. R. Sitespecific antibody drug conjugates for cancer therapy. mAbs 2014, 6, 34−45. (7) Agarwal, P.; Bertozzi, C. R. Site-Specific Antibody−Drug Conjugates: The Nexus of Bioorthogonal Chemistry, Protein Engineering, and Drug Development. Bioconjugate Chem. 2015, 26, 176−192. (8) Harris, S. J.; Brown, J.; Lopez, J.; Yap, T. A. Immuno-oncology combinations: raising the tail of the survival curve. Cancer Biol. Med. 2016, 13, 171−193. (9) Gerber, H.; Sapra, P.; Loganzo, F.; May, C. Combining antibody−drug conjugates and immune-mediated cancer therapy: What to expect? Biochem. Pharmacol. 2016, 102, 1−6.
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DOI: 10.1021/acsmedchemlett.6b00421 ACS Med. Chem. Lett. 2016, 7, 972−973
