Compositions and methods for inhibiting endogenous immunoglobulin genes and producing transgenic human idiotype antibodies

Abstract

The invention relates to transgenic animals lacking endogenous Ig and capable of producing transgenic antibodies, as well as methods of making the same. The invention further relates to Methods for producing transgenic antibodies in such animals, and transgenic antibodies so produced.

1 - 34 . (canceled) 
     
     
         35 . A chimeric monoclonal antibody comprising a non-human IgG constant region, a light chain and/or heavy chain, and a human idiotype, and wherein the non-human constant region comprises a rat IgG CH2 and CH3 domain. 
     
     
         36 . The chimeric monoclonal antibody of  claim 35 , wherein the non-human constant region further comprises a human IgG CH1 domain. 
     
     
         37 . The chimeric monoclonal antibody of  claim 35 , wherein the monoclonal antibody comprises a heavy chain and a light chain. 
     
     
         38 . The chimeric monoclonal antibody of  claim 35 , wherein the monoclonal antibody is a heavy chain only antibody. 
     
     
         39 . The chimeric monoclonal antibody of  claim 35 , wherein the non-human constant region comprises an IgG CH2 and CH3 domain and lacks a CH1 domain. 
     
     
         40 . A polyclonal antiserum comprising a plurality of chimeric antibodies, wherein the individual chimeric antibodies comprise a non-human IgG constant region, a heavy chain and/or light chain, and a human idiotype, and wherein the non-human constant region comprises a rat IgG CH2 and CH3 domain. 
     
     
         41 . The polyclonal antiserum of  claim 40 , wherein the non-human constant region further comprises a human IgG CH1 domain. 
     
     
         42 . The polyclonal antiserum of  claim 40 , wherein the individual chimeric antibodies comprise a heavy chain and a light chain. 
     
     
         43 . The polyclonal antiserum of  claim 40 , wherein the individual chimeric antibodies are heavy chain only antibodies. 
     
     
         44 . The polyclonal antiserum of  claim 40 , wherein the non-human constant region comprises an IgG CH2 and CH3 domain and lacks a CH1 domain. 
     
     
         45 . The polyclonal antiserum of  claim 40 , wherein the antiserum is:
 a. a bird antiserum;   b. a chicken antiserum;   c. a weasel antiserum;   d. a rodent antiserum; or   e. a rat antiserum.   
     
     
         46 . A diversified repertoire of chimeric immunoglobulins, wherein the individual chimeric immunoglobulins comprise a non-human IgG constant region, a heavy chain and/or light chain, and a human idiotype, and wherein the non-human constant region comprises a rat IgG CH2 and CH3 domain. 
     
     
         47 . The diversified repertoire of  claim 46 , wherein the non-human constant region further comprises a human IgG CHI domain. 
     
     
         48 . The diversified repertoire of  claim 46 , wherein the individual chimeric antibodies comprise a heavy chain and a light chain. 
     
     
         49 . The diversified repertoire of  claim 46 , wherein the individual chimeric antibodies are heavy chain only antibodies. 
     
     
         50 . The diversified repertoire of  claim 46 , wherein the non-human constant region comprises an IgG CH2 and CH3 domain and lacks a CH1 domain. 
     
     
         51 . The diversified repertoire of  claim 46 , wherein the repertoire is in a transgenic non-human animal which is nullizygous for endogenous Ig light chain loci and/or endogenous heavy chain loci. 
     
     
         52 . The diversified repertoire of  claim 51 , wherein the transgenic non-human animal comprises an artificial Ig locus comprising:
 a. an artificial constant region gene;   b. at least one human V gene segment;   c. one or more D gene segments; and   d. one or more J gene segments.   
     
     
         53 . The diversified repertoire of  claim 51 , wherein the transgenic non-human animal is selected from the group consisting of a bird, a rodent, a chicken, a weasel, a rat, and a mouse. 
     
     
         54 . A nucleic acid encoding a chimeric monoclonal antibody comprising a non-human IgG constant region, a heavy chain and/or light chain, and a human idiotype, and wherein the non-human constant region comprises a rat IgG CH2 and CH3 domain. 
     
     
         55 . The nucleic acid of  claim 54 , wherein the non-human IgG constant region encoded by the nucleic acid comprises a human IgG CH1 domain. 
     
     
         56 . The nucleic acid of  claim 54 , wherein the nucleic acid encodes a heavy chain only antibody. 
     
     
         57 . The nucleic acid of  claim 54 , wherein the nucleic acid encodes a non-human constant region that comprises an IgG CH2 and CH3 domain and lacks a CH1 domain. 
     
     
         58 . A host cell comprising the nucleic acid of any one of  claims 54  to  57 . 
     
     
         59 . A chimeric antibody according to any one of  claims 35  to  39 , which is derived from a transgenic animal that comprises an artificial Ig locus comprising an artificial constant region (C) gene encoding a rat IgG CH2 and CH3 domain and optionally a human IgG CH1 domain. 
     
     
         60 . The chimeric monoclonal antibody of  claim 59 , wherein the transgenic animal from which the chimeric monoclonal antibody is derived comprises an inactivated endogenous Ig locus. 
     
     
         61 . The chimeric monoclonal antibody of  claim 60 , wherein the transgenic animal from which the chimeric monoclonal antibody is derived comprises at least one genomic meganuclease expression construct. 
     
     
         62 . A diversified repertoire of chimeric immunoglobulins according to any one of  claims 46  to  53 , which is derived from a transgenic animal that comprises an artificial Ig locus comprising an artificial constant region (C) gene encoding a rat IgG CH2 and CH3 domain and optionally a human IgG CH1 domain. 
     
     
         63 . The diversified repertoire of  claim 62 , wherein the transgenic animal from which the individual chimeric antibodies are derived comprises an inactivated endogenous Ig locus. 
     
     
         64 . The diversified repertoire of  claim 62 , wherein the transgenic animal from which the individual chimeric antibodies are derived comprises at least one genomic meganuclease expression construct.