Interleukin-12 (IL-12) is a potent pro-inflammatory cytokine that promotes high levels of interferon gamma secretion from T cells and NK cells, thereby increasing their cytotoxicity and the immunogenicity of the tumor microenvironment by making tumor antigens more visible to the immune system. Prior clinical studies have demonstrated IL-12 has significant anti-tumor activity; however, its toxicity and rapid clearance have limited its therapeutic potential.
XmAb662 is a potency-reduced IL12-Fc fusion protein designed to increase anti-tumor activity. Xencor’s reduced potency approach to engineered cytokine therapeutics may provide longer drug exposure, superior tumor penetration, and greater potential tolerability, compared to previous generations of cytokines tested in clinical studies. Xencor’s XmAb® Bispecific Fc Domain provides a stable protein scaffold and improves XmAb662’s pharmacologic properties, and Xencor’s Xtend™ Fc technology enhances its circulating half-life.
In preclinical testing, Xencor’s engineered IL12-Fc fusions demonstrated an improved pharmacokinetic profile and therapeutic window compared to a native IL12-Fc fusion, with superior exposure, a more gradual dose response and more sustained interferon gamma response. XmAb662 demonstrated significant anti-tumor activity, along with increases in NK cells, T cells, serum IP-10 and interferon gamma, which were further enhanced when combined with an anti-PD-1 antibody.
Xencor is conducting Phase 1 study of XmAb662 in patients with advanced solid tumors.