Suppression of endogenous immunoglobulin expression in transgenic non-human animals expressing humanized or human antibodies
First Claim
1. A method of producing humanized or human antibodies comprising:
- (a) treating a transgenic non-human animal in which rearrangement of immunoglobulin genes substantially stops early in life, engineered to express one or more humanized or human immunoglobulin loci, with at least one antibody specific for the endogenous surface IgM and/or IgD heavy and/or light chains produced by early B cells of said animal, whereby early B cells expressing said surface IgM and/or IgD heavy and/or light chains are depleted, and (b) expressing said humanized or human immunoglobulin loci in said animal.
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Abstract
The invention provides a novel approach for suppression of endogenous antibody expression in non-human transgenic animals genetically engineered to express one or several human or humanized immunoglobulin transloci. Polyclonal or one or several monoclonal antibodies specific for endogenous IgM and/or IgE heavy and/or light chains are administered to the transgenic animals such that B-cells expressing their endogenous immunoglobulin are depleted and consequently expression of endogenous immunoglobulin is suppressed. Alternatively endogenous immunoglobulin expression may be inhibited through the expression of transgenes encoding such antibodies, including antibody fragments. This method allows the dominant expression of transloci coding for humanized or human antibodies in the blood, milk and eggs of transgenic animals.
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Citations
28 Claims
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1. A method of producing humanized or human antibodies comprising:
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(a) treating a transgenic non-human animal in which rearrangement of immunoglobulin genes substantially stops early in life, engineered to express one or more humanized or human immunoglobulin loci, with at least one antibody specific for the endogenous surface IgM and/or IgD heavy and/or light chains produced by early B cells of said animal, whereby early B cells expressing said surface IgM and/or IgD heavy and/or light chains are depleted, and (b) expressing said humanized or human immunoglobulin loci in said animal. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15)
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- 16. A method for suppressing endogenous immunoglobulin expression in a non-human animal comprising expressing in said animal one or more transgenes encoding one or more antibodies specific for the endogenous surface IgM and/or IgD heavy and/or light chains produced by early B cells of said non-human animal.
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24. A method for producing a non-human, non-rodent transgenic animal in which endogenous immunoglobulin production is suppressed, comprising treating said non-human, non-rodent transgenic animal with at least one antibody specific for the endogenous surface IgM and/or IgD heavy and/or light chains produced by early B cells of said animal.
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25. A method for producing a non-human transgenic animal in which endogenous immunoglobulin production is suppressed, comprising expressing in said non-human transgenic animal one or more transgenes encoding one or more antibodies specific for the endogenous surface IgM and/or IgD heavy and/or light chains produced by early B cells of said animal.
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26. A non-human transgenic animal dominantly expressing human or humanized antibodies, wherein said animal (1) uses primarily gene conversion and/or other mutational processes to diversify the primary antibody repertoire;
- (2) expresses a transgene comprising a human immunoglobulin gene or an immunoglobulin gene of said animal modified to express at least part of a human immunoglobulin molecule, and (3) expresses a transgene coding for one or several antibodies specific for endogenous surface IgM and/or IgD heavy and/or light chains produced by early B cells of said animal
- View Dependent Claims (27, 28)
Specification