B7x (B7-H4 or B7S1) is a member of the B7 family that can inhibit T cell function. B7x protein is absent in most normal human tissues and immune cells, but it is overexpressed in human cancers and often correlates with negative clinical outcome. The expression pattern and function of B7x suggest that it may be a potent immunosuppressive pathway in human cancers. Here, we determined the crystal structure of the human B7x immunoglobulin variable (IgV) domain at 1.59 Å resolution and mapped the epitopes recognized by monoclonal antibodies. We developed an in vivo system to screen therapeutic monoclonal antibodies against B7x and found that the clone 1H3 significantly inhibited growth of B7xexpressing tumors in vivo via multiple mechanisms. Furthermore, the surviving mice given 1H3 treatment were resistant to tumor rechallenge. Our data suggest that targeting B7x on tumors is a promising cancer immunotherapy and humanized 1H3 may be efficacious for immunotherapy of human cancers.
Bibliographical noteFunding Information:
This work was supported by NIH R01CA175495 and DOD PC131008 (X.Z.), NIH GM094662 and GM094665 (S.C.A.), UL1TR000086 (M.J.), F31CA183493 (K.C.O.), and T32GM007288 (J.M.C.). We also acknowledge support from the Albert Einstein Cancer Center (P30CA013330), Diabetes Research Center (P60DK020541), Center for AIDS Research (AI51519), and Institute for Aging Research (P30AG038072).