Abstract 815: Improved tolerability and tumor specific delivery of a therapeutic bispecific T cell engager using a pH-sensitive nanoparticle platform

Bispecific antibodies are an emerging class of therapeutics for immune-oncology applications. T cell engagers (TCEs) target tumor-associated antigens (TAA) to eradicate cancer cells. TCEs for solid tumors have demonstrated encouraging preclinical efficacy but development has been challenging with dose-limiting toxicities due to on-target/off-tumor effect. To overcome the issue, we have developed ON-BOARD, an ultra-pH sensitive nanoparticle platform for masked and targeted delivery of payloads to the acidic tumor microenvironment (TME). Herein we report efficacious masked delivery of a TCE to tumors in mice using ON-BOARD demonstrating significantly improved tolerability and potential for clinical translation. TCEs were encapsulated in ON-BOARD nanoparticles and characterized for particle properties. The formulations were assessed in vitro under neutral or acid-activated conditions in TDCC assays. In vivo studies were performed in mice bearing “immune desert” pancreatic cancer. ON-BOARD tumor localization was measured by fluorescence while unencapsulated TCE and ON-BOARD/TCE pharmacokinetics was evaluated. PD studies evaluated immune-phenotype changes in tumors and draining lymph nodes, and systemic cytokine levels. Efficacy studies were performed in tumor-bearing mice comparing unencapsulated TCE to ON-BOARD-TCE as monotherapy and in combination with anti-4-1BB agonist therapy. ON-BOARD encapsulated TCEs have high encapsulation efficiency (>88%) in uniformly distributed stable particles (Dh