Abstract 2912: INBRX-130, a 5T4-targeted CONTRA-MAB, is a potent CD3 bispecific antibody engineered to have minimal off-tumor activity
Authors: Willis Katelyn M. , Haerr Margaret , Meza Marchelle , Ahn Sae Jeong , Kaplan Michael , Ortiz-Barquero Georgina , Pandit Rajay , Abalos Rafael , Chen Yao , Holley Samuel , Lozano Raul , Hwang Iljin , Rowell Emily , Eckelman Brendan P. 
Published: June 2022

Abstract
Bispecific T cell engagers that target CD3 on T cells and cell-surface antigens on tumor cells have demonstrated meaningful clinical activity against hematological cancers but have yet to achieve similar efficacy for the treatment of solid tumors. A variety of factors may be contributing to this lack of success in the solid tumor setting, including insufficient exposure of tumor cells to these targeted therapeutics due to target-independent interactions with peripheral T cells. Not only can circulating cells act as a sink for CD3 bispecifics but these interactions can lead to cytokine release syndrome (CRS), a common and dose-limiting toxicity for this class of therapeutics. We have developed a CD3 bispecific platform, CONTRA-MAB® (Constrained T Cell Redirecting and Activating Multispecific Antibody), that combines high-affinity tumor-associated antigen binding single-domain antibodies (sdAbs) with a constrained CD3-targeting VH/VL pair that has been strategically positioned and affinity engineered to minimize T cell activation and cytokine production in the absence of target antigen engagement. INBRX-130 is a CONTRA-MAB® that targets trophoblast glycoprotein (TPBG; 5T4), a cell-surface protein that is upregulated across many solid tumor indications but has restricted expression on normal adult tissues. As determined by flow cytometry, INBRX-130 exhibits specific and high-affinity binding to 5T4-positive cells but shows no detectable binding to T cells, absent target, at concentrations up to one micromolar. Additionally, treatment of peripheral blood mononuclear cells (PBMCs) with high concentration INBRX-130 does not result in production of detectable levels of CRS-associated inflammatory cytokines. Upon binding to 5T4-expressing tumor cells in vitro, INBRX-130 potently induces T cell activation, proliferation, cytokine production, and cytotoxicity, resulting in target cell death. INBRX-130 has favorable pharmacokinetic properties and the capacity to effect regression of 5T4+ tumors in humanized mice, even in models that display minimal initial T-cell infiltrate. INBRX-130 is well-tolerated by cynomolgus monkeys at the maximally administered dose of 2 mg/kg without the requirement of a priming dose. Preliminary in vitro data with CONTRA-MABs® targeting other solid tumor antigens supports the broad applicability of this unique T cell engager platform. CONTRA-MABs® have the potential to have enhanced accumulation in solid tumors relative to other CD3 bispecific antibodies as a result of reduced systemic engagement of T cells and increased tolerability at high doses. These attributes, coupled with the broad tumor biased expression of 5T4 across solid tumors, may enable INBRX-130 to have a greater therapeutic index and provide a significant benefit to patients in need.
Citation Format: Katelyn M. Willis, Margaret Haerr, Marchelle Meza, Sae Jeong Ahn, Michael Kaplan, Georgina Ortiz-Barquero, Rajay Pandit, Rafael Abalos, Yao Chen, Samuel Holley, Raul Lozano, Iljin Hwang, Emily Rowell, Brendan P. Eckelman. INBRX-130, a 5T4-targeted CONTRA-MAB, is a potent CD3 bispecific antibody engineered to have minimal off-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2912.