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Cardiovascular Diseases

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Recombinant protein

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Recombinant protein	1

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C3(Complement C3)	1

AbstractDecay‐accelerating factor (DAF, CD55) is a glycophosphatidyl inositol‐anchored glycoprotein that regulates the activity of C3 and C5 convertases. In addition to understanding the mechanism of complement inhibition by DAF through structural studies, there is also an interest in the possible therapeutic potential of the molecule. In this report we describe the cloning, expression inEscherichia coli, isolation and membrane‐targeting modification of the four short consensus repeat domains of soluble human DAF with an additional C‐terminal cysteine residue to permit site‐specific modification. The purified refolded recombinant protein was active against both classical and alternative pathway assays of complement activation and had similar biological activity to soluble human DAF expressed inPichia pastoris. Modification with a membrane‐localizing peptide restored cell binding and gave a large increase in antihemolytic potency. These data suggested that the recombinant DAF was correctly folded and suitable for structural studies as well as being the basis for a DAF‐derived therapeutic. Crystals of theE. coli‐derived protein were obtained and diffracted to 2.2 Å, thus permitting the first detailed X‐ray crystallography studies on a functionally active human complement regulator protein with direct therapeutic potential.

01 Nov 2002·Biochemical Society TransactionsQ2 · BIOLOGY

Targeting anticomplement agents

Q2 · BIOLOGY

Review

Author: Smith, R. A. G.

Biological targeting is normally thought of as a process of specific direction of one molecule (the agent) to another (the target) in vivo. However, an addressive approach in which the agent is concentrated, first within the vasculature and then at a disease site containing one or more targets, may be more suitable for delivering therapeutic quantities of certain drugs. This approach has been applied to complement regulatory molecules expressed in recombinant soluble forms and attached post-translationally to highly soluble synthetic peptide derivatives comprising two addressin units, one with affinity for the membrane bilayer interior and the other for phospholipid headgroups. This combination conferred affinity for outer cell membranes in general, and areas of translocated acidic phospholipid in particular. Large increases in potency in cell-based antihaemolytic assays accompanied modification and were shown to be associated with membrane binding. Modified agents co-localized with glycosylphosphatidyl-inositol-anchored proteins in lipid rafts on cell membranes. One agent, a modified fragment of human complement receptor-1 (APT070), has been prepared on a large scale and has been shown to be an active anti-inflammatory agent when administered locally and systemically in animal models of vascular shock, rheumatoid arthritis and transplantation reperfusion injury. APT070 has been shown to be well tolerated in human subjects when given intravenously and is currently under study in rheumatoid arthritis patients to explore the therapeutic potential of localized complement inhibition in the synovial space.

01 Oct 2002·Biochemical Society Transactions

Targeting anticomplement agents

Author: Smith, Richard A.G.

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100 Translational Medicine associated with Adprotech Ltd.

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Pipeline

Pipeline Snapshot as of 22 Nov 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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Current Projects

Drug(Targets)	Indications	Global Highest Phase

Mirococept ( C3 )	Myocardial Reperfusion Injury More	Phase 3
ABT-2384 ( Coagulation factor )	Thromboembolism More	Discontinued
APT-2384 ( thrombin )	Myocardial Infarction More	Pending
APT-3088	Bacterial Infections More	Pending