Use of chimeric vaccinia virus complement control proteins to in

Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...

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435 697, C07K 1646

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active

061404721

ABSTRACT:
Disclosed are chimeric proteins that are useful for inhibiting complement. The chimeric protein termed VCPFc is a fusion protein in which (i) an immunoglobulin Fc region is fused to (ii) a polypeptide that comprises a portion of a vaccinia virus complement control protein which binds complement components C4b and C3b, but not iC3b rosettes. This protein can be used in xenograft transplantation methods (e.g., by treating the donor mammal or organ) and in methods for treating complement-mediated disorders (e.g., inflammation) generally. In a second chimeric protein, a transmembrane anchoring domain is fused to a polypeptide that comprises a portion of a vaccinia virus complement control protein which binds complement components C4b and C3b, but not iC3b rosettes. The transmembrane anchoring domain can be, for example, short consensus regions 3 through 15 of human complement receptor 2 protein. Expression of the transmembrane-anchored fusion protein in a transgenic animal provides a well-suited organ donor for xenograft transplantation.

REFERENCES:
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McKenzie et al. "Regulation of Complement Activity by Vaccinia Virus Complement-Control Protein", The Journal of Infectious Diseases, 1992, vol. 166, pp. 1245-1250.
Kroushus et al., "Complement Inhibition iwth an Anti-C5 Monoclonal Antibody Prevents Acute Cardiac Tissue Injury in an Ex Vivo Model of Pig-To-Human Xenotransplantation", Transplantation. Dec. 15, 1995, vol. 60, pp. 1194-1202.
Hackl-Ostreicher et al., "Functional Activity of the Membrane-Associated Complement Inhibitor CD59 in a Pig-To-Human in vitro Model for Hyperacute Xenograft Rejection", Clin. Exp. Immunol., 1995, vol. 102, pp. 589-595.
White et al., "Production of Pigs Transgenic for Human DAF to Overcome Complement-Mediated Hyperacute Xenograft Rejection in Man", Res. Immunol., Feb. 1996, vol. 147, pp. 88-94.
Miller et al., Virology, 299: 126-133. 1997.

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