Context - Model CTIM-76 - Claudin 6 x CD3 Bispecific Antibody
There is growing interest in applying antibody modalities including bispecifics, antibody-drug conjugates, and CART to solid tumors. However, identifying appropriate tumor-specific targets that avoid adverse effects in healthy tissue has been challenging. The tight junction protein Claudin 6 (CLDN6) is a validated therapeutic target for many solid tumor types, including ovarian, endometrial, testicular, and gastric. It is differentially expressed on cancer cells with no or limited expression in normal, healthy tissue.
Despite being an attractive target, therapeutic monoclonal antibodies (MAbs) targeting CLDN6 are difficult to discover due to an abundance of closely related family members and an absolute need for high specificity. There are 27 human CLDN family members, and most are broadly expressed and highly conserved. The extracellular region of CLDN6 closely resembles the widely expressed CLDN9 (3 amino acids different). The few CLDN6 MAbs in clinical development have demonstrated significant binding to other CLDN family members and most have now been halted from development. Using Integral Molecular’s MPS antibody discovery platform, we have been able to isolate, and optimize rare antibodies against CLDN6 that do not cross-react with other CLDN family members.
Context’s lead candidate, CTIM-76, is a CLDN6 x CD3 bispecific antibody that incorporates a highly selective CLDN6 binding arm and a CD3 binding single-chain Fv domain 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. Research has demonstrated that CTIM-76 is potent with specific lysis of CLDN6+ 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 studies suggest 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 CTIM-76 therapy.