Mice that make heavy chain antibodies

1. A genetically modified non-human animal whose germline genome comprises a modified endogenous non-human immunoglobulin (Ig) heavy chain locus,

wherein the modified endogenous non-human Ig heavy chain locus comprises unrearranged human Ig heavy chain variable region V H , D H , and J H gene segments operably linked to a modified endogenous non-human Ig heavy chain constant region nucleic acid sequence comprising

(i) an endogenous non-human IgG1 constant region gene modified to

(1) comprise

a nucleotide sequence comprising from 5′ to 3′: an endogenous non-human switch region, an IgG1 CH2 exon, an IgG1 CH2 intron, and an IgG1 CH3 exon, and

a deletion in a sequence encoding an IgG1 CH1 domain and an IgG1 hinge region such that the nucleotide sequence further comprises, at the deletion point, a nucleotide sequence set forth as SEQ ID NO:17, and

(2) encode an endogenous non-human IgG1 constant domain that is devoid of a CH1 domain and a hinge region and that consists essentially of an endogenous non-human IgG1 CH2 domain and an endogenous non-human IgG1 CH3 domain; and

(ii) an endogenous non-human IgM constant region gene that encodes an endogenous non-human IgM constant domain comprising an IgM CH1 domain,

such that the non-human animal expresses (i) a chimeric human/non-human IgG1 immunoglobulin heavy chain that comprises, from N-terminal to C-terminal, a human Ig heavy chain variable domain operably linked to the endogenous non-human IgG1 constant domain that is devoid of a CH1 domain and a hinge region, and that consists essentially of an endogenous non-human IgG1 CH2 domain and an endogenous non-human IgG1 CH3 domain, and (ii) a chimeric human/non-human IgM immunoglobulin heavy chain that comprises a human Ig heavy chain variable domain operably linked to the endogenous non-human IgM constant domain comprising an IgM CH1 domain; and

wherein the non-human animal is a rat or a mouse.

2. The non-human animal of claim 1 , wherein the non-human animal expresses:

(a) antibodies comprising an endogenous non-human IgG3 constant domain comprising an IgG3 CH1 domain, an IgG3 hinge region, an IgG3 CH2 domain, and an IgG3 CH3 domain;

(b) antibodies comprising an endogenous non-human IgG2a constant domain comprising an IgG2a CH1 domain, an IgG2a hinge region, an IgG2a CH2 domain, and an IgG2a CH3 domain; and

(c) antibodies comprising an endogenous non-human IgG2b constant domain comprising an IgG2b CH1 domain, an IgG2b hinge region, an IgG2b CH2 domain, and an IgG2b CH3 domain.

3. The non-human animal of claim 2 , further characterized in that the non-human animal additionally expresses:

(d) antibodies comprising an endogenous non-human IgD constant domain comprising an IgD CH1 domain, an IgD hinge region, an IgD CH2 domain, and an IgD CH3 domain;

(e) antibodies comprising an endogenous non-human IgA constant domain comprising an IgA CH1 domain, an IgA hinge region, an IgA CH2 domain, and an IgA CH3 domain; and

(g) antibodies comprising an endogenous non-human IgE constant domain comprising an IgE CH1 domain, an IgE CH2 domain, and an IgE CH3 domain.

4. The non-human animal of claim 1 , wherein the non-human animal expresses the chimeric human/non-human IgM immunoglobulin heavy chain associated with a cognate light chain.

5. The non-human animal of claim 1 , wherein the non-human animal is from a mouse strain selected from the group consisting of a 129 strain, a C57BL/6 strain, and a mixed 129xC57BL/6 strain.

6. The non-human animal of claim 5 , wherein the mouse is 50% 129 and 50% C57BL/6.

7. The non-human animal of claim 1 , wherein the unrearranged human Ig heavy chain variable region V H , D H , and J H gene segments replace one or more endogenous non-human Ig heavy chain variable region gene segments.

8. The non-human animal of claim 1 , wherein the modified endogenous non-human Ig heavy chain constant region nucleic acid sequence further comprises:

(iii) a deletion of an endogenous non-human IgD constant region gene;

(iv) a deletion of an endogenous non-human IgG3 constant region gene;

(v) a deletion of an endogenous non-human IgG2b constant region gene;

(vi) a deletion of an endogenous non-human IgE constant region gene; and

(vii) a deletion of an endogenous non-human IgA constant region gene.

9. The non-human animal of claim 1 , wherein the modified endogenous non-human Ig heavy chain constant region nucleic acid sequence further comprises:

(iii) a deletion of an endogenous non-human IgD constant region gene;

(iv) a deletion of an endogenous non-human IgG3 constant region gene;

(v) a deletion of an endogenous non-human IgG2a constant region gene;

(vi) a deletion of an endogenous non-human IgG2b constant region gene;

(vii) a deletion of an endogenous non-human IgE constant region gene; and

(viii) a deletion of an endogenous non-human IgA constant region gene.

10. A non-human animal B cell isolated from the non-human animal of claim 1 , comprising a rearranged human Ig heavy chain variable region gene operably linked to the endogenous non-human IgG1 constant region gene modified to

(1) comprise

a nucleotide sequence comprising from 5′ to 3′: an endogenous non-human switch region, an IgG1 CH2 exon, an IgG1 CH2 intron, and an IgG1 CH3 exon, and

a deletion in a sequence encoding an IgG1 CH1 domain and an IgG1 hinge region such that the nucleotide sequence further comprises, at the deletion point, a nucleotide sequence set forth as SEQ ID NO:17, and

(2) encode an endogenous non-human IgG1 constant domain that is devoid of a CH1 domain and hinge region, and that consists essentially of an endogenous non-human IgG1 CH2 domain and an endogenous non-human IgG1 CH3 domain,

wherein the rearranged human Ig heavy chain variable region gene encodes a human heavy chain variable domain, and

wherein the non-human animal B cell is a rat B cell or a mouse B cell.

11. The non-human animal B cell of claim 10 , wherein the B cell secretes

an IgG1 antibody comprising a chimeric human/non-human IgG1 immunoglobulin heavy chain comprising, from N-terminal to C-terminal, a human Ig heavy chain variable domain operably linked to an endogenous non-human IgG1 constant domain that is devoid of a CH1 domain and a hinge region, and that consists essentially of an endogenous non-human IgG1 CH2 domain and an endogenous non-human IgG1 CH3 domain.

12. A human heavy chain variable domain isolated from the non-human animal B cell of claim 10 , or from a hybridoma produced therefrom.

13. A hybridoma made from the B cell of claim 10 .

14. A nucleic acid comprising a rearranged human heavy chain variable region gene that encodes a human heavy chain variable domain isolated from the non-human B cell of claim 10 , or from a hybridoma produced therefrom.

15. A method for isolating a human Ig heavy chain variable domain and/or a rearranged human Ig heavy chain variable region gene encoding the same comprising:

obtaining a lymphocyte from the non-human animal of claim 1 , or hybridoma produced therefrom, wherein the lymphocyte or hybridoma expresses:

(i) a chimeric human/non-human IgG1 immunoglobulin heavy chain that comprises, from N-terminal to C-terminal, the human Ig heavy chain variable domain operably linked to the endogenous non-human IgG1 constant domain that is devoid of a CH1 domain and a hinge region, and that consists essentially of an endogenous non-human IgG1 CH2 domain and an endogenous non-human IgG1 CH3 domain, or

(ii) a chimeric human/non-human IgM immunoglobulin heavy chain that comprises the human Ig heavy chain variable domain operably linked to the endogenous non-human IgM constant domain comprising an IgM CH1 domain; and

isolating the human Ig heavy chain variable domain and/or the rearranged human Ig heavy chain variable region gene encoding the same from the isolated lymphocyte, or hybridoma produced therefrom.

16. The method of claim 15 , further comprising expressing the rearranged human Ig heavy chain variable region gene encoding the human Ig heavy chain variable domain in a host cell.

17. A non-human animal embryonic stem (ES) cell comprising in its genome a modified endogenous non-human Ig heavy chain locus that comprises unrearranged human Ig heavy chain variable region V H , D H , and J H gene segments operably linked to a modified endogenous non-human Ig heavy chain constant region nucleic acid sequence comprising

(i) an endogenous non-human IgG1 constant region gene modified to

(1) comprise

a nucleotide sequence comprising from 5′ to 3′: an endogenous non-human switch region, an IgG1 CH2 exon, an IgG1 CH2 intron, and an IgG1 CH3 exon, and

a deletion in a sequence encoding an IgG1 CH1 domain and an IgG1 hinge region such that the nucleotide sequence further comprises, at the deletion point, a nucleotide sequence set forth as SEQ ID NO:17, and

(2) encode an endogenous non-human IgG1 constant domain that is devoid of a CH1 domain and hinge region, and that consists essentially of an endogenous non-human IgG1 CH2 domain and an endogenous non-human IgG1 CH3 domain; and

(ii) an endogenous non-human IgM constant region gene that encodes an endogenous non-human IgM constant domain comprising an IgM CH1 domain,

wherein the unrearranged human Ig heavy chain variable region V H , D H , and J H gene segments are capable of recombining in a B cell of a non-human animal to form a rearranged human Ig heavy chain variable region gene operably linked to the modified endogenous non-human Ig heavy chain constant region such that the modified endogenous non-human Ig heavy chain locus in the B cell encodes i) a chimeric human/non-human IgG1 immunoglobulin heavy chain that comprises, from N-terminal to C-terminal, a human Ig heavy chain variable domain operably linked to the endogenous non-human IgG1 constant domain that is devoid of a CH1 domain and a hinge region, and that consists essentially of an endogenous non-human IgG1 CH2 domain and an endogenous non-human IgG1 CH3 domain, and (ii) a chimeric human/non-human IgM immunoglobulin heavy chain that comprises a human Ig heavy chain variable domain operably linked to the endogenous non-human IgM constant domain comprising an IgM CH1 domain, and

wherein the non-human animal ES cell is a rat ES cell or a mouse ES cell, and the non-human animal is a rat or a mouse.

18. The non-human animal ES cell of claim 17 , wherein the ES cell is from a mouse strain selected from the group consisting of a 129 strain, a C57BL/6 strain, and a mixed 129xC57BL/6 strain.

19. The non-human animal ES cell of claim 18 , wherein the ES cell is 50% 129 and 50% C57BL/6.

20. A mouse embryo made from or comprising the non-human animal ES cell of claim 18 .

21. A non-human animal embryo made from or comprising the non-human animal ES cell of claim 17 , wherein the non-human animal embryo is a rat embryo or a mouse embryo.

22. The non-human animal ES cell of claim 17 , wherein the modified endogenous non-human Ig heavy chain constant region nucleic acid sequence further comprises a deletion of an endogenous non-human IgG2a constant region gene and a deletion of an endogenous non-human IgG2b constant region gene.

23. The non-human animal ES cell of claim 17 , wherein the modified endogenous non-human Ig heavy chain constant region nucleic acid sequence further comprises:

(iii) a deletion of an endogenous non-human IgD constant region gene;

(iv) a deletion of an endogenous non-human IgG3 constant region gene;

(v) a deletion of an endogenous non-human IgG2b constant region gene;

(vi) a deletion of an endogenous non-human IgE constant region gene; and

(vii) a deletion of an endogenous non-human IgA constant region gene.

24. The non-human animal ES cell of claim 17 , wherein the modified endogenous non-human Ig heavy chain constant region nucleic acid sequence further comprises:

(iii) a deletion of an endogenous non-human IgD constant region gene;

(iv) a deletion of an endogenous non-human IgG3 constant region gene;

(v) a deletion of an endogenous non-human IgG2a constant region gene;

(vi) a deletion of an endogenous non-human IgG2b constant region gene;

(vii) a deletion of an endogenous non-human IgE constant region gene; and

(viii) a deletion of an endogenous non-human IgA constant region gene.