Importance and Considerations of Antibody Engineering in Antibody-Drug Conjugates Development from a Clinical Pharmacologist's Perspective

Overview

Journal Antibodies (Basel)

Date 2021 Aug 27

PMID 34449544

Citations 15

Authors

Andrew T Lucas

Amber Moody

Allison N Schorzman

William C Zamboni

Affiliations

Soon will be listed here.

Abstract

Antibody-drug conjugates (ADCs) appear to be in a developmental boom, with five FDA approvals in the last two years and a projected market value of over $4 billion by 2024. Major advancements in the engineering of these novel cytotoxic drug carriers have provided a few early success stories. Although the use of these immunoconjugate agents are still in their infancy, valuable lessons in the engineering of these agents have been learned from both preclinical and clinical failures. It is essential to appreciate how the various mechanisms used to engineer changes in ADCs can alter the complex pharmacology of these agents and allow the ADCs to navigate the modern-day therapeutic challenges within oncology. This review provides a global overview of ADC characteristics which can be engineered to alter the interaction with the immune system, pharmacokinetic and pharmacodynamic profiles, and therapeutic index of ADCs. In addition, this review will highlight some of the engineering approaches being explored in the creation of the next generation of ADCs.

Citing Articles

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References

Iznaga-Escobar N, Mishra A, Perez-Rodriguez R . Factors affecting pharmacokinetics of monoclonal antibodies: A review article. Methods Find Exp Clin Pharmacol. 2004; 26(2):123-7. DOI: 10.1358/mf.2004.26.2.800065. View

Moore K, Borghaei H, OMalley D, Jeong W, Seward S, Bauer T . Phase 1 dose-escalation study of mirvetuximab soravtansine (IMGN853), a folate receptor α-targeting antibody-drug conjugate, in patients with solid tumors. Cancer. 2017; 123(16):3080-3087. PMC: 6896318. DOI: 10.1002/cncr.30736. View

Modi S, Saura C, Yamashita T, Park Y, Kim S, Tamura K . Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. N Engl J Med. 2019; 382(7):610-621. PMC: 7458671. DOI: 10.1056/NEJMoa1914510. View

Lucas A, Robinson R, Schorzman A, Piscitelli J, Razo J, Zamboni W . Pharmacologic Considerations in the Disposition of Antibodies and Antibody-Drug Conjugates in Preclinical Models and in Patients. Antibodies (Basel). 2019; 8(1). PMC: 6640706. DOI: 10.3390/antib8010003. View

Nakada T, Masuda T, Naito H, Yoshida M, Ashida S, Morita K . Novel antibody drug conjugates containing exatecan derivative-based cytotoxic payloads. Bioorg Med Chem Lett. 2016; 26(6):1542-1545. DOI: 10.1016/j.bmcl.2016.02.020. View

Boesch A, Brown E, Cheng H, Ofori M, Normandin E, Nigrovic P . Highly parallel characterization of IgG Fc binding interactions. MAbs. 2014; 6(4):915-27. PMC: 4171026. DOI: 10.4161/mabs.28808. View

Dotan I, Ron Y, Yanai H, Becker S, Fishman S, Yahav L . Patient factors that increase infliximab clearance and shorten half-life in inflammatory bowel disease: a population pharmacokinetic study. Inflamm Bowel Dis. 2014; 20(12):2247-59. DOI: 10.1097/MIB.0000000000000212. View

Capone E, Lamolinara A, Pastorino F, Gentile R, Ponziani S, Di Vittorio G . Targeting Vesicular LGALS3BP by an Antibody-Drug Conjugate as Novel Therapeutic Strategy for Neuroblastoma. Cancers (Basel). 2020; 12(10). PMC: 7650653. DOI: 10.3390/cancers12102989. View

Kantarjian H, Thomas D, Jorgensen J, Kebriaei P, Jabbour E, Rytting M . Results of inotuzumab ozogamicin, a CD22 monoclonal antibody, in refractory and relapsed acute lymphocytic leukemia. Cancer. 2013; 119(15):2728-36. PMC: 3720844. DOI: 10.1002/cncr.28136. View

10.

Walter R, Gooley T, van der Velden V, Loken M, van Dongen J, Flowers D . CD33 expression and P-glycoprotein-mediated drug efflux inversely correlate and predict clinical outcome in patients with acute myeloid leukemia treated with gemtuzumab ozogamicin monotherapy. Blood. 2007; 109(10):4168-70. PMC: 1885511. DOI: 10.1182/blood-2006-09-047399. View

11.

Lefevre P, Shackelton L, Vande Casteele N . Factors Influencing Drug Disposition of Monoclonal Antibodies in Inflammatory Bowel Disease: Implications for Personalized Medicine. BioDrugs. 2019; 33(5):453-468. DOI: 10.1007/s40259-019-00366-1. View

12.

Moore K, Martin L, OMalley D, Matulonis U, Konner J, Perez R . Safety and Activity of Mirvetuximab Soravtansine (IMGN853), a Folate Receptor Alpha-Targeting Antibody-Drug Conjugate, in Platinum-Resistant Ovarian, Fallopian Tube, or Primary Peritoneal Cancer: A Phase I Expansion Study. J Clin Oncol. 2016; 35(10):1112-1118. PMC: 5559878. DOI: 10.1200/JCO.2016.69.9538. View

13.

Mulleman D, Chu Miow Lin D, Ducourau E, Emond P, Ternant D, Magdelaine-Beuzelin C . Trough infliximab concentrations predict efficacy and sustained control of disease activity in rheumatoid arthritis. Ther Drug Monit. 2010; 32(2):232-6. DOI: 10.1097/FTD.0b013e3181cc6fef. View

14.

Tolcher A . The Evolution of Antibody-Drug Conjugates: A Positive Inflexion Point. Am Soc Clin Oncol Educ Book. 2020; 40:1-8. DOI: 10.1200/EDBK_281103. View

15.

Dosio F, Brusa P, Cattel L . Immunotoxins and anticancer drug conjugate assemblies: the role of the linkage between components. Toxins (Basel). 2011; 3(7):848-83. PMC: 3202854. DOI: 10.3390/toxins3070848. View

16.

Lucas A, Price L, Schorzman A, Storrie M, Piscitelli J, Razo J . Factors Affecting the Pharmacology of Antibody-Drug Conjugates. Antibodies (Basel). 2019; 7(1). PMC: 6698819. DOI: 10.3390/antib7010010. View

17.

Sun F, Wang Y, Luo X, Ma Z, Xu Y, Zhang X . Anti-CD24 Antibody-Nitric Oxide Conjugate Selectively and Potently Suppresses Hepatic Carcinoma. Cancer Res. 2019; 79(13):3395-3405. DOI: 10.1158/0008-5472.CAN-18-2839. View

18.

Lipovsek D, Carvajal I, Allentoff A, Barros Jr A, Brailsford J, Cong Q . Adnectin-drug conjugates for Glypican-3-specific delivery of a cytotoxic payload to tumors. Protein Eng Des Sel. 2018; 31(5):159-171. PMC: 6158766. DOI: 10.1093/protein/gzy013. View

19.

Mulcahy L, Pink R, Carter D . Routes and mechanisms of extracellular vesicle uptake. J Extracell Vesicles. 2014; 3. PMC: 4122821. DOI: 10.3402/jev.v3.24641. View

20.

Scully M, Cataland S, Peyvandi F, Coppo P, Knobl P, Kremer Hovinga J . Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura. N Engl J Med. 2019; 380(4):335-346. DOI: 10.1056/NEJMoa1806311. View