Antibody therapeutics discovery: Focus on bispecifics and immune checkpoint modulators
Using a unique sequence-based discovery approach along with proprietary transgenic rats, we have created a large collection of fully human anti-CD3 antibodies with diverse T-cell agonist activities. Our novel discovery platform combines antibody repertoire deep sequencing, high-throughput gene assembly, and recombinant expression. Our approach generates a large diversity of sequence-defined antibodies that we characterized in high-throughput T-cell agonist assays. Using machine learning tools, we were able to rapidly establish sequence-activity relationships and identify key residues and variable region positions in the antibody repertoire that had desired agonist behavior. The CD3 antibodies identified by our platform show diverse in vitro T-cell activation profiles measured by CD69 upregulation, IL2, and IFNg production. We also generated human domain antibodies targeting a variety of tumor antigens that we combined with our unique CD3 antibodies to create bispecific molecules that mediate redirected T-cell killing of tumor cells. In one particular example, we have created a panel of aCD3:aBCMA bispecific antibodies for the treatment of multiple myeloma that stimulate different levels of T-cell activity. Using a multiple myeloma tumor cell line along with primary human PBMCs, we demonstrate a spectrum of in vitro tumor cell killing activity with varied levels of cytokine release using our bispecific molecules with diverse CD3 binding activities. In summary, we have created a T-cell engaging bispecific antibody platform with tuned T-cell agonism that can be used to optimize the therapeutic index for a variety of tumor antigens.