Immune checkpoint inhibitors (ICIs) have advanced significantly in immuno-oncology (IO). The first marketed ICI, Ipilimumab, targets cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) on T cells, promoting effective attack against cancer cells. While effective, this therapy is frequently associated with immune-related adverse events (irAEs) stemming from systemic immune overactivation. In a clinical trial of 131 patients with unresectable melanoma treated with ipilimumab, 61% experienced irAEs, most notably dermatologic, gastrointestinal, endocrine, and hepatic toxicities. To mitigate irAEs while preserving Ipilimumab's therapeutic effect, we developed pro-Ipilimumab by linking an autologous hinge to the N-terminal variable domains of Ipilimumab via a matrix metalloproteinase (MMP)-2/9 substrate. Once pro-Ipilimumab reaches the tumor, MMP-2/9 cleaves the antibody lock, selectively activating Ipilimumab to enhance T-cell activation within the tumor microenvironment, enabling T-cells to attack the tumor while reducing irAEs. Pro-Ipilimumab exhibited a 178-fold antigen-blocking effect, comparable to Ipilimumab, and fully restored its binding ability after MMP-2/9 treatment. In transgenic mice, two out of seven achieved complete tumor eradication, demonstrating efficacy equal to Ipilimumab. In humanized mice, pro-Ipilimumab maintained a 100% survival rate by day 42, compared to 25% in the Ipilimumab group. Additionally, pro-Ipilimumab-treated mice showed stable body weight and reduced organ damage, including minimal inflammation and no fibrosis in the spleen or liver. We anticipate that pro-Ipilimumab will significantly reduce irAEs while maintaining efficacy, thereby preventing treatment discontinuation or withdrawal. This improved safety profile underscores its future clinical translation potential, particularly for synergistic combination therapies. By overcoming the toxicity of Ipilimumab, pro-Ipilimumab represents a revolutionary advancement in IO therapy.
Huang et al. (Sun,) studied this question.