An antibody against human interleukin-2 showing minimal binding to neonatal Fc receptor: Potent anti-tumor activity and reduced systemic toxicity in mice.

The anti-tumor efficacy of immune checkpoint inhibitors can be enhanced by combining them with interleukin-2 (IL-2), which promotes the clonal expansion of antigen-activated CD8 T cells and natural killer cells. However, IL-2 can simultaneously bind to endothelial cells and regulatory T cells to induce adverse and immunosuppressive effects. Such off-target binding can be inhibited by co-administering IL-2 with anti-IL-2 antibodies, but these antibodies can interact with neonatal Fc receptor to protect the IL-2 from lysosomal degradation, leading to substantial toxicity. Here we developed and humanized a mouse monoclonal antibody against human IL-2 and introduced two mutations (H310A and H435Q) in the Fc segment in order to weaken binding to the neonatal Fc receptor. The humanized antibody bound tightly to IL-2 but minimally to neonatal Fc receptor. Hydrogen deuterium exchange mass spectrometry indicated that the antibody binds to IL-2 at the site where the cytokine binds to subunit α (CD25) of the trimeric IL-2 receptor. Co-administering the antibody with human IL-2 improved the cytokine's ability to slow growth of two types of colorectal tumor xenografts (CT26, MC38) in immunocompetent mice. Co-administration to mice with CT26 xenografts strongly expanded CD8 T cells, without expanding regulatory T cells in spleen or blood. Co-administration to mice with MC38 xenografts downregulated PD-1 and CD44, while upregulating CD62L and CD69, on tumor-infiltrating CD8 T cells. Notably, co-administration synergized with anti-PD-1 antibody to slow growth of MC38 xenografts. Our results suggest that the combination of human IL-2 and our novel antibody shows promise for providing more effective, less toxic cancer immunotherapy.