(P 34) EXPRESSION OF ONCOFETAL ANTIGEN 5T4 IN SARCOMA SUBTYPES AND PRECLINICAL ACTIVITY OF TUB-030, A NOVEL 5T4-TARGETING ANTIBODY-DRUG CONJUGATE (ADC)

Objective: 5T4 is an oncofetal surface glycoprotein with restricted normal tissue expression, mainly limited to the developing placenta. 5T4 overexpression is observed in a variety of solid malignancies and functions in cell adhesion, epithelial-mesenchymal transition, and oncogenic signaling, making it an attractive target for therapeutic development. A previous study showed 5T4 expression in soft tissue sarcoma (STS) subtypes, including non-uterine leiomyosarcoma, undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma, and rhabdomyosarcoma. TUB-030 is a novel 5T4-targeting ADC under clinical development with optimized biophysical properties, an effector function-silenced antibody, and the topoisomerase I inhibitor exatecan as payload.

Methods: To further define 5T4 expression in sarcoma subtypes, histological sections of human osteosarcoma, chondrosarcoma, uterine and non-uterine LMS, rhabdomyosarcoma, fibrosarcoma, and liposarcoma were stained with anti-5T4 antibody, imaged, and H-scores calculated based on the percentage of 5T4-positive tumor cells and their expression intensity (0 to 3+). Mice bearing PDX models with high 5T4 expression (Sarc10562 (5T4high), Sarc10642 (5T4high); UPS subtype) were treated with a single dose of TUB-030 and tumor growth was monitored until the humane endpoint or 60 days was reached.

Results: Strong 5T4 surface staining was observed in osteosarcoma and chondrosarcoma; of N=61 samples analyzed, 14% showed low expression (H-score < 100), 46% medium (100-250) and 39% high 5T4 expression (>250). Liposarcoma showed no 5T4 signal, while other STS subtypes (N=59) had 36% low, 41% medium, and 24% high expression. In PDX models, complete tumor regression and durable control were maintained for 60 days after a single i.v. dose of TUB-030. A phase I/IIa multi-center, first-in-human clinical trial (5-STAR 1-01) evaluating TUB-030 is underway in patients with advanced solid tumors, including selected soft tissue and bone sarcomas (NCT06657222).

Conclusion: 5T4 is broadly expressed in sarcoma subtypes and preclinical data provide rationale for further investigation of TUB-030 in patients with sarcomas.