PF-08046033（GPS）：一种同类首创的auristatin S抗体偶联药物，用于治疗GPNMB表达的实体瘤

Glycoprotein non-metastatic melanoma protein B (GPNMB) is a type 1a transmembrane protein that is markedly upregulated in several cancers, including NSCLC, ESCC, HNSCC, and BRCA. GPNMB is associated with poor patient prognosis and plays diverse roles in cancer biology, contributing to processes such as cell differentiation, proliferation, invasion, and migration. Low GPNMB expression in normal tissues, contrasted with high expression in primary and metastatic tumors, makes GPNMB a compelling target for antibody-drug conjugate (ADC) therapies. A previous GPNMB-targeting ADC, Glembatumumab vedotin (GV), comprised of a monoclonal antibody (mAb) conjugated to the microtubule disrupting agent monomethyl auristatin E (MMAE), showed early signs of efficacy. However, its development was constrained by dose-limiting toxicities, the majority of which were likely driven by the released MMAE payload. We hypothesized that pairing the GPNMB-targeted mAb with the novel Auristatin S (AurS), a payload engineered to be less permeable compared to MMAE, may widen the therapeutic window. Thus, we developed PF-08046033 (GPS), a novel investigational ADC composed of the human IgG1 anti-GPNMB mAb (hCR011) conjugated to the novel microtubule disrupting agent AurS using the clinical validated, protease-cleavable MC-Val-Cit linker with an average drug-to-antibody ratio (DAR) of 4. In this study, we evaluated the expression of GPNMB across multiple solid tumors, assessed the antitumor activity of GPS in vitro and in vivo in a variety of xenograft tumor models, and examined its safety profile in non-human primate (NHP) toxicology studies. GPS bound and internalized the GPNMB/ADC complex from the surface of cancer cells, leading to release of the AurS payload that induced apoptosis following G2/M cell-cycle arrest. GPS demonstrated comparable efficacy to GV in multiple GPNMB-expressing xenograft models. Notably, in NHP toxicology studies, GPS was tolerated at 15 mg/kg, which is five-fold higher than GV. Altogether, these data support the evaluation of PF-08046033 (GPS) in a first-in-human phase 1 clinical trial for the treatment of multiple solid tumors.