Transgenic mammals having human ig loci including plural vh and vk regions and antibodies produced therefrom

Abstract

The present invention relates to transgenic non-human animals that are engineered to contain human immunoglobulin gene loci. In particular, animals in accordance with the invention possess human Ig loci that include plural variable (V H and V K ) gene regions. Advantageously, the inclusion of plural variable region genes enhances the specificity and diversity of human antibodies produced by the animal. Further, the inclusion of such regions enhances and reconstitutes B-cell development to the animals, such that the animals possess abundant mature B-cells secreting extremely high affinity antibodies.

1 . A transgenic non-human mammal having a genome, the genome comprising modifications, the modifications comprising:
 an inactivated endogenous immunoglobulin (Ig) locus, such that the mammal would not display normal B-cell development;   an inserted human heavy chain Ig locus in substantially germline configuration, the human heavy chain Ig locus comprising a human mu constant region and regulatory and switch sequences thereto, a plurality of human J H  genes, a plurality of human D H  genes, and a plurality of human V H  genes; and   an inserted human kappa light chain Ig locus in substantially germline configuration, the human kappa light chain Ig locus comprising a human kappa constant region, a plurality of Jκ genes, and a plurality of V κ  genes,   wherein the number of V H  and V K  genes inserted are selected to substantially restore normal B-cell development in the mammal.   
     
     
         2 - 15 . (canceled) 
     
     
         16 . A method for the production of human antibodies, comprising:
 inoculating a mammal of anyone of  claim 1  with an antigen;   collecting and immortalizing lymphocytic cells to obtain immortal cell lines secreting human antibodies that specifically bind to the antigen with an affinity of greater than 10 9 M −1 ;  and   isolating the antibodies from the immortal cell lines.   
     
     
         17 - 22 . (canceled) 
     
     
         23 . An anti-TNF-α antibody produced by the method of  claim 16 . 
     
     
         24 - 28 . (canceled)