Human antibodies from transgenic rodents with multiple heavy chain immunoglobulin loci

1. A transgenic non-human rodent comprising at least one inactivated endogenous immunoglobulin (lg) locus and a plurality of artificial transgenic lg heavy chain loci integrated in the animal's genome at different chromosomal sites,

wherein a first artificial transgenic lg heavy chain locus comprises in the 5′-3′ order:

(i) an HC30 locus comprising the human variable gene segments

IgHV3-74, IgHV3-73, IgHV3-72, IgHV2-70, IgHV1-69,

IgHV3-66, IgHV3-64, IgHV4-61, IgHV4-59, IgHV1-58, IgHV3-53,

IgHV5-51, IgHV3-49, IgHV3-48, IgHV1-46, IgHV1-45, IgHV3-43,

IgHV3-21, IgHV3-20, IgHV1-18, IgHV3-15, IgHV3-13, and IgHV6-1, as illustrated in FIG. 1 B ;

(ii) human heavy chain D segments;

(iii) human heavy chain JH1-6; and

(iv) a rat constant region gene spanning from Eμ to a rat 3′ enhancer sequence; and

wherein a second artificial transgenic lg heavy chain locus comprises in the 5′-3′

(i) an HC14 locus comprising the human variable gene segments

IgHV4-39, IgHV3-38, IgHV3-35, IgHV4-34, IgHV3-33, IgHV4-31,

IgHV3-30, IgHV4-28, IgHV2-26, IgHV1-24, IgHV3-23, IgHV3-22-2,

IgHV3-11, IgHV3-9, IgHV1-8, IgHV3-7, IgHV2-5, IgHV7-4, IgHV4-4,

IgHV1-3, IgHV1-2 and IgHV6-1, as illustrated in FIG. 1 A ;

(ii) human heavy chain D segments;

(iii) human heavy chain JH1-6; and

(iv) a rat constant region gene spanning from Ell to a rat 3′ enhancer sequence.

2. The transgenic non-human rodent of claim 1 , wherein said inactivated endogenous immunoglobulin (Ig) locus lacks one of the following: a functional endogenous Ig light chain locus, or a functional endogenous Ig heavy chain locus.

3. The transgenic non-human rodent of claim 1 , wherein said transgenic non-human animal optionally lacks a functional Ig light chain locus and is capable of producing heavy chain-only antibodies.

4. The transgenic non-human rodent of claim 1 , wherein the constant region gene comprises a constant region gene selected from the group consisting of Cμ and Cγ.

5. The transgenic non-human rodent of claim 1 , comprising a nucleic acid sequence having at least 85% sequence identity to bacterial artificial chromosome (BAC) Annabel, or a portion thereof, wherein BAC Annabel has the sequence of SEQ ID NO: 10.

6. The transgenic non-human rodent of claim 1 comprising variable (V), diversity (D) and joining (J) regions structured as V-D-J regions, wherein said V-D-J regions are rearranged and form a complete exon encoding a heavy chain variable domain.

7. A method for producing antibodies, comprising immunizing the transgenic non-human rodent of claim 1 with an immunogen.

8. A method for producing a chimeric monoclonal antibody, comprising:

(i) immunizing the transgenic non-human rodent of claim 1 with an immunogen,

(ii) isolating a monoclonal antibody producing cell from said transgenic animal wherein said monoclonal antibody producing cell produces a chimeric monoclonal antibody that specifically binds to said immunogen;

(iii) using said monoclonal antibody producing cell to isolate a nucleic acid encoding the chimeric monoclonal antibody from said transgenic nonhuman rodent wherein said chimeric monoclonal antibody specifically binds to said immunogen; and

(iv) using said chimeric monoclonal antibody nucleic acid to produce said chimeric monoclonal antibody that specifically binds to said immunogen.

9. A method for producing a fully human monoclonal antibody, comprising:

(i) immunizing the transgenic non-human rodent of claim 1 with an immunogen,

(ii) isolating a monoclonal antibody producing cell from said transgenic animal wherein said monoclonal antibody producing cell produces a chimeric monoclonal antibody that specifically binds to said immunogen;

(iii) using said monoclonal antibody producing cell to isolate a nucleic acid encoding a chimeric monoclonal antibody from said transgenic non-human rodent wherein said chimeric monoclonal antibody specifically binds to said immunogen;

(iv) modifying said chimeric monoclonal antibody nucleic acid to produce a recombinant nucleic acid encoding a fully human monoclonal antibody; and

(v) using said recombinant nucleic acid encoding a fully human monoclonal antibody to produce the encoded fully human monoclonal antibody.

10. The transgenic non-human rodent of claim 1 , wherein the rat 3′ enhancer comprises the sequence set forth in SEQ ID NO: 1.