Abstract B142: Legumain-activated pan-RAS/DXd dual-payload ADC for RAS-mutant, RAS-wild-type, and single-payload-resistant tumors

Abstract

In addition to oncogenic RAS mutations inducing uncontrolled pancreatic tumor growth, overexpression of wild-type (WT) pan-RAS in tumor cells is also a major cause of aberrant proliferation. However, systemic pan-RAS inhibition can cause skin toxicity because keratinocytes in skin need the RAS signaling pathway for proliferation and differentiation. To selectively suppress RAS signaling in tumors while minimizing toxicity to normal tissues, we developed a dual-targeting and dual-payload ADC strategy to maximize antitumor efficacy. EGFR and c-MET are both highly expressed in pancreatic cancer tissues, with IHC positivity rates exceeding 85% for EGFR and 70% for c-MET. AI-assisted target combination analysis further indicated that dual targeting of EGFR and c-MET can address heterogeneous single-antigen expression in pancreatic cancer. We therefore conjugated DXd and a pan-RAS inhibitor as dual payloads (at a DAR of 8+8) to an EGFR/c-MET bispecific antibody using a legumain-cleavable-linker (TMEAlinker, a tumor microenvironment-activated linker). This design is intended to enhance tumor selectivity as skin keratinocytes express low levels of EGFR and c-MET, but no legumain expression. A potent pan-RAS inhibitor has been selected based on its cytotoxicity and synergistic effects with DXd in vitro across several RAS-WT tumor cells. EGFR/c-MET-TMEAlinker-pan-RASi/DXd (IMD-2773) demonstrated strong synergistic antitumor activity compared with two corresponding single-payload ADCs in the RAS-WT pancreatic cancer and lung cancer animal models. IMD-2773 also exhibited curative effects in the DXd-resistant, KRAS G12D-mutant AsPC-1 pancreatic cancer CDX model, and the KRAS G12C-mutant LUN#2156-4 lung cancer PDX model resistant to KRAS G12C inhibitors. Moreover, IMD-2773 showed favorable tolerability in safety studies in mouse and nonhuman primate, suggesting a higher therapeutic index than single-payload ADCs in RAS-WT cancers. Overall, these results demonstrate that tumor-selective delivery of pan-RASi together with DXd can broaden antitumor activity across RAS-mutant and RAS-WT tumors while overcoming resistance to single-payload therapies. It supports a novel dual-payload ADC strategy that uses pan-RASi as a cytotoxic payload for patients who may benefit from pan-RAS pathway inhibition despite lacking a RAS mutation.