Fifty years of monoclonals: the past, present and future of antibody therapeutics

In 1975, Köhler and Milstein invented hybridoma technology for the generation of murine monoclonal antibodies with predetermined antigen-binding specificity. The transformative impact of monoclonal antibodies is demonstrated by their ubiquitous use as biomedical research reagents and the worldwide approval of at least 212 antibody therapeutics with tens of millions of patients treated to date. Advances in antibody technologies, such as humanization and robust methods for human antibody generation, mitigated the major limitations of murine antibodies as therapeutics. These technologies, combined with progress in biomanufacturing, helped to launch this modern era of antibody therapeutics. Beyond IgG, antibody therapeutics have blossomed into multiple alternative formats, including bispecific antibodies and antibody–drug conjugates. Additionally, antibody fragments have been developed as stand-alone therapeutics and to target cell therapies, notably chimeric antigen receptor T cells. These advances in antibody technologies, plus innovation enabling subcutaneous delivery, have improved the therapeutic benefits and convenience of antibody treatment for many patients. This concept is illustrated here by multiple generations of antibody therapeutics for human epidermal growth factor receptor 2 (HER2)+ cancers and B cell-targeted therapies for haematological cancers and immunological diseases. Finally, we opine briefly on some of the many promising future directions with antibody therapeutics, including the application of artificial intelligence for antibody identification and multi-parameter optimization. Fifty years ago, Köhler and Milstein introduced the world to hybridoma technology for the generation of monoclonal antibodies. Scientists have subsequently built upon this seminal discovery to develop antibody-based therapies for numerous diseases, with millions of patients benefiting from such drugs. To mark 50 years of monoclonal antibodies, this Review from Chan, Martyn and Carter provides an overview of how antibody engineering strategies have continued to improve antibody-based therapeutics, chiefly focusing on antibody-mediated targeting of B cells and also human epidermal growth factor receptor 2 (HER2)+ cancers. The authors also highlight the promise of emerging tools, including artificial intelligence, for development of the next generation of antibody-based therapeutics.