Abstract 1164: SOT106, a novel best-in-class antibody-drug conjugate targeting LRRC15, to treat sarcomas and other advanced solid cancers

Abstract The leucine-rich repeat containing protein 15 (LRRC15) is crucial for cell-cell and cell-extracellular matrix interactions. Normal tissue expression is minimal and primarily restricted to the placenta, hair follicles in the skin, and is also increased in activated fibroblasts during wound healing. In cancer, LRRC15 is overexpressed in mesenchymal malignancies including sarcomas and glioblastoma, and in cancer-associated fibroblasts (CAFs) of various epithelial tumors including head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), or pancreatic ductal adenocarcinoma (PDAC). Thus, LRRC15 is a promising therapeutic target, particularly for disrupting tumor-stroma interactions that support tumor growth and hinder chemotherapy effectiveness. SOT106 is a novel antibody-drug conjugate (ADC) targeting LRRC15, comprised of a proprietary humanized monoclonal antibody conjugated to monomethyl auristatin E (MMAE) via a beta-glucuronidase (GUSB) cleavable linker for tumor specific payload release. In in vitro studies, SOT106 showed strong antigen-specific binding, efficient internalization, and cytotoxicity in the low nanomolar range. Strong and durable dose-dependent tumor growth reduction was observed in several disease-relevant mouse models, with complete responses achieved following administration of a well-tolerated and clinically relevant dose of 1 mg/kg. Importantly, SOT106 achieved efficacy at a lower dose and with less frequent administration compared to the clinical benchmark. In an exploratory study in cynomolgus monkeys, SOT106 demonstrated favorable pharmacokinetic properties with a half-life of 4.5 to 6 days without premature payload release, a preliminary non-severely toxic dose (HNSTD) of approx. 10 mg/kg, and a broad therapeutic index of 40 based on allometric scaling. Further, significantly increased plasma stability was observed over the course of 14 days. Dose-limiting toxicities were consistent with the known MMAE-mediated effects. In parallel, we have also developed a highly specific proprietary diagnostic antibody to be used for prospective patient selection in Phase I/Phase II clinical trial. In summary, SOT106 is a highly effective and well-tolerated LRRC15 targeted ADC that holds promise for the clinical treatment of patients with sarcomas and other LRRC15-positive tumors. Citation Format: Michaela Fojtu, Iva Valentová, Eliška Kohelová, Tomáš Zimmermann, Šárka Stehlíková, Irena Adkins, Nataliia Kalynovska, Lenka Palová Jelínková, Filip Jabůrek, Ann Ranger, Ulrich Moebius, Martin Steegmaier, Amy Jensen-Smith, Radek Špíšek. SOT106, a novel best-in-class antibody-drug conjugate targeting LRRC15, to treat sarcomas and other advanced solid cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1164.