Anti-tumor Activity of HPN217, a BCMA-targeting Tri-Specific T Cell Engager, is Enhanced by Γ-Secretase Inhibitors in Preclinical Models

HPN217 is a Tri-specific T Cell-Activating Construct (TriTAC) currently being evaluated in a phase 1 clinical trial for relapsed or refractory multiple myeloma (MM) (NCT04184050). It consists of a single domain antibody (sdAb) specific for B-cell maturation antigen (BCMA), a serum albumin-specific sdAb for half-life extension, and a single chain Fv (scFv) specific for the CD3ε subunit of the T cell receptor (TCR) complex for T cell engagement. BCMA is a cell surface receptor highly expressed on malignant plasma cells in MM patients and plays an important role in B-cell proliferation and survival. Soluble BCMA (sBCMA) is produced when the extracellular domain of BCMA is cleaved by γ-secretase and enters circulation. sBCMA may act as a sink for BCMA targeted therapies, potentially decreasing anti-tumor efficacy. Previous studies have shown γ-secretase inhibitors (GSIs) can increase membrane bound BCMA expression on MM cells and decrease sBCMA concentrations, providing a rationale for combining GSIs with HPN217. Here we describe preclinical studies evaluating that combination in vitro and in vivo. To evaluate the effects of GSIs on BCMA expression, MM cell lines MOLP8, KMS-12-BM, and MM.1S were incubated with GSIs LY3039478, PF03084014, or RO4929097overnight. GSI treatment led to a 3-7-fold increase in BCMA expression on MM cell surface. To determine the effects of increased BCMA expression mediated by GSIs on the activity of HPN217, an in vitro T cell dependent cell cytotoxicity assay (TDCC) was conducted. GSIs enhanced the activity of HPN217, in some cases leading to a 3.5-fold increase in potency compared to HPN217 alone. Next, the impact of the combination was tested in vivo using a disseminated MOLP-8 xenograft model engrafted with T cells from a healthy human donor. Vehicle treated mice succumbed to disease burden with a median survival of 23 days as assessed by body weight loss and clinical observations. A suboptimal dose of 4 ug/kg HPN217 protected mice from disease burden for an additional 3 days. By contrast, the combination of HPN217 and LY3039478 led to a significant increase in survival compared to vehicle or either monotherapy, with a median survival of 43 days. Taken together these results demonstrate the potential utility of GSIs to enhance the anti-tumor activity of HPN217 and supports further investigation of this combinatorial approach in patients. Citation Format: Payton C. Laurie, Mary Ellen Molloy, Patrick P. Ng, Banmeet S. Anand. Anti-tumor activity of HPN217, a BCMA-targeting tri-specific T cell engager, is enhanced by γ-secretase inhibitors in preclinical models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5081.