XmAb808,一种B7H3靶向的CD28双特异性抗体,共刺激T细胞,增强临床活性CD3 T细胞衔接器的抗肿瘤活性

CD3 bispecific T-cell engagers (CD3-TCEs) represent a promising therapeutic modality for solid tumors, with multiple candidates in clinical development. These agents bridge tumor-associated antigens and CD3 on T cells to form an immune synapse, delivering Signal 1 for T-cell activation. However, solid tumors, unlike professional antigen-presenting cells, typically lack CD28 ligands required for Signal 2 costimulation. T cells receiving Signal 1 without Signal 2 risk developing anergy, potentially limiting CD3-TCE efficacy. A key advancement in costimulatory immunotherapy involves tumor-targeted CD28 bispecific antibodies that strictly depend on concurrent Signal 1 for activation. These bispecifics engage tumor associated antigens to cluster CD28 at the immune synapse, delivering Signal 2 to T cells. We developed XmAb808, a novel B7H3xCD28 bispecific incorporating a nonsuperagonistic, monovalent CD28-binding domain and a high-avidity, bivalent B7H3-binding domain. In proof-of-concept studies, XmAb808 potently amplified the in vitro and in vivo anti-tumor efficacy of CD3-TCEs targeting prototype tumor antigens. Exploring potential combination opportunities, we found co-expression of B7H3 with CLDN6 in ovarian tumors and co-expression with STEAP1 in prostate tumors. Notably, XmAb808 synergistically enhanced the activity of XmAb541 (CLDN6xCD3) and an analog of xaluritamig (STEAP1xCD3), two programs with clinically observed anti-tumor activity. These XmAb808 combinations induced robust IL-2 secretion from activated T cells, which in turn promoted T cell proliferation and Bcl-xL-dependent survival. Moreover, in a T cell restimulation assay, XmAb808 was able to overcome apparent T cell exhaustion promoted by xaluritamig, strongly recovering xaluritamig's reduced anti-tumor activity weeks into the assay. The addition of targeted costimulation translated to superior T cell-mediated cytotoxicity in vitro and markedly improved anti-tumor responses in humanized xenograft models, highlighting XmAb808's potential to synergize with TCE-based immunotherapies.