Abstract
B7-H3 plays an important role in tumor apoptosis, proliferation, adhesion, angiogenesis, invasion, migration, and evasion of immune surveillance. It is overexpressed in various human solid tumor tissues. In patients, B7-H3 overexpression correlates with advanced stages, poor clinical outcomes, and resistance to therapy. The roles of B7-H3 in tumor progression make it a potential candidate for targeted therapy. Here, we generated a mouse anti-human B7-H3 antibody and demonstrated its binding activity via Tongji University Suzhou Instituteprotein-based and cell-based assays. We then developed a novel format anti-B7-H3 × anti-CD3 bispecific antibody based on the antibody-binding fragment of the anti-B7-H3 antibody and single-chain variable fragment structure of anti-CD3 antibody (OKT3) and demonstrated that this bispecific antibody mediated potent cytotoxic activities against various B7-H3-positive tumor cell lines in vitro by improving T cell activation and proliferation. This bispecific antibody also demonstrated potent antitumor activity in humanized mice xenograft models. These results revealed that the novel anti-B7-H3 × anti-CD3 bispecific antibody has the potential to be employed in treatment of B7-H3-positive solid tumors.
Highlights
Over the past few years, the number of reports demonstrating the development and effects of therapeutic bispecific antibodies has increased rapidly
Many bsTCEs targeting classical solid tumor antigens, such as HER2, EGFRvIII, PSMA, EpCAM, and CEA, are being explored in clinical practice, and multiple other tumor-associated antigen (TAA) are currently pursued in preclinical studies [3]
B7-H3 is a co-inhibitory molecule that overexpressed in various solid tumor tissues and limited in normal tissues, making it an attractive target for bsAb therapy
Summary
Over the past few years, the number of reports demonstrating the development and effects of therapeutic bispecific antibodies (bsAbs) has increased rapidly. Various bsAbs for cancer therapy are under clinical development, and bispecific T cell engager (bsTCEs) represent the largest group. The treatment of solid tumors is difficult owing to several factors such as antigen expression in critical normal tissues, immunosuppressive tumor microenvironment, disordered tumor vasculature, and less effector cells infiltration in tumor tissues. One of the hurdles is selection of a tumor-associated antigen (TAA) targeting solid tumor, as expression on critical normal tissues of solid tumor TAA can lead to adverse events by on-target off-tumor T cell reactivity [3]. B7-H3 overexpression in tumor tissues correlates with decreased T cell infiltration, poor prognosis, increased metastasis, advanced clinical stage, and resistance to therapy [15,24,25,26,27]. B7-H3 expression is limited at low levels in healthy tissues [28]
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