STRO-006：一种整合素beta-6靶向ADC在临床前实体瘤中展示出良好的安全性特征和强效抗肿瘤活性

Integrin beta-6 (ITGb6) is a heterodimeric, cell-surface glycoprotein highly expressed in multiple solid tumor indications, including non-small cell lung cancer, esophageal cancer, head and neck cancers, breast and gastric cancers. Its expression has been associated with pro-tumorigenic activities including proliferation, migration, and invasion. ITGb6 has restricted expression in adult tissues, making it a highly promising target for cancer therapy using antibody drug conjugates (ADCs). STRO-006 is an investigational ADC composed of an ITGb6 targeted human IgG1 antibody conjugated to exatecan, a topoisomerase 1 inhibitor, via a b-glucuronidase-cleavable linker. The anti-ITGb6 antibody was discovered from a Fab ribosome display library using Sutro's XpressCF+® system. The drug-linker is functionalized with dibenzylcyclooctyne (DBCO) and allows rapid and selective site-specific conjugation to the azide-containing non-natural amino acid p -azidomethylphenylalanine (pAMF) incorporated into the antibody (Ab) sequence using XpressCF+®. This site-specific conjugation is highly efficient, resulting in a well-defined, homogeneous ADC with a drug-antibody ratio (DAR) of 8. The STRO-006 antibody binds specifically to the alpha-v beta-6 heterodimer and has high affinity to human and cynomolgus ITGb6. It demonstrates rapid and efficient internalization, ideal for an ADC mechanism of action. Importantly, the STRO-006 antibody does not compete for LAP binding and therefore does not interfere with TGFb signaling. STRO-006 is optimized for a stable pharmacokinetic profile and exhibits extended half-life of ~7 days, low clearance of ~5 mL/d/kg and maintains a stable DAR over the course of 21-days in non-human primates. In preclinical studies, STRO-006 demonstrates potent anti-tumor activity at clinically relevant dose in both PDX and xenograft models of non-small cell lung, head and neck squamous cell and pancreatic carcinomas. STRO-006 demonstrates a favorable safety and pharmacokinetic profile in non-human primates. These results suggest that STRO-006 is a promising candidate for the treatment of multiple carcinomas and supports further clinical investigation. A Phase 1, first-in-human study is planned to assess the safety and activity of STRO-006.