(P 257) TARGETING LEUCINE-RICH REPEAT-CONTAINING PROTEIN 15 (LRRC15): SOT106 ANTIBODY-DRUG CONJUGATE FOR SOFT TISSUE SARCOMA AND OSTEOSARCOMA TREATMENT

Objective: Soft tissue sarcomas (STS) and osteosarcoma (OS) are difficult to treat and associated with poor prognoses. Current therapies are limited to chemotherapy and surgery, with few effective targeted treatments. LRRC15, a protein overexpressed in many sarcomas, has emerged as a promising therapeutic target.

Methods: SOT106, a novel LRRC15-targeted antibody-drug conjugate (ADC) conjugated with monomethyl auristatin E (MMAE) via a beta-glucuronidase cleavable linker, was developed for targeted cytotoxic payload release. In vitro assays evaluated binding, internalization, and cytotoxicity. In vivo efficacy was assessed using multiple mouse and patient-derived xenograft (PDX) sarcoma models. Pharmacokinetics and toxicity profiles were examined in cynomolgus monkeys. A diagnostic antibody was also developed for patient selection in upcoming clinical trials.

Results: SOT106 showed potent, antigen-specific cytotoxicity in vitro with nanomolar activity and a robust bystander effect. In vivo, it achieved dose-dependent tumor regression, including complete responses at 1 mg/kg. It outperformed current benchmarks in both soft tissue sarcoma and osteosarcoma PDX models, even in tumors with low-to-medium LRRC15 expression and in orthotopic models of osteosarcoma. In non-human primates, SOT106 showed favorable pharmacokinetics (half-life of 4.5–6 days), no premature payload release, and a high therapeutic index. Dose-limiting toxicities aligned with known MMAE effects.

Conclusion: SOT106 is a highly effective and well-tolerated LRRC15-targeted ADC with significant promise for treating sarcomas and potentially other LRRC15-positive malignancies. Its preclinical profile supports further clinical development.