Introduction

Efalizumab is a humanized monoclonal antibody binding to the lymphocyte function-associated antigen (LFA-1). LFA-1 belongs to the family of |32 integrins and is expressed on the surface of T cells (CD4+ cells, T-helper cells; CD8+ cells, cytotoxic T cells). LFA-1 is essential for every step in the process of immune surveillance and mounting an immune response (Dustin et al. 2004): (1) firm adherence to the wall of blood vessels under blood flow, (2) scanning by T cells of other cells within tissues, and (3) formation of the immuno-logical synapse between T cells and antigen-presenting cells (APCs).

LFA-1, Mac-1 and p159,95, members of the (3 2 inte-grin family, are heterodimeric molecules consisting of a (3-subunit (CD18), common to all three molecules, which is non-covalently linked to the respective a-chain CD11a (LFA-1), CD11b (Mac-1), and CD11c (p159,95). T cells mainly express LFA-1 (CD11a/CD18).

LFA-1 expression is regulated by activation of T cells which may induce a conformation change in the molecule resulting in a switch of the LFA-1 affinity from a low- to a high-affinity state as the T cell moves on from a resting to an activated state. The LFA-1 affinity maturation is influenced by a whole complex of so called "inside-out" signals, like activation of specific G-pro-tein-coupled receptors, cytokine stimulation of motility, and T-cell-receptor-mediated signals following antigen binding by the respective T-cell receptor (TCR).

The ligands for LFA-1 are intercellular adhesion molecules (ICAMs). They include ICAM-1, expressed on leucocytes, vascular endothelium cells and epithelial cells, including keratinocytes, ICAM-2 expressed on resting endothelium and lymphocytes and ICAM-3, expressed on monocytes and resting lymphocytes.

ICAM expression can be triggered by pro-inflammatory mediators, such as tumour necrosis factor-(TNF-a) and interferon^ (IFN-y).

LFA-1 antagonism has the potential to differentially affect functions of distinct T-cell populations as LFA-1 is expressed at higher levels on memory than on nai've T-cell populations. Monoclonal antibodies (mAbs) to LFA-1 or its ligands have been found to inhibit T-cell activation in vitro, to inhibit T-cell-dependent T-cell responses, to inhibit lymphocyte proliferation responses, to reduce lymphocyte trafficking and homing, and to reduce adhesion of T cells to endothelial cells in vitro. Therefore, it may be proposed that the inhibition of LFA-1/ICAM interaction leads to a suppression of several T-cell-dependent immune functions, which are crucial for the pathogenesis of inflammatory autoimmune diseases, namely (auto)-antigen presentation (Fig. 5.1a) and immune cell migration from blood flow to the target tissue (Fig. 5.1b). Results derived from animal models imply that inhibiting LFA-1/ICAM interaction by anti-CD11a antibodies may have a clinical benefit in certain T-cell-dependent diseases. CD11a blockade is predicted to produce less global immune suppression compared with CD18 blockade because T cells are relatively dependent on CD11a/CD18 (LFA-1) in contrast to other types of leucocytes.

A humanized monoclonal anti-CD11a IgG1 antibody, efalizumab, therefore showed clinical efficacy in psoriasis and other T-cell-mediated autoimmune diseases and is actually registered for the indication plaque psoriasis.

5.2 Development and Characterization of the Antibody

LFA1

LFA1

CD28 CD2

Fig. 5.1. a Scheme of antigen presentation by an antigen-presenting cell (APC) to T cells. Open circle indicates the participation of LFA-1/ICAM-1 interaction in the formation of the immunological synapse. b Scheme of adhesion molecule interaction between leucocytes and endothelial cells. Asterisk indicates LFA-1/ICAM-1 interaction

Fig. 5.2. Humanized monoclonal antibody efalizumab. CDR complementarity determining regions, FR framework regions, VH variable part of the heavy chain, VL variable part of the light chain a4p7

Endothelial cell Inflammatory celt

Fig. 5.1. a Scheme of antigen presentation by an antigen-presenting cell (APC) to T cells. Open circle indicates the participation of LFA-1/ICAM-1 interaction in the formation of the immunological synapse. b Scheme of adhesion molecule interaction between leucocytes and endothelial cells. Asterisk indicates LFA-1/ICAM-1 interaction

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