NEOK002（ABL209）：重新设计具有良好抗肿瘤活性和增强治疗窗口的 EGFRxMUC1 双特异性 TOP1i ADC

NEOK002 (ABL209) is a bispecific antibody-drug conjugate (ADC) designed to enhance the impact of dual targeting of Epidermal Growth Factor Receptor (EGFR) and Mucin-1 (MUC1). NEOK002 is a heterodimeric 1+1 bispecific ADC with a drug-antibody ratio (DAR) of 4, conjugated with SYNtecan E TM , a linker-payload containing the topoisomerase I inhibitor exatecan. 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 well-established tumor-associated antigen characterized by aberrant glycosylation and overexpression, but expression can be heterogeneous and the MUC1 extracellular domain is shed from the tumor, limiting monospecific targeting of MUC1. NEOK002, a dual targeting ADC, was designed to reduce EGFR affinity to minimize interference with EGFR signaling and potential toxicity while targeting the SEA domain of membrane-bound MUC1, avoiding binding to the shed, circulating form. Internalization was assessed with the Incucyte system, and in vitro cytotoxicity by WST-8 assay. We have selected 36 patient-derived xenograft (PDX) models across six indications, based on their expression of EGFR and MUC1 and tested efficacy of NEOK002. The in vivo potency of NEOK002 was also assessed on CFPAC-1, NCI-H1373, and an osimertinib-resistant PDX model. Non-human primate multi-dose GLP toxicity studies were carried out at 20, 40, and 60 mg/kg with dosing on Day 1 and Day 22 with four weeks recovery. NEOK002 demonstrated enhanced cell binding and internalization compared to monospecific EGFR or MUC1 ADC. NEOK002 did not inhibit proliferation of human epidermal keratinocytes in vitro , unlike cetuximab-based ADC molecules. In vivo , NEOK002 resulted in complete regressions with single doses as low as 1.5 mg/kg in a CFPAC-1 pancreatic CDX model. In a PDX screening study, NEOK002 caused tumor growth inhibition in all 36-tested models and induced tumor regressions in 75% of PDXs across lung, head and neck, esophageal, pancreatic, colorectal, and bladder tumors, and showed strong efficacy in 6 of 9 KRAS-mutant models. Co-treatment of the KRAS-mutant NCI-H1373 model with the KRAS G12C inhibitor sotorasib demonstrated rapid and prolonged tumor regression, which was sustained up to Day 57. In non-human primates, anticipated, reversible gastrointestinal toxicity, cytopenias, and skin erythema/hyperpigmentation were observed in a dose-dependent manner. The HNSTD of NEOK002 in cynomolgus monkeys was established at 40 mg/kg, which is associated with a free exatecan C max of <3 ng/mL. NEOK002 is a potential best-in-class bispecific EGFRxMUC1 ADC effectively leveraging the benefits of co-targeting these antigens yielding enhanced antitumor activity across a wide range of tumors, and reducing the liabilities through attenuated EGFR-related toxicity and reduced impact of binding to shed MUC1.