Costimulatory CD28 bispecific antibodies synergize with conventional and targeted chemotherapy to elicit potent anti-tumor responses II

ABSTRACT: Costimulatory bispecific antibodies (TAAxCD28) designed to cluster tumor-associated antigens (TAA) on tumor cells to CD28 receptor on T cells represent a significant innovation in immunotherapy, offering transformative opportunities for combination strategies to combat treatment-resistant cancers. Here, we demonstrate for the first time that TAAxCD28 bispecifics synergize with both conventional and targeted chemotherapy agents to significantly enhance antitumor efficacy in humanized murine tumor models. Mechanistically, an EGFRxCD28 bispecific, when combined with 5-fluorouracil (5-FU). Promotes the expansion and clonal diversification of tumor-infiltrating effector CD8+ T cells, which associates with markedly improved tumor growth control and survival benefit. Further, the combination therapy reprograms the immunosuppressive tumor microenvironment, by rewiring suppressive tumor myeloid cells to immunostimulatory phenotypes, upregulating costimulatory molecules, and increasing the expression of intratumoral proinflammatory cytokines and chemokines. Additionally, we show that a novel HER2xCD28 bispecific antibody, in combination with Trastuzumab-deruxtecal (Tras-Dxd, Enhertu) – an emerging front-line cancer cell-targeted antibody drug conjugate (ADC) – elicits potent tumor clearance, also by expanding and increasing the clonal diversity of tumor infiltrating effector CD8+ T cells. Collectively, our findings highlight a previously underexplored potential of CD28 costimulatory bispecific antibodies to deliver a highly effective combination strategy alongside frontline chemotherapies and ADCs, thereby expanding therapeutic options for hard-to-treat malignancies and supporting their advancement into clinical application.

ORGANISM(S): Mus musculus

PROVIDER: GSE330851 | GEO | 2026/09/08

REPOSITORIES: GEO