Bi-functional anti-LAG-3-IL-2c enhances immune checkpoint inhibitor and CAR T-cell therapy for cancer.

The effectiveness of cancer immunotherapies in solid tumors is often limited by challenges such as transient efficacy and low response rates. T-cell exhaustion is one key mechanism that impairs T-cell function in the tumor microenvironment (TME), compounded by the absence of immune-stimulatory signals. In this study, we developed a strategy leveraging an engineered fusion protein, anti-LAG-3-IL-2c, which combines an anti-LAG-3 antibody for targeting tumor-reactive T-cells with an interleukin-2 mutein complex (IL-2c). The fusion protein is designed to boost therapeutic efficacy while minimizing toxicity. Our in vitro and in vivo studies showed that anti-LAG-3-IL-2c selectively targets activated T-cells and CAR T-cells. In addition, combining anti-LAG-3-IL-2c with anti-PD-1 further enhanced antitumor activities. Furthermore, our results demonstrated that anti-LAG-3-IL-2c significantly improved the efficacy of CAR T-cell therapy for solid tumors. Our findings underscore the potential of targeted IL-2 delivery through anti-LAG-3 antibodies as a promising and effective approach to cancer immunotherapy.