一种 fc 工程化的 NKG2D × B7-H3 双特异性抗体通过协调细胞毒性淋巴细胞增强抗肿瘤活性

B7-H3, an immune-checkpoint molecule that is overexpressed in several cancer types, has been identified as a promising immunotherapy target.

However, most immunotherapy approaches against B7-H3 + tumor cells focus on manipulating the T cells. Natural killer (NK) cells, another important part of the cellular immune system, also exhibit anti-tumor properties and play complementary roles in tumor eradication with T cells. In this study, natural killer group 2D (NKG2D), an activating receptor in most cytotoxic immune cells, was selected for engaging NK cells.

We obtained specific anti-NKG2D nanobodies via phage display and developed a series of B7-H3 × NKG2D bispecific antibodies (bsAb) with different formats to fight against the B7-H3 + tumor cells. Through functional comparison of candidate antibodies in vitro, B1-C53 was selected and further modified with the optimized Fc fragment (known as FC-C53) to enhance anti-tumor immunity by antibody-dependent cell-mediated cytotoxicity (ADCC).

Stronger tumor lysis mediated by FC-C53 was demonstrated both in vitro and in vivo when simultaneously directed at both NK cells and CD8 + T cells, particularly after the additional administration of a B7-H3 × CD3 bispecific T cell engager that targets B7-H3 with another epitope.

Overall, we provided a strategy based on the B7-H3 × NKG2D antibody to improve the anti-B7-H3 immunotherapy approaches by orchestrating cytotoxic lymphocytes.