Transgenic Mice That Produce Fully Humanized Antibodies -- Abgenix Granted Patent
Abgenix Inc. (Fremont, CA) has received a patent covering a key step used to generate transgenic mice that produce fully-human antibodies. The patent issued as U.S. Patent No. 5,939,598, entitled: Method of Making Transgenic Mice Lacking Endogenous Heavy Chains.These transgenic mouse strains, referred to as XenoMouse, make use of the natural power of the mouse immune system to respond to human disease targets by making multiple high affinity antibodies. However, unlike some related technologies that create chimeric or partly humanized proteins, the antibodies produced by these mice are 100% human protein.
Abgenix's approach to generating fully human antibodies employs genetically engineered strains of mice in which endogenous mouse antibody gene expression is suppressed by removing the J-chain, effectively disabling the antibody generating system of the host. Into these host animals is transferred megabase-sized fragments from the human heavy and kappa light chain loci encompassing roughly 80% of the human immunoglobin gene in germ-line configuration, including some 34 of a possible 41 variable regions. Hence, rather than engineering individual antibody molecules against specific antigens, a time-consuming and technically difficult process, XenoMouse technology has the animal do all the work, using the intact host immune system to generate a repertoire of high affinity antibodies.
XenoMouse technology offers the following advantages:
- It produce antibodies with fully human protein sequences, reducing the possibility of human anti-mouse antibody response, observed in patients treated with monoclonal or chimeric antibodies
- It generates a diverse antibody response to essentially any disease target appropriate for antibody therapy
- It generates high affinity antibodies which do not require further engineering
- It enables efficient product development; and flexibility in choosing manufacturing processes.
Importantly, these transgenic mice can generate antibodies to human antigens because the only human products expressed in the mice (and therefore recognized as "self") are the antibodies themselves. Any other human tissue or protein is thus recognized as a foreign antigen by the mouse and an immune response will be mounted. Recent work published by Abgenix scientists showed that a humanized antibody produced in Xenomouse against human epidermal growth factor receptor prevented completely the formation of human epidermoid carcinoma A431 xenografts in athymic mice, and the eradication of established tumors without chemotherapy (reference 1).
Separately, Abgenix has also received a patent covering a new method for the generation of antibody manufacturing cell lines. The patent issued as U.S. Patent No. 5,916,771, entitled: Production of a Multimeric Protein by Cell Fusion Method.
"These patents reflect the company's important contributions to antibody technology research,'' stated R. Scott Greer, president and chief executive officer of Abgenix. "They also strengthen the barriers to entry into our business.''
Abgenix is a biopharmaceutical company that develops antibody therapeutic products for the treatment of various disease conditions, including transplant-related diseases, inflammatory and autoimmune disorders, cardiovascular disease and cancer. Abgenix has collaborative arrangements with a number of pharmaceutical and biotechnology companies involving its XenoMouse technology. In addition, Abgenix has four proprietary antibody product candidates that are under development internally, two in human clinical trials.
Contact: R. Scott Greer, CEO, Abgenix Inc., 7601 Dumbarton Circle, Fremont, CA 94555, 510-608-6500, Phone, 510- 608-6511, Fax
Reference: Yang XD, Jia XC, Corvalan JR, Wang P, Davis CG, Jakobovits A, " Eradication of established tumors by a fully human monoclonal antibody to the epidermal growth factor receptor without concomitant chemotherapy", Cancer Res 1999 Mar 15;59(6):1236-43.