SCR-A019, a first-in-class biparatopic ADC targeting MSLN, with a novel topoisomerase I inhibitor demonstrates encouraging efficacy in preclinical models

Background: Mesothelin (MSLN) is a GPI-anchored glycoprotein that is expressed on many cancers but limited in normal tissues, which makes it an attractive target for antibody-based cancer therapy. However, MSLN is shed from surface of cells at high levels via proteases that cleave at its membrane-proximal C-terminal region. Shed MSLN accumulates in patient fluids and tumors and can block anti-MSLN antibodies from killing cancer cells. To overcome the challenge of MSLN shedding, we developed a novel biparatopic ADC which prefers binding to membrane MSLN rather than soluble MSLN. Method & Results: The biparatopic ADC SCR-A019 is conjugated with novel topoisomerase 1 inhibitor (CPT116) via a hydrophilic cleavable linker at DAR 6. SCR-A019 specifically recognizes human MSLN with high affinity and showed enhanced internalization and binding capacity compared to parental monoclonal antibody ADC and benchmark ADC in multiple tumor cell lines. In vitro cytotoxicity experiment demonstrated that SCR-A019 induced tumor cell lysis. Compared to benchmark ADC, SCR-A019 drived potent cytotoxicity in the presence of soluble MSLN. In vivo, SCR-A019 showed specific, dose-dependent anti-tumor efficacy toward MSLN positive tumor xenografts including lung and ovary cancer cells. Besides, SCR-A019 exhibited stronger anti-tumor activity than their parental monoclonal-ADC or benchmark ADC. SCR-A019 also have very good stability and favorable developability. Conclusion: These preclinical data demonstrated SCR-A019 could be a potential first-in-class biparatopic BsADC to overcome the obstacles in antibody-based MSLN-targeting cancer therapy.