Targeting anticomplement agents.
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.
Smith
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Adprotech Ltd, Chesterford Research Park, Little Chesterford, Saffron Walden, Essex CB10 1XL, UK. R.A.Smith@adpro.co.uk
D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D002462:Cell Membrane / Q000378:metabolism; D003169:Complement Inactivator Proteins / Q000737:chemistry*; D015195:Drug Design; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D019814:Myristic Acid / Q000378:metabolism; D010455:Peptides / Q000737:chemistry
D003169:Complement Inactivator Proteins; D010455:Peptides; C012749:anticomplement; D019814:Myristic Acid