Development of lifitegrast: a novel T-cell inhibitor for the treatment of dry eye disease

Abstract

Dry eye disease (DED) is a multifactorial disorder of the ocular surface characterized by symptoms of discomfort, decreased tear quality, and chronic inflammation that affects an estimated 20 million patients in the US alone. DED is associated with localized inflammation of the ocular surface and periocular tissues leading to homing and activation of T cells, cytokine release, and development of hyperosmolar tears. This inflammatory milieu results in symptoms of eye dryness and discomfort. Homing of T cells to the ocular surface is influenced by the binding of lymphocyte function-associated antigen-1 (LFA-1; CD11a/CD18; αLβ2), a cell surface adhesion protein, to its cognate ligand, intercellular adhesion molecule-1 (ICAM-1; CD54), which is expressed on inflamed ocular/periocular epithelium and vascular endothelium. LFA-1/ICAM-1 binding within the immunologic synapse enables both T-cell activation and cytokine release. Lifitegrast is a novel T-cell integrin antagonist that is designed to mimic the binding epitope of ICAM-1. It serves as a molecular decoy to block the binding of LFA-1/ICAM-1 and inhibits the downstream inflammatory process. In vitro studies have demonstrated that lifitegrast inhibits T-cell adhesion to ICAM-1-expressing cells and inhibits secretion of pro-inflammatory cytokines including interferon gamma, tumor necrosis factor alpha, macrophage inflammatory protein 1 alpha, interleukin (IL)-1α, IL-1β, IL-2, IL-4, and IL-6, all of which are known to be associated with DED. Lifitegrast has the potential to be the first pharmaceutical product approved in the US indicated for the treatment of both symptoms and signs of DED. Clinical trials involving over 2,500 adult DED patients have demonstrated that topically administered lifitegrast 5.0% ophthalmic solution can rapidly reduce the symptoms of eye dryness and decrease ocular surface staining with an acceptable long-term safety profile. The purpose of this review is to highlight the developmental story - from bench top to bedside - behind the scientific rationale, engineering, and clinical experience of lifitegrast for the treatment of DED.

Keywords: ICAM-1; LFA-1; drug development; inflammation; ocular surface disease.

Figure 1

Immunologic synapse. Notes: LFA-1 on the surface of T-cell binds with ICAM-1 expressed on APC allowing interaction of TCR with MHC. Abbreviations: APC, antigen-presenting cell; ICAM-1, intercellular adhesion molecule-1; LFA-1, lymphocyte function-associated antigen-1; MHC, major histocompatibility complex; TCR, T-cell receptor.

Figure 2

The evolution of the lifitegrast design targeting LFA-1. Notes: (A) The space-filling model of the first two domains of ICAM-1 as determined by X-ray crystallography; (B) ribbon diagram of the first two domains of ICAM-1 with the superimposed binding residues of E34, K39, M64, Y66, N68, and Q73 in domain 1; (C) space-filling depiction of the six amino acid side chain binding residues identified by alanine point mutagenesis of the ICAM-1 epitope that binds to LFA-1; (D) the molecular structure of lifitegrast represented using a space-filling model; (E) the three-dimensional structural form of lifitegrast as represented from image D; (F) the structural formula of lifitegrast. Abbreviations: ICAM-1, intercellular adhesion molecule-1; LFA-1, lymphocyte function-associated antigen-1.