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.

Amino Acid Sequence, Animals, Base Sequence, Camelids, New World/*genetics/immunology, Exons/genetics, Gene Rearrangement, B-Lymphocyte/genetics/immunology, Genetic Markers/immunology, Humans, Immunoglobulin Heavy Chains/*biosynthesis/genetics, Immunoglobulin Variable Region/biosynthesis/genetics, Mice, Mice, Transgenic, Molecular Sequence Data, Mutant Chimeric Proteins/genetics/immunology, RNA Splice Sites/*genetics
dx.doi.org/10.1073/pnas.0601108103, hdl.handle.net/1765/14099
Proceedings of the National Academy of Sciences of the United States of America
Erasmus MC: University Medical Center Rotterdam

Janssens, R, Dekker, S, Hendriks, R.W, Panayotou, G, van Remoortere, A, San, J.K, … Drabek, D.D. (2006). Generation of heavy-chain-only antibodies in mice. Proceedings of the National Academy of Sciences of the United States of America, 103(41), 15130–15135. doi:10.1073/pnas.0601108103