Polyreactivity and Polyspecificity in Therapeutic Antibody Development: Risk Factors for Failure in Preclinical and Clinical Development Campaigns

Overview

Journal MAbs

Specialty Allergy & Immunology

Date 2021 Nov 15

PMID 34780320

Citations 31

Authors

Orla Cunningham

Martin Scott

Zhaohui Sunny Zhou

William J J Finlay

Affiliations

Soon will be listed here.

Abstract

Antibody-based drugs, which now represent the dominant biologic therapeutic modality, are used to modulate disparate signaling pathways across diverse disease indications. One fundamental premise that has driven this therapeutic antibody revolution is the belief that each monoclonal antibody exhibits exquisitely specific binding to a single-drug target. Herein, we review emerging evidence in antibody off-target binding and relate current key findings to the risk of failure in therapeutic development. We further summarize the current state of understanding of structural mechanisms underpining the different phenomena that may drive polyreactivity and polyspecificity, and highlight current thinking on how de-risking studies may be best implemented in the screening triage. We conclude with a summary of what we believe to be key observations in the field to date, and a call for the wider antibody research community to work together to build the tools needed to maximize our understanding in this nascent area.

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References

Guthmiller J, Lan L, Fernandez-Quintero M, Han J, Utset H, Bitar D . Polyreactive Broadly Neutralizing B cells Are Selected to Provide Defense against Pandemic Threat Influenza Viruses. Immunity. 2020; 53(6):1230-1244.e5. PMC: 7772752. DOI: 10.1016/j.immuni.2020.10.005. View

Schoch A, Kettenberger H, Mundigl O, Winter G, Engert J, Heinrich J . Charge-mediated influence of the antibody variable domain on FcRn-dependent pharmacokinetics. Proc Natl Acad Sci U S A. 2015; 112(19):5997-6002. PMC: 4434771. DOI: 10.1073/pnas.1408766112. View

Finlay W, Coleman J, Edwards J, Johnson K . Anti-PD1 'SHR-1210' aberrantly targets pro-angiogenic receptors and this polyspecificity can be ablated by paratope refinement. MAbs. 2018; 11(1):26-44. PMC: 6343799. DOI: 10.1080/19420862.2018.1550321. View

Doyle H, Mamula M . Autoantigenesis: the evolution of protein modifications in autoimmune disease. Curr Opin Immunol. 2012; 24(1):112-8. PMC: 3288476. DOI: 10.1016/j.coi.2011.12.003. View

Granier C, de Guillebon E, Blanc C, Roussel H, Badoual C, Colin E . Mechanisms of action and rationale for the use of checkpoint inhibitors in cancer. ESMO Open. 2017; 2(2):e000213. PMC: 5518304. DOI: 10.1136/esmoopen-2017-000213. View

Kanyavuz A, Marey-Jarossay A, Lacroix-Desmazes S, Dimitrov J . Breaking the law: unconventional strategies for antibody diversification. Nat Rev Immunol. 2019; 19(6):355-368. DOI: 10.1038/s41577-019-0126-7. View

Smith L, Kelleher N . Proteoform: a single term describing protein complexity. Nat Methods. 2013; 10(3):186-7. PMC: 4114032. DOI: 10.1038/nmeth.2369. View

Tucker D, Sullivan J, Mattia K, Fisher C, Barnes T, Mabila M . Isolation of state-dependent monoclonal antibodies against the 12-transmembrane domain glucose transporter 4 using virus-like particles. Proc Natl Acad Sci U S A. 2018; 115(22):E4990-E4999. PMC: 5984492. DOI: 10.1073/pnas.1716788115. View

Colcher D, Pavlinkova G, Beresford G, Booth B, Batra S . Single-chain antibodies in pancreatic cancer. Ann N Y Acad Sci. 1999; 880:263-80. DOI: 10.1111/j.1749-6632.1999.tb09531.x. View

10.

Bostrom J, Yu S, Kan D, Appleton B, Lee C, Billeci K . Variants of the antibody herceptin that interact with HER2 and VEGF at the antigen binding site. Science. 2009; 323(5921):1610-4. DOI: 10.1126/science.1165480. View

11.

Finton K, Larimore K, Larman H, Friend D, Correnti C, Rupert P . Autoreactivity and exceptional CDR plasticity (but not unusual polyspecificity) hinder elicitation of the anti-HIV antibody 4E10. PLoS Pathog. 2013; 9(9):e1003639. PMC: 3784475. DOI: 10.1371/journal.ppat.1003639. View

12.

Mason D, Friedensohn S, Weber C, Jordi C, Wagner B, Meng S . Optimization of therapeutic antibodies by predicting antigen specificity from antibody sequence via deep learning. Nat Biomed Eng. 2021; 5(6):600-612. DOI: 10.1038/s41551-021-00699-9. View

13.

Tunyasuvunakool K, Adler J, Wu Z, Green T, Zielinski M, Zidek A . Highly accurate protein structure prediction for the human proteome. Nature. 2021; 596(7873):590-596. PMC: 8387240. DOI: 10.1038/s41586-021-03828-1. View

14.

Wojciak J, Zhu N, Schuerenberg K, Moreno K, Shestowsky W, Hiraiwa M . The crystal structure of sphingosine-1-phosphate in complex with a Fab fragment reveals metal bridging of an antibody and its antigen. Proc Natl Acad Sci U S A. 2009; 106(42):17717-22. PMC: 2764929. DOI: 10.1073/pnas.0906153106. View

15.

Moss C, Matthews S, Lamont D, Watts C . Asparagine deamidation perturbs antigen presentation on class II major histocompatibility complex molecules. J Biol Chem. 2005; 280(18):18498-503. DOI: 10.1074/jbc.M501241200. View

16.

Xu Y, Roach W, Sun T, Jain T, Prinz B, Yu T . Addressing polyspecificity of antibodies selected from an in vitro yeast presentation system: a FACS-based, high-throughput selection and analytical tool. Protein Eng Des Sel. 2013; 26(10):663-70. DOI: 10.1093/protein/gzt047. View

17.

Igawa T, Tsunoda H, Tachibana T, Maeda A, Mimoto F, Moriyama C . Reduced elimination of IgG antibodies by engineering the variable region. Protein Eng Des Sel. 2010; 23(5):385-92. DOI: 10.1093/protein/gzq009. View

18.

Clarke S . Aging as war between chemical and biochemical processes: protein methylation and the recognition of age-damaged proteins for repair. Ageing Res Rev. 2003; 2(3):263-85. DOI: 10.1016/s1568-1637(03)00011-4. View

19.

Lickliter J, Gan H, Voskoboynik M, Arulananda S, Gao B, Nagrial A . A First-in-Human Dose Finding Study of Camrelizumab in Patients with Advanced or Metastatic Cancer in Australia. Drug Des Devel Ther. 2020; 14:1177-1189. PMC: 7090185. DOI: 10.2147/DDDT.S243787. View

20.

Haynes B, Fleming J, St Clair E, Katinger H, Stiegler G, Kunert R . Cardiolipin polyspecific autoreactivity in two broadly neutralizing HIV-1 antibodies. Science. 2005; 308(5730):1906-8. DOI: 10.1126/science.1111781. View