Structure of CTLA-4 complexed with a pH-sensitive cancer immunotherapeutic antibody
Han Gao, Haiyan Cai, Jia Liu, Xiaoxiao Wang, Pan Zheng, Martin Devenport, Ting Xu, Fei Dou, Yang Liu, Aiwu Zhou
Abstract
Antibodies that target the immune system rather than the cancer cells have had a transformative impact for cancer therapy 1 . Ipilimumab, an antibody targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) 2 , was the first to receive regulatory approval for clinical use and thus played a major role in this breakthrough 3 . CTLA-4 has higher binding affinity to B7 ligands than CD28. CD28 is expressed on both naive and activated but not exhausted T cells and is required for T-cell activation. CTLA-4 is expressed after T-cell activation and was considered a negative regulator of T-cell function, although more recent studies demonstrated that CTLA-4 controls immune tolerance by enabling regulatory T (T reg ) cells to rip B7 off the antigen-presenting cells, a process termed transendocytosis 4 . Anti-CTLA-4 antibodies have been shown to enhance T-cell proliferation and cytokine production in vitro 5 , 6 . However, numerous recent studies have shown that specific depletion of T reg cells within the tumor microenvironment is associated with anti-CTLA-4-induced tumor rejection 7 , 8 . Ipilimumab, a fully human anti-CTLA-4 monoclonal antibody produced by Bristol Myers Squibb, could significantly increase overall survival in patients with advanced melanoma 3 . Several other CTLA-4 antibodies such as tremelimumab are also under development. However, the clinical usage of these CTLA-4 antibodies is often associated with severe immunotherapy-related adverse events (irAEs) 9 . These irAEs of CTLA-4 antibodies not only cause human suffering but also limit their doses and duration in cancer therapy, resulting in a suboptimal therapeutic outcome.