Abstract 1853: A novel anti-CTLA-4 checkpoint inhibitor prodrug to address on-target off-tumor toxicity for cancer immunotherapy

Abstract

Abstract As the first approved immune checkpoint inhibitor targeting CTLA-4, ipilimumab has achieved great clinical success in cancer immunotherapy, particularly in combination with anti-PD-1 therapy. However, ipilimumab can also induce severe and sometimes fatal immune-mediated adverse reactions due to autoimmune responses in normal tissues, which may involve any organ system and cause enterocolitis, hepatitis, dermatologic adverse effects, endocrinopathies, pneumonitis, and nephritis with renal dysfunction, restricting its clinical applications. Thus, development of next generation anti-CTLA-4 antibodies with enhanced antitumor efficacy and improved safety profile is urgently needed. ADG126 is a novel anti-CTLA-4 fully human IgG1 antibody prodrug generated with Adagene SAFEbody technology, which is designed to be activated preferentially in the tumor microenvironment, limiting on-target off-tumor toxicities in normal tissues. This is realized by attaching an optimized peptide through library screening to the N-terminus of the light chain consisting of a masking moiety followed by a cleavage moiety. The masking moiety functions to block ADG126 binding to CTLA-4, however, after cleavage by proteases known to be highly expressed and active in tumor tissues but not in normal tissues, the masking moiety is released, and the antibody is then activated and able to bind and inhibit CTLA-4 function in situ, which has the potential to minimize the side effects and widen the therapeutic window compared to traditional antibodies. Nonclinical pharmacological studies demonstrate that unmasked or activated ADG126 (but not masked or inactive ADG126) binds to a unique and conserved epitope of CTLA-4 with multiple species cross-reactivity and effectively blocks the CTLA-4/B7 ligands interactions. Activated ADG126 potentiates T cell activation inducing elevated IL-2 cytokine production in the presence of a primary stimulatory signal, depletes immunosuppressive Treg activity through enhanced ADCC, and reduces immunosuppressive Treg activity specifically in the tumor microenvironment to mediate anti-tumor responses. ADG126 demonstrates efficacious anti-tumor activity in multiple syngeneic murine tumor models as single agent, as well as in combination with other immune modulatory agents. Nonclinical toxicology studies demonstrate that ADG126 is well-tolerated in cynomolgus monkeys. These results suggest that the design to have activation of ADG126 prodrug preferentially in tumors may allow treatments to deliver higher efficacious dose levels specific to the local tumor microenvironment concomitant with a superior systemic safety profile compared with other traditional anti-CTLA-4 antibodies. Thus, ADG126 may hold great promises to achieve much better efficacy and safety profile for immunotherapy against a broad spectrum of human cancers. Citation Format: Guizhong Liu, Xiaohong She, Yan Li, Felix Du, Peter Luo. A novel anti-CTLA-4 checkpoint inhibitor prodrug to address on-target off-tumor toxicity for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1853.