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  • Review Article
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Bispecific and multispecific antibodies in oncology: opportunities and challenges

Abstract

Research into bispecific antibodies, which are designed to simultaneously bind two antigens or epitopes, has advanced enormously over the past two decades. Owing to advances in protein engineering technologies and considerable preclinical research efforts, bispecific antibodies are constantly being developed and optimized to improve their efficacy and to mitigate toxicity. To date, >200 of these agents, the majority of which are bispecific immune cell engagers, are in either preclinical or clinical evaluation. In this Review, we discuss the role of bispecific antibodies in patients with cancer, including history and development, as well as innovative targeting strategies, clinical applications, and adverse events. We also discuss novel alternative bispecific antibody constructs, such as those targeting two antigens expressed by tumour cells or cells located in the tumour microenvironment. Finally, we consider future research directions in this rapidly evolving field, including innovative antibody engineering strategies, which might enable more effective delivery, overcome resistance, and thus optimize clinical outcomes.

Key points

  • Following the approval of blinatumomab in 2014 for use in patients with relapsed and/or refractory B cell acute lymphoblastic leukaemia, a further ten bispecific antibodies have been approved by regulators globally and a further >200 bispecific antibodies, with increasingly diverse designs and mechanisms of action, are currently in preclinical or clinical development.

  • Identifying the most appropriate target antigen is a major challenge for the successful development of bispecific antibodies, especially in solid tumours, and holds the key to creating safe and effective off-the-shelf agents for clinical application.

  • Bispecific antibodies are able to recruit immune cells into the vicinity of tumours and enable them to thrive in the immunosuppressive tumour microenvironment owing to their ability to overcome the effects of various inhibitory factors and provide stimulatory signals capable of restoring antitumour activity.

  • Bispecific antibodies targeting two or more pathways involved in tumour progression simultaneously might reduce the risks of drug resistance and tumour progression compared to monotherapy with agents targeting one of the same pathways.

  • Strategies to mitigate cytokine release syndrome have been identified, such as pretreatment with steroids, step-up dosing, subcutaneous administration, modification of CD3ε affinities and prodrug concepts.

  • The optimal clinical use, including treatment sequencing and the identification of possible combination therapies, remains uncertain for most of these agents.

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Fig. 1: Immune cell-activating bispecific antibodies and their mechanisms of action.
Fig. 2: Crosslinking bispecific antibodies.
Fig. 3: Bispecific antibodies targeting signalling pathways, immune checkpoints and/or cytokines.

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Acknowledgements

The authors particularly thank A. Wenzl from the University Hospital Würzburg for graphic design support.

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Correspondence to Maria-Elisabeth Goebeler.

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M.-E.G. has acted as a consultant and/or adviser to Amgen, AvenCell, Bristol-Myers Squibb, Janssen-Cilag, Novartis and Roche. G.S. holds patents on the hemibody technology and has acted as a consultant to Veraxa Biotech GmbH. R.C.B. has acted as a consultant and/or adviser to Amgen, Avencell, Bristol-Myers Squibb Catalym, Janssen-Cilag, Novartis and Roche, and holds a patent for blinatumomab, from which he receives royalties.

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Bispecific Antibody Development Programs Guidance for Industry: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/bispecific-antibody-development-programs-guidance-industry.

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Goebeler, ME., Stuhler, G. & Bargou, R. Bispecific and multispecific antibodies in oncology: opportunities and challenges. Nat Rev Clin Oncol 21, 539–560 (2024). https://doi.org/10.1038/s41571-024-00905-y

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