Transgenic Rabbits to Prepare Pharmaceutical Proteins

  • Louis-Marie Houdebine
  • Geneviève Jolivet
  • Pierre-Jean Ripoll

Abstract

The preparation of recombinant pharmaceutical proteins is one of the major challenges of biotechnology. Mammalian cells are required for a number of proteins which must be modified posttranscriptionally. Animal cell lines cultured in fermentors are presently the major source of complex proteins. The milk of transgenic animals proved to be a possible source of pharmaceutical proteins and one of them, human antithrombin III, has been approved by the EU (EMEA) and US (FDA) medicament agencies. Several species are being implemented for this purpose. Rabbits are one of these species. It offers several advantages: low cost to produce transgenic founders, rapid reproduction, easy and cheap scaling up, easy breeding in pathogen-free conditions and insensitivity to prion diseases. Rabbits are thus an efficient tool to prepare several kilograms of a recombinant protein per year.

Keywords

Pharmaceutical proteins transgenic blood milk antibodies 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Bijvoet AG, Van Hirtum H, Kroos MA, Van de Kamp EH, Schoneveld O, Visser P, Brakenhoff JP, Weggeman M, van Corven EJ, Van der Ploeg AT, Reuser AJ. (1999) Human acid alpha- glucosidase from rabbit milk has therapeutic effect in mice with glycogen storage disease type II. Hum Mol Genet 8: 2145–2153.PubMedCrossRefGoogle Scholar
  2. Bösze Zs, Houdebine LM. (2006) Application of rabbits in biomedical research: review. World Rabbit Sci 14: 1–14.Google Scholar
  3. Brem G, Hartl P, Besenfelder U, Wolf E, Zinovieva N, Pfaller R. (1994) Expression of synthetic cDNA sequences encoding human insulin-like growth factor-1 (IGF-1) in the mammary gland of transgenic rabbits. Gene 149: 351–355.PubMedCrossRefGoogle Scholar
  4. Brem G, Besenfelder U, Zinovieva N, Seregi J, Solti L, Hartl P. (1995) Mammary gland specific expression of chymosin constructs in transgenic rabbits. Theriogenology 43: 175–175.CrossRefGoogle Scholar
  5. Buelow R, van Schooten W. (2006) The future of antibody therapy. Ernst Schering Found Symp Proc 4: 83–106.PubMedCrossRefGoogle Scholar
  6. Buhler TA, Bruyere T, Went DF, Stranzinger G, Burki K. (1990) Rabbit beta-casein promoter directs secretion of human interleukin-2 into the milk of transgenic rabbits. Biotechnology (NY) 8: 140–143.CrossRefGoogle Scholar
  7. Chesné P, Adenot PG, Viglietta C, Baratte M, Boulanger L, Renard JP. (2002) Cloned rabbits produced by nuclear transfer from adult somatic cells. Nat Biotechnol 20: 366–369.PubMedCrossRefGoogle Scholar
  8. Chrenek P, Ryban L, Vetr H, Makarevich AV, Uhrin P, Paleyanda RK, Binder BR. (2007) Expression of recombinant human factor VIII in milk of several generations of transgenic rabbits. Transgenic Res 16: 353–361.PubMedCrossRefGoogle Scholar
  9. Coulibaly S, Besenfelder U, Fleischmann M, Zinovieva N, Grossmann A, Wozny M, Bartke I, Tögel M, Müller M, Brem G. (1999) Human nerve growth factor beta (hNGF-beta): mammary gland specific expression and production in transgenic rabbits. FEBS Lett 444: 111–116.PubMedCrossRefGoogle Scholar
  10. Coulibaly S, Besenfelder U, Miller I, Zinovieva N, Lassnig C, Kotler T, Jameson JL, Gemeiner M, Müller M, Brem G. (2002) Expression and characterization of functional recombinant bovine follicle-stimulating hormone (boFSHalpha/beta) produced in the milk of transgenic rabbits. Mol Reprod Dev 63: 300–308.PubMedCrossRefGoogle Scholar
  11. Edmunds T, Van Patten SM, Pollock J, Hanson E, Bernasconi R, Higgins E, Manavalan P, Ziomek C, Meade H, McPherson JM, Cole ES. (1998) Transgenically produced human antithrombin: structural and functional comparison to human plasma-derived antithrombin. Blood 91: 4561–4571.PubMedGoogle Scholar
  12. Galet C, Le Bourhis CM, Chopineau M, Le Griec G, Perrin A, Magallon T, Attal J, Viglietta C, Houdebine LM, Guillou F. (2001) Expression of a single betaalpha chain protein of equine LH/CG in milk of transgenic rabbits and its biological activity. Mol Cell Endocrinol 174: 31–40.PubMedCrossRefGoogle Scholar
  13. Giraldo P, Rival-Gervier S, Houdebine LM, Montoliu L. (2003) The potential benefits of insulators on heterogonous constructs in transgenic. Transgenic Res 12: 751–755.PubMedCrossRefGoogle Scholar
  14. Gordon K, Lee E, Vitale JA, Smith AE, Westphal H, Hennighausen L. (1987) Production of human tissue plasminogen activator in transgenic mouse milk. Bio/Technol 5: 1183–1187.CrossRefGoogle Scholar
  15. Hammer RE, Pursel VG, Rexroad CE Jr, Wall RJ, Bolt DJ, Ebert KM, Palmiter RD, Brinster RL. (1985) Production of transgenic rabbits, sheep and pigs by microinjection. Nature 315: 680–683.PubMedCrossRefGoogle Scholar
  16. Han J Y. (2008) Germ cells and transgenesis in chicken. Comp Immunol Microbiol Infect Dis 32: 61–80.PubMedCrossRefGoogle Scholar
  17. Houdebine LM. (2002) Antibody manufacture in transgenic animals, comparisons with other systems. Curr Opin Biotechnol 13: 625–629.PubMedCrossRefGoogle Scholar
  18. Houdebine LM. (2007) Transgenic animal models and target validation. Meth Mol Biol 360: 163–202.Google Scholar
  19. Houdebine LM. (2008) Methods to generate transgenic animals in ethics of science and technology assessment. Springer. Heildelberg/Berlin/New York 34: 31–48.Google Scholar
  20. Houdebine LM. (2009) Production of pharmaceutical proteins by transgenic animals. Comparative Immunology, Microbiology & Infectious Diseases 32: 107–121.CrossRefGoogle Scholar
  21. Jeffris R (2006) A sugar switch for anti-inflammatory antibodies Nat Biotechnol 24: 1230–1231.CrossRefGoogle Scholar
  22. Korhonen VP, Tolvanen M, Hyttinen JM, Uusi-Oukari M, Sinervirta R, Alhonen L, M, Jänne OA, Jänne J. (1997) Expression of bovine beta-lactoglobulin/human erythropoietin fusion protein in the milk of transgenic mice and rabbits. Eur J Biochem. 245: 482–489.PubMedCrossRefGoogle Scholar
  23. Koles K, van Berkel PH, Pieper FR, Nuijens JH, Mannesse ML, Vliegenthart JF, Kamerling JP. (2004a) N- and O-glycans of recombinant human C1 inhibitor expressed in the milk of trans-genic rabbits. Glycobiology 14: 51–64.CrossRefGoogle Scholar
  24. Koles K, van Berkel PH, Mannesse ML, Zoetemelk R, Vliegenthart JF, Kamerling JP. (2004b) Influence of lactation parameters on the N-glycosylation of recombinant human C1 inhibitor isolated from the milk of transgenic rabbits. Glycobiology 14: 979–986.CrossRefGoogle Scholar
  25. Lillico SG, Sherman A, McGrew MJ, Robertson CD, Smith J, Haslam C, Barnard P, Radcliffe PA, Mitrophanous KA, Elliot EA, Sang HM. (2007) Oviduct-specific expression of two therapeutic proteins in transgenic hens. Proc Natl Acad Sci U S A 104: 1771–1776.PubMedCrossRefGoogle Scholar
  26. Limonta J, Pedraza A, Rodriguez A, Freyre FM, Barral AM, Castro FO, et al. (1995) Production of active anti-CD6 mouse/human chimeric antibodies in the milk of transgenic mice. Immunotech 1: 107–113.CrossRefGoogle Scholar
  27. Massoud M, Bischoff R, Dalemans W, Pointu H, Attal J, Schultz H, Clesse D, Stinnakre MG, Pavirani A, Houdebine LM. (1991) Expression of active recombinant human alpha 1-antitrypsin in transgenic rabbits. J Biotechnol 18: 193–203.PubMedCrossRefGoogle Scholar
  28. Massoud M, Attal J, Thépot D, Pointu H, Stinnakre MG, Théron MC, Lopez C, Houdebine LM. (1996) The deleterious effects of human erythropoietin gene driven by the rabbit whey acidic protein gene promoter in transgenic rabbits. Reprod Nutr Dev 36: 555–563.PubMedCrossRefGoogle Scholar
  29. McKee C, Gibson A, Dalrymple M, Emslie L, Garner I, Cottingham I. (1998) Production of biologically active salmon calcitonin in the milk of transgenic rabbits. Nat Biotechnol 16: 647–651.PubMedCrossRefGoogle Scholar
  30. Millot B, Fontaine ML, Thépot D and Devinoy E. (2001) A distal region, hypersensitive to DNase I, plays a key role in regulating rabbit whey acidic protein gene expression. Biochem J 359: 557–565.PubMedCrossRefGoogle Scholar
  31. Moreira PN, Pozueta J, Pérez-Crespo M, Valdivieso F, Gutiérrez-Adán A, Montoliu L. (2007) Improving the generation of genomic-type transgenic mice by ICSI. Transgenic Res 16: 163–168.PubMedCrossRefGoogle Scholar
  32. Palmiter RD, Brinster RL, Hammer RE, Trumbauer ME, Rosenfeld MG, Birnberg NC, Evans RM. (1982) Dramatic growth of mice that develop from eggs microinjected with metallothionein-growth hormone fusion genes. Nature 300: 611–615.PubMedCrossRefGoogle Scholar
  33. Pera MF, Hasegawa K. (2008) Simpler and safer cell reprogramming. Nat Biotechnol 26: 59–60.PubMedCrossRefGoogle Scholar
  34. Rival S, Attal J, Delville-Giraud C, Yerle M, Laffont P, Rogel-Gaillard C, Houdebine LM. (2001) Cloning, transcription and chromosomal localization of the porcine whey acidic protein gene and its expression in HC11 cell line. Gene 267: 37–47.PubMedCrossRefGoogle Scholar
  35. Rival-Gervier S, Viglietta C, Maeder C, Attal J, Houdebine LM. (2002) Position-independent and tissue-specific expression of porcine whey acidic protein gene from a bacterial artificial chromosome in transgenic mice. Mol Reprod Dev 63: 161–167.PubMedCrossRefGoogle Scholar
  36. Rival-Gervier S, Maeder C,Viglietta C, Prince S and Houdebine LM. (2003) Effect of 5'HS4 insulator on rabbit WAP gene action in transgenic mice. Transgenic Res 12: 12723–12730.CrossRefGoogle Scholar
  37. Rodriguez A, Castro FO, Aguilar A, Ramos B, Del Barco DG, Lleonart R, De la Fuente J. (1995) Expression of active human erythropoietin in the mammary gland of lactating transgenic mice and rabbits. Biol Res 28: 141–153.PubMedGoogle Scholar
  38. Saidi S, Rival-Gervier S, Daniel-Carlier N, Thépot D, Morgenthaler C, Viglietta C, Prince S, Passet B, Houdebine LM and Jolivet G. (2007) Distal control of the pig whey acidic protein (WAP) locus in transgenic mice. Gene 401: 97–107.PubMedCrossRefGoogle Scholar
  39. Shen W, Li L, Pan Q, Min L, Dong H, Deng J. (2006) Efficient and simple production of trans-genic mice and rabbits using the new DMSO-sperm mediated exogenous DNA transfer method. Mol Reprod Dev 73: 589–594.PubMedCrossRefGoogle Scholar
  40. Shinohara ET, Kaminski JM, Segal DJ, Pelczar P, Kolhe R, Ryan T, Coates CJ, Fraser MJ, Handler AM, Yanagimachi R, Moisyadi S. (2007) Active integration: new strategies for trans-genesis. Transgenic Res 16: 333–339.PubMedCrossRefGoogle Scholar
  41. Smith K, Spadafora C. (2005) Sperm mediated gene transfer: applications and implications. BioEssays 27: 551–562.PubMedCrossRefGoogle Scholar
  42. Soler E, Le Saux A, Guinut F, Passet B, Cohen R, Merle C, Charpilienne A, Fourgeux C, Sorel V, Piriou A, Schwartz-Cornil I, Cohen J, and Houdebine LM. (2005) Production of two vaccinating recombinant rotavirus proteins in the milk of transgenic rabbits. Transgenic Res 14: 833–844.PubMedCrossRefGoogle Scholar
  43. Strömqvist M, Houdebine LM, Andersson JO, Edlund A, Johansson T, Viglietta C, Puissant C, Hansson L. (1996) Recombinant human extracellular superoxide dismutase produced in milk of transgenic rabbits. Transgenic Res 6: 271–278.CrossRefGoogle Scholar
  44. Van de Lavoir MC, Diamond JH, Leighton PA, Mather-Love C, Heyer BS, Bradshaw R, Kerchner A, Hooi LT, Gessara TM, Swanberg SE, Delany ME, Etches RJ. (2006) Germline transmission of genetically modified primordial germ cells. Nature 441: 766–769.PubMedCrossRefGoogle Scholar
  45. Weidle UH, Lenz H, Brem G. (1991) Genes encoding a mouse monoclonal antibody are expressed in transgenic mice, rabbits and pigs. Gene 98: 185–191.PubMedCrossRefGoogle Scholar
  46. Wolf E, Jehle PM, Weber MM, Sauerwein H, Daxenberger A, Breier BH, Besenfelder U, Frenyo L, Brem G (1997) Human insulin-like growth factor I (IGF-I) produced in the mammary glands of transgenic rabbits: yield, receptor binding, mitogenic activity, and effects on IGF-binding proteins.Endocrinology 138: 307–313.PubMedCrossRefGoogle Scholar
  47. Yong HY, Hao Y, Lai L, Li R, Murphy CN, Rieke A, Wax D, Samuel M, Prather RS. (2006) Production of a transgenic piglet by a sperm injection technique in which no chemical or physical treatments were used for oocytes or sperm. Mol Reprod Dev 73: 595–599.PubMedCrossRefGoogle Scholar
  48. Zinovieva N, Lassnig C, Schams D, Besenfelder U, Wolf E, Müller S, Frenyo L, Seregi J, Müller M, Brem G. (1998) Stable production of human insulin-like growth factor 1 (IGF-1) in the milk of hemi- and homozygous transgenic rabbits over several generations. Transgenic Res 7: 437–447.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media B.V. 2009

Authors and Affiliations

  • Louis-Marie Houdebine
    • Geneviève Jolivet
      • Pierre-Jean Ripoll
        • 1
      1. 1.BioProtein Technologies Domaine de VilvertJouy en JosasFrance

      Personalised recommendations