Anti-PD-1 and anti-PD-l1 antibodies as immunotherapy against cancer: a structural perspective

ABSTRACT Programmed cell death protein 1 (PD-1) and its ligand, programmed death-ligand-1 (PD-L1), play key roles in the suppression of the cytotoxic activity of T cells. PD-L1 is overexpressed on various types of cancer cells, leading to immune evasion. In the past decade, therapeutic antibodies that target the PD-1/PD-L1 axis have been developed to inhibit the immune suppression triggered by these two proteins. At present, five antibodies (two anti-PD-1 and three anti-PD-L1) have received approval by regulatory agencies in the US and Europe. In this work, we aimed to review their clinical applications and adverse effects. Furthermore, using their reported crystal structures, we discuss the similarities and differences between the PD-1/PD-L1 interface and the epitopes that are recognized by the antibodies. Detailed analyses of the contact residues involved in the ligand-receptor and target-antibody interactions have shown partial overlap. Altogether, the data presented here demonstrate that: (1) in contrast to other therapeutic antibodies, anti-PD-1/PD-L1 has a wide range of clinical applications; (2) these targeted therapies are not exempt from adverse effects; and (3) the characterization of the structural domains that are recognized by the antibodies can guide the development of new PD-1- and PD-L1-blocking agents. (REV INVEST CLIN. 2021;73(1):8-16)

Differential expression of the costimulatory molecules CD86, CD28, CD152 and PD-1 correlates with the host-parasite outcome in leprosy

Leprosy is a spectral disease exhibiting two polar sides, namely, lepromatous leprosy (LL) characterised by impaired T-cell responses and tuberculoid leprosy in which T-cell responses are strong. Proper T-cell activation requires signalling through costimulatory molecules expressed by antigen presenting cells and their ligands on T-cells. We studied the influence of costimulatory molecules on the immune responses of subjects along the leprosy spectrum. The expression of the costimulatory molecules was evaluated in in vitro-stimulated peripheral blood mononuclear cells of lepromatous and tuberculoid patients and healthy exposed individuals (contacts). We show that LL patients have defective monocyte CD86 expression, which likely contributes to the impairment of the antigen presentation process and to patients anergy. Accordingly, CD86 but not CD80 blockade inhibited the lymphoproliferative response to Mycobacterium leprae. Consistent with the LL anergy, there was reduced expression of the positive signalling costimulatory molecules CD28 and CD86 on the T-cells in these patients. In contrast, tuberculoid leprosy patients displayed increased expression of the negative signalling molecules CD152 and programmed death-1 (PD-1), which represents a probable means of modulating an exacerbated immune response and avoiding immunopathology. Notably, the contacts exhibited proper CD86 and CD28 expression but not exacerbated CD152 or PD-1 expression, suggesting that they tend to develop a balanced immunity without requiring immunosuppressive costimulatory signalling.