A Novel Targeted T-Cell Modulator, Efalizumab, for Plaque Psoriasis

Lebwohl, Mark; Tyring, Stephen K.; Hamilton, Tiffani K.; Toth, Darryl; Glazer, Scott D.; Tawfik, Naji H.; Walicke, Patricia A.; Dummer, Wolfgang; Wang, Xiaolin; Garovoy, Marvin R.; Pariser, David M.

doi:10.1056/nejmoa030002

Cited by 539 publications

(518 citation statements)

References 25 publications

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“…Many LFA-1 antibodies, including AL-57, block leukocyte adhesion (13,38), and LFA-1 blocking mAbs are effective in attenuating inflammatory disease in mouse models and in treating psoriasis patients (39,40). Targeted siRNA delivery using blocking LFA-1 antibodies might produce additive or synergistic effects by both silencing proinflammatory molecules and inhibiting LFA-1-mediated cell adhesion.…”

Section: Discussionmentioning

confidence: 99%

Selective gene silencing in activated leukocytes by targeting siRNAs to the integrin lymphocyte function-associated antigen-1

Peer

Zhu

Carman

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

258

201

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Section: Discussionmentioning

confidence: 99%

Selective gene silencing in activated leukocytes by targeting siRNAs to the integrin lymphocyte function-associated antigen-1

Peer

Zhu

Carman

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

258

201

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“…A humanized antibody to ␣ L ␤ 2 that blocks its binding to the ligand ICAM-1 has been approved by the FDA for treatment of psoriasis, a T cellmediated autoimmune disease of the skin (9,10). Furthermore, small molecule antagonists of ␣ L ␤ 2 have been discovered and are in development (11)(12)(13)(14)(15)(16)(17).…”

mentioning

confidence: 99%

A Small Molecule Agonist of an Integrin, αLβ2

Yang

Carman

Kim

et al. 2006

Journal of Biological Chemistry

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Integrins are a large family of ␣/␤ heterodimeric cell surface receptors that mediate cell-cell and cell-extracellular matrix adhesion and transduce signals bidirectionally across the plasma membrane. Integrin ␣ L ␤ 2 (lymphocyte function associated antigen-1 (LFA-1)) 5 belongs to the ␤ 2 integrin subfamily and is constitutively expressed on all leukocytes. ␣ L ␤ 2 remains in a low affinity state in resting lymphocytes and undergoes dramatic conformational change during lymphocyte activation, which greatly increases its binding affinity for its ligands intercellular adhesion molecule -1, -2, and -3 (ICAM-1, -2, and -3). Regulation of ␣ L ␤ 2 activation is pivotal for controlling leukocyte trafficking and immune responses in health and diseases (1-3).␣ L ␤ 2 is an important pharmaceutical target for treating autoimmune and inflammatory diseases (4 -8). A humanized antibody to ␣ L ␤ 2 that blocks its binding to the ligand ICAM-1 has been approved by the FDA for treatment of psoriasis, a T cellmediated autoimmune disease of the skin (9, 10). Furthermore, small molecule antagonists of ␣ L ␤ 2 have been discovered and are in development (11)(12)(13)(14)(15)(16)(17).␣ L ␤ 2 contains two von Willebrand factor-type A domains, the inserted (I) domains in the ␣ L and the ␤ 2 subunits (18 -20). Both ␣ L I and ␤ 2 I domains have a Rossman fold (i.e. a central ␤-sheet surrounded by ␣-helices) with a metal ion-dependent adhesion site (MIDAS) formed by ␤-␣ loops at the "top" face of the domain (20 -23). In ligand binding the Mg 2ϩ ion in the MIDAS of the ␣ L I domain coordinates directly to a Glu residue that is in the center of the ligand binding sites in domain 1 of 24). The affinity of the ␣ L I domain for ICAMs is regulated by downward axial displacement of its C-terminal ␣7 helix, which is conformationally linked to reshaping of MIDAS loops and increases affinity for ligand by up to 10,000-fold (25, 26). During activation, the ␤ I domain undergoes similar ␣7 helix downward axial movement, which is induced by the swing out of the hybrid domain (27)(28)(29)(30). 6 Previous data suggested that when activated, the ␤ 2 I domain binds (through the Mg 2ϩ in its MIDAS) to the Glu residue (Glu-310) in the C-terminal linker of the ␣ L I domain, exerts a downward pull on its ␣7 helix, and thereby activates the ␣ L I domain (Fig. 1A) (32, 33).Two distinct classes of small molecule antagonists of ␣ L ␤ 2 have been developed as anti-inflammatory agents. One group of antagonists binds the hydrophobic pocket underneath the ␣7 helix of the ␣ L I domain (e.g. LFA703 or BIRT377), blocks the downward axial movement of the ␣7 helix, and inhibits ligand binding of ␣ L ␤ 2 allosterically by stabilizing the ␣ L I domain in the low affinity conformation (11)(12)(13)(14)34). These antagonists are called ␣ I allosteric inhibitors. The other group of antagonists appears to bind to the ␤ 2 I domain MIDAS near a key regulatory interface with the ␣ L I domain, blocking communication of conformational change to the ␣ L I domain while at the same time ac...

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“…20,674 articles were found, of which 20,592 were excluded, resulting in 82 articles in which 41 clinical trials comparing biologics with placebo (six adalimumab 17,18,19,20,21,22,23,24,25,26,27 , three alefacept 28,29,30,31,32,33,34,35,36,37 , one briakinumab 38,39 , one certolizumab 40 , seven efalizumab 41,42,43,44,45,46,47,48,49,50,51 , eight etanercept 52,53,54,55,56,57,58,59,60,61,62,63,64 , one golimumab 65,66 , eight infliximab …”

Section: Study Selectionmentioning

confidence: 99%

Efficacy and safety of biologics in the treatment of moderate to severe psoriasis: a comprehensive meta-analysis of randomized controlled trials

et al. 2013

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Efficacy and safety of biologics in the treatment of moderate to severe psoriasis: a comprehensive meta-analysis of randomized controlled trials Eficácia e segurança de agentes biológicos no tratamento da psoríase moderada a grave: uma meta-análise de ensaios clínicos randomizados e controlados Eficacia y seguridad de los agentes biológicos en el tratamiento de la psoriasis moderada a severa: un metaanálisis de ensayos aleatorios y controlados

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A Novel Targeted T-Cell Modulator, Efalizumab, for Plaque Psoriasis

Abstract: Efalizumab therapy resulted in significant improvements in plaque psoriasis in subjects with moderate-to-severe disease. Extending treatment from 12 to 24 weeks resulted in both maintenance and improvement of responses.

Cited by 539 publications

References 25 publications

Selective gene silencing in activated leukocytes by targeting siRNAs to the integrin lymphocyte function-associated antigen-1

Selective gene silencing in activated leukocytes by targeting siRNAs to the integrin lymphocyte function-associated antigen-1

A Small Molecule Agonist of an Integrin, αLβ2

Efficacy and safety of biologics in the treatment of moderate to severe psoriasis: a comprehensive meta-analysis of randomized controlled trials

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