title: Delayed toxicity associated with soluble anthrax toxin receptor decoy-Ig fusion protein treatment.
abstract: Soluble receptor decoy inhibitors, including receptor-immunogloubulin (Ig) fusion proteins, have shown promise as candidate anthrax toxin therapeutics. These agents act by binding to the receptor-interaction site on the protective antigen (PA) toxin subunit, thereby blocking toxin binding to cell surface receptors. Here we have made the surprising observation that co-administration of receptor decoy-Ig fusion proteins significantly delayed, but did not protect, rats challenged with anthrax lethal toxin. The delayed toxicity was associated with the in vivo assembly of a long-lived complex comprised of anthrax lethal toxin and the receptor decoy-Ig inhibitor. Intoxication in this system presumably results from the slow dissociation of the toxin complex from the inhibitor following their prolonged circulation. We conclude that while receptor decoy-Ig proteins represent promising candidates for the early treatment of B. anthracis infection, they may not be suitable for therapeutic use at later stages when fatal levels of toxin have already accumulated in the bloodstream.
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Diane
authors.initials: D
authors.lastname: Thomas
authors.forename: John
authors.initials: J
authors.lastname: Naughton
authors.forename: Christopher
authors.initials: C
authors.lastname: Cote
authors.forename: Susan
authors.initials: S
authors.lastname: Welkos
authors.forename: Marianne
authors.initials: M
authors.lastname: Manchester
authors.forename: John A T
authors.initials: JA
authors.lastname: Young
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000737:chemistry / Q000633:toxicity*; D001427:Bacterial Toxins / Q000737:chemistry / Q000633:toxicity*; D001665:Binding Sites; D001667:Binding, Competitive; D006207:Half-Life; D007136:Immunoglobulins / Q000737:chemistry / Q000627:therapeutic use*; D020011:Protective Agents / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats; D018000:Receptors, Peptide / Q000737:chemistry; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D007136:Immunoglobulins; D020011:Protective Agents; D018000:Receptors, Peptide; D011993:Recombinant Fusion Proteins; C030325:anthrax toxin; C070309:anthrax toxin receptors