US2015113669A1PendingUtilityA1

Animal Models and Therapeutic Molecules

69
Assignee: KYMAB LTDPriority: Jul 8, 2009Filed: Sep 25, 2014Published: Apr 23, 2015
Est. expiryJul 8, 2029(~2.9 yrs left)· nominal 20-yr term from priority
Inventors:Allan BradleyE-Chiang LeeQi LiangWei Wang
A01K 67/0275C07K 16/18C07K 16/1239C07K 2317/92C07K 2317/565C07K 2317/51C07K 2317/21C07K 2317/14A01K 2217/072C12N 2015/8518C07K 2317/76C07K 2317/567C07K 2317/52C07K 2317/515C07K 16/1203A61K 2039/505A61K 39/35A61K 39/107A01K 2217/15A01K 2217/075A01K 67/0276A01K 67/0271C07K 16/462C07K 2317/24C12N 15/8509C07K 16/00A01K 2267/01A01K 2227/105A01K 2217/052A01K 2207/15C07K 2317/56A01K 2217/05A01K 67/0278A61P 37/02A01K 67/027C07K 16/461C12N 5/0606C12N 15/85
69
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Claims

Abstract

The invention discloses methods for the generation of chimaeric human—non-human antibodies and chimaeric antibody chains, antibodies and antibody chains so produced, and derivatives thereof including fully humanised antibodies; compositions comprising said antibodies, antibody chains and derivatives, as well as cells, non-human mammals and vectors, suitable for use in said methods.

Claims

exact text as granted — not AI-modified
1 - 146 . (canceled) 
     
     
         147 . A genetically modified mouse whose genome comprises:
 (a) an ADAM6 gene away from its endogenous locus position; and   (b) a human immunoglobulin heavy chain variable region locus comprising an insertion of one or more human VH gene segments, one or more human DH gene segments, and one or more human JH gene segments into the endogenous mouse heavy chain locus,   wherein the human VH, DH and JH gene segments are operably linked to a heavy chain constant region gene; so that the mouse is characterized in that:   (i) it is fertile; and   (ii) when it is immunized with an antigen, it generates antibodies comprising heavy chain variable domains encoded by the one or more human VH, one or more human DH, and one or more human JH gene segments, linked to heavy chain constant domains encoded by the heavy chain constant region gene, wherein the antibodies show specific binding to the antigen.   
     
     
         148 . The mouse of  claim 147 , wherein the one or more human VH gene segments, one or more human DH gene segments, and one or more human JH gene segments are inserted into mouse chromosome 12. 
     
     
         149 . The mouse of  claim 147 , wherein the ADAM6 gene is moved away from its endogenous locus position. 
     
     
         150 . The mouse of  claim 147 , wherein the ADAM6 gene position results from an insertion of one or more human VH gene segments into mouse chromosome 12. 
     
     
         151 . The mouse of  claim 147 , wherein the ADAM6 gene position results from an inversion of mouse chromosome 12 from coordinate 119753123 to coordinate 114666436, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         152 . The mouse of  claim 147 , wherein the ADAM6 gene position results from an inversion of mouse chromosome 12 from coordinate 119659458 to coordinate 114666436, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         153 . The mouse of  claim 147 , wherein the ADAM6 gene position results from an inversion of mouse chromosome 12 from coordinate 12091806 to coordinate 114666436, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         154 . The mouse of  claim 147 , wherein the insertion of one or more human VH gene segments, one or more human DH gene segments, and one or more human JH gene segments is between coordinates 114,667,090 and 114,665,190 on mouse chromosome 12, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         155 . The mouse of  claim 147 , wherein the insertion of one or more human VH gene segments, one or more human DH gene segments, and one or more human JH gene segments is at coordinate 114,667,091, after 114,667,090 on mouse chromosome 12, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         156 . The mouse of  claim 147 , wherein the insertion of one or more human VH gene segments, one or more human DH gene segments, and one or more human JH gene segments is between coordinates 114,667,089 and 114,667,090 on mouse chromosome 12, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         157 . The mouse of  claim 147 , wherein the insertion of one or more human VH gene segments, one or more human DH gene segments, and one or more human JH gene segments is between coordinates 114,666,183 and 114,666,725 on mouse chromosome 12, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         158 . The mouse of  claim 147 , wherein the insertion of one or more human VH gene segments, one or more human DH gene segments, and one or more human JH gene segments is between coordinates 114,666,435 and 114,666,436 on mouse chromosome 12, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         159 . The mouse of  claim 147 , wherein the mouse is of the C57BL/6J strain. 
     
     
         160 . The mouse of  claim 147 , wherein the mouse is of the 129/SvJ strain. 
     
     
         161 . The mouse of  claim 147 , wherein the ADAM6 gene is present at a position other than the human heavy chain variable gene locus. 
     
     
         162 . The mouse of  claim 147 , wherein the ADAM6 gene includes mouse ADAM6a gene and/or mouse ADAM6b gene. 
     
     
         163 . The mouse of  claim 147 , wherein the one or more human VH gene segments includes at least 11 human VH gene segments. 
     
     
         164 . The mouse of  claim 147 , wherein the human immunoglobulin heavy chain variable region locus comprises at least 11 human VH gene segments, at least 27 human DH gene segments, and at least 6 human JH gene segments. 
     
     
         165 . The mouse of  claim 147 , wherein the human immunoglobulin heavy chain variable region locus comprises 51 human VH gene segments, 27 human DH gene segments, and 6 human JH gene segments. 
     
     
         166 . The mouse of  claim 147 , wherein the constant region gene is a mouse constant region gene. 
     
     
         167 . The mouse of  claim 147 , further comprising an insertion of one or more human Vκ gene segments and one or more human Jκ gene segments into the endogenous κ light chain locus. 
     
     
         168 . The mouse of  claim 167 , wherein the one or more human Vκ gene segments and one or more human Jκ gene segments are inserted into mouse chromosome 6. 
     
     
         169 . The mouse of  claim 167 , wherein the insertion of one or more human Vκ gene segments and one or more human Jκ gene segments is between coordinates 70673899 and 70675515 on mouse chromosome 6, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         170 . The mouse of  claim 167 , wherein the insertion of one or more human Vκ gene segments and one or more human Jκ gene segments is between coordinates 70673918 and 70675517 on mouse chromosome 6, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         171 . The mouse of  claim 167 , wherein the one or more human Vκ gene segments and one or more human Jκ gene segments are operably linked to a rodent light chain constant region gene. 
     
     
         172 . An isolated mouse cell whose genome comprises:
 (a) an ADAM6 gene away from its endogenous locus position; and   (b) a human immunoglobulin heavy chain variable region locus comprising an insertion of one or more human VH gene segments, one or more human DH gene segments, and one or more human JH gene segments into the endogenous heavy chain locus, wherein the human VH, DH and JH gene segments are operably linked to a heavy chain constant region gene.   
     
     
         173 . The isolated cell of  claim 172 , wherein the one or more human VH gene segments, one or more human DH gene segments, and one or more human JH gene segments are inserted into mouse chromosome 12. 
     
     
         174 . The isolated cell of  claim 172 , wherein the ADAM6 gene is moved away from its endogenous locus position. 
     
     
         175 . The isolated cell of  claim 172 , wherein the ADAM6 gene position results from an insertion of one or more human VH gene segments into mouse chromosome 12. 
     
     
         176 . The isolated cell of  claim 172 , wherein the ADAM6 gene position results from an inversion of mouse chromosome 12 from coordinate 119753123 to coordinate 114666436, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         177 . The isolated cell of  claim 172 , wherein the ADAM6 gene position results from an inversion of mouse chromosome 12 from coordinate 119659458 to coordinate 114666436, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         178 . The isolated cell of  claim 172 , wherein the ADAM6 gene position results from an inversion of mouse chromosome 12 from coordinate 12091806 to coordinate 114666436, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         179 . The isolated cell of  claim 172 , wherein the insertion of one or more human VH gene segments, one or more human DH gene segments, and one or more human JH gene segments is between coordinates 114,667,090 and 114,665,190 on mouse chromosome 12, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         180 . The isolated cell of  claim 172 , wherein the insertion of one or more human VH gene segments, one or more human DH gene segments, and one or more human JH gene segments is at coordinate 114,667,091, after 114,667,090 on mouse chromosome 12, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         181 . The isolated cell of  claim 172 , wherein the insertion of one or more human VH gene segments, one or more human DH gene segments, and one or more human JH gene segments is between coordinates 114,667,089 and 114,667,090 on mouse chromosome 12, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         182 . The isolated cell of  claim 172 , wherein the insertion of one or more human VH gene segments, one or more human DH gene segments, and one or more human JH gene segments is between coordinates 114,666,183 and 114,666,725 on mouse chromosome 12, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         183 . The isolated cell of  claim 172 , wherein the insertion of one or more human VH gene segments, one or more human DH gene segments, and one or more human JH gene segments is between coordinates 114,666,435 and 114,666,436 on mouse chromosome 12, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         184 . The isolated cell of  claim 172 , wherein the mouse is of the C57BL/6J strain. 
     
     
         185 . The isolated cell of  claim 172 , wherein the mouse is of the 129/SvJ strain. 
     
     
         186 . The isolated cell of  claim 172 , wherein the cell is an embryonic stem cell. 
     
     
         187 . A mouse embryo generated from the embryonic stem cell of  claim 186 . 
     
     
         188 . The isolated cell of  claim 172 , wherein the cell is a B cell. 
     
     
         189 . A hybridoma made from the B cell of  claim 188 . 
     
     
         190 . An immortalized cell made from the isolated cell of  claim 172 . 
     
     
         191 . A method of providing an antibody specific for an antigen of interest, the method comprising the steps of:
 (a) immunizing a mouse of  claim 147  with the antigen of interest, which mouse has a genome comprising (a) and (b) of  claim 147 ;   (b) isolating at least one B cell from the mouse producing an antibody specific against the antigen; and   (c) culturing at least one cell producing the antibody of step b) and obtaining said produced antibody.   
     
     
         192 . The method of  claim 191 , wherein step (c) further comprises making a hybridoma employing the cell of step (b) and culturing the hybridoma. 
     
     
         193 . The method of  claim 191 , wherein the at least one B cell obtained in step (b) is derived from the spleen of the mouse from step (a). 
     
     
         194 . The method of  claim 191 , wherein immunizing with the antigen of interest in step (a) is carried out with protein. 
     
     
         195 . A mouse whose genome comprises
 (a) an insertion of one or more human VH, one or more human DH, and one or more human JH gene segments upstream of an endogenous heavy chain constant region gene; and   (b) an insertion of one or more human VL and one or more human JL gene segments upstream of an endogenous light chain constant region gene; and   (c) a nucleic acid sequence that encodes an Adam6 protein away from its endogenous locus position wherein the Adam6 protein is functional in the mouse, so that the mouse is characterized in that:   (i) it is fertile; and   (ii) when it is immunized with an antigen, it generates antibodies comprising:
 (A) heavy chain variable domains encoded by the one or more human VH, one or more human DH, and one or more human JH gene segments, linked to heavy chain constant domains encoded by the heavy chain constant region gene; and 
 (B) light chain variable domains encoded by the one or more human VL and one or more human JL gene segments linked to light chain constant domains encoded by the endogenous light chain constant region gene, 
   wherein the antibodies specifically bind the antigen.   
     
     
         196 . The mouse of  claim 195 , wherein the nucleic acid sequence that encodes an Adam6 protein is moved away from its endogenous locus position. 
     
     
         197 . The mouse of  claim 195 , wherein the nucleic acid sequence position results from an insertion of one or more human VH gene segments into mouse chromosome 12. 
     
     
         198 . The mouse of  claim 195 , wherein the insertion of one or more human VH, one or more human DH, and one or more human JH gene segments is between coordinates 114,667,090 and 114,665,190 on mouse chromosome 12, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         199 . The mouse of  claim 195 , wherein the insertion of one or more human VH, one or more human DH, and one or more human JH gene segments is at coordinate 114,667,091, after 114,667,090 on mouse chromosome 12, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         200 . The mouse of  claim 195 , wherein the insertion of one or more human VH, one or more human DH, and one or more human JH gene segments is between coordinates 114,667,089 and 114,667,090 on mouse chromosome 12, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         201 . The mouse of  claim 195 , wherein the insertion of one or more human VH, one or more human DH, and one or more human JH gene segments is between coordinates 114,666,183 and 114,666,725 on mouse chromosome 12, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         202 . The mouse of  claim 195 , wherein the insertion of one or more human VH, one or more human DH, and one or more human JH gene segments is between coordinates 114,666,435 and 114,666,436 on mouse chromosome 12, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         203 . The mouse of  claim 195 , wherein the nucleic acid sequence position results from an inversion of mouse chromosome 12 from coordinate 119753123 to coordinate 114666436, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         204 . The mouse of  claim 195 , wherein the nucleic acid sequence position results from an inversion of mouse chromosome 12 from coordinate 119659458 to coordinate 114666436, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         205 . The mouse of  claim 195 , wherein the nucleic acid sequence position results from an inversion of mouse chromosome 12 from coordinate 12091806 to coordinate 114666436, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         206 . The mouse of  claim 195 , wherein the insertion of one or more human VL and one or more human JL gene segments is between coordinates 70,673,899 and 70,675,515 on mouse chromosome 6, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         207 . The mouse of  claim 195 , wherein the insertion of one or more human VL and one or more human JL gene segments is between coordinates 70,673,918 and 70,675,517 on mouse chromosome 6, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         208 . The mouse of  claim 195 , wherein the insertion of one or more human VL and one or more human JL gene segments is between coordinates 19,027,763 and 19,061,845 on mouse chromosome 16, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         209 . The mouse of  claim 195 , wherein the mouse is of the C57BL/6J strain. 
     
     
         210 . The mouse of  claim 195 , wherein the mouse is of the 129/SvJ strain. 
     
     
         211 . The mouse of  claim 195 , wherein the nucleic acid sequence that encodes an Adam6 protein away from its endogenous locus position is present at the endogenous heavy chain locus. 
     
     
         212 . The mouse of  claim 195 , wherein the insertion comprises at least 11 human VH, at least 27 human DH, and at least 6 human JH gene segments. 
     
     
         213 . The mouse of  claim 195 , wherein the insertion comprises 51 human VH, 27 human DH, and 6 human JH gene segments. 
     
     
         214 . The mouse of  claim 195 , wherein the mouse endogenous VH, DH and JH gene segments are inactivated. 
     
     
         215 . The mouse of  claim 195 , wherein the one or more human VL and one or more human JL gene segments are Vκ and Jκ gene segments. 
     
     
         216 . The mouse of  claim 215 , wherein the endogenous light chain constant region is a mouse Cκ region. 
     
     
         217 . The mouse of  claim 215 , wherein the insertion comprises 40 human Vκ and 5 human Jκ gene segments. 
     
     
         218 . The mouse of  claim 215 , wherein the mouse endogenous Vκ and Jκ gene segments are inactivated. 
     
     
         219 . An isolated mouse cell whose genome comprises:
 (a) an insertion of one or more human VH, one or more human DH, and one or more human JH gene segments upstream of an endogenous heavy chain constant region; and   (b) an insertion of one or more human VL and one or more human JL gene segments upstream of an endogenous light chain constant region; and   (c) a nucleic acid sequence that encodes an Adam6 protein away from its endogenous locus position wherein the Adam6 protein is functional in the mouse.   
     
     
         220 . The isolated cell of  claim 219 , wherein the nucleic acid sequence that encodes an Adam6 protein is moved away from its endogenous locus position. 
     
     
         221 . The isolated cell of  claim 219 , wherein the nucleic acid sequence position results from an insertion of one or more human VH gene segments into mouse chromosome 12. 
     
     
         222 . The isolated cell of  claim 219 , wherein the insertion of one or more human VH, one or more human DH, and one or more human JH gene segments is between coordinates 114,667,090 and 114,665,190 on mouse chromosome 12, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         223 . The isolated cell of  claim 219 , wherein the insertion of one or more human VH, one or more human DH, and one or more human JH gene segments is at coordinate 114,667,091, after 114,667,090 on mouse chromosome 12, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         224 . The isolated cell of  claim 219 , wherein the insertion of one or more human VH, one or more human DH, and one or more human JH gene segments is between coordinates 114,667,089 and 114,667,090 on mouse chromosome 12, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         225 . The isolated cell of  claim 219 , wherein the insertion of one or more human VH, one or more human DH, and one or more human JH gene segments is between coordinates 114,666,183 and 114,666,725 on mouse chromosome 12, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         226 . The isolated cell of  claim 219 , wherein the insertion of one or more human VH, one or more human DH, and one or more human JH gene segments is between coordinates 114,666,435 and 114,666,436 on mouse chromosome 12, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         227 . The isolated cell of  claim 219 , wherein the nucleic acid sequence position results from an inversion of mouse chromosome 12 from coordinate 119753123 to coordinate 114666436, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         228 . The isolated cell of  claim 219 , wherein the nucleic acid sequence position results from an inversion of mouse chromosome 12 from coordinate 119659458 to coordinate 114666436, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         229 . The isolated cell of  claim 219 , wherein the nucleic acid sequence position results from an inversion of mouse chromosome 12 from coordinate 12091806 to coordinate 114666436, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         230 . The isolated cell of  claim 219 , wherein the insertion of one or more human VL and one or more human JL gene segments is between coordinates 70,673,899 and 70,675,515 on mouse chromosome 6, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         231 . The isolated cell of  claim 219 , wherein the insertion of one or more human VL and one or more human JL gene segments is between coordinates 70,673,918 and 70,675,517 on mouse chromosome 6, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         232 . The isolated cell of  claim 219 , wherein the insertion of one or more human VL and one or more human JL gene segments is between coordinates 19,027,763 and 19,061,845 on mouse chromosome 16, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         233 . The isolated cell of  claim 219 , wherein the mouse is of the C57BL/6J strain. 
     
     
         234 . The isolated cell of  claim 219 , wherein the mouse is of the 129/SvJ strain. 
     
     
         235 . The isolated cell of  claim 219 , wherein the cell is an embryonic stem (ES) cell. 
     
     
         236 . A method of making a mouse comprising introducing the ES cell of  claim 235  into a host embryo gestating the host embryo in a surrogate mother, and allowing the surrogate mother to give birth to progeny derived in whole or in part from the ES cell. 
     
     
         237 . The isolated cell of  claim 219 , wherein the cell is a B cell. 
     
     
         238 . A hybridoma made from the B cell of  claim 237 . 
     
     
         239 . A mouse comprising
 (a) an insertion of one or more human VH, one or more human DH, and one or more human JH gene segments upstream of an endogenous heavy chain constant region; and   (b) an insertion of one or more human VL and one or more human JL gene segments upstream of an endogenous light chain constant region; and   (c) a nucleic acid sequence that encodes an Adam6 protein away from its endogenous locus position wherein the Adam6 protein is functional in the mouse.   
     
     
         240 . The mouse of  claim 239 , wherein the nucleic acid sequence that encodes an Adam6 protein is moved away from its endogenous locus position. 
     
     
         241 . The mouse of  claim 239 , wherein the nucleic acid sequence position results from an insertion of one or more human VH gene segments into mouse chromosome 12. 
     
     
         242 . The mouse of  claim 239 , wherein the insertion of one or more human VH, one or more human DH, and one or more human JH gene segments is between coordinates 114,667,090 and 114,665,190 on mouse chromosome 12, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         243 . The mouse of  claim 239 , wherein the insertion of one or more human VH, one or more human DH, and one or more human JH gene segments is at coordinate 114,667,091, after 114,667,090 on mouse chromosome 12, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         244 . The mouse of  claim 239 , wherein the insertion of one or more human VH, one or more human DH, and one or more human JH gene segments is between coordinates 114,667,089 and 114,667,090 on mouse chromosome 12, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         245 . The mouse of  claim 239 , wherein the insertion of one or more human VH, one or more human DH, and one or more human JH gene segments is between coordinates 114,666,183 and 114,666,725 on mouse chromosome 12, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         246 . The mouse of  claim 239 , wherein the insertion of one or more human VH, one or more human DH, and one or more human JH gene segments is between coordinates 114,666,435 and 114,666,436 on mouse chromosome 12, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         247 . The mouse of  claim 239 , wherein the nucleic acid sequence position results from an inversion of mouse chromosome 12 from coordinate 119753123 to coordinate 114666436, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         248 . The mouse of  claim 239 , wherein the nucleic acid sequence position results from an inversion of mouse chromosome 12 from coordinate 119659458 to coordinate 114666436, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         249 . The mouse of  claim 239 , wherein the nucleic acid sequence position results from an inversion of mouse chromosome 12 from coordinate 12091806 to coordinate 114666436, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         250 . The mouse of  claim 239 , wherein the insertion of one or more human VL and one or more human JL gene segments is between coordinates 70,673,899 and 70,675,515 on mouse chromosome 6, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         251 . The mouse of  claim 239 , wherein the insertion of one or more human VL and one or more human JL gene segments is between coordinates 70,673,918 and 70,675,517 on mouse chromosome 6, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         252 . The mouse of  claim 239 , wherein the insertion of one or more human VL and one or more human JL gene segments is between coordinates 19,027,763 and 19,061,845 on mouse chromosome 16, wherein the coordinates correspond to NCBIM37 for the mouse C57BL/6J strain. 
     
     
         253 . The mouse of  claim 239 , wherein the mouse is of the C57BL/6J strain. 
     
     
         254 . The mouse of  claim 239 , wherein the mouse is of the 129/SvJ strain. 
     
     
         255 . The mouse of  claim 239 , wherein the nucleic acid sequence that encodes an Adam6 protein away from its endogenous locus position is present at the endogenous heavy chain locus. 
     
     
         256 . The mouse of  claim 239 , wherein the insertion comprises at least 11 human VH, at least 27 human DH, and at least 6 human JH gene segments. 
     
     
         257 . The mouse of  claim 239 , wherein the insertion comprises 51 human VH, 27 human DH, and 6 human JH gene segments. 
     
     
         258 . The mouse of  claim 239 , wherein the mouse endogenous VH, DH and JH gene segments are inactivated. 
     
     
         259 . The mouse of  claim 239 , wherein the one or more human VL and one or more human JL gene segments are Vκ and Jκ gene segments. 
     
     
         260 . The mouse of  claim 259 , wherein the endogenous light chain constant region is a mouse Cκ region. 
     
     
         261 . The mouse of  claim 259 , wherein the insertion comprises 40 human Vκ and 5 human Jκ gene segments. 
     
     
         262 . The mouse of  claim 259 , wherein the mouse endogenous Vκ and Jκ gene segments are inactivated. 
     
     
         263 . An isolated cell of the mouse of  claim 239 . 
     
     
         264 . The isolated cell of  claim 263 , wherein the cell is an embryonic stem (ES) cell. 
     
     
         265 . A method of making a mouse using the ES cell of  claim 264 . 
     
     
         266 . The isolated cell of  claim 263 , wherein the cell is a B cell. 
     
     
         267 . A hybridoma made from the B cell of  claim 266 .

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