Claudin-6 (CLDN6) is a tumor-associated antigen overexpressed in ovarian cancer and other solid tumors, and its heightened expression in cancerous tissue makes CLDN6 an intriguing target for CD3 bispecific antibodies. Many members of the claudin family, which are small transmembrane proteins, have high sequence identity, complicating the design of antibodies selective among claudins.
XmAb541 is a tumor-targeted, T-cell engaging XmAb® 2+1 bispecific antibody in development for patients with ovarian cancer. XmAb541 engages the immune system and activates T cells for highly potent and targeted killing of tumor cells expressing CLDN6. XmAb541 was engineered with the XmAb 2+1 bispecific antibody format, and the tumor binding domain was further engineered for improved selectivity of CLDN6 over similar claudin family members, such as CLDN9, CLDN3 and CLDN4. Xencor’s XmAb Bispecific Fc Domain serves as the scaffold for these binding domains and provides long circulating half-life, stability and ease of manufacture.
Xencor plans to submit an investigational new drug application for XmAb541 and conduct a Phase 1 study in patients with ovarian cancer.
XmAb® 2+1 Bispecific Antibodies
T-cell engaging bispecific antibodies with single tumor-antigen binding domains (1+1 formats) cannot always be designed to selectively target tumor antigens, particularly when the antigen is expressed on normal tissues. Limited selectivity for tumor cells may lead to the killing of normal tissues that express the antigen at lower levels, including critical organs, which can cause poor tolerability in clinical testing.
With two tumor-antigen binding domains and one T-cell binding domain, Xencor’s multivalent XmAb 2+1 format enables antibodies to bind more avidly to – and selectively kill – tumor cells with higher antigen density, potentially sparing normal cells. The XmAb 2+1 bispecific antibody format may be a particularly powerful tool for developing drug candidates against solid tumors.