Genetically modified non-human animals with humanized immunoglobulin locus

1. A genetically-modified rodent comprising at an endogenous heavy chain immunoglobulin gene locus human Immunoglobulin Heavy Variable (IGHV) genes, human Immunoglobulin Heavy Diversity (IGHD) genes, and human Immunoglobulin Heavy Joining (IGHJ) genes at the heavy chain immunoglobulin gene locus of human chromosome 14 from a human cell, wherein the human IGHV genes, the human IGHD genes, and the human IGHJ genes are operably linked and can undergo VDJ rearrangement, wherein a contiguous human sequence is integrated into the endogenous chromosome by recombination, and the human sequence is at least 500 kb, wherein the modification can be detected by PCR using one or more primer pairs selected from the group consisting of:

(a) SEQ ID NO: 13 and SEQ ID NO: 14;

(b) SEQ ID NO: 15 and SEQ ID NO: 16;

(c) SEQ ID NO: 17 and SEQ ID NO: 18;

(d) SEQ ID NO: 19 and SEQ ID NO: 20;

(e) SEQ ID NO: 21 and SEQ ID NO: 22;

(f) SEQ ID NO: 23 and SEQ ID NO: 24; and

(g) SEQ ID NO: 25 and SEQ ID NO: 26.

2. The rodent of claim 1 , wherein the rodent comprises a disruption in the rodent's endogenous heavy chain immunoglobulin gene locus.

3. The rodent of claim 2 , wherein the rodent is a mouse and the disruption in the endogenous heavy chain immunoglobulin gene locus comprises a deletion of a contiguous sequence starting from mouse IGHV1-85 gene to mouse IGHJ4 gene.

4. The rodent of claim 1 , wherein the rodent is homozygous with respect to the integrated human sequence at the endogenous heavy chain immunoglobulin gene locus.

5. The rodent of claim 1 , wherein the rodent comprises a disruption in the rodent's endogenous light chain immunoglobulin gene locus.

6. The rodent of claim 1 , wherein the rodent further comprises at an endogenous light chain immunoglobulin gene locus, one or more human Immunoglobulin Kappa Variable (IGKV) genes, and one or more human Immunoglobulin Kappa Joining (IGKJ) genes.

7. The rodent of claim 6 , wherein the rodent further comprises all human IGKV genes and all human IGKJ genes at the endogenous light chain immunoglobulin gene locus.

8. The rodent of claim 7 , wherein the rodent can detectably express IGKVID-12, IGKV2D-30, IGKV1-27, IGKV6-21, IGKV1-6, IGKV1-39, IGKV1-16, IGKV1-17, IGKV2D-29, IGKV3-11, IGKV1-5, IGKV1-12, IGKV1-9, IGKV3-20, IGKV3-15, IGKV2-28, IGKV2-30, IGKV1-33, IGKV4-1, IGKV6D-41, IGKV3D-11, IGKV2D-24, IGKVID-43, IGKVID-17, IGKV7-3, IGKV2D-26, IGKV1-37, IGKV2-29, IGKV1-13, IGKV5-2, IGKV2-40, IGKV3-7, IGKV3D-20, IGKV1D-8, IGKV6D-21, IGKV1-8, IGKV2-24, and IGKV3D-15.

9. The rodent of claim 1 , wherein the rodent can produce a humanized antibody.

10. A cell obtained from the rodent of claim 1 .

11. The rodent of claim 1 , wherein the rodent is a mouse.

12. The rodent of claim 1 , wherein the rodent comprises human IGHV3-64D and IGHV5-10-1 at the endogenous heavy chain immunoglobulin gene locus.

13. The rodent of claim 1 , wherein the rodent comprises human IGHV(III)-82, IGHV7-81, IGHV4-80, IGHV3-79, IGHV(II)-78-1, IGHV5-78, IGHV7-77, IGHV(III)-76-1, IGHV3-76, IGHV3-75, and IGHV(II)-74-1 at the endogenous heavy chain immunoglobulin gene locus.

14. The rodent of claim 1 , wherein the rodent can detectably express IGHV3-15, IGHV3-53, IGHV3-66, IGHV5-51, IGHV1-24, IGHV1-18, IGHV1-69, IGHV3-7, IGHV3-74, IGHV3-23, IGHV3-43, IGHV3-21, IGHV3-30-3, IGHV4-59, IGHV6-1, IGHV3-48, IGHV4-34, IGHV4-39, IGHV3-33, IGHV3-30, IGHV4-61, IGHV3-47, IGHV3-NL1, IGHV3-69-1, IGHV7-4-1, IGHV1-58, IGHV4-28, IGHV2-26, IGHV2-5, IGHV3-64, IGHV3-20, IGHV2-70, IGHV3-11, IGHV4-30-2, IGHV3-13, IGHV3-49, IGHV5-10-1, IGHV3-72, IGHV1-2, IGHV4-30-4, IGHV1-46, IGHV3-64D, IGHV1-3, IGHV3-73, IGHV4-4, and IGHV4-31.

15. The rodent of claim 1 , wherein the rodent comprises at the endogenous heavy chain immunoglobulin gene locus one short flippase recognition target (FRT) site and one loxP recognition sequence, wherein the integrated human sequence is between the FRT site and the loxP recognition sequence.

16. The rodent of claim 1 , wherein the modification can be detected by PCR using the primer pair of SEQ ID NO: 13 and SEQ ID NO: 14.

17. The rodent of claim 1 , wherein the modification can be detected by PCR using the primer pair of SEQ ID NO: 15 and SEQ ID NO: 16.

18. The rodent of claim 1 , wherein the modification can be detected by PCR using the primer pair of SEQ ID NO: 17 and SEQ ID NO: 18.

19. The rodent of claim 1 , wherein the modification can be detected by PCR using the primer pair of SEQ ID NO: 19 and SEQ ID NO: 20.

20. The rodent of claim 1 , wherein the modification can be detected by PCR using the primer pair of SEQ ID NO: 21 and SEQ ID NO: 22.

21. The rodent of claim 1 , wherein the modification can be detected by PCR using the primer pair of SEQ ID NO: 23 and SEQ ID NO: 24.

22. The rodent of claim 1 , wherein the modification can be detected by PCR using the primer pair of SEQ ID NO: 25 and SEQ ID NO: 26.