ALM-502：一种用于实体瘤治疗的高效ADC——通过分子设计增强载荷递送

Antibody-drug conjugates (ADCs) have transformed cancer therapy, yet their efficacy in solid tumors remains constrained by heterogeneous antigen expression, limited tumor penetration, low therapeutic index and the emergence of resistance mechanisms. ALM-502 is a highly differentiated, biparatopic ADC designed to address these challenges through innovative antibody architecture, enabling enhanced payload delivery. ALM-502 targets ALPP/ALPPL2, developmental proteins which are over-expressed in multiple solid tumor indications but have undetectable protein expression on normal adult tissues. Additionally, ALPP/ALPPL2 are upregulated in response to standard of care treatments, providing additional therapeutic opportunities in the drug-resistant setting. The upregulation in multiple solid tumors, undetectable normal tissue expression and role in drug resistance make ALPP/ALPPL2 highly attractive targets for ADC approaches. ALM-502 exploits multiple design features to deliver optimized performance: • A biparatopic binding mode increases the effective number of binding sites on the tumor cells and increases payload delivery. • A clinically proven, small antibody architecture is employed for enhanced tumor penetration. • A low payload drug-to-antibody ratio (DAR) of 2 is used to enable higher ADC dosing and plasma levels. • Payload attachment is via site specific conjugation to engineered sites providing a homogeneous product with excellent stability. • A clinically proven payload matched to indications of interest is used which delivers a strong bystander effect and is a potent inducer of immunogenic cell death. • The single chain antibody architecture coupled with site specific payload attachment and optimized physicochemistry facilitate high yield manufacture. • Improved payload delivery (for a given amount of circulating ADC) drives the therapeutic index. ALM-502 targets two distinct epitopes and is highly selective for ALPP/ALPPL2. In in vitro assays, this biparatopic mode of binding delivers enhanced internalization into cancer cells compared to a canonical ADC. The design features of ALM-502 translate into excellent anti-tumor efficacy in ALPP/ALPPL2 positive cell-line derived xenograft (CDX) and patient-derived xenograft (PDX) models of gastric, pancreatic, ovarian and bladder cancers, which display a range of target expression. In benchmarking studies, ALM-502 consistently delivers improved efficacy over a full length DAR4 ADC on a payload equivalents basis, in both single dose and multi-dose studies. ALM-502 has an excellent PK profile in preclinical species together with strong developability and manufacturability characteristics. These features, coupled with an ultra-low immunogenicity profile mean that ALM-502 has the potential to deliver significantly improved patient outcomes across a range of solid tumor indications with high unmet need.