Characterization and root cause analysis of immunogenicity to pasotuxizumab (AMG 212), a prostate-specific membrane antigen-targeting bispecific T-cell engager therapy

Frontiers in Immunology

Immunology

Sabine Wittemer-Rump¹  Gökben Koca¹  Bin Wu²  Kelly Hainline³  Hweixian Leong Penny³  Daniel T. Mytych³  Mason McComb⁴  Sabine Stienen⁵  Tobias Eggert⁶  Carsten Grüllich⁷  Ben Tran⁸  Christian Webhofer⁹  Christian Brandl^1,10  Wolfgang Loidl^1,11  Nathaniel Theoharis^1,12  Horst-Dieter Hummel^1,13  Ralf C. Bargou^1,13 

[1] Bayer AG, Research and Development Oncology (RED Onc), Pharmaceuticals, Berlin, Germany;Department of Biologics, Amgen, Thousand Oaks, CA, United States;Department of Clinical Immunology, Amgen, Thousand Oaks, CA, United States;Department of Clinical Pharmacology, Modeling & Simulation, Amgen, Thousand Oaks, CA, United States;Department of Early Development (Oncology), Amgen Research (Munich) GmbH, Munich, Germany;Department of Early Development (Oncology), Amgen, Thousand Oaks, CA, United States;Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Medical Center, Heidelberg, Germany;Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia;Department of Process Development, Amgen Research (Munich) GmbH, Munich, Germany;Department of Translational Safety & Bioanalytical Sciences, Amgen Research (Munich) GmbH, Munich, Germany;Department of Urology, Ordensklinikum Linz GmbH, Linz, Austria;Labcorp, Translational Biomarker Solutions, Greenfield, IN, United States;Translational Oncology/Early Clinical Trial Unit (ECTU), Comprehensive Cancer Center Mainfranken, University Hospital Wurzburg, Wurzburg, Germany;

关键词: immunogenicity;    BiTE;    T cell engager;    ADA;    prostate cancer;   

DOI  :  10.3389/fimmu.2023.1261070

 received in 2023-07-18, accepted in 2023-10-02,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionIn oncology, anti-drug antibody (ADA) development that significantly curtails response durability has not historically risen to a level of concern. The relevance and attention ascribed to ADAs in oncology clinical studies have therefore been limited, and the extant literature on this subject scarce. In recent years, T cell engagers have gained preeminence within the prolific field of cancer immunotherapy. These drugs whose mode of action is expected to potently stimulate anti-tumor immunity, may potentially induce ADAs as an unintended corollary due to an overall augmentation of the immune response. ADA formation is therefore emerging as an important determinant in the successful clinical development of such biologics. MethodsHere we describe the immunogenicity and its impact observed to pasotuxizumab (AMG 212), a prostate-specific membrane antigen (PSMA)-targeting bispecific T cell engager (BiTE®) molecule in NCT01723475, a first-in-human (FIH), multicenter, dose-escalation study in patients with metastatic castration-resistant prostate cancer (mCRPC). To explain the disparity in ADA incidence observed between the SC and CIV arms of the study, we interrogated other patient and product-specific factors that may have explained the difference beyond the route of administration. ResultsTreatment-emergent ADAs (TE-ADA) developed in all subjects treated with at least 1 cycle of AMG 212 in the subcutaneous (SC) arm. These ADAs were neutralizing and resulted in profound exposure loss that was associated with contemporaneous reversal of initial Prostate Surface Antigen (PSA) responses, curtailing durability of PSA response in patients. Pivoting from SC to a continuous intravenous (CIV) administration route remarkably yielded no subjects developing ADA to AMG 212. Through a series of stepwise functional assays, our investigation revealed that alongside a more historically immunogenic route of administration, non-tolerant T cell epitopes within the AMG 212 amino acid sequence were likely driving the high-titer, sustained ADA response observed in the SC arm.DiscussionThese mechanistic insights into the AMG 212 ADA response underscore the importance of performing preclinical immunogenicity risk evaluation as well as advocate for continuous iteration to better our biologics.

【 授权许可】

Unknown   
Copyright © 2023 Penny, Hainline, Theoharis, Wu, Brandl, Webhofer, McComb, Wittemer-Rump, Koca, Stienen, Bargou, Hummel, Loidl, Grüllich, Eggert, Tran and Mytych

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