Abstract 2892: Development of claudin 6 bispecific antibodies for treatment of ovarian cancer
Authors: Rucker Joseph , Doolan Kyle , Tyrell Breanna , Lobley Anna , Molino Nick , Shema Kristen , Guldner Kyle , Cunningham Alyssa , Chambers Ross , Payne Riley 
Published: June 2022

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 reported 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 26 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.

The exquisite specificity of our CLDN6 antibodies makes them amenable to use as the tumor-targeting arm of bispecific T-Cell Engagers. Starting with highly specific CLDN6 antibodies with a range of affinities, we engineered a large set (&gt; 50) of CLDN6xCD3 bispecific antibodies (CLDN6 bispecifics) using multiple formats and CD3 arms that encompass different valencies and geometries. We designed the CLND6 arms to include antibody moieties with different affinities, epitopes, and stoichiometries, as these factors are expected to play a critical role in the potency of these molecules both in in vitro and in vivo. The full panel of bispecifics has been functionally tested in in vitro T cell cytotoxicity assays cells and has demonstrated potent killing of CLDN6-expressing cells with minimal killing of cells expressing other closely related claudin family members. We have also extensively characterized this panel of bispecific antibodies for detailed binding to both CD3 and CLDN6, selectivity against closely related claudin family members, and developability. The bispecifics were also screened for specificity against ~6,000 membrane proteins, representing &gt; 95% of the entire human membrane proteome.

Solid tumors lead to 580,000 deaths annually in the US, and safe and effective therapeutics for many late-stage solid tumors are lacking. Ovarian cancer alone kills 14,000 people each year, and many patients do not respond to currently available treatments. The exquisite specificity of our CLDN6xCD3 bispecifics suggests their potential to address the need for potent therapeutic modalities for ovarian and other cancers without compromising patient safety.

Citation Format: Joseph Rucker, Kyle Doolan, Breanna Tyrell, Anna Lobley, Nick Molino, Kristen Shema, Kyle Guldner, Alyssa Cunningham, Ross Chambers, Riley Payne. Development of claudin 6 bispecific antibodies for treatment of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2892.