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|||||III US005476995A United States Patent (19) 11 Patent Number: 5,476,995 Clark Et Al |||||III US005476995A United States Patent (19) 11 Patent Number: 5,476,995 Clark et al. 45 Date of Patent: * Dec. 19, 1995 54 PEPTIDE PRODUCTION Townes et al., Erythroid-specific expression of human B-globin genes in transgenic mice, The EMBO Journal 75) Inventors: Anthony J. Clark, Edinburgh, 4(7):1715-1723 (1985). Scotland; Richard Lathe, Strasbourg, Van Brunt, J., Molecular Farming: Transgenic Animals as France Bioreactors, Bio/Technology 6(10): 1149-1154 (1988). Palmiter et al., Transgenic Mice, Cell 41:343-345 (1985). 73 Assignee: PPL Therapeutics (Scotland) Ltd., Shani, M., Tissue-specific expression of rat myosin Edinburg, Scotland light-chain 2 gene in transgenic mice, Nature 314:283-286 (1985). * Notice: The portion of the term of this patent Stewart et al., Spontaneous Mammary Adenocarcinomas in subsequent to Jun. 21, 2011, has been Transgenic Mice That Carry and Express MTV/myc Fusion disclaimed. Genes, Cell 38:627-637 (1984). McKnight et al., Expression of the Chicken Transferrin 21 Appl. No.: 931,864 Gene in Transgenic Mice, Cell 34:335-341 (1983). Mercier et al., Construction and identification of recombi 22 Filled: Aug. 18, 1992 nant plasmids carrying cDNAs coding for ovine OSl-, OS2-, Related U.S. Application Data B-, k-casein and f-lactoglobulin . , Biochimie 67:959-971 (1985). 63 Continuation of Ser. No. 796,917, Nov. 22, 1991, Pat. No. Palmiter et al., Dramatic growth of mice that develop from 5,322,755, which is a continuation of Ser. No. 165.988, Apr. eggs microinjected with metallothionein growth hormone 29, 1988, abandoned. fusion genes, Nature 300:61-6.15 (1982). Krumlauf et al., Developmental Regulation of 30 Foreign Application Priority Data B-Fetoprotein Genes in Transgenic Mice, Molecular and Jun. 30, 1986 GB United Kingdom ................... 8615942 Cellular Biology 5(7):1639-1648 (1985). Lacy et al., A Foreign B-Globin Gene in Transgenic Mice: (51) Int. Cl. ............................................. C12N 15100 Integration at Abnormal Chromosomal Positions and 52 U.S. C. ....................... 800/2; 800/DIG. 1; 435/69.1; Expression in Inappropriate Tissues, Cell 34:343-358 435/1723; 435/317.1; 435/320.1; 935/11; (1983). 935/111 Magram et al., Developmental regulation of a cloned adult 58 Field of Search ................................... 800/2, DIG. 1; B-globin gene in transgenic mice, Nature 315:338-340 435/172.3, 69.1, 317.1; 935/11, 111 (1985). Hanahan, D., Heritable formation of pancreatic B-cell 56) References Cited tumors in transgenic mice expressing recombinant insulin/ U.S. PATENT DOCUMENTS simian virus 40 oncogenes, Nature 315:115-122 (1985). Hochi et al., Successful Production of Transgenic Rats, 4,736,866 4/1988 Leder et al. ................................ 800, Animal Biotechnology 1(2):175-184 (1990). 4,870,009 971989 Evans et ai. ... ... 435/70 Illmensee et al., Nuclear and Gene Transplantation in the 4,873,316 10/1989 Meade et al. ........................... 5307412 Mouse, Developmental Biology Using Purified Genes, Aca FOREIGN PATENT DOCUMENTS demic Press, Inc., pp. 607-619 (1981). Gordon et al., Gene Transfer into Mouse Embryos: Produc 0264166 4/1988 European Pat. Off.. tion of Transgenic Mice by Pronuclear Injection, Methods in WO82,04443 2/1982 WPO. Enzymology 101:411–433 (1983). OTHER PUBLICATIONS Hammer et al., Production of transgenic rabbits, sheep and pigs by microinjection, Nature 315:680-683 (1985). Andres et al., Experientia 42(6): 673 (1986). Campbell et al., Nucleic Acids Res. 12(22): 8685–8697 (List continued on next page.) (1984). Richards et al., J. Biol. Chem. 256(1): 526-532 (1981). Primary Examiner-Jasemine C. Chambers Wilmut et al., A revolution in animal breeding, New Scientist Attorney, Agent, or Firm-Sterne, Kessler, Goldstein & Fox 7:56-59 (1989). 57) ABSTRACT Wright et al., High Level Expression of Active Human Alpha-1-Antitrypsin in the Milk of Transgenic Sheep, Bio/ A method of producing a proteinaceous compound, involves Technology 9:830–834 (1991). incorporating a DNA sequence coding for polypeptide into van der Putten et al., Developmental fate of a human insulin a gene of a mammal (such as a sheep) coding for a milk gene in a transgenic mouse, Mol. Gen. Genet. 198:128-138 whey protein in such a way that the DNA sequence is (1984). expressed in the mammary gland of the adult female mam Wagner et al., Microinjection of a rabbit 3-globin gene into mal. The proteinaceous compound may be a (optionally Zygotes and its subsequent expression in adult mice and their modified) protein such as a blood coagulation factor. The offspring, Proc. Natl. Acad. Sci. USA 78:6376-6380 (1981). DNA sequence is preferably inserted into the first exon of a Wall et al., High-level synthesis of a heterologous milk gene coding for a whey protein such as beta-lactoglobulin. protein in the mammary glands of transgenic swine, Proc. The proteinaceous compound will generally be recovered Natl. Acad. Sci. USA 88:1696-1700 (1991). from milk of the female mammal, but may (for example if Swift et al., Tissue-Specific Expression of the Rat Pancre it is an enzyme) be used in situ. atic Elastase I Gene in Transgenic Mice, Cell 38:639-646 (1984). 4 Claims, 9 Drawing Sheets 5,476,995 Page 2 OTHER PUBLICATIONS Clark et al., Pharmaceuticals from transgenic livestock, Hammer et al., Partial correction of murine hereditary TIBTECH 5:20-24 (1987). growth disorder by germ-line incorporation of a new gene, Brinster et al., Expression of a microinjected immunoglo Nature 311:65-67 (1984). bulin gene in the spleen of transgenic mice, Nature Clark et al., The germline manipulation of livestock: 306:332-336 (1983). progress during the past five years, Proceedings of the New Brinster et al., Somatic Expression of Herpes Thymidine Zealand Society of Animal Production 50:167-180 (1990). Kinase in Mice following Injection of a Fusion Gene into First et al., The Production and Potential Use of Transgenic Eggs, Cell 27:223-231 (1981). Livestock, Proc. 39th Ann. Reciprocal Meat Conf. 41-46 Brinster et al., Factors affecting the efficiency of introducing (1986). foreign DNA into mice by microinjecting eggs, Proc. Natl. Gordon et al., Genetic transformation of mouse embryos by Acad. Sci. USA 82:4438-4442 (1985). microinjection of purified DNA, Proc. Natl. Acad. Sci. USA Anson et al., The gene structure of human anti-haemophilic 77(12):7380-7384 (1980). factor IX, The EMBO Journal 3(5):1053-1060 (1984). Buhler et al., Rabbit B-Casein Promoter Directs Secretion of Brem and Weidle, "Production of Proteins with Antibody Human Interleukin-2 into the Milk of Transgenic Rabbits, Activity in Transgenic Mammals', Frontiers of Biotechnol Bio/Technology 8:140-143 (1990). ogy in Agriculture Meetings, 1991 (Abstract). Burki et al., Transplantation of the human insulin gene into Brem and Hartl, "High-level Expression of Prochymosin in fertilized mouse eggs, The EMBO Journal 1(1):127-131 the Milk of Transgenic Rabbits', Frontiers of Biotechnology (1982). in Agriculture Meeting, 1991 (Abstract). U.S. Patent Dec. 19, 1995 Sheet 1 of 9 5,476,995 |SSDDQUID) THODEIITAd IIIpUIHIDQXIHOUEI?ds!IHOJE U.S. Patent Dec. 19, 1995 Sheet 2 of 9 5,476,995 | 0–IITAd O-ITAd | U.S. Patent Dec. 19, 1995 Sheet 3 of 9 5,476,995 |SSDpQUID) THOJEInºd U.S. Patent 5,476,995 U.S. Patent 5,476,995 IIIpu?H U.S. Patent Dec. 19, 1995 Sheet 6 of 9 5,476,995 | on 211+ 2.5 1:100 SStgxs - 211+ 2.5A 1:500 SStgxs FIG. 5g U.S. Patent Dec. 19, 1995 Sheet 7 of 9 5,476,995 U.S. Patent Dec. 19, 1995 Sheet 8 of 9 5,476,995 U.S. Patent Dec. 19, 1995 Sheet 9 of 9 5,476,995 o- INTAL DILUTION OF NORMAL POOL PLASMA 1/10 TO 1/1280 MADE IN 0.25% GELATIN Tris/HCL BUFFER X---X INITIAL OLUTION OF NORMAL POOL PLASMA 1/1O TO 1/1280 MADE IN NEAT CONTROL MILK FREEZE DRIED (RESUSPENDED) T2 i 1280 640 320 160 80 40 2O 10 RECIPROCAL OF DILUTION OF NORMAL POOL PASMA A/G8 5,476,995 1. 2 PEPTIDE PRODUCTION mammal coding for a milk whey protein in such a way that the DNA sequence is expressed in the mammary gland of the This application is a continuation of application Ser. No. adult female mammal, whereafter it catalyses the formation 07/796,917, filed Nov. 22, 1991, now U.S. Pat. No. 5,322, of the reaction product from one or more substrates of the 755. Ser. No. 07/796,917 is a continuation of Ser. No. enzyme. The reaction product will generally be recovered 07,165.988, filed Apr. 29, 1988, now abandoned. from milk of the adult female mammal. This invention relates to a method of producing a sub stance comprising a polypeptide. More particularly, the The DNA sequence coding for the peptide (“the DNA invention relates to protein production and to the production sequence of interest”) is preferably incorporated in vitro into of biological materials whose formation is catalysed by a milk whey protein gene which is expressible in the enzymic proteins. O mammary gland of an adult female mammal to form a fusion Recombinant DNA technology has been used increas gene and the fusion gene is incorporated into the germline by ingly over the past decade for the production of commer injection into a fertilized egg of the mammal, whereafter the cially important biological materials. To this end, the DNA injected fertilized egg is allowed to develop into an adult sequences encoding a variety of medically important human female mammal. It is to be expected that not all the injected proteins have been cloned. These include insulin, plasmi 5 eggs will develop into adult females expressing the DNA nogen activator, alpha-antitrypsin and coagulation factors sequence of interest.
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