Ungulates with genetically modified immune systems

a technology of immune system and ungulate, which is applied in the field of ungulate animals with genetically modified immune systems, can solve the problems of insufficient human antibody availability for therapeutic and prophylactic therapies, inability to induce protective response by vaccination, and large abandonment of wide-scale serum therapy, etc., and achieve the effect of eliminating the expression of xenoantigens

Inactive Publication Date: 2008-01-31
REVIVICOR INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0077] In other embodiments, animals or cells lacking expression of functional immunoglobulin, produced according to the process, sequences and/or constructs described herein, can contain additional genetic modifications to eliminate the expression of xenoantigens. Such animals can be modified to eliminate the expression of at least one allele of the alpha-1,3-galactosyltransferase gene, the CMP-Neu5Ac hydroxylase gene (see, for example, U.S. Ser. No. 10/863,116), the iGb3 synthase gene (see, for example, U.S. Patent Application 60/517,524), and/or the Forssman synthase gene (see, for example, U.S. Patent Application 60/568,922). In additional embodiments, the

Problems solved by technology

However, wide scale serum therapy was largely abandoned in the 1940s because of the toxicity associated with the administration of heterologous sera and the introduction of effective antimicrobial chemotherapy.
Thus, there is an inherent limitation in the amount of human antibody available for therapeutic and prophylactic therapies.
Unfortunately, inducing a protective response by vaccination may take longer than the time between exposure and onset of disease.
Moreover, many vaccines require multiple doses to achieve a protective immune response, which would limit their usefulness in an emergency to provide rapid prophylaxis after an attack.
In addition, not all vaccine recipients mount a protective response, even after receiving the recommended immunization schedule.
Drugs can provide protection when administered after exposure to certain agents, but none are available against many potential agents of biological warfare.
Currently, no small-molecule drugs are available that prevent disease following exposure to preformed toxins.
Despite the recent popularity of monoclonal antibodies as therapeutics, there are some obstacles for their use.
However, murine monoclonal antibodies have inherent disadvantages as human therapeutics.
More critically, repeated administration of murine immunoglobulin creates the likelihood that the human immune system will recognize the mouse protein as foreign, generating a human anti-mouse antibody response, which can cause a severe allergic reaction.
In addition, while monoclonals have limited therapeutic activity against infectious agents, polyclonals can both neutralize toxins and direct immune re

Method used

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  • Ungulates with genetically modified immune systems
  • Ungulates with genetically modified immune systems
  • Ungulates with genetically modified immune systems

Examples

Experimental program
Comparison scheme
Effect test

example 1

Porcine Heavy Chain Targeting and Generation of Porcine Animals that Lack Expression of Heavy Chain

[0285] A portion of the porcine Ig heavy-chain locus was isolated from a 3× redundant porcine BAC library. In general, BAC libraries can be generated by fragmenting pig total genomic DNA, which can then be used to derive a BAC library representing at least three times the genome of the whole animal. BACs that contain porcine heavy chain immunoglobulin can then be selected through hybridization of probes selective for porcine heavy chain immunoglobulin as described herein.

[0286] Sequence from a clone (Seq ID 1) was used to generate a primer complementary to a portion of the J-region (the primer is represented by Seq ID No. 2). Separately, a primer was designed that was complementary to a portion of Ig heavy-chain mu constant region (the primer is represented by Seq ID No. 3). These primers were used to amplify a fragment of porcine Ig heavy-chain (represented by Seq ID No. 4) that led...

example 2

Porcine Kappa Light Chain Targeting and Generation of Porcine Lacking Expression of Kappa Light Chain

[0293] A portion of the porcine Ig kappa-chain locus was isolated from a 3× redundant porcine BAC library. In general, BAC libraries can be generated by fragmenting pig total genomic DNA, which can then be used to derive a BAC library representing at least three times the genome of the whole animal. BACs that contain porcine kappa chain immunoglobulin can then be selected through hybridization of probes selective for porcine kappa chain immunoglobulin as described herein.

[0294] A fragment of porcine Ig light-chain kappa was amplified using a primer complementary to a portion of the J-region (the primer is represented by Seq ID No. 10) and a primer complementary to a region of kappa C-region (represented by Seq ID No.11). The resulting amplimer was cloned into a plasmid vector and maintained in Stable2 cells at 30° C. (Seq ID No. 12). See FIG. 2 for a schematic illustration.

[0295] ...

example 3

Characterization of the Porcine Lambda Gene Locus

[0302] To disrupt or disable porcine lambda, a targeting strategy has been devised that allows for the removal or disruption of the region of the lambda locus that includes a concatamer of J to C expression cassettes. BAC clones that contain portions of the porcine genome can be generated. A portion of the porcine Ig lambda-chain locus was isolated from a 3× redundant porcine BAC library. In general, BAC libraries can be generated by fragmenting pig total genomic DNA, which can then be used to derive a BAC library representing at least three times the genome of the whole animal. BACs that contain porcine lambda chain immunoglobulin can then be selected through hybridization of probes selective for porcine lambda chain immunoglobulin as described herein.

[0303] BAC clones containing a lambda J-C flanking region (see FIG. 3), can be independently fragmented and subcloned into a plasmid vector. Individual subdlones have been screened by...

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Abstract

The present invention provides ungulate animals, tissue and organs as well as cells and cell lines derived from such animals, tissue and organs, which lack expression of functional endogenous immunoglobulin loci. The present invention also provides ungulate animals, tissue and organs as well as cells and cell lines derived from such animals, tissue and organs, which express xenogenous, such as human, immunoglobulin loci. The present invention further provides ungulate, such as porcine genomic DNA sequence of porcine heavy and light chain immunogobulins. Such animals, tissues, organs and cells can be used in research and medical therapy. In addition, methods are provided to prepare such animals, organs, tissues, and cells.

Description

FIELD OF THE INVENTION [0001] The present invention provides ungulate animals, tissue and organs as well as cells and cell lines derived from such animals, tissue and organs, which lack expression of functional endogenous immunoglobulin loci. The present invention also provides ungulate animals, tissue and organs as well as cells and cell lines derived from such animals, tissue and organs, which express xenogenous, such as human, immunoglobulin loci. The present invention further provides ungulate, such as porcine genomic DNA sequence of porcine heavy and light chain immunogobulins. Such animals, tissues, organs and cells can be used in research and medical therapy. In addition, methods are provided to prepare such animals, organs, tissues, and cells. BACKGROUND OF THE INVENTION [0002] An antigen is an agent or substance that can be recognized by the body as ‘foreign’. Often it is only one relatively small chemical group of a larger foreign substance which acts as the antigen, for e...

Claims

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Application Information

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IPC IPC(8): C12N15/00
CPCA01K67/0275C12N2800/30A01K2207/15A01K2217/00A01K2217/075A01K2227/101A01K2227/102A01K2227/103A01K2227/108A01K2267/01A01K2267/02A01K2267/025C12N15/8509C12N15/873C12N2800/204C12N2800/206A01K67/0276A01K2267/0387C12N2015/8536
Inventor WELLS, KEVINAYARES, DAVID
Owner REVIVICOR INC
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