Structural basis for cancer immunotherapy by the first-in-class checkpoint inhibitor ipilimumab

Abstract

Rational modulation of the immune response with biologics represents one of the most promising and active areas for the realization of new therapeutic strategies. In particular, the use of function blocking monoclonal antibodies targeting checkpoint inhibitors such as CTLA-4 and PD-1 have proven to be highly effective for the systemic activation of the human immune system to treat a wide range of cancers. Ipilimumab is a fully human antibody targeting CTLA-4 that received FDA approval for the treatment of metastatic melanoma in 2011. Ipilimumab is the first-in-class immunotherapeutic for blockade of CTLA-4 and significantly benefits overall survival of patients with metastatic melanoma. Understanding the chemical and physical determinants recognized by these mAbs provides direct insight into the mechanisms of pathway blockade, the organization of the antigen-antibody complexes at the cell surface, and opportunities to further engineer affinity and selectivity. Here, we report the 3.0 Å resolution X-ray crystal structure of the complex formed by ipilimumab with its human CTLA-4 target. This structure reveals that ipilimumab contacts the front β-sheet of CTLA-4 and intersects with the CTLA-4:Β7 recognition surface, indicating that direct steric overlap between ipilimumab and the B7 ligands is a major mechanistic contributor to ipilimumab function. The crystallographically observed binding interface was confirmed by a comprehensive cell-based binding assay against a library of CTLA-4 mutants and by direct biochemical approaches. This structure also highlights determinants responsible for the selectivity exhibited by ipilimumab toward CTLA-4 relative to the homologous and functionally related CD28.immunotherapy | X-ray crystallography | CTLA-4 | ipilimumab | cancer

Immune-Related Adverse Events: Pneumonitis

“…Ipilimumab is the only CTLA-4 inhibitor approved by the Food and Drug Administration (FDA) at this time. Ipilimumab binds to the front β-sheet of CTLA-4 and interferes with the formation of CTLA-4:B7 complexes [36]. Another CTLA-4 inhibitor, tremelimumab, is in development, but not yet approved by the FDA and is beyond the scope of this chapter.…”

Determinants of Resistance to Checkpoint Inhibitors

“…For example, B7-1 and B7-2 are degraded in CTLA-4+ cells, resulting in reduced co-stimulation through CD28 [7]. Immunotherapy using CTLA-4 blockade aims to sterically hinder interactions with B7 ligands [8] and thereby facilitate continued positive co-stimulation with CD28. This promotes antitumor response through expansion of tumor-infiltrating T cells and possibly the depletion of regulatory T-cell (Treg) populations, which are immunosuppressive and downregulate the activation and proliferation of effector T cells [9].…”

Structure and Optimization of Checkpoint Inhibitors

“…Ipilimumab, which binds to CTLA-4, was the first CPI to be licensed in 2011, and was initially used for the treatment of metastatic melanoma but is now indicated in multiple tumor types. It has a high surface area at its binding site and has a dissociation constant of 5.25 nM, with a large surface area buried at its binding surface with CTLA-4 [31] (Table 1). Tremelimumab is another monoclonal antibody targeting CTLA-4 but has not yet been licensed for any indication, although it has orphan drug status for treatment of mesothelioma.…”