Enhanced Anti-Tumor Efficacy of HexaBody-CD38: Insights from Preclinical Hematological Malignancy Models

HexaBody-CD38 (GEN3014) is an innovative human IgG1 antibody designed to target CD38 with improved complement-dependent cytotoxicity (CDC) due to its hexamerization-enhanced structure. The E430G mutation in HexaBody-CD38 promotes the formation of antibody hexamers, which enhances binding to the complement component C1q, thus boosting CDC activity. This antibody is distinct from daratumumab, a clinically established CD38 monoclonal antibody, as it binds to a different epitope and is being considered for its potential as a backbone therapy for multiple myeloma.

Preclinical studies have shown that HexaBody-CD38 is highly potent in CDC-mediated tumor cell killing in vitro against various hematological malignancies, including multiple myeloma, B cell lymphoma, and acute myeloid leukemia. At a concentration of 10 μg/mL, it induced nearly twice as much CDC-mediated lysis compared to daratumumab. Notably, HexaBody-CD38 demonstrated superior CDC activity in cell lines responsive to daratumumab and unlocked CDC activity in cell lines that were not sensitive to daratumumab. It also effectively killed multiple myeloma cells from patients in ex vivo CDC assays, including a patient who had relapsed from daratumumab treatment.

In addition to its superior CDC, HexaBody-CD38 induced comparable antibody-dependent cell-mediated cytotoxicity (ADCC) and phagocytosis (ADCP) to daratumumab. It also showed more efficient inhibition of CD38 cyclase activity, which may contribute to reducing immune suppression in the tumor microenvironment. Treatment with HexaBody-CD38 resulted in the removal of CD38 from the cell membrane of CD38-expressing cells, including T regulatory cells, suggesting a potential mechanism to reduce CD38-generated metabolites and associated immune suppression.

HexaBody-CD38 also demonstrated promising anti-tumor activity in vivo in patient-derived xenograft models of diffuse large B cell lymphoma in nude mice, with activity associated with CD38 expression levels.

In summary, HexaBody-CD38 is a novel CD38 antibody with a superior capacity to induce CDC-mediated tumor cell killing compared to daratumumab, including in tumor samples from multiple myeloma patients. It also induces FcγR-mediated effector functions and effectively inhibits CD38 enzymatic activity, either directly or indirectly by removing CD38 from the cell membrane, which may contribute to immune activation. The potential therapeutic benefits of HexaBody-CD38 in daratumumab-naïve and -refractory multiple myeloma patients, as well as in CD38-positive tumors where daratumumab lacks single-agent efficacy, such as diffuse large B cell lymphoma and acute myeloid leukemia, warrant further clinical investigation. The disclosures section indicates various affiliations and financial interests related to Genmab BV and other entities for several individuals involved in the study.