Potent preclinical activity of HexaBody-DR5/DR5 in relapsed and/or refractory multiple myeloma

Apoptosis induction by death receptor (DR)-specific agonistic antibodies is a potentially effective antitumor therapy. Nonetheless, to date, all conventional DR-targeting antibodies 3 that induce apoptosis via Fc gamma R-dependent DR clustering failed to show clinical efficacy. HexaBody-DR5/DR5 (GEN1029) has been developed to overcome full Fc gamma R dependence. HexaBody-DRS/DRS is a mixture of 2 noncompeting DRS-specific immunoglobulin G1 (IgG1) antibodies, each with an E430G mutation in the Fc domain. This mutation enhances Fc-Fc interactions, resulting in antibody hexamerization, followed by Fc gamma R-independent clustering of DR5 molecules. This unique combination of dual epitope targeting and increased IgG hexamerization resulted in potent preclinical antitumor activity in various solid cancers. In this study, we explored the preclinical activity of HexaBody-DRS/DRS in multiple myeloma (MM), because MM cells are known to express DRS. In bone marrow samples from 48 MM patients, HexaBody-DR5/DR5 induced potent cytotoxicity of primary MM cells. Importantly, HexaBody-DRS/DRS mediated the highest cytotoxic activity in samples from relapsed/refractory MM patients, including those who are refractory to daratumumab. This improved cytotoxic activity was observed only in patients who received their last anti-MM treatment <1 month ago, suggesting that anti-MM drugs sensitized MM cells to HexaBody-DRS/DRS. Supporting this, bortezomib combined with HexaBody-DR5/DR5 synergistically increased cytotoxicity in MM cells in 7 of 11 newly diagnosed patients. Lenalidomide also synergized with HexaBody-DRS/DRS, but only via its immunomodulatory effects, presumably by enhancing the antibody-dependent cellular cytotoxicity activity of HexaBody-DRS/DRS. Daratumumab showed additive effects when combined with HexaBody-DRS/DRS. In conclusion, the results of this preclinical study indicate a therapeutic potential for HexaBody-DRS/DRS, especially in recently treated relapsed/refractory MM patients.

Automated summary

HexaBody-DRS/DRS antibodies show potential therapeutic efficacy in multiple myeloma, especially exhibiting the highest cytotoxic activity in relapsed/refractory patients who have recently been treated, with synergistic effects observed when combined with other anti-MM drugs such as bortezomib, lenalidomide, and daratumumab.