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Background MSLN is a cell surface protein highly expressed in many solid tumors, absent in most normal tissues, and with lower expression in mesothelial tissues (pleura, peritoneum, pericardium). The extracellular domain of MSLN is shed and can be detected in the serum. However, the expression of tumor cell membrane bound mesothelin is much higher than circulating shed MSLN. This significant overexpression of cell surface bound MSLN in many cancers makes it an attractive target for cancer therapy. CT-95 is a MSLN x CD3 bispecific T cell-redirecting antibody. CT-95 is affinity tuned to target and bind to a membrane bound proximal epitope of MSLN and avidity enhanced to promote binding to tumor cells with high MSLN expression reducing the potential for off-tumor binding to normal cells. The first-in-human study of CT-95 in patients with advanced ovarian, pancreatic, mesothelioma, non-small cell lung and colorectal cancers ( NCT06756035) is described here.Methods Part 1a dose escalation will explore 8 ascending dose levels with a Bayesian optimal interval (BOIN) design. The first two dose levels are single patient cohorts (0.1 µg/kg starting MABEL dose). CT-95 is delivered as weekly IV infusions, with steroid premedication to minimize cytokine release syndrome. Cohort 3 and higher will receive a priming dose on C1D1. Approximately 30 patients with platinum resistant ovarian cancer, pancreatic, mesothelioma, non-small cell lung, or colorectal cancers, relapsed after standard of care, will be enrolled. Tumors from patients with non-small cell lung cancer or colorectal cancer require prospective MSLN-positive confirmation by immunohistochemistry (10% ≥ 1+); ovarian, pancreatic and mesothelioma cancer patients will not require prospective screening due to the known uniformly high prevalence of MSLN. The primary objective is to evaluate safety and tolerability and establish the recommended dose for expansion. Secondary objectives include assessment of antitumor activity (RECIST v1.1, iRECIST, mRECIST), pharmacokinetics, and pharmacodynamic correlates of immune activation. Part 1a dose optimization will evaluate two doses in approximately 40 patients, with efficacy and further safety as primary objectives. The first patient was dosed 1 in April 2025.Conclusions Approved by Salus IRB on Dec 12, 2024 (NEXT Oncology)Ethics Approval This study has been approved by the following Institutional Review Boards (earliest date cited): Salus on 12 December 2024 WCG on 14 March 2025 All participants were informed about the study, had the opportunity to ask questions, and voluntarily agreed to participate.