Enhanced Complement-Dependent Cytotoxicity of DuoHexaBody-CD37 in Preclinical B-Cell Malignancy Models

CD37 is a protein frequently found on B-cells and is being explored as a target for treating B-cell related cancers. However, CD37-targeting antibodies that are in development have not been very effective at inducing complement-dependent cytotoxicity (CDC), a critical immune response for eliminating cancer cells. To address this, a new bispecific antibody called DuoHexaBody-CD37 has been developed. This humanized IgG1 antibody is designed to target two distinct CD37 epitopes and has been enhanced with a mutation (E430G) to improve its hexamer formation, leading to more efficient C1q binding and complement activation.

The DuoHexaBody-CD37 has been shown to be significantly more effective at inducing CDC compared to individual antibodies or their combination, both in vitro across various B-cell lines and ex vivo using tumor samples from chronic lymphocytic leukemia (CLL) patients. Notably, in a CDC assay with tumor cells from a patient with relapsed/refractory CLL, DuoHexaBody-CD37 achieved nearly complete lysis, outperforming the individual antibodies and their combined effect.

In addition to its strong CDC activity, DuoHexaBody-CD37 also demonstrated potent antibody-dependent cellular cytotoxicity (ADCC) against Daudi cells, a human lymphoma cell line. It efficiently bound to B-cells and depleted the B-cell population in whole blood assays from healthy donors. Furthermore, the antibody significantly inhibited tumor growth in mouse xenograft models of Burkitt's lymphoma and CLL at relatively low doses.

In summary, DuoHexaBody-CD37, which combines the DuoBody and HexaBody platforms, has shown robust CDC and ADCC activities in preclinical models. These results suggest that DuoHexaBody-CD37 could be a promising therapeutic monoclonal antibody for treating B-cell malignancies.