NL019：基于NanoOne™平台开发的新一代TROP2/NECTIN4双靶点纳米抗体ADC

Background: While antibody-drug conjugates (ADCs) have transformed oncology treatment, conventional IgG-based ADCs are constrained by suboptimal tumor penetration, heterogeneous antigen expression, and Fc receptor-mediated immune toxicity. NanoOne™, developed by Naliean Therapeutics, is an innovative nanobody-based modular ADC platform that redefines ADC engineering through molecular miniaturization, structural precision, and payload flexibility. Methods: NanoOne™ integrates multiple VHH nanobody modules (<54 kDa) to achieve deep tumor penetration and broad recognition of tumors with diverse tumor-associated antigen (TAA) profiles. Its proprietary Site-Specific Dual-Payload Conjugation enables precise stoichiometric control (1:2, 2:1, 2:2, etc.) for single or dual payloads with outstanding homogeneity. The design incorporates a highly hydrophilic and stable linker that confers excellent developability. Fc domains are removed to avoid Fc receptor-mediated toxicity to immune cells while maintaining optimal half-life and enhancing tumor microenvironment accumulation. Results: NL019, a TROP2/NECTIN4 dual-target ADC armed with a microtubule inhibitor, demonstrated potent and synergistic activity in vitro-including dual-target binding, internalization, and cytotoxicity-while minimizing on-target toxicities seen in single-target ADCs. In multiple xenograft and CDX models, NL019 achieved superior, dose-dependent antitumor efficacy versus benchmark ADCs targeting TROP2 or NECTIN4. Conclusions: NL019 exemplifies the disruptive potential of NanoOne™, combining advanced molecular architecture, precision one/dual-payload conjugation, and superior tumor selectivity. Supported by strong preclinical efficacy and developability, NL019 is advancing toward first-in-human trials. Given the broad expression of TROP2 and NECTIN4 across epithelial malignancies, NL019 has the potential to establish a new generation of broad-spectrum ADC therapeutics.