B7.1/NHS76: A New Costimulator Fusion Protein for the Immunotherapy of Solid Tumors

Abstract

Tumor evasion from immune surveillance is due to the anergic status of tumor-infiltrating lymphocytes, especially T cells. Inappropriate or absent expression of costimulatory molecules such as B7.1 and B7.2 lead to anergy and apoptosis of tumor-infiltrating T cells. To reverse this situation, a tumor-targeted fusion protein, human B7.1/NHS76, was generated by molecular engineering, which retains both the costimulatory activity of B7.1 and the tumor-targeting ability of NHS76 antibody. NHS76 is a human tumor necrosis therapy monoclonal antibody derived from phage display, and is capable of binding intracellular antigens, which are accessible and abundant in necrotic regions of tumors. As human B7.1 can interact functionally with murine B7.1 counter-receptors, the immunotherapeutic potential of this fusion protein was tested in 3 mouse tumor models (Colon 26, RENCA, and MAD109), and animal studies showed a 35% to 55% reduction in tumor volume. To modulate the immune inhibitory microenvironment in tumors, naturally occurring CD4+ CD25+ Treg cells were depleted by cytotoxic CD4 or CD25 antibodies. Combination therapy with anti-Treg and B7.1/NHS76 produced complete regression of established tumors and was associated with increased effector T-cell infiltration in tumors. Rechallenge experiments performed 3 months after mice attained complete remission by combination therapy showed that immunologic memory was established by these treatments. These studies indicate that the targeting of B7.1 to necrotic areas of tumors, where both the release of tumor antigens and infiltrating lymphocytes are prevalent, may be a new approach for the immunotherapy of solid tumors. Our results also suggest that the manifestation of immune-inhibitory factors such as the presence of Treg cells at the tumor site and associated draining lymph nodes may be a major cause for immune system failure to eradicate solid tumors.