Integral Molecular, the industry leader in antibody discovery for membrane proteins, has published the targeting mechanism enabling best-in-class specificity of its Claudin 6 (CLDN6) antibody CTIM-76 being developed for cancer therapy with Context Therapeutics. CLDN6 is a tumor-specific protein found in multiple solid tumors—including ovarian, endometrial, lung, gastric, and testicular—but absent from healthy adult tissues. Until now, its structural complexity and similarity to related proteins has hindered efforts to develop safe and selective therapeutics, with most CLDN6 antibody clinical trials being halted due to specificity-related safety issues. The similarity of the target to widely expressed Claudins 3, 4 and 9 means that non-specific binding could kill otherwise healthy tissues.

In their recent publication (Screnci et al., iScience December 2022), Integral Molecular scientists describe the isolation of highly specific CLDN6 antibodies that use a single atomic contact point centered around amino acid 156 to derive exquisite specificity. This interaction site allows the antibody to bind CLDN6 but not any of the other 24 claudin family members.

Key findings include:

• Best-in-class specificity of CLDN6 antibodies compared to clinical benchmarks
• Unusual steric hindrance mechanism of the gamma carbon on Q156 discovered as critical for absolute specificity of antibodies for CLDN6 versus CLDN9
• CLDN6 antibodies exhibited excellent developability

"We are thrilled to be progressing high-specificity antibodies to safely target Claudin 6-positive tumors," said Ross Chambers, PhD, VP of Antibody Discovery at Integral Molecular. "The ability of our antibodies to interact specifically with Claudin 6 is extraordinary since the target and related proteins differ by just a few atoms at the binding site."

Integral Molecular's MPS Antibody Discovery Platform is tailored to discover rare antibodies with maximal epitope diversity. Integral Molecular is co-developing CTIM-76 with Context Therapeutics to treat ovarian cancer and other solid tumors. CTIM-76 is a CLDN6xCD3 antibody that brings cytotoxic T cells into proximity with CLDN6-expressing tumor cells to initiate cell killing. Investigational New Drug (IND)-enabling studies are currently underway, and Context expects to submit an IND application for CTIM-76 to the U.S. Food and Drug Administration for first-in-human trials in the first quarter of 2024.