Enabling the next steps in cancer immunotherapy: from antibody-based bispecifics to multispecifics, with an evolving role for bioconjugation chemistry

In the past two decades, immunotherapy has established itself as one of the leading strategies for cancer treatment, as illustrated by the exponentially growing number of related clinical trials. This trend was, in part, prompted by the clinical success of both immune checkpoint modulation and immune cell engagement, to restore and/or stimulate the patient's immune system's ability to fight the disease. These strategies were sustained by progress in bispecific antibody production. However, despite the decisive progress made in the treatment of cancer, toxicity and resistance are still observed in some cases. In this review, we initially provide an overview of the monoclonal and bispecific antibodies developed with the objective of restoring immune system functions to treat cancer (cancer immunotherapy), through immune checkpoint modulation, immune cell engagement or a combination of both. Their production, design strategy and impact on the clinical trial landscape are also addressed. In the second part, the concept of multispecific antibody formats, notably MuTICEMs (Multispecific Targeted Immune Cell Engagers & Modulators), as a possible answer to current immunotherapy limitations is investigated. We believe it could be the next step to take for cancer immunotherapy research and expose why bioconjugation chemistry might play a key role in these future developments.