Landmark advances in the engineering and development of bispecific antibodies (bsAbs) are enabling unprecedented versatility in therapeutic antibody concepts. Currently more than 20 different commercialized technology platforms are available for bsAb creation and development, two bsAbs are marketed, of which one in cancer, and over 85 are in clinical development. A defining bsAb feature is their potential for novel functionalities — that is, activities that do not exist in mixtures of the parental or reference antibodies. These so-called obligate bsAb have high potential for the development of novel and differentiating cancer drugs. Bispecific T cell engagers (bs-TCE) are a prominent class of obligate bsAb for targeted cancer immunotherapy. Classical bs-TCE designs consist of a tumor antigen-binding domain combined with a binding domain against the CD3 T-cell receptor-signaling complex. Irrespective of the bispecific antibody format used, CD3-based bs-TCEs have a number of disadvantages, which in part are explained by the fact that they activate all T-cells irrespective of lineage, which associates with serious adverse events as a result of exaggerated T cell activation and cytokine release in some patients, and limited efficacy due to T suppressor cell activation in others. The development of bs-TCEs with increased tumor selectivity to widen the therapeutic window has high potential. The engagement of γδ T cells, and Vγ9Vδ2-T cells in particular, is in this context of particular interest. This γδ T cell subset has been shown to display powerful innate anti-tumor immune effector activity with an ability to infiltrate human tumors in which its abundance has been shown to positively correlate with patient survival. The potential of bsTCEs designed to engage Vγ9Vδ2-T cells as an approach for the development of novel cancer immunotherapies will be discussed.

Citation Format: Paul W H I Parren. Maximizing the potential of bispecific antibodies for cancer drug development [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr CN01-02. doi:10.1158/1535-7163.TARG-19-CN01-02