INCA036873, a first-in-class CD70×CD3 T cell-redirecting bispecific antibody, for the treatment of CD70-positive malignancies

CD70 is a member of the tumor necrosis factor ligand superfamily, with CD27 being its sole receptor. Under normal physiological conditions, CD70-CD27 signaling promotes T-cell activation, survival, and differentiation. In normal tissues, CD70 expression is restricted to activated T, B, and dendritic cells. Aberrant CD70 expression is observed in various malignancies, including renal cell carcinoma (RCC), ovarian cancer, acute myeloid leukemia, and non-Hodgkin's lymphoma. This highly selective upregulation in tumor cells and restricted expression in normal tissues make CD70 an attractive therapeutic target. INCA036873 is a novel Biclonics® bispecific antibody designed to redirect and activate T cells to specifically kill CD70-expressing tumor cells. INCA036873 binds CD70 with high affinity (K D = 0.4 nM) and CD3 with moderate affinity (K D = 115 nM), enabling selective T-cell activation, while minimizing systemic immune activation and cytokine release. INCA036873 induced potent CD70-dependent T cell-mediated cytotoxicity of tumor cells. In vitro, INCA036873 demonstrated robust killing across multiple CD70-expressing tumor cell lines as well as freshly disassociated primary patient-derived RCC tumor cells. In vivo, INCA036873 showed strong antitumor efficacy in multiple cell line xenograft models such as 786-O (RCC) and SKOV3 (ovarian cancer), as well as RCC patient-derived xenograft models in human CD34 - positive humanized NSG mice. Importantly, INCA036873 exhibited a favorable safety profile, with limited cytokine release in human whole blood cytokine release assays and no adverse findings at doses up to 3.0 mg/kg (>15-fold above the projected therapeutic exposure) in a 4-week toxicology study in huCD70/huCD3EDG knock-in mice. INCA036873 also demonstrated desirable pharmacokinetics in cynomolgus monkeys. Overall, these data support the advancement of INCA036873 as a promising, potential, first-in-class bispecific T-cell engager antibody for CD70-positive malignancies.