Local activator and T cell engager (LocATE) selectively blocks PD-L1 at the cytolytic synapse for deeper responses in multiple myeloma.

Abstract

8045 Background: The BCMA-targeting bispecific T-cell engager AMG420 emerged as the first bispecific that achieved responses similar to CAR-T therapies in patients with relapsed/refractory (RR) multiple myeloma (MM). Despite improved ORR, the median duration until relapse is currently limited to approximately 12 months. Persistent minimal residual disease drives relapse and is characterized by increased expression of PD-1/PD-L1. Efficacy with checkpoint inhibitors is compromised by 1) their activity not been targeted specifically to the immune synapse between T cells and cancer cells, and 2) dose-limiting broadly distributed immune-related adverse events, which has halted several clinical trials. This underscores the need for localized checkpoint inhibition within the cytolytic synapse. We developed a Local Activator and T cell Engager (LocATE) antibody that combines binding to CD3 and BCMA with selective blockade of PD-L1 at the immune synapse in just one scaffold. Selectivity is achieved via low afffinity for PD-L1 and high affinity for BCMA. Methods: Antibody mediated Cytotoxicity (LDH assay) and T cell activation (IL-2 release) was measured in vitro using MM cell lines together with isolated human CD3+ T cells. Human ex vivo T cell activity and redirection was evaluated on fresh bone marrow biopsies from MM patients with different disease stages by automated microscopy (pharmacoscopy) and image analysis. Results: The LocATE antibody showed a 5-fold increase in T cell activation and MM cell killing in vitro compared to a BCMAxCD3 BiTE. Furthermore, patient-derived MM cells showed up to a 19-fold increase in T cell activation as compared to a BCMAxCD3 BiTE or a combination of BiTE and PD-L1 inhibitor, while no activity was observed on healthy cells. Conclusions: These results suggest that T cell redirection with simultaneous checkpoint inhibition in the synapse is highly potent while minimizing off-tumor toxicity, therefore, has high therapeutic potential for patients with relapsed MM.