Immunogenicity assessment of bispecific antibody-based immunotherapy in oncology

Abstract

With increasing numbers of bispecific antibodies (BsAbs) and multispecific products entering the clinic, recent data highlight immunogenicity as an emerging challenge in the development of such novel biologics. This review focuses on the immunogenicity risk assessment (IgRA) of BsAb-based immunotherapies for cancer, highlighting several risk factors that need to be considered. These include the novel scaffolds consisting of bioengineered sequences, the potentially synergistic immunomodulating mechanisms of action (MOAs) from different domains of the BsAb, as well as several other product-related and patient-related factors. In addition, the clinical relevance of anti-drug antibodies (ADAs) against selected BsAbs developed as anticancer agents is reviewed and the advances in our knowledge of tools and strategies for immunogenicity prediction, monitoring, and mitigation are discussed. It is critical to implement a drug-specific IgRA during the early development stage to guide ADA monitoring and risk management strategies. This IgRA may include a combination of several assessment tools to identify drug-specific risks as well as a proactive risk mitigation approach for candidate or format selection during the preclinical stage. The IgRA is an on-going process throughout clinical development. IgRA during the clinical stage may bridge the gap between preclinical immunogenicity prediction and clinical immunogenicity, and retrospectively guide optimization efforts for next-generation BsAbs. This iterative process throughout development may improve the reliability of the IgRA and enable the implementation of effective risk mitigation strategies, laying the foundation for improved clinical success.

Enhanced immunogenic potential of cancer immunotherapy antibodies in human IgG1 transgenic mice

“…The identification of Fc-associated mechanisms preserving unresponsiveness to conventional antibodies prompted us to address the widely observed strong immunogenic potential of bispecific therapeutic antibodies. 1 Thus, we extended our studies to two forms of CitAbs, based on the same CEA-specific scaffold antibody. The structure of CEA-based CitAbs used is shown in Figure 4A .…”

“…To do so, we used an experimental system of lethally irradiated mice reconstituted with a mix of bone marrow cells. The mix is composed of 80% bone marrow cells from mice homozygous for the Igh-J tm 1 Cgn targeted mutation (JhT −/− ), and thus lacking functional B cells, and of 20% bone marrow cells derived from MHC-II deficient mice (MHC-II −/− ) in order to create a system where only B cells are deficient for MHC-II expression. A mix containing 20% bone marrow cells from wild-type mice serves as a control.…”

“…Despite intensive efforts in the development of bispecific antibody therapeutics specifically designed for cancer immunotherapy, few have reached the market. 1 Doubtless, antibody therapy based on CitAbs and related biotherapeutics has the potential to be highly efficacious in cancer treatment. 5 , 18 Given that immunogenicity represents one of the major liabilities of this class of anti-tumor drugs, the preclinical assessment of their immunogenic properties is the objective of intensive research efforts.…”

“…In some cases, ADA can cause substantial exposure loss that affects efficacy, with the potential to provoke undesired adverse events. 1 Presently, it is unknown which factors, in addition to foreign immunogenic protein sequences, contribute to the onset of ADA production by some therapeutic antibodies and not by others. In a recent survey, the collected ADA data from 60 clinical antibodies revealed that the majority (76%) of these antibodies display an immunogenicity rate of less than 10% and the minority (10%) of the antibodies tested cause an ADA rate higher than 20%.…”

“…In contrast, bispecific, immunomodulatory antibodies frequently used in cancer immunotherapy (CIT) – herein referred to as CitAbs – appear to cause ADA with a higher incidence than expected, given their generally human/humanized origin. 1 , 3 Therefore, it is crucial to better understand the mechanisms involved in breaking tolerance toward CitAbs, leading to ADA responses.…”