CT-95 Program

CT-95: Mesothelin x CD3 Bispecific Antibody

A novel therapeutic target

There is growing interest in applying antibody modalities including bispecifics, antibody-drug conjugates, and CAR-T to solid tumors. However, identifying appropriate tumor-specific targets that avoid adverse effects in healthy tissue has been challenging. Mesothelin (MSLN) is an attractive therapeutic target because of its high expression on the cell surface of several human cancers, including mesothelioma, ovarian cancer, pancreatic adenocarcinoma, non-small cell lung cancer, and triple-negative breast cancer. Mesothelin expression on normal cells is primarily in the mesothelial cell layer. It is estimated that there are 100,000 patients with MSLN-positive metastatic solid tumors in the United States, and no approved targeted treatment options exist.

Overcoming shed mesothelin

Mesothelin (MSLN) is bound to tumor cells via a glycosylphosphatidylinositol (GPI) anchor. Like many GPI-anchored proteins, MLSN can be cut into smaller fragments. Fragmented MLSN, also referred to as shed or soluble MLSN, serves as a competitive sink, preventing antibodies from binding to the tumor, which can lead to suboptimal drug exposure and efficacy.

CT-95: mesothelin x CD3 clinical candidate

CT-95 is a mesothelin (MSLN) x CD3 bispecific antibody that incorporates two moderate affinity MSLN binding arms and two CD3 binding single-chain Fv domains in an IgG format with a silenced Fc that is designed to be functionally monovalent to avoid aberrant T-cell activation and to enhance the safety profile. CT-95 is designed to overcome the fragmented (shed) MSLN sink. CT-95 binds to membrane-proximal MSLN to avoid unwanted binding to shed MSLN. Additionally, cooperative binding through the two MSLN binding arms makes for high affinity and thermodynamically stable binding of CT-95 to tumor. Research has demonstrated that CT-95 is potent with specific lysis of MSLN-positive cancer cells over normal cells and can activate cytotoxic T cells without concomitant activation of free cytokines – critical determinants of immunotherapy safety and activity. Preclinical research suggests the potential for convenient dosing with low immunogenicity risk and manufacturing can be scalable to address the significant number of patients who are potentially eligible for CT-95 therapy.

Additionally, preclinical studies illustrate the potential of CT-95 to treat MSLN-positive tumors including:

  • CT-95 was shown to have high potency and target selectivity in both binding and cytotoxicity assays.

  • In in vivo xenograft experiments, CT-95 induced dose-proportional tumor regressions and was well tolerated.

  • In IND-enabling toxicology studies, CT-95 was well tolerated, and a potential first-in-human dose was identified.

  • Clones of competitor clinical-stage MSLN-targeted molecules were generated for benchmarking purposes. Compared to benchmark antibodies, CT-95 activity was retained across a range of cell lines expressing with low through high MSLN even in the presence of shed MSLN.