American Cyanamid Company

Other

Baxter International Inc.

Mayo Foundation for Medical Education and Research

Dnx Biotherapeutics

Nextran Inc.

John S Logan

Ajay K Sharma

Lisa E Diamond

Ramesh Kumar

Bosco S Wang

William R Baumbach

Ian C Hart

Homayoun Sadeghi

Susan Mancini Cady

Brian Lee Buckwalter

Deborah Tardy Chaleff

Gerald W Stockton

Cunqi Cui

Alexander Schwarz

Thomas A Davis

Guerard W Byrne

Geurard W Byrne

Porcine nucleic acid sequences flanking potentially infectious porcine endogenous retroviral (PERV) insertion sites have been identified and isolated. The unique flanking sequences include porcine nucleic acid sequences that flank the 3' end and porcine nucleic acid sequences that flank the 5&#x2032; end of PERV insertion sites. The present invention provides compositions and methods for detecting presence of PERV in a sample, particularly those with infectious potential. In addition, the invention relates to breeding of pigs or selection of porcine tissue that is free of infectious PERV for use as a xenotransplant tissue.

Elimination of endogenous porcine retrovirus

One aspect of the present invention relates to methods and compositions for attenuating xenograft rejection by administering, to an animal receiving the xenograft, an amount of a polymer-derivatized xenoantigen (hereinafter &ldquo;xenopolymer&rdquo;) effective for inhibiting or lessening the severity of hyperacute rejection response (HAR), or other immunological response to the graft, that is dependent on the presence of the xenoantigen on the grafted tissues or cells. In certain embodiments, the xenopolymer is administered in an amount sufficient to neutralize host antibodies (&ldquo;xenoreactive antibodies&rdquo; or &ldquo;XNA&rdquo;) immunoreactive with the xenoantigen. The xenopolymer may additionally, or alternatively, be used as a tolerogen (or anergen) for the xenoantigen, e.g., able to suppress, to some degree, the production/secretion of XNAs by the immune system of the host.

Inhibition of xenoreactive antibodies

A method of xenotransplanting organs, tissues, cells or non-viable components which reduces or prevents antibody-mediated rejections, including hyperacute rejection, is provided wherein transgenic animals are produced that express at least one enzyme which masks or reduces the level of the antigenic Gal.alpha.(1,3)Gal or gal epitope, and at least one complement inhibitor such as CD59, DAF and/or MCP. The transgenic animals which express both a gal epitope-reducing enzyme and a complement inhibitor will have masked or reduced levels of the gal epitope and will be much less likely to produce an antibody-mediated rejection following transplantation, and the expression of the complement inhibitor will also suppress complement activation and reduce even further a severe immune reaction following the transplantation of donor organs, tissue, cells or non-viable components from the transgenic animals so produced. In addition, transgenic animals are provided which express a plurality of complement inhibitors or other proteins from a locus of genes at a single integration site. The present invention is thus advantageous in that it can provide xenogeneic organs, tissues, cells and non-viable components which can be transplanted safely and effectively into humans with a reduction or elimination of antibody-mediated rejection to an extent not previously possible, and which will significantly reduce the need to obtain donor organs, tissues, cells or non-viable components from human or primate donors.

Method of producing transgenic animals for xenotransplantation

The present invention concerns a method and compositions of matter useful for the method of making, in transgenic animals, a human hemoglobin that is more stable and more readily purified from the endogenous hemoglobins of the transgenic animal than hemoglobin A. The hemoglobins produced by the invention include hemoglobin A.sub.2, which is an .alpha..sub.2 .delta..sub.2 tetramer, as well as other hemoglobins having similar properties to hemoglobin A.sub.2 and have .beta./.delta. chimeric globins. The specification discloses a chimeric gene, encoding a human .delta.-globin that is expressed in transgenic animals at levels approximating the level of expression of the .alpha. or .beta. globin.

Production of hemoglobin having a .delta.-like globin

Novel modified or derivatized recombinant animal somatotropins. Methods for stabilizing recombinant animal somatotropins by modification or deletion of the Cysteine residues utilizing site directed mutagenesis to replace from one to four of the cysteine amino acid residues of said somatotropins with one or more different amino acid residues or by derivatization of (1) both cysteine amino acid residues in the small loop of said somatotropin, both cysteine amino acid residues in the large loop or the four cysteine amino acid residues in both loops of said somatotropin.

Stabilization of somatotropins by modification of cysteine residues

The present invention concerns a method and compositions of matter useful for the method of making, in transgenic animals, a human hemoglobin that is more stable and more readily purified from the endogenous hemoglobins of the transgenic animal than hemoglobin A. The hemoglobins produced by the invention include hemoglobin A.sub.2, which is an .beta..sub.2 .delta..sub.2 tetramer, as well as other hemoglobins having similar properties to hemoglobin A.sub.2 and have .beta./.delta.chimeric globins. The specification discloses a chimeric gene, encoding a human .delta.-globin that is expressed in transgenic animals at levels approximating the level of expression of the .alpha. or .beta. globin.

Production of hemoglobin having a delta-like globin

The present invention is directed to antibodies, in particular monoclonal antibodies, which specifically bind to somatotropin binding proteins of animals, but not with the corresponding somatotropin receptors. The antibodies may be used alone to enhance the growth of animals, or may be used together with somatotropin to potentiate the effect of somatotropin in animals. The antibodies may also be used to assay the level of somatotropin binding protein of animals.

Antibodies specifically recognizing somatotropin binding proteins

The present invention is directed to antibodies, in particular monoclonal antibodies, which specifically bind to somatotropin binding proteins of animals, but not with the corresponding somatotropin receptors. The antibodies may also be used to assay the level of somatotropin binding protein of animals.

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Robbinsville, NJ, United States of America

John S Logan