ABL209 (NEOK002): Designing an EGFR × MUC1 Bispecific TOP1i ADC with Promising Antitumor Activity and Enhanced Therapeutic Window

Abstract ABL209 (NEOK002) is a bispecific antibody–drug conjugate (ADC) designed to enhance efficacy and therapeutic window through dual targeting of the epidermal growth factor receptor (EGFR) and mucin 1 (MUC1). EGFR is a key oncogenic driver in multiple tumor types; however, clinical targeting of EGFR is limited by dose-dependent skin toxicity. MUC1 is a tumor-associated antigen characterized by aberrant glycosylation and overexpression, but its expression can be heterogeneous, and the MUC1 extracellular domain is shed from the tumor, limiting monospecific targeting of MUC1. ABL209 is a heterodimeric 1 + 1 bispecific ADC with a drug-to-antibody ratio of 4, conjugated with tavatecan. ABL209 demonstrated enhanced cell binding and internalization compared with monospecific EGFR or MUC1 ADCs. ABL209 did not seem to inhibit the proliferation of human epidermal keratinocytes in vitro, unlike cetuximab-based ADCs. In vivo, ABL209 resulted in complete regression of tumors with single doses as low as 1.5 mg/kg in a CFPAC-1 pancreatic cell line–derived xenograft model. ABL209 demonstrated tumor growth inhibition across all 36 tested patient-derived xenograft models, inducing tumor regressions in 78% of models and showing efficacy in 6 of 10 KRAS-mutant tumors. Cotreatment with sotorasib prolonged tumor regression in a KRAS-mutated NCI-H1373 model for 58 days following treatment. ABL209 showed a favorable pharmacokinetic profile with a half-life of 5.2 days at 10 mg/kg in monkeys. ABL209 was well tolerated in monkeys up to 40 mg/kg. Our data suggest that a bispecific ADC leverages the benefits of cotargeting two antigens, resulting in enhanced antitumor activity while reducing liabilities through attenuated target-related toxicities.