B7-H3: An Attractive Target for Antibody-based Immunotherapy

Abstract

The recent impressive clinical responses to antibody-based immunotherapy have prompted the identification of clinically relevant tumor antigens that can serve as targets in solid tumors. Among them, B7-H3, a member of the B7 ligand family, represents an attractive target for antibody-based immunotherapy, it is overexpressed on differentiated malignant cells and cancer-initiating cells, with limited heterogeneity, and high frequency (60% of 25,000 tumor samples) in many different cancer types, but has a limited expression at low level in normal tissues. In nonmalignant tissues, B7-H3 has a predominantly inhibitory role in adaptive immunity, suppressing T-cell activation and proliferation. In malignant tissues, B7-H3 inhibits tumor antigen–specific immune responses, leading to a protumorigenic effect. B7-H3 also has nonimmunologic protumorigenic functions, such as promoting migration and invasion, angiogenesis, chemoresistance, and endothelial-to-mesenchymal transition, as well as affecting tumor cell metabolism. As a result, B7-H3 expression in tumors is associated with poor prognosis. Although experimental B7-H3 silencing reduces cancer cell malignant potential, there has been limited emphasis on the development of B7-H3–blocking antibodies, most likely because the B7-H3 receptor remains unknown. Instead, many antibody-based strategies utilizing distinct effector mechanisms to target B7-H3–expressing cancer cells have been developed. These strategies have demonstrated potent antitumor activity and acceptable safety profiles in preclinical models. Ongoing clinical trials are assessing their safety and efficacy in patients. Identification of the B7-H3 receptor will improve our understanding of its role in tumor immunity, and will suggest rational strategies to develop blocking antibodies, which may enhance the therapeutic efficacy of tumor immunity.

Targeting B7-H3 via chimeric antigen receptor T cells and bispecific killer cell engagers augments antitumor response of cytotoxic lymphocytes

“…HRP-conjugated rabbit anti-goat IgG antibodies were purchased from Jackson ImmunoResearch. Rabbit antihuman PD-L1 antibody (13,684), HRP-conjugated anti-β-actin and anti-GAPDH antibodies were purchased from Cell Signaling.…”

“…B7-H3 contributes to a co-inhibitory immune signal during modulation of cytotoxic lymphocyte function in cancer immunity [12]. While B7-H3 protein is expressed at low levels in most normal tissues, it is aberrantly expressed on differentiated malignant cells and cancer-initiating cells, with limited heterogeneity, and in multiple tumor types, including lung, colon, breast and ovarian cancers [13]. In head and neck squamous cell cancer and pancreatic ductal adenocarcinoma, high B7-H3 expression is observed on cancer-initiating cells.…”

Treating Prostate Cancer by Antibody–Drug Conjugates

“…B7-H3, also referred to as CD276, is an important immunomodulatory molecule. B7-H3 is a 316-amino-acid-long type I transmembrane protein expressed on the surface of tumor cells, antigen presenting cells, natural killer cells and tumor endothelial cells [ 67 ]. In tumor tissues, B7-H3 inhibits immune response as well as promote the migration and invasion, angiogenesis and endothelial-to-mesenchymal transition of tumor cells [ 67 ].…”

“…B7-H3 is a 316-amino-acid-long type I transmembrane protein expressed on the surface of tumor cells, antigen presenting cells, natural killer cells and tumor endothelial cells [ 67 ]. In tumor tissues, B7-H3 inhibits immune response as well as promote the migration and invasion, angiogenesis and endothelial-to-mesenchymal transition of tumor cells [ 67 ]. It has been shown that B7-H3 expression promotes prostate cancer progression in vivo by reducing myeloid-derived suppressor cell apoptosis [ 68 ].…”

Targeting Radiation-Resistant Prostate Cancer Stem Cells by B7-H3 CAR T Cells

“…Clinical targeting of B7-H3 with the mAb enoblituzumab has resulted in tumor regression in patients with treatment-refractory prostate cancer (25). Recent studies have found strong evidence that B7-H3 regulates T-cell-mediated immune response and inhibition of B7-H3 results in T-cell proliferation (26,27). Moreover, blocking activated T cells with a bispecific anti-CD3 x anti-B7-H3 antibody enhanced T-cell cytotoxicity and increased cytokine production of IFNg, TNFa, and IL2 (28).…”