This study developed MSLN490, a novel T cell-binding bispecific antibody (TCB) targeting mesothelin, which exhibits exceptional anti-tumor activity while maintaining stability in the presence of soluble MSLN. MSLN490 demonstrates enhanced anti-tumor efficacy when combined with Atezolizumab or TAA × CD28 antibodies, and synergistic effects with paclitaxel in non-inflammatory tumor models.
Literature Overview
This article titled "T cell-redirecting antibody for treatment of solid tumors via targeting mesothelin", published in Acta Pharmacologica Sinica, reviews T cell-redirecting antibody research targeting mesothelin (MSLN) for solid tumor therapy. The study constructs a novel T cell-binding bispecific antibody (MSLN490) and evaluates its anti-tumor activity in vitro and in vivo, while investigating its stability against soluble MSLN interference and combination potential with multiple therapeutic agents.
Background Knowledge
MSLN is a GPI-anchored glycoprotein highly expressed in various cancers (e.g., pancreatic, gastric, ovarian cancers, and mesothelioma), making it an attractive target for cancer immunotherapy. While T cell-binding bispecific antibodies (TCBs) have been extensively studied for hematological malignancies, their application in solid tumors remains limited due to insufficient T cell infiltration and immunosuppressive tumor microenvironment. MSLN490 overcomes these challenges through structural optimization (IgG-[L]-scFv) and affinity engineering, demonstrating potent anti-tumor activity in both in vitro and in vivo models. Notably, the antibody tolerates soluble MSLN interference and shows enhanced therapeutic effects when combined with other agents (Atezolizumab, TAA × CD28 BsAbs, and paclitaxel), providing new preclinical evidence for MSLN-targeted immunotherapy.
Research Methods and Experiments
The research team screened antibodies with varying MSLN affinities from parental antibody M912 using CDR walking and phage display technology, followed by constructing multiple bispecific antibodies (BsAbs). Antibody binding capacity, cytotoxicity, and in vivo anti-tumor activity were evaluated through flow cytometry, cell viability assays, T cell activation assays, Jurkat-NFAT reporter systems, and animal models (NCI-N87, AsPC-1, MKN45). Additionally, MSLN490's stability against soluble MSLN interference was assessed, along with combination therapies involving Atezolizumab, TAA × CD28 BsAbs, and paclitaxel.
Key Conclusions and Perspectives
Research Significance and Prospects
MSLN490 provides a novel strategy for MSLN-targeted solid tumor immunotherapy. Its structural optimization enables effective T cell activation and tumor cell killing even under soluble MSLN conditions. Future research should evaluate combination therapies in preclinical models and explore applications across multiple tumor indications. The synergistic effects with paclitaxel suggest potential advantages in non-inflammatory tumor treatment, warranting validation in additional preclinical models.
Conclusion
This study successfully developed and validated MSLN490, a novel mesothelin-targeting T cell-redirecting bispecific antibody. MSLN490 demonstrates potent anti-tumor activity in vitro and in vivo while maintaining stability under soluble MSLN conditions. Combination therapies with Atezolizumab, TAA × CD28 BsAbs, and paclitaxel further enhance its tumor suppression capabilities, highlighting significant clinical potential for solid tumor immunotherapy. The findings establish a solid experimental foundation for future clinical trials targeting MSLN-overexpressing tumors (e.g., ovarian, gastric, and pancreatic cancers).
