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OMT has invented a novel genetic engineering approach to generate fully human antibodies using transgenic rats.
The rat is a widely used laboratory animal with a well characterized immune system, a nearly complete genome sequence, and established transgenesis and hybridoma technologies.
Dr. Buelow made two strategic innovations in OMT's genetic engineering - one which eliminated the suboptimal signaling by the B-cell receptor complex and the other which inactivated endogenous rat immunoglobulin genes.
Elimination of suboptimal signaling: OMT used hybrid constant region genes consisting of a human CH1-domain and rat CH2, CH3 and CH4 domains to overcome suboptimal signaling by the B-cell receptor complex.
Inactivation of endogenous rat immunoglobulin genes: OMT collaborated with Sangamo Biosciences, Inc. to use a Zinc Finger Nuclease (ZFN) to delete critical regions of the rat immunoglobulin locus and create functional silencing of endogenous antibody expression. Science featured the targeted immunoglobulin knockout rat in "Knockout Rats Produced via Embryo Microinjection of Designed Zinc Finger Nucleases" (2009, 325:433). In 2010, the European Journal of Immunology described the knockout rat in "Characterization of Immunoglobulin Heavy Chain Knockout Rats" (2010, 40:2932-2941).
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