Xencor, Inc (MONROVIA, California), a company developing protein and antibody therapeutics, announced positive preclinical data for XProâ„¢1595 DN-TNFâ„¢, a highly selective, dominant-negative (DN) inhibitor of soluble TNFα and a first-in-class protein therapeutic drug candidate for the treatment of inflammatory diseases such as rheumatoid arthritis (RA). XPro1595 was shown to selectively inhibit the soluble form of TNFα in both human and mouse cell lines and blocked inflammation in two mouse arthritis models (prophylactic  dosing in a mouse collagen antibody-induced arthritis model and therapeutic dosing in a mouse collagen-induced arthritis model). XPro1595 did not, however, inhibit the transmembrane form of TNFα nor suppress innate immunity to infection as assayed in mouse infection models. Marketed treatments that target TNFα and several other drug candidates in clinical development each nonselectively targets both soluble TNFα and membrane-bound TNFα. Xencor's data demonstrate that inflammation in mouse arthritis models is primarily driven by soluble TNF, and suggest that preservation of the key role of membrane-bound TNFα in innate infection resistance and immune function may reduce drug-associated adverse side effects, including severe infections and tuberculosis.

XPro1595, a microbially-expressed engineered variant of human TNFα in late preclinical stage development, neither binds to nor signals through the TNF receptors TNFR1 or TNFR2 but rapidly exchanges subunits with native soluble TNF homotrimers to form inactive mixed heterotrimers. The end result prevents the signaling of soluble TNF-mediated inflammatory responses. Xencor believes that the selectivity of DN-TNF for soluble TNFα over the membrane-bound form of the protein has the potential to maintain the therapeutic benefits of targeting soluble TNFα without the adverse events from off-target inhibition. XPro1595, which possesses a greatly increased half-life by modification via pegylation, is being developed for the treatment of RA and other inflammatory diseases and will be administered as a subcutaneous injection.

Xencor has engineered DN inhibitors of other members of the TNF structural superfamily such as RANKL for the treatment of osteoporosis and metastatic bone disease, and BLyS/BAFF for systemic lupus erythematosus and other autoimmune disorders.

—A. Techman