顺式靶向 IL-2 突变蛋白增强工程化 T 细胞的抗肿瘤活性

Adoptively transferred T cells require cytokine stimulation, which is achieved using lymphodepleting chemotherapy with or without administration of exogenous interleukin 2 (IL-2). Lymphodepleting chemotherapy (LDC) is associated with cytopenias and attendant complications, while high dose IL-2 causes severe infusion toxicity and can stimulate undesirable cell populations.

To address these challenges, we developed cis-targeted IL-2 fusion molecules which are comprised of an IL-2 mutein with attenuated binding to IL-2R and IL-2R linked to an antibody that targets a cell-surface molecule expressed specifically on engineered T cells. Using T cells from healthy donors as well as from lymphoma and melanoma patients, we selectively stimulated CAR-T cells or engineered TILs and enhanced their antitumor function in multiple tumor models.

We also showed that cis-targeted IL-2 can mediate CART expansion and B cell aplasia in the absence of lymphodepletion in a nonhuman primate model.