Anti-adhesion therapies
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
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