Abstract IA004: Preclinical development of DuoBody®-CD3xB7H4, a novel CD3 bispecific antibody for the treatment of solid cancers

Abstract

Abstract Several clinical trials are currently underway to investigate the effectiveness of CD3 bispecific antibodies (bsAb) in solid tumors. Given the number of approved CD3 bsAb therapies thus far, the development of these bsAbs appears to be more challenging in solid cancer compared to hematological malignancies. The choice of an appropriate tumor-specific target and CD3 affinity are important considerations for the development of effective and safe CD3 bsAbs. The immune checkpoint protein B7H4 is differentially expressed between normal and tumor tissue, showing high expression in various solid cancers. Therefore, B7H4 provides an attractive target for a CD3 bsAb. We explored the preclinical mechanism of action (MoA) and pharmacodynamic (PD) markers of two B7H4-targeting CD3 bsAbs with different CD3 affinities. By crosslinking CD3 on T cells with B7H4 on tumor cells, CD3xB7H4 bsAbs will induce T-cell mediated cytotoxicity in B7H4-expressing tumor cells, associated with T-cell activation and cytokine production. In comparative preclinical characterization studies in vitro, we showed that both bsAbs induced target-specific, dose-dependent, and complete tumor cell kill in a panel of tumor cell lines expressing varying levels of B7H4, albeit with different potency. Moreover, both molecules demonstrated an acceptable safety profile in cynomolgus monkeys. DuoBody-CD3xB7H4 (GEN1047), the variant with lower CD3 affinity, was selected as clinical candidate, to leverage its observed propensity for lower cytokine production. In a patient-derived xenograft model of ovarian cancer in NCG-HIS mice examined in vivo, DuoBody-CD3xB7H4 showed dose-dependent antitumor activity, which was associated with increased numbers of intratumoral T cells and with peripheral PD biomarkers of T-cell activation and cytokine production. Currently, DuoBody-CD3xB7H4 is being investigated in a first-in-human clinical trial for the treatment of solid tumors known to express B7H4 (NCT05180474), in which the MoA and PD, including biomarkers of response, will be clinically explored. Citation Format: Louise A Koopman, Farshid Alemdehy, Madelon Paauwe, Laura Smits-de Vries, Frosso Karaiskaki, Marcel Brandhorst, Patrick Franken, Theo S Plantinga, Mischa A Houtkamp, Stefanie A.H. de Poot, Esther C.W. Breij. Preclinical development of DuoBody®-CD3xB7H4, a novel CD3 bispecific antibody for the treatment of solid cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr IA004.