Anti-adhesion therapies

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Cell adhesion molecules are key mediators of inflammatory processes and are attractive targets for discovery of novel therapeutics. There have been significant positive advances in both basic research and clinical development in this area. Basic research has yielded detailed insight into the structural basis of cell adhesion molecule function, especially the interaction of integrins with their ligands. Co-crystals of several integrin–ligand complexes have been published, including αvβ3 with ligand fragments, αIIbβ3 with multiple therapeutic ligands and αLβ2 (leukocyte function-associated antigen-1 [LFA-1]) with its cell-based ligand intercellular adhesion molecule-1. This has stimulated development of models of integrin function and also the mode of action of small-molecule inhibitors. The most exciting recent advances in the field of clinical development have come with the successful approval of two new anti-adhesion therapeutics: efalizumab (Raptiva™) targeting LFA-1 for the treatment of chronic plaque psoriasis, and natalizumab (Tysabri/Antegren™) targeting very late antigen-4 for the treatment of relapsing-remitting multiple sclerosis. However, the latter therapeutic ran into a surprising safety issue earlier this year and was withdrawn from the market, casting a shadow over what had seemed a promising new drug.

Introduction

The field of leukocyte cell adhesion held considerable promise as a source of novel and potent targets for treatment of inflammation and autoimmune diseases. There was an explosion of new targets — receptor-ligand pairings — discovered in the late 1980s, continuing through to the late 1990s. Several distinct families of targets were identified including, but not restricted to, the selectins, immunoglobulin super-family members and integrins [1, 2]. The selectins — E, P and L — bind multivalent glycan ligands expressed on numerous surface proteins. They are involved in the initial adhesion events, capturing leukocytes out of vascular flow and adhering them to the vascular wall. Immunoglobulin super-family members bind integrins: leukocyte function-associated antigen-1 (LFA-1) binds to the ligands intercellular adhesion molecule (ICAM)-1, ICAM-2 and ICAM-3, and very late antigen-4 (VLA-4) to vascular cellular adhesion molecule (VCAM) and fibronectin. These IgSF–integrin interactions are pivotal in the next step of leukocyte spreading and transmigration across vascular endothelium into tissue spaces [3].

Of the two major approaches to antagonizing these targets — protein therapeutics (including monoclonal antibodies and receptor–Fc chimeric fusion proteins) and small-molecule-based drugs — both have yielded several approved therapies. There are now five approved anti-adhesion drugs: three antibodies and two small molecules (although none are orally available). Surprisingly, the progress in development of orally available small-molecule antagonists has been considerably slower and more problematic than first hoped and envisioned. Recently, there have been updates on the progress in clinical development of oral drug agents in this class, so the promise of additional approved adhesion inhibitors is not too distant.

There have been key recent advances in the structural analysis of integrins that could yield a new wave of drug discovery as we better understand, firstly, the interactions of integrins with their ligands and, secondly, how to modulate their binding activity [4•, 5••]. It has been proposed that small-molecule antagonists of integrin function can be categorized into three distinctive modes of action: ligand-mimetic α/β I-like competitive antagonists, α/β I-like allosteric antagonists or α I allosteric antagonists [6].

To give context, it is important to provide a brief reminder of the first adhesion antagonists, namely inhibitors of the platelet integrin αIIbβ3. There have been recent advances in our knowledge of how these integrins interact with the approved therapeutics, and these are reviewed here.

Section snippets

Anti-gpIIb/IIIa antagonists

The first anti-adhesion therapies approved were inhibitors of the platelet integrin αIIbβ3 for the treatment of reperfusion injury following percutaneous coronary artery balloon angioplasty [7, 8]. The three approved therapies comprise an antibody fragment, ReoPro™ (abciximab; Centocor, now JandJ [http://www.jnj.com]), and two small-molecule inhibitors, Integrilin™ (eptifibatide; Millennium/ScheringPlough [http://www.millennium.com]) and Aggrastat™ (tirofiban, Merck [http://www.merck.com]).

Anatagonists of LFA-1/ICAM interactions

The LFA-1/ICAM interaction is another key mediator of cell adhesion between leukocytes and vascular endothelium and, as both molecules are expressed on leukocytes, they are involved in modulating immune responses. In the early 1990s, the lead antagonists were anti-ICAM monoclonal antibodies, particularly enlimomab, which was based on the original murine antibody R6.5 [14]. Results with this antibody in numerous inflammatory and auto-immune diseases were disappointing and failed to reach their

Anti-VLA-4 approaches

Throughout the 1990s, considerable effort was applied to the discovery and development of antibodies and small-molecule inhibitors of the leukocyte integrin α4β1/VLA-4 in an attempt to block the interactions with its ligands VCAM and fibronectin. This is a key integrin–ligand interaction that allows leukocytes to adhere strongly to vascular endothelium and trigger subsequent shape changes in the leukocyte, ultimately leading to transmigration. Antibodies and small-molecule antagonists are

Tysabri™, an anti-VLA monoclonal antibody — rise and fall?

Up to Februray 2005, the most promising agent targeting α4β1 was the monoclonal antibody nataluzimab, originally discovered at Athena Neuroscience (now Elan) and subsequently co-developed by Elan and Biogen (now BiogenIdec) [33]. The key role of α4β1 in animal models of MS was first demonstrated by scientists at Elan with the use of a murine antibody that was subsequently humanized to yield the therapeutic antibody nataluzimab [34]. Originally named Antegren, the final product — Tysabri™ — was

Tysabri™ — positive efficacy data

Tysabri™ is administered as an intravenous infusion every four weeks. The AFFIRM study is a two-year, randomized, multi-centre, placebo-controlled, double-blinded study in which patients were randomized to receive either 300 mg intravenous infusion of Tysabri™ or placebo every four weeks. It reduced the rate of clinical relapses by 66% relative to placebo (annualized relapse rate was 0.25 for Tysabri™-treated patients versus 0.74 for placebo-treated patients). Tysabri™ was also effective in

Tysabri™ — safety issues

Tysabri™ was launched in November 2004 and looked set to be a successful therapy. However, on February 28th 2005, BiogenIdec and Elan jointly withdrew it from the market and suspended all clinical trials owing the discovery of two cases of a potentially fatal neurological pathology, PML, in patients taking the drug. In one case, the patient died; in the other case, the patient lived but both cases have been confirmed as PML. Both patients received more than two years of Tysabri™ treatment in

Conclusions

Research on cell adhesion molecules has yielded a clear map of the most important players in a range of inflammatory diseases. Development of effective therapeutics has yielded several novel, first-in-class approved drugs including three monoclonal antibodies (ReoPro™, Raptiva™ and Tysabri™, until its recent withdrawal) and two small molecules (Integrilin™ and Aggrastat™). There are also several small molecule and antibody programs in active clinical development that might produce additional

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

References (38)

  • S. Ghosh et al.

    Donoghue: Natalizumab for active Crohn's Disease

    N Engl J Med

    (2003)
  • U.H. Von Andrian et al.

    T-cell function and migration: two sides of the same coin

    N Engl J Med

    (2000)
  • J.M. Harlan et al.

    Leukocyte-endothelial interactions: clinical trials of anti-adhesion therapy

    Crit Care Med

    (2002)
  • T. Xiao et al.

    Structural basis for allostery in integrins and binding to fibrinogen-mimetic therapeutics

    Nature

    (2004)
  • M. Shimaoka et al.

    Therapeutic antagonists and conformational regulation of integrin function

    Nat Rev Drug Discov

    (2003)
  • J.S. Bennett

    Novel platelet inhibitors

    Annu Rev Med

    (2001)
  • B.S. Coller

    Platelet GPIIb/IIIa antagonists: the first anti-integrin receptor therapeutics

    J Clin Invest

    (1997)
  • J.J. Popma et al.

    Anti-thrombotic therapy in patients undergoing angioplasty

    Chest

    (1998)
  • J.P. Xiong et al.

    Crystal structure of the extra-cellular segment of the integrin αvβ3

    Science

    (2001)
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