Abstract 3434: APVO442 is a distinct PSMA x CD3 targeted bispecific candidate designed to optimize T cell fitness and distribution to solid tumors

APVO442 is a bispecific therapeutic candidate targeting PSMA and CD3 for redirection of T cell responses against PSMA-expressing solid tumors. The candidate bispecific was designed to have unique pharmacokinetic and safety properties to potentially maximize robust anti-tumor responses. APVO442 is designed with Aptevo’s ADAPTIR-FLEX࣪ technology to generate a molecule with low-affinity monovalent CD3 engagement, paired with high-affinity bivalent PSMA binding intended to be tumor - dependent while inducting optimal T-cell stimulation within the tumor microenvironment. The unique engineering of APVO442 reduces the potential peripheral CD3 T cell binding, minimizing the potential for on-target toxicity, such as peripheral cytokine release, while simultaneously increasing the likelihood to deliver an effective concentration of APVO442 locally within solid tumors. Preclinical data demonstrate that APVO442 is able to activate T cells and mediate directed cytotoxicity against PSMA-expressing tumor targets with comparable potency to α-PSMA x α-CD3 constructs with varying CD3 affinity or avidity both in vitro and in vivo. The CD3 activity is dependent on PSMA crosslinking as activity is not observed in the absence of tumor target, in line with the silenced Fc engineered into APVO442. Importantly, cytokine release was not observed in peripheral immune subsets in the absence of tumor targets, despite a beneficial cytokine profile observed in the presence of PSMA positive tumor cell lines. The unique biology elicited by APVO442 induces distinct kinetic activation of downstream transcriptional regulators following monovalent TCR engagement of APVO442 associated with reduced early signaling, but overall, a more sustained activation than higher affinity variants. In addition, APVO442 induces a distinct phenotypic profile on human T cells associated with optimal function and memory responses only in the presence of tumor targets. Further, combination of APVO442 with additional costimulatory agonists supports improved T cell activation and anti-tumor cytotoxicity in vitro. These data support the potential for unique clinical combination of APVO442 with immuno-oncology modalities that may support improved benefit in PSMA positive indications such as metastatic castration resistant prostate cancer. APVO442 is undergoing further preclinical in vitro and in vivo characterization in support of the IND-enabling package. Citation Format: Rebecca Gottschalk, Robert Miller, Brian Wo