High-Affinity IgG Antibodies Develop Naturally in Ig-Knockout Rats Carrying Germline Human IgH/Ig kappa/Ig lambda Loci Bearing the Rat C-H Region

作者：O**orn Michael J; Ma Biao; Avis Suzanne; Binnie Ashleigh; Dilley Jeanette; Yang Xi; Lindquist Kevin; Menoret Severine; Iscache Anne Laure; Ouisse Laure Helene; Rajpal Arvind; Anegon Ignacio; Neuberger Michael S; Buelow Roland; Brueggemann Marianne

来源：The Journal of Immunology, 2013, 190(4): 1481-1490.

DOI：10.4049/jimmunol.1203041

Mice transgenic for human Ig loci are an invaluable resource for the production of human Abs. However, such mice often do not yield human mAbs as effectively as conventional mice yield mouse mAbs. Suboptimal efficacy in delivery of human Abs might reflect imperfect interaction between the human membrane IgH chains and the mouse cellular signaling machinery. To obviate this problem, in this study we generated a humanized rat strain (OmniRat) carrying a chimeric human/rat IgH locus (comprising 22 human V(H)s, all human D and J(H) segments in natural configuration linked to the rat C-H locus) together with fully human IgL loci (12 V kappa s linked to J kappa-C kappa and 16 V lambda s linked to J lambda-C lambda). The endogenous Ig loci were silenced using designer zinc finger nucleases. Breeding to homozygosity resulted in a novel transgenic rat line exclusively producing chimeric Abs with human idiotypes. B cell recovery was indistinguishable from wild-type animals, and human V(D)J transcripts were highly diverse. Following immunization, the OmniRat strain performed as efficiently as did normal rats in yielding high-affinity serum IgG. mAbs, comprising fully human variable regions with subnanomolar Ag affinity and carrying extensive somatic mutations, are readily obtainable, similarly to conventional mAbs from normal rats. The Journal of Immunology, 2013, 190: 1481-1490.

• 出版日期2013-2-15