Hanjugator喜树碱平台：高效、低毒设计最大化抗体功能并递送潜在的同类最佳EGFR/cMet双特异性抗体药物偶联物

Introduction: High toxin potency in antibody-drug conjugates (ADCs) limits clinical doses to those below optimal antibody levels, diminishing signal blockade potential and emphasizing chemotherapeutic effects. To address this limitation, we developed Hanjugator, a customizable, modular camptothecin-based linker-payload platform with tunable potency-from threefold lower than deruxtecan to comparable with exatecan-enabling a broader therapeutic window and preserving antibody functionality. We applied medium-potency payload to an EGFR/cMet bispecific ADC, a target combination known to require higher clinical doses for optimal receptor occupancy and efficacy. Methods: Cytotoxicity of toxin candidates and ADCs was assessed via CellTiter-Glo (CTG) assay in immortalized cell lines. ADC binding and internalization were evaluated by flow cytometry on cells with varying antigen expression levels. Pharmacokinetics (PK) of LPA003-based ADC were determined in rats following single intravenous 5 mg/kg dosing. Bystander killing was quantified by co-incubating antigen-positive and -negative (Jurkat) cells, with Jurkat viability measured via CTG assay. In vivo efficacy of EGFR/cMet-LPA003 was tested in multiple xenograft models (LU387, SW48, HT29, NCI-H1975). For preliminary toxicology, cynomolgus monkeys were treated with three doses of 30 or 60 mg/kg of the test article, administered every three weeks (Q3W). Results: The Hanjugator platform delivers a series of highly hydrophilic linker-payloads with excellent compatibility for non-standard, hydrophobic antibodies and superior thermal, plasma, and freeze-thaw stability. These conjugates exhibit bystander killing over 10-fold stronger compared with deruxtecan and outperform multiple clinical-stage linker-payload systems in efficacy studies, despite some competitors' higher intrinsic payload potency. The platform's wide toxin potency range broadens its applications. Medium-potency LPA003, conjugated to EGFR/cMet bispecific antibody, induced significant tumor regression at single 3 mg/kg doses in various xenograft models, outperforming AZD9592 in the HT29 CDX model. Preliminary toxicology shows EGFR/cMet-LPA003 is well tolerated in cynomolgus monkeys after 3 doses at 60 mg/kg Q3W. Conclusion: We have developed Hanjugator, a versatile camptothecin-based linker-payload platform with tunable toxin potency. This modular design accommodates diverse targets and ADC programs, optimizing dosing regimens and broadening clinical applications. The LPA003-conjugated EGFR/cMet bispecific ADC exhibits a superior therapeutic index, maximizing antibody-mediated signaling blockade, and positions as best-in-class molecule with Investigational New Drug submission anticipated in Q1 2026.