Generation of heavy-chain-only antibodies in mice.
We have generated transgenic mice containing hybrid llama/human antibody loci that contain two llama variable regions and the human D, J, and Cmu and/or Cgamma constant regions. Such loci rearrange productively and rescue B cell development efficiently without LC rearrangement. Heavy-chain-only antibodies (HCAb) are expressed at high levels, provided that the CH1 domain is deleted from the constant regions. HCAb production does not require an IgM stage for effective pre-B cell signaling. Antigen-specific heavy-chain-only IgM or IgGs are produced upon immunization. The IgG is dimeric, whereas IgM is multimeric. The chimeric HCAb loci are subject to allelic exclusion, but several copies of the transgenic locus can be rearranged and expressed successfully on the same allele in the same cell. Such cells are not subject to negative selection. The mice produce a full antibody repertoire and provide a previously undescribed avenue to produce specific human HCAb in the future.
Janssens
Rick
R
*Departments of Cell Biology and Immunology, ErasmusMC, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands.
Dekker
Sylvia
S
Hendriks
Rudi W
RW
Panayotou
George
G
van Remoortere
Alexandra
A
San
John Kong-a
JK
Grosveld
Frank
F
Drabek
Dubravka
D
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002161:Camelids, New World / Q000235:genetics* / Q000276:immunology; D005091:Exons / Q000235:genetics; D015322:Gene Rearrangement, B-Lymphocyte / Q000235:genetics / Q000276:immunology; D005819:Genetic Markers / Q000276:immunology; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis* / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D050506:Mutant Chimeric Proteins / Q000235:genetics / Q000276:immunology; D022821:RNA Splice Sites / Q000235:genetics*
D005819:Genetic Markers; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D050506:Mutant Chimeric Proteins; D022821:RNA Splice Sites