 CTLA4 receptor and uses thereof |
| OF THE INVENTION DEFINITION As used in this application, the following words or phrases have the ... |
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| CTLA4/CD28Ig hybrid fusion proteins and uses thereof |
| OF THE INVENTION DEFINITION As used in this application, the following words or phrases have the ... |
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| Method of regulating cellular processes mediated by B7 and CD28 |
| Accordingly, the present invention identifies the B7 antigen as a ligand recognized by the CD28 ... |
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| Methods of inhibiting T cell proliferation or IL-2 accumulation with CTLA4- specific antibodies |
| This invention is based, at least in part, on the discovery of novel ligands which bind a T cell ... |
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| Method for generating and identifying antibodies directed against a B7 |
| Accordingly, the present invention identifies the B7 antigen as a ligand recognized by the CD28 ... |
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| Polypeptide that interacts with heat shock proteins |
| Described herein are the isolation and characterization of a polypeptide, particularly a ... |
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| 1,2-Biguanides |
| What is claimed is: 1. A substituted biguanide of the formula ##EQU8## wherein R.sub.1 is alkyl of 1... |
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| Biguanide salts |
| OF THE INVENTION The invention relates to biguanide salts. In another aspect, the invention ... |
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| Inhibitors of dipeptidyl-aminopeptidase type IV |
| What is claimed is: 1. A method for treating transplant rejection in a patient comprising ... |
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| Process for preparing anti-obesity protein |
| OF THE INVENTION For purposes of the present invention, as disclosed and claimed herein, the ... |
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Transgenic non-human animals for producing heterologous antibodies
| Details |
Inventors: Lonberg, Nils; Kay, Robert M.;
Assignee: GenPharm International Inc. (Palo Alto, CA)
Primary Examiner: Ziska; Suzanne E.
Assistant Examiner:
Attorney, Agent or Firm: Townsend and Townsend and Crew LLP
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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DETAILED DESCRIPTION As has been discussed supra, it is desirable to produce human immunoglobulins that are reactive with specific human antigens that are promising therapeutic and/or diagnostic targets.
However, producing human immunoglobulins that bind specifically with human antigens is problematic.
First, the immunized animal that serves as the source of B cells must make an immune response against the presented antigen.
In order for an animal to make an immune response, the antigen presented must be foreign and the animal must not be tolerant to the antigen.
Thus, for example, if it is desired to produce a human monoclonal antibody with an idiotype that binds to a human protein, self-tolerance will prevent an immunized human from making a substantial immune response to the human protein, since the only epitopes of the antigen that may be immunogenic will be those that result from polymorphism of the protein within the human population (allogeneic epitopes).
Second, if the animal that serves as the source of B-cells for forming a hybridoma (a human in the illustrative given example) does make an immune response against an authentic self antigen, a severe autoimmune disease may result in the animal.
Where humans would be used as a source of B-cells for a hybridoma, such autoimmunization would be considered unethical by contemporary standards.
Thus, developing hybridomas secreting human immunoglobulin chains specifically reactive with predetermined human antigens is problematic, since a reliable source of human antibody-secreting B cells that can evoke an antibody response against predetermined human antigens is needed.
One methodology that can be used to obtain human antibodies that are specifically reactive with human antigens is the production of a transgenic mouse harboring the human immunoglobulin transgene constructs of this invention.
Briefly, transgenes containing all or portions of the human immunoglobulin heavy and light chain loci, or transgenes containing synthetic "miniloci" (described infra, and in copending applications U
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