靶向 T 细胞受体 β 链的抗体融合分子激活并扩增 T 细胞亚群以促进抗肿瘤活性

Despite the success of programmed cell death-1 (PD-1) and PD-1 ligand (PD-L1) inhibitors in treating solid tumors, only a proportion of patients respond.

Here, we describe a first-in-class bifunctional therapeutic molecule, STAR0602, that comprises an antibody targeting germline V 6 and V 10 T cell receptors (TCRs) fused to human interleukin-2 (IL-2) and simultaneously engages a nonclonal mode of TCR activation with costimulation to promote activation and expansion of T cell subsets expressing distinct variable (V ) TCR chains. In solution, STAR0602 binds IL-2 receptors in cis with V 6/V 10 TCRs on the same T cell, promoting expansion of human V 6 and V 10 CD4 + and CD8 + T cells that acquire an atypical central memory phenotype. Monotherapy with a mouse surrogate molecule induced durable tumor regression across six murine solid tumor models, including several refractory to anti-PD-1.

Analysis of murine tumor-infiltrating lymphocyte (TIL) transcriptomes revealed that expanded V T cells acquired a distinct effector memory phenotype with suppression of genes associated with T cell exhaustion and TCR signaling repression.

Sequencing of TIL TCRs also revealed an increased T cell repertoire diversity within targeted V T cell subsets, suggesting clonal revival of tumor T cell responses. These immunological and antitumor effects in mice were recapitulated in studies of STAR0602 in nonhuman primates and human ex vivo models, wherein STAR0602 boosted human antigen-specific T cell responses and killing of tumor organoids.

Thus, STAR0602 represents a distinct class of T cell-activating molecules with the potential to deliver enhanced antitumor activity in checkpoint inhibitor-refractory settings.