Structure-activity relationships within the N-terminal short consensus repeats (SCR) of human CR1 (C3b / C4b receptor, CD35): SCR 3 plays a critical role in inhibition of the classical and alternative pathways of complement activation

Mossakowska, Danuta E.; Dodd, Ian C.; Pindar, Wendy; Smith, Richard A.

doi:10.1002/(sici)1521-4141(199906)29:06<1955::aid-immu1955>3.3.co;2-f

Cited by 4 publications

(3 citation statements)

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“…This region may be regarded as a minimized CR1 pharmacophere that retains excellent classical and alternative pathway inhibitory activity and both decayaccelerating and cofactor activity in vitro (18). The agent has been modified by the addition of a "2-addressin" membrane-targeting peptide derivative, combining an electrostatic interaction with charged phospholipid headgroups and hydrophobic interactions with the membrane bilayer interior to mediate binding to outer cell membranes.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic efficacy of a novel membrane-targeted complement regulator in antigen-induced arthritis in the rat

Linton

Williams

Dodd³

et al. 2000

Arthritis & Rheumatism

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Objective. Complement system activation is strongly implicated as a factor in the pathogenesis of chronic synovitis in human rheumatoid arthritis. The objective of this study was to explore the therapeutic potential and local retention of a novel membrane-targeting complement regulatory protein, derived from human complement receptor 1, in the experimental setting of rat antigen-induced arthritis. Methods. Sensitized animals were treated at the time of arthritis induction with a single intraarticular (IA) dose of the membrane-targeting regulator APT070, a non-membrane-targeting control regulator (APT898), or vehicle control, and disease was assessed clinically and histo-logically. In addition, immunocytochemical analysis was performed on sections from normal rat knee joints at various time points after IA injection with APT070. Results. Animals treated with APT070 showed a dose-dependent therapeutic effect, with significantly milder clinical and histologic disease compared with both other treatment groups (P < 0.008 at the higher dose) and minimal evidence of erosive disease at study end in the active treatment group. Immunoperoxidase and immunofluorescence studies demonstrated local retention of APT070 on cell surface membranes within the normal joint up to 48 hours after IA injection. Conclusion. These results show that IA complement inhibition represents an effective therapeutic strategy in experimental arthritis, by demonstrating that the exogenous delivery of a membrane-targeting complement regulator can result in prolonged synovial cell surface binding and significant clinical benefit in vivo. Complement inhibitory strategies of this type should be considered as novel therapies in human inflammatory arthritis.

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Section: Discussionmentioning

confidence: 99%

Therapeutic efficacy of a novel membrane-targeted complement regulator in antigen-induced arthritis in the rat

Linton

Williams

Dodd³

et al. 2000

Arthritis & Rheumatism

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“…Several complement regulatory molecules expressed in recombinant soluble forms have been modified posttranslationally by addition of a membrane-targeting tag (addressin) comprising a peptide sequence with affinity for phospholipid headgroups as well as for the membrane bilayer interior [61][62][63]. A fragment of CR1, previously shown to be an active complement inhibitor [64], was fused to such addressins and the hybrid molecule, termed APT070, is currently in clinical trials in the United Kingdom in patients with rheumatoid arthritis [61]. The usefulness of APT070 for inhibiting immune hemolysis remains to be tested.…”

Section: Selective Inhibitionmentioning

confidence: 99%

Controlling the complement system for prevention of red cell destruction

Yazdanbakhsh¹

2005

Current Opinion in Hematology

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“…A protein with complement inhibitory effects but less potent than CR1 was produced by expressing the first 3 SCR domains of the A-allotype of CR1 in Escherichia coli [7]. Enhanced membrane targeting by using the myristoyl electrostatic switch process resulted in a compound APT070 (Adprotech Ltd, Saffron Walden, UK), with more than 100 times the potency of SCR 1-3 alone [8].…”

Section: Introductionmentioning

confidence: 99%