AACR 2021: Novel human B7-H3 knock-in mice demonstrate efficacy of anti-B7-H3 immunotherapy in vivo

AACR 2021: Novel human B7-H3 knock-in mice demonstrate efficacy of anti-B7-H3 immunotherapy in vivo

Author: Lei Zhao, Huilin Li, Yujie Liu, Eugene Lin, Zhaoxue (Luke) Yu

In recent years, immune checkpoint inhibitors (ICIs), particularly against PD-1/PD-L1, have revolutionized cancer treatment. However, ICI monotherapy only benefits a portion of cancer patients, while co-blockade of PD-1/PD-L1 and CTLA-4 is associated with increased IrAEs. Combined targeting of other immune checkpoints with PD-1/PD-L1 rather than CTLA-4 may be safer. B7-H3, also known as CD276, is a newer member of the same B7/CD28 superfamily as PD-1 and PD-L1. Its transcripts are ubiquitously expressed in normal tissues and solid tumors, but the protein is expressed in tumor tissues and by antigen-presenting cells, such as DC or macrophages, where it inhibits T cells and contributes to tumor immune evasion. Importantly, B7-H3 is overexpressed on a wide range of human solid cancers and correlates with negative prognosis and poor clinical outcome in patients (Wang L, et al. 2014). Recent studies have shown that B7-H3 also drives tumor growth, invasion, migration, angiogenesis, and metastasis beyond its immune regulatory roles. Thus, B7-H3 is an interesting new target for immunotherapy.

To investigate B7-H3 function in vitro and evaluate in vivo efficacy of B7-H3 antibodies, Biocytogen generated a B7-H3 humanized mouse (B-hB7-H3) and B7-H3-expressing MC38 cell line (MC38-hB7-H3). In the mice, exons 3-4 of the mouse B7-H3 gene, which encode the extracellular domain, are replaced by human B7-H3 exons 3-6. Human B7-H3 mRNA was detectable in spleen and bone marrow of only B-hB7-H3 mice, and B7-H3 antibodies bound well to hB7-H3+ MC38 cells. Furthermore, using the MC38-hB7-H3 and EL4-hB7-H3 tumor models, we showed robust efficacy of anti-human B7-H3 antibodies in inhibiting tumor growth in vivo, which was amplified in mice receiving combined human B7-H3 and mouse PD-1 blockade. Taken together, B7-H3 humanized mice are a useful tool for in vivo efficacy evaluation and selection of candidate human B7-H3 antibodies for advancement to clinical trials. In addition, Biocytogen has generated B7-H3/PD-1 and B7-H3/PD-1/PD-L1 multi-gene humanized mice to evaluate B7-H3/PD-1/PD-L1 combination therapies in vivo.

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