A novel T-cell bispecific antibody platform for efficient T-cell mediated killing of tumor cells with minimal cytokine release.

209Background: Bispecific antibodies that recruit cytotoxic T cells to kill tumor cells are popular due to their targeted mechanism of action. Despite their attractiveness, there are limitations in the clinic due to undesirable toxicities associated with cytokine release. We describe here a platform for generation of a large collection of human anti-CD3 antibodies obtained from custom transgenic rats. Combining these unique anti-CD3 arms with different tumor targeting arms enables creation of bispecific antibodies of varying tumor cell killing capability. These anti-CD3 arms were combined with tumor antigen binding arms, namely, an anti-BCMA arm for multiple myeloma therapy, or an anti-CD22 arm for B-cell acute lymphoblastic leukemia therapy. Methods: Our platform utilizes a discovery approach involving antibody repertoire deep sequencing, high-throughput gene assembly, and recombinant expression, generating a highly diverse panel of antibodies with varying affinities. The CD3 antibodies were tested in in...