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Integrin Α4β7 Antagonists 118 Current Immunology Reviews, 2012, 8, 118-134 Integrin 47 Antagonists: Activities, Mechanisms of Action and Therapeutic Prospects Dulce Soler-Ferran*,1 and Michael J. Briskin2 1Former Affiliation: Millennium Pharmaceuticals. Currently at Centers for Therapeutic Innovation (CTI), Pfizer, Inc., 3 Blackfan Circle, Boston, MA 02115, USA 2Former Affiliation: Millennium Pharmaceuticals and Merrimack Pharmaceuticals; Currently at Biotechnology Consulting, 28 Harbell Street, Lexington, MA 02421, USA Abstract: The 47 integrin is a leukocyte homing receptor with selective tissue tropism for the gastrointestinal tract through its interaction with MAdCAM-1, an adhesion receptor expressed on the endothelium of the gut mucosa. Crohn’s disease (CD) and ulcerative colitis (UC), two inflammatory bowel diseases resulting from intestinal immune- dysregulation, are associated with pronounced infiltration of 47 positive lymphocytes. This has triggered the development of inhibitors of the 47/MAdCAM-1 homing pathway. Vedolizumab is a humanized monoclonal antibody selective for 47 that demonstrated efficacy in early clinical studies for the treatment of CD and UC and is currently in phase 3 clinical trials. Targeting of 47 is also achieved by less selective therapeutic modalities which also block one of the two other leukocyte integrins that share a subunit with 47, namely, 41 and E7. Natalizumab is an anti-4 monoclonal antibody and dual 41 and 47 antagonist approved for the treatment of multiple sclerosis and CD. Other therapies in development include antibodies targeting the 7 subunit of 47 and E7, MAdCAM-1, and dual 4 small molecule antagonists. This review will focus on the mechanism of action, pharmacology, efficacy and safety properties as well as future opportunities that may arise from this unique class of leukocyte anti-adhesion antagonists. Keywords: 47, 41, and E7, integrin, inflammatory bowel disease (IBD), mucosal addressin cell adhesion molecule 1 (MAdCAM-1), natalizumab, progressive multifocal leukoencephalopathy (PML), vedolizumab. INTRODUCTION tissue-tropism is most elegantly illustrated in the gastro- intestinal tract by the imprinting of the gut-homing Chronic inflammatory diseases arise from dysregulated lymphocyte receptors, the integrin 47 and the chemokine innate and adaptive immune responses and are characterized receptor CCR9. These homing receptors are induced via by large inflammatory infiltrates, which come about as a interaction with dendritic cells of the inductive gut result of expansion and excessive trafficking of particular associated lymphoid tissues (GALT), the Peyer’s patches leukocyte subsets [1]. Regulation of lymphocyte trafficking (PPs) and mesenteric lymph nodes (MLNs) [5-7]. The into lymphoid and non-lymphoid tissues involves a complex expression of 47 is associated with homing to both the multi-step process that requires the sequential engagement of hi + large and small intestine while 47 CCR9 lymphocyte unique combinations of particular adhesive and signaling populations preferentially migrate to the small intestine [8- molecules on the surface of the lymphocyte with their 10]. The regulation of these receptors during memory respective ligands/receptors on the endothelial cell at the acquisition dictates the specification and segregation of sites of leukocyte extravasation [2, 3]. This molecular intestinal versus systemic (or non intestinal) immune diversity provides a mechanism for the regional responses. specialization of adaptive immune responses. Targeting the Increased expression of MAdCAM-1 and associated molecular mechanisms that confer tissue-selectivity to the hi trafficking of lymphocytes is a novel therapeutic strategy for trafficking of 47 subsets in the gastrointestinal tract have modulating pathogenic adaptive immune responses and long suggested that these receptors might play a role in treating organ-specific chronic inflammatory diseases induction and maintenance of intestinal inflammation. The without causing significant systemic immunosuppression. two major forms of inflammatory bowel diseases (IBD) Crohn’s disease (CD) and ulcerative colitis (UC), are still Naïve lymphocytes exert their immune surveillance fraught with lack of understanding of etiology and function by circulating continuously between the blood and mechanism but are both characterized by amplified cellular the lymphoid organs in search of cognate antigens. Upon hi infiltrates consisting of 47 lymphocytes and increased antigen encounter and activation in different regional expression of MAdCAM-1 [11-15]. It is thought that lymphoid organs, lymphocytes acquire homing receptors initiation of these diseases partially results from defects in which imprint them with capacities to migrate to the tissues innate immunity which cause altered adaptive immune where antigen was first encountered [4]. This selective responses which lead to the chronic inflammatory states that characterize these debilitating disorders [1, 16]. Crohn’s disease can affect the entire gastrointestinal tract; it is *Address correspondence to this author at the Centers for Therapeutic Innovation (CTI), Pfizer, Inc., 3 Blackfan Circle, Boston, MA 02115, USA; characterized by discontinuous lesions, transmural pathology Tel: 617-599-7377; and often granulomas and fistulae. UC pathology however, is E-mails: [email protected], [email protected] restricted to the large bowel and is characterized by 1875-631X/12 $58.00+.00 © 2012 Bentham Science Publishers Integrin 47 Antagonists Current Immunology Reviews, 2012, Vol. 8, No. 2 119 continuous superficial lesions of the mucosal layer. Current and mediate important immune cell functions. 41 binding management of CD and UC is often unsatisfactory because to its endothelial receptor, VCAM-1 (vascular cell adhesion of either lack of efficacy and durable response or side molecule-1) mediates lymphocyte recruitment into several effects. Recently, anti-TNF biologics have been shown to inflamed tissues outside the gastrointestinal tract including be effective for induction and maintenance of response in the brain, the lung, synovium and the heart. The predominant IBD [17]. However, a significant proportion of patients fail ligand for 47, mucosal addressin cell adhesion molecule to respond or become refractory to anti-TNF therapy. In (MAdCAM-1), exhibits a more restricted tissue expression. addition, anti-TNF agents are frequently associated with It is preferentially and constitutively expressed at sites of serious complications [18]. Consequently, there is a need for extravasation of intestinal lymphoid tissue and intestinal new therapies for IBD that induce and maintain remission lamina propria where it mediates the migration of gut- and cause minimal immunosuppression or other complications. homing lymphocyte subsets. A number of studies discussed below suggest that integrin interacting with MAdCAM- Decreasing immune cell infiltration in the chronically 4 7 1 plays a critical role in lymphocyte recirculation to inflamed gut tissue by blocking the interaction of the gut intestinal tissues but not to non-intestinal tissues. homing 47 integrin on circulating leukocytes with its endothelial counter receptor, MAdCAM-1, represents a promising novel therapeutic modality for the treatment of IBD. Current antagonists of 47 in development include a selective anti- 47 monoclonal antibody, vedolizumab; a selective MAdCAM-1 antibody; and dual anti-4 ( and 4 1 47) and anti-7 (47 and E7) monoclonal antibodies. Natalizumab, the dual 4 antibody, is used clinically for the treatment of multiple sclerosis and in the US for Crohn’s disease. This review will focus on the current status in the development of these novel anti-adhesive therapeutics as well as their mechanism of action and pharmacologic properties. We will also discuss potential efficacy and safety advantages and disadvantages, small molecule antagonists of 47 as well as other potential therapeutic indications for therapies targeting the 47/MAdCAM-1 pathway. ROLE OF 47 AND MADCAM-1 IN LYMPHOCYTE RECRUITMENT TO THE GASTROINTESTINAL TRACT The intestinal adaptive immune system plays an essential role in protecting against constant exposure to pathogens and in maintaining tolerance to commensal antigens and normal flora. Lymphocytes in the intestine are found in the gut- associated lymphoid tissues (GALT) (e.g. Peyer’s patches, Fig. (1). Classical view of multistep adhesion cascade. Initial mesenteric lymph nodes (MNL)), diffused through the lymphocyte endothelial cell interactions characterized by leukocyte lamina propria and embedded in the epithelium (IELs rolling, are typically mediated by selectin family members and intraepithelial lymphocytes), reaching these sites by various carbohydrate containing glycoprotein ligands. Some species extravasation from the vasculature. of MAdCAM-1 are also decorated with selectin binding determi- Leukocyte migration from the circulation into lymphoid nants and can bind L-selectin. 47 can thus mediate leukocyte and non-lymphoid tissues takes place following a sequence rolling as well, but upon chemokine triggering it mediates firm of molecular events (Fig. 1). The first is the tethering or adhesion to MAdCAM-1 on the vessel wall after which rolling of the leukocyte along the vessel wall through a series transmigration ensues. of weak and reversible interactions typically mediated by members of the selectin family of proteins and their 47 Integrin carbohydrate ligands on the endothelium. This allows for sampling of signaling
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