Tumor cells outsmart the immune system by using their surface proteins to bind to inhibitory protein receptors on T and natural killer (NK) cells—an interaction that puts the brakes on attacks from both types of immune cells. Cancer immunotherapies are monoclonal antibodies that prevent this tumor cell/T/NK cell interaction—by binding to the tumor-cell protein or to the T/NK-cell receptor. Most marketed immunotherapies inhibit two proteins in particular: PD-L1 on tumor cells and PD-1 on T cells. In 2013, Albert Einstein College of Medicine’s Xingxing Zang, M.Med., Ph.D., discovered a different tumor-cell protein called HHLA2. He and other researchers later found that HHLA2 is: over-expressed in many human cancers; associated with more severe pathology and worse prognosis in many cancers; and is more frequently expressed than PD-L1 in many tumor types.  For those reasons, HHLA2 is an attractive target for cancer immunotherapy. But until now, researchers had not identified the T/NK-cell inhibitory receptor to which HHLA2 binds.

In a study published online on July 9 in Science Immunology, Dr. Zang and colleagues characterized HHLA2’s inhibitory receptor, called KIR3DL3. The researchers determined the function of the new HHLA2-KIR3DL3 immune checkpoint pathway and developed anti-KIR3DL3 monoclonal antibodies that successfully interfered with the interaction between KIR3DL3 and HHLA2. These monoclonal antibodies inhibited human tumor growth by enhancing immune cell function, the researchers found, and could therefore serve as a new human cancer immunotherapy. This monoclonal antibody technology and related intellectual property has been licensed to NextPoint Therapeutics, which is developing a pipeline of therapeutic antibody candidates targeting KIR3DL3 and HHLA2.

Dr. Zang is professor of microbiology & immunology, of medicine, of urology, the Louis Goldstein Swan Chair in Cancer Research at Einstein, and a member of the National Cancer Institute-designated Albert Einstein Cancer Center. Drs. Yao Wei and Xiaoxin Ren, two postdoctoral fellows in Dr. Zang’s laboratory, are co-first authors of the manuscript.