Ransgenic non-human animals for producing heterologous antibodies
First Claim
1. A method for producing heterologous immunoglobulins from a transgenic mouse, the method comprising:
- contacting said transgenic mouse with a pre-selected antigen, said transgenic mouse having a genome comprising germline copies of at least one transgene having human sequences VH segment genes, human D segment genes, and human JH segment genes, wherein the transgene undergoes isotype switching from a transgene-encoded mu isotype to a transgene-encoded downstream human gamma isotype in vivo, wherein the number of nucleotides between the gene segments within the transgene that encode said mu and said human gamma isotypes is less than the number of nucleotides between the gene segments encoding human mu and said human gamma isotype in the human germline; and
,collecting heterologous human gamma immunoglobulins which bind to said preselected antigen.
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Abstract
The invention relates to transgenic non-human animals capable of producing heterologous antibodies and transgenic non-human animals having inactivated endogenous immunoglobulin genes. In one aspect of the invention, endogenous immunoglobulin genes are suppressed by antisense polynucleotides and/or by antiserum directed against endogenous immunoglobulins. Heterologous antibodies are encoded by immunoglobulin genes not normally found in the genome of that species of non-human animal. In one aspect of the invention, one or more transgenes containing sequences of unrearranged heterologous human immunoglobulin heavy chains are introduced into a non-human animal thereby forming a transgenic animal capable of functionally rearranging transgenic immunoglobulin sequences and producing a repertoire of antibodies of various isotypes encoded by human immunoglobulin genes. Such heterologous human antibodies are produced in B-cells which are thereafter immortalized, e.g., by fusing with an immortalizing cell line such as a myeloma or by manipulating such B-cells by other techniques to perpetuate a cell line capable of producing a monoclonal heterologous antibody. The invention also relates to heavy and light chain immunoglobulin transgenes for making such transgenic non-human animals as well as methods and vectors for disrupting endogenous immunoglobulin loci in the transgenic animal.
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Citations
14 Claims
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1. A method for producing heterologous immunoglobulins from a transgenic mouse, the method comprising:
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contacting said transgenic mouse with a pre-selected antigen, said transgenic mouse having a genome comprising germline copies of at least one transgene having human sequences VH segment genes, human D segment genes, and human JH segment genes, wherein the transgene undergoes isotype switching from a transgene-encoded mu isotype to a transgene-encoded downstream human gamma isotype in vivo, wherein the number of nucleotides between the gene segments within the transgene that encode said mu and said human gamma isotypes is less than the number of nucleotides between the gene segments encoding human mu and said human gamma isotype in the human germline; and
,collecting heterologous human gamma immunoglobulins which bind to said preselected antigen. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)
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Specification