Producing Recombinant Human Milk Proteins in the Milk of Livestock Species

  • Zsuzsanna Bösze
  • Mária Baranyi
  • C. Bruce
  • A. Whitelaw
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 606)


Recombinant human proteins produced by the mammary glands of genetically modified transgenic livestock mammals represent a special aspect of milk bioactive components. For therapeutic applications, the often complex posttranslational modifications of human proteins should be recapitulated in the recombinant products. Compared to alternative production methods, mammary gland production is a viable option, underlined by a number of transgenic livestock animal models producing abundant biologically active foreign proteins in their milk. Recombinant proteins isolated from milk have reached different phases of clinical trials, with the first marketing approval for human therapeutic applications from the EMEA achieved in 2006.


Mammary Gland Cystic Fibrosis Transmembrane Conductance Regulator Livestock Species Whey Acidic Protein Human Lactoferrin 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Archer, J. S., Kennan, W. S., Gould, M. N.,&Bremel, R. D. (1994). Human growth hormone (hGH) secretion in milk of goats after direct transfer of the hGH gene into the mammary gland by using replication-defective retrovirus vectors. Proceedings of the National Academy of Sciences USA, 91, 6840–6844.Google Scholar
  2. Baguisi, A., Behboodi, E., Melican, D. T., Pollock, J. S., Destrempes, M. M., Cammuso, C., Williams, J. L., Nims, S. D., Porter, C. A., Midura, P., Palacios, M. J., Ayres, S. L., Denniston, R. S., Hayes, M. L., Ziomek, C. A., Meade, H. M., Godke, R. A., Gavin, W. G., Overstrom, E. W.,&Echelard, Y. (1999). Production of goats by somatic cell nuclear transfer. Nature Biotechnology, 17, 456–461.CrossRefGoogle Scholar
  3. Baranyi, M., Brignon, G., Anglade, P.,&Ribadeau-Dumas, B. (1995). New data on the proteins of rabbit (Oryctolagus cuniculus) milk. Comparative Biochemistry and Physiology B: Biochemistry and Molecular Biology, 111, 407–415.CrossRefGoogle Scholar
  4. Bijvoet, A. G., Van Hirtum, H., Kroos, M. A., Van de Kamp, E. H., Schoneveld, O., Visser, P., Brakenhoff, J. P., Weggeman, M., van Corven, E. J., Van der Ploeg, A. T.,&Reuser, A .J. (1999). Human acid alpha-glucosidase from rabbit milk has therapeutic effect in mice with glycogen storage disease type II. Human Molecular Genetics, 8, 2145–2153.CrossRefGoogle Scholar
  5. Bodrogi, L., Brands, R., Raaben, W., Seinen, W., Baranyi, M., Fiechter, D.,&Bösze, Z. (2006). High level expression of tissue-nonspecific alkaline phosphatase in the milk of transgenic rabbits. Transgenic Research, 15, 627–636.CrossRefGoogle Scholar
  6. 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.CrossRefGoogle Scholar
  7. Brem, G., Besenfelder, U., Castro, F. O.,&Muller, M. (1998). In F. O. Castro and J. Janne (Eds.) Mammary Gland Transgenisis:Therapeutic Protein Production(pp. 107–142), Berlin: Springer.Google Scholar
  8. Brinster, R. L., Allen, J. M., Behringer, R. R., Gelinas, R. E.,&Palmiter, R. D. (1988). Introns increase transcriptional efficiency in transgenic mice. Proceedings of the National Academy of Sciences USA, 85, 836–840.CrossRefGoogle Scholar
  9. Bühler, T. A., Bruyere, T., Went, D. F., Stranzinger, G.,&Bürki, 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
  10. Butler, S. P., van Cott, K., Subrumanian, A., Gwazduaskas, F. C.,&Velander, W. H. (1997). Current progress in the production of recombinant human fibrinogen in the milk of transgenic animals. Thrombosis and Haemostasis, 78, 537–542.Google Scholar
  11. Castro, F. O., Limonta, J., Rodriguez, A., Aguirre, A., de la Fuente, J., Aguilar, A., Ramos B.,&Hayes, O. (1999). Transgenic rabbits for the production of biologically-active recombinant proteins in the milk. Genetic Analysis, 15, 179–187.Google Scholar
  12. Chan, A. W., Homan, E. J., Ballou, L. U., Burns, J. C.,&Bremel, R. D. (1998). Transgenic cattle produced by reverse-transcribed gene transfer in oocytes. Proceedings of the National Academy of Sciences USA, 95, 14028–14033.CrossRefGoogle Scholar
  13. Clark, A. J., Bessos, H., Bishop, J. O., Brown, P., Harris, S., Lathe, R., McClenaghan, M., Prowse, C., Simons, J. P., Whitelaw, C. B. A.,&Wilmut, I. (1989). Expression of human anti-hemophilic factor IX in the milk of transgenic sheep. Bio/Technology, 7, 487–492 (abstract).CrossRefGoogle Scholar
  14. Clark, J.,&Whitelaw, B. (2003). A future for transgenic livestock. Nature Review Genetics, 4, 825–833.CrossRefGoogle Scholar
  15. Colman, A. (1996). Production of proteins in the milk of transgenic livestock: Problems, solutions, and successes. American Journal of Clinical Nutrition, 63, 639S–645S.Google Scholar
  16. Coulibaly, S., Besenfelder, U., Fleischmann, M., Zinovieva, N., Grossmann, A., Wozny, M., Bartke, I., Togel, M., Muller, M.,&Brem, G. (1999). Human nerve growth factor beta (hNGF-β): Mammary gland specific expression and production in transgenic rabbits. FEBS Letters, 444, 111–116.CrossRefGoogle Scholar
  17. Coulibaly, S., Besenfelder, U., Miller, I., Zinovieva, N., Lassnig, C., Kotler, T., Jameson, J.L., Gemeiner, M., Muller, M.,&Brem, G. (2002). Expression and characterization of functional recombinant bovine follicle-stimulating hormone (boFSHα/β) produced in the milk of transgenic rabbits. Molecular Reproduction and Development, 63, 300–308.CrossRefGoogle Scholar
  18. Dayal, R., Hurlimann, J., Suard, Y. M.,&Kraehenbuhl, J. P. (1982). Chemical and immunochemical characterization of caseins and the major whey proteins of rabbit milk. Biochemistry Journal, 201, 71–79.Google Scholar
  19. Denman, J., Hayes, M., O'Day, C., Edmunds, T., Bartlett, C., Hirani, S., Ebert, K. M., Gordon, K.,&McPherson, J. M. (1991). Transgenic expression of a variant of human tissue-type plasminogen activator in goat milk: Purification and characterization of the recombinant enzyme. Biotechnology (NY), 9, 839–843.CrossRefGoogle Scholar
  20. Devinoy, E., Thepot, D., Stinnakre, M. G., Fontaine, M. L., Grabowski, H., Puissant, C., Pavirani, A.,&Houdebine, L. M. (1994). High level production of human growth hormone in the milk of transgenic mice: The upstream region of the rabbit whey acidic protein (WAP) gene targets transgene expression to the mammary gland. Transgenic Research, 3, 79–89.CrossRefGoogle Scholar
  21. DiTullio, P., Cheng, S. H., Marshall, J., Gregory, R .J., Ebert, K. M., Meade, H. M.,&Smith, A. E. (1992). Production of cystic fibrosis transmembrane conductance regulator in the milk of transgenic mice. Biotechnology (NY), 10, 74–77.CrossRefGoogle Scholar
  22. Dyck, M. K., Lacroix, D., Pothier, F.,&Sirard, M. A. (2003). Making recombinant proteins in animals—Different systems, different applications. Trends in Biotechnology, 21, 394–399.CrossRefGoogle Scholar
  23. Ebert, K. M., Selgrath, J. P., DiTullio, P., Denman, J., Smith, T. E., Memon, M. A., Schindler, J. E., Monastersky, G. M., Vitale, J. A.,&Gordon, K. (1991). Transgenic production of a variant of human tissue-type plasminogen activator in goat milk: Generation of transgenic goats and analysis of expression. Biotechnology (NY), 9, 835–838.CrossRefGoogle Scholar
  24. Ebert, K. M., DiTullio, P., Barry, C. A., Schindler, J. E., Ayres, S. L., Smith, T. E., Pellerin, L. J., Meade, H. M., Denman, J.,&Roberts, B. (1994). Induction of human tissue plasminogen activator in the mammary gland of transgenic goats. Biotechnology (NY), 12, 699–702.CrossRefGoogle Scholar
  25. Edmunds, T., Van Patten, S. M., Pollock, J., Hanson, E., Bernasconi, R., Higgins, E., Manavalan, P., Ziomek, C., Meade, H., McPherson, J. M.,&Cole, E. S. (1998). Transgenically produced human antithrombin: Structural and functional comparison to human plasma-derived antithrombin. Blood. 91, 4561–4571.Google Scholar
  26. Farrell, P. J., Lu, M., Prevost, J., Brown, C., Behie, L.,&Iatrou, K. (1998). High-level expression of secreted glycoproteins in transformed lepidopteran insect cells using a novel expression vector. Biotechnology and Bioengineering, 60, 656–663.CrossRefGoogle Scholar
  27. Fujiwara, Y., Miwa, M., Takahashi, R., Hirabayashi, M., Suzuki, T.,&Ueda, M. (1997). Position-independent and high-level expression of human alpha-lactalbumin in the milk of transgenic rats carrying a 210-kb YAC DNA. Molecular Reproduction and Development, 47, 157–163.CrossRefGoogle Scholar
  28. Fujiwara, Y., Takahashi, R. I., Miwa, M., Kameda, M., Kodaira, K., Hirabayashi, M., Suzuki, T.,&Ueda, M. (1999). Analysis of control elements for position-independent expression of human alpha-lactalbumin YAC. Molecular Reproduction and Development, 54, 17–23.CrossRefGoogle Scholar
  29. Garner, I.,&Colman, A. (1998). Therapeutic proteins from livestock. In A. J. Clark (Ed.), Animal Breeding: Technology for the 21st Century (pp. 64–71, London: CRC Press.Google Scholar
  30. Genzyme Transgenics (1996). Production of recombinant antibodies in the milk of transgenic animals (abstract).Google Scholar
  31. Gordon, J. W., Scangos, G. A., Plotkin, D. J., Barbosa, J. A.,&Ruddle, F. H. (1980). Genetic transformation of mouse embryos by microinjection of purified DNA. Proceedings of the National Academy of Sciences USA, 77, 7380–7384.CrossRefGoogle Scholar
  32. Hammer, R. E., Pursel, V. G., Rexroad, C. E., Jr., Wall, R. J., Bolt, D. J., Ebert, K. M., Palmiter, R. D.,&Brinster, R. L. (1985). Production of transgenic rabbits, sheep and pigs by microinjection. Nature, 315, 680–683.CrossRefGoogle Scholar
  33. Han, Z. S., Li, Q. W., Zhang, Z. Y., Xiao, B., Gao, D. W., Wu, S. Y., Li, J., Zhao, H. W., Jiang, Z. L.,&Hu, J. H. (2007). High-level expression of human lactoferrin in the milk of goats by using replication-defective adenoviral vectors. Protein Expression and Purification, doi:10.1016/j.pep.2006.11.019.Google Scholar
  34. Hiripi, L., Makovics, F., Halter, R., Baranyi, M., Paul, D., Carnwath, J. W., Bösze, Z.,&Niemann, H. (2003). Expression of active human blood clotting factor VIII in mammary gland of transgenic rabbits. DNA Cell Biology, 22, 41–45.CrossRefGoogle Scholar
  35. Huszar, D., Balling, R., Kothary, R., Magli, M. C., Hozumi, N., Rossant, J.,&Bernstein, A. (1985). Insertion of a bacterial gene into the mouse germ line using an infectious retrovirus vector. Proceedings of the National Academy of Sciences USA, 82, 8587–8591.CrossRefGoogle Scholar
  36. Jacobs, K., Shoemaker, C., Rudersdorf, R., Neill, S. D., Kaufman, R. J., Mufson, A., Seehra, J., Jones, S. S., Hewick, R., Fritsch, E. F., et al. (1985). Isolation and characterization of genomic and cDNA clones of human erythropoietin. Nature, 313, 806–810.CrossRefGoogle Scholar
  37. Jahner, D., Haase, K., Mulligan, R.,&Jaenisch, R. (1985). Insertion of the bacterial gpt gene into the germ line of mice by retroviral infection. Proceedings of the National Academy of Sciences USA, 82, 6927–6931.CrossRefGoogle Scholar
  38. Keefer, C. L., Baldassarre, H., Keyston, R., Wang, B., Bhatia, B., Bilodeau, A. S., Zhou, J. F., Leduc, M., Downey, B. R., Lazaris, A.,&Karatzas, C. N. (2001). Generation of dwarf goat (Capra hircus) clones following nuclear transfer with transfected and nontransfected fetal fibroblasts and in vitro-matured oocytes. Biological Reproduction, 64, 849–856.CrossRefGoogle Scholar
  39. Kim, N. Y., Kim, J. H.,&Kim, H. J. (2005). Effect of low adapted temperature and medium composition on growth and erythropoietin (EPO) production by Chinese hamster ovary cells. Archives of Pharmaceutical Research, 28, 220–226.CrossRefGoogle Scholar
  40. Klinge, L., Straub, V., Neudorf, U., Schaper, J., Bosbach, T., Gorlinger, K., Wallot, M., Richards, S.,&Voit, T. (2005). Safety and efficacy of recombinant acid alpha-glucosidase (rhGAA) in patients with classical infantile Pompe disease: Results of a phase II clinical trial. Neuromuscular Disorders, 15, 24–31.CrossRefGoogle Scholar
  41. Koles, K., van Berkel, P. H., Mannesse, M. L., Zoetemelk, R., Vliegenthart, J. F.,&Kamerling, J. P. (2004a). 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
  42. Koles, K., van Berkel, P. H., Pieper, F. R., Nuijens, J. H., Mannesse, M. L., Vliegenthart, J. F.,&Kamerling, J. P. (2004b). N- and O-glycans of recombinant human C1 inhibitor expressed in the milk of transgenic rabbits. Glycobiology, 14, 51–64.CrossRefGoogle Scholar
  43. Korhonen, V. P., Tolvanen, M., Hyttinen, J. M., Uusi-Oukari, M., Sinervirta, R., Alhonen, L., Jauhiainen, M., Janne, O. A.,&Janne, J. (1997). Expression of bovine beta-lactoglobulin/human erythropoietin fusion protein in the milk of transgenic mice and rabbits. European Journal of Biochemistry, 245, 482–489.CrossRefGoogle Scholar
  44. Krantz, S. B. (1991). Erythropoietin. Blood, 77, 419–434.Google Scholar
  45. Krimpenfort, P., Rademakers, A., Eyestone, W., van der Schans, A., van den Broek, S., Kooiman, P., Kootwijk, E., Platenburg, G., Pieper, F., Strijker, R., et al. (1991). Generation of transgenic dairy cattle using “in vitro” embryo production. Biotechnology (NY), 9, 844–847.CrossRefGoogle Scholar
  46. Limonta, J. M., Castro, F. O., Martinez, R., Puentes, P., Ramos, B., Aguilar, A., Lleonart, R. L.,&de la Fuente, J. (1995). Transgenic rabbits as bioreactors for the production of human growth hormone. Journal of Biotechnology, 40, 49–58.CrossRefGoogle Scholar
  47. Lipinski, D., Jura, J., Kalak, R., Plawski, A., Kala, M., Szalata, M., Jarmuz, M., Korcz, A., Slomska, K., Jura, J., Gronek, P., Smorag, Z., Pienkowski, M.,&Slomski, R. (2003). Transgenic rabbit producing human growth hormone in milk. Journal of Applied Genetics, 44, 165–174.Google Scholar
  48. Lubon, H.,&Paleyanda, R. K. (1997). Vitamin K-dependent protein production in transgenic animals. Thrombosis and Haemostasis, 78, 532–536.Google Scholar
  49. Martin, S. L., Downey, D., Bilton, D., Keogan, M. T., Edgar, J.,&Elborn, J. S. (2006). Safety and efficacy of recombinant alpha(1)-antitrypsin therapy in cystic fibrosis. Pediatric Pulmonology, 41, 177–183.CrossRefGoogle Scholar
  50. Massoud, M., Attal, J., Thepot, D., Pointu, H., Stinnakre, M. G., Theron, M. C., Lopez, C.,&Houdebine, L. M. (1996). The deleterious effects of human erythropoietin gene driven by the rabbit whey acidic protein gene promoter in transgenic rabbits. Reproduction Nutrition Development, 36, 555–563.CrossRefGoogle Scholar
  51. McCreath, K. J., Howcroft, J., Campbell, K. H., Colman, A., Schnieke, A. E.,&Kind, A. J. (2000). Production of gene-targeted sheep by nuclear transfer from cultured somatic cells. Nature, 405, 1066–1069.CrossRefGoogle Scholar
  52. 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. Nature Biotechnology, 16, 647–651.CrossRefGoogle Scholar
  53. Mercier, J. C.,&Vilotte, J. L. (1993). Structure and function of milk protein genes. Journal of Dairy Science, 76, 3079–3098.CrossRefGoogle Scholar
  54. Nagy, A., Gocza, E., Diaz, E. M., Prideaux, V. R., Ivanyi, E., Markkula, M.,&Rossant, J. (1990). Embryonic stem cells alone are able to support fetal development in the mouse. Development, 110, 815–821.Google Scholar
  55. Niemann, H., Halter, R., Carnwath, J. W., Herrmann, D., Lemme, E.,&Paul, D. (1999). Expression of human blood clotting factor VIII in the mammary gland of transgenic sheep. Transgenic Research, 8, 237–247.CrossRefGoogle Scholar
  56. Paleyanda, R. K., Velander, W. H., Lee, T. K., Scandella, D. H., Gwazdauskas, F. C., Knight, J. W., Hoyer, L. W., Drohan, W. N.,&Lubon, H. (1997). Transgenic pigs produce functional human factor VIII in milk. Nature Biotechnology, 15, 971–975.CrossRefGoogle Scholar
  57. Park, J. K., Lee, Y. K., Lee, P., Chung, H. J., Kim, S., Lee, H. G., Seo, M. K., Han, J. H., Park, C. G., Kim, H. T., Kim, Y. K., Min, K. S., Kim, J. H., Lee, H. T.,&Chang, W. K. (2006). Recombinant human erythropoietin produced in milk of transgenic pigs. Journal of Biotechnology, 122, 362–371.CrossRefGoogle Scholar
  58. Parker, M. H., Birck-Wilson, E., Allard, G., Masiello, N., Day, M., Murphy, K. P., Paragas, V., Silver, S.,&Moody, M. D. (2004). Purification and characterization of a recombinant version of human α-fetoprotein expressed in the milk of transgenic goats. Protein Expression and Purification, 38, 177–183.CrossRefGoogle Scholar
  59. Riego, E., Limonta, J., Aguilar, A., Perez, A., de Armas, R., Solano, R., Ramos, B., Castro, F. O.,&de la Fuente, J. (1993). Production of transgenic mice and rabbits that carry and express the human tissue plasminogen activator cDNA under the control of a bovine alpha S1 casein promoter. Theriogenology, 39, 1173–1185.CrossRefGoogle Scholar
  60. Rival-Gervier, S., Viglietta, C., Maeder, C., Attal, J.,&Houdebine, L. M. (2002). Position-independent and tissue-specific expression of porcine whey acidic protein gene from a bacterial artificial chromosome in transgenic mice. Molecular Reproduction and Development, 63, 161–167.CrossRefGoogle Scholar
  61. Rudolph, N. S. (1999). Biopharmaceutical production in transgenic livestock. Trends in Biotechnology, 17, 367–374.CrossRefGoogle Scholar
  62. Salamone, D., Baranao, L., Santos, C., Bussmann, L., Artuso, J., Werning, C., Prync, A., Carbonetto, C., Dabsys, S., Munar, C., Salaberry, R., Berra, G., Berra, I., Fernandez, N., Papouchado, M., Foti, M., Judewicz, N., Mujica, I., Munoz, L., Alvarez, S. F., Gonzalez, E., Zimmermann, J., Criscuolo, M.,&Melo, C. (2006). High level expression of bioactive recombinant human growth hormone in the milk of a cloned transgenic cow. Journal of Biotechnology, 124, 469–472.CrossRefGoogle Scholar
  63. Sanchez, O., Toledo, J. R., Rodriguez, M. P.,&Castro, F. O. (2004). Adenoviral vector mediates high expression levels of human growth hormone in the milk of mice and goats. Journal of Biotechnology, 114, 89–97.CrossRefGoogle Scholar
  64. Schnieke, A. E., Kind, A. J., Ritchie, W. A., Mycock, K., Scott, A. R., Ritchie, M., Wilmut, I., Colman, A.,&Campbell, K. H. (1997). Human factor IX transgenic sheep produced by transfer of nuclei from transfected fetal fibroblasts. Science, 278, 2130–2133.CrossRefGoogle Scholar
  65. Semeniuk, D. J., Boismenu, R., Tam, J., Weissenhofer, W.,&Murgita, R. A. (1995). Evidence that immunosuppression is an intrinsic property of the α-fetoprotein molecule. Advances in Experimental Medicine and Biology, 383, 255–269.Google Scholar
  66. Shen, W., Lan, G., Yang, X., Li, L., Min, L., Yang, Z., Tian, L., Wu, X., Sun, Y., Chen, H., Tan, J., Deng, J.,&Pan, Q. (2006). Targeting the exogenous htPAm gene on goat somatic cell β-casein locus for transgenic goat production. Molecular Reproduction and Development, 74, 428–434.CrossRefGoogle Scholar
  67. Simons, J. P., Wilmut, I., Clark, A. J., Archibald, A. L., Bishop, J. O.,&Lathe, R. (1988). Gene transfer to sheep. Bio/Technology, 6, 179–183 (abstract).CrossRefGoogle Scholar
  68. Soriano, P., Cone, R. D., Mulligan, R. C.,&Jaenisch, R. (1986). Tissue-specific and ectopic expression of genes introduced into transgenic mice by retroviruses. Science, 234, 1409–1413.CrossRefGoogle Scholar
  69. Soulier, S., Hudrisier, M., Da Silva, J. C., Maeder, C., Viglietta, C., Besnard, N.,&Vilotte, J. L. (2003). Substitution of the α-lactalbumin transcription unit by a CAT cDNA within a BAC clone silenced the locus in transgenic mice without affecting the physically linked Cyclin T1 gene. Genetics Selection Evolution, 35, 239–247.CrossRefGoogle Scholar
  70. Stinnakre, M. G., Soulier, S., Schibler, L., Lepourry, L., Mercier, J. C.,&Vilotte, J. L. (1999). Position-independent and copy-number-related expression of a goat bacterial artificial chromosome α-lactalbumin gene in transgenic mice. Biochemistry Journal, 339 (Pt 1), 33–36.CrossRefGoogle Scholar
  71. Stromqvist, M., Houdebine, M., Andersson, J. O., Edlund, A., Johansson, T., Viglietta, C., Puissant, C.,&Hansson, L. (1997). Recombinant human extracellular superoxide dismutase produced in milk of transgenic rabbits. Transgenic Research, 6, 271–278.CrossRefGoogle Scholar
  72. Subramanian, A., Paleyanda, R. K., Lubon, H., Williams, B. L., Gwazdauskas, F. C., Knight, J. W., Drohan, W. N.,&Velander, W. H. (1996). Rate limitations in posttranslational processing by the mammary gland of transgenic animals. Annals of the New York Academy of Sciences, 782, 87–96.CrossRefGoogle Scholar
  73. Swartz, J. R. (2001). Advances in Escherichia coli production of therapeutic proteins. Current Opinion in Biotechnology, 12, 195–201.CrossRefGoogle Scholar
  74. Thomassen, E. A., van Veen, H. A., van Berkel, P. H., Nuijens, J. H.,&Abrahams, J. P. (2005). The protein structure of recombinant human lactoferrin produced in the milk of transgenic cows closely matches the structure of human milk-derived lactoferrin. Transgenic Research, 14, 397–405.CrossRefGoogle Scholar
  75. Toledo, J. R., Sanchez, O., Segui, R. M., Garcia, G., Montanez, M., Zamora, P. A., Rodriguez, M. P.,&Cremata, J. A. (2006). High expression level of recombinant human erythropoietin in the milk of non-transgenic goats. Journal of Biotechnology, 123, 225–235.CrossRefGoogle Scholar
  76. van Berkel, P. H., Welling, M. M., Geerts, M., van Veen, H. A., Ravensbergen, B., Salaheddine, M., Pauwels, E. K., Pieper, F., Nuijens, J. H.,&Nibbering, P. H. (2002). Large scale production of recombinant human lactoferrin in the milk of transgenic cows. Nature Biotechnology, 20, 484–487.CrossRefGoogle Scholar
  77. Van Cott, K. E., Butler, S. P., Russell, C. G., Subramanian, A., Lubon, H., Gwazdauskas, F. C., Knight, J., Drohan, W. N.,&Velander, W. H. (1999). Transgenic pigs as bioreactors: a comparison of gamma-carboxylation of glutamic acid in recombinant human protein C and factor IX by the mammary gland. Genetic Analysis, 15, 155–160.Google Scholar
  78. Van Cott, K. E., Lubon, H., Gwazdauskas, F. C., Knight, J., Drohan, W. N.,&Velander, W. H. (2001). Recombinant human protein C expression in the milk of transgenic pigs and the effect on endogenous milk immunoglobulin and transferrin levels. Transgenic Research, 10, 43–51.CrossRefGoogle Scholar
  79. van der Putten, H., Botteri, F. M., Miller, A. D., Rosenfeld, M. G., Fan, H., Evans, R. M.,&Verma, I. M. (1985). Efficient insertion of genes into the mouse germ line via retroviral vectors. Proceedings of the National Academy of Sciences USA, 82, 6148–6152.CrossRefGoogle Scholar
  80. Van Hove, J. L., Yang, H. W., Wu, J. Y., Brady, R. O.,&Chen, Y. T. (1996). High-level production of recombinant human lysosomal acid α-glucosidase in Chinese hamster ovary cells which targets to heart muscle and corrects glycogen accumulation in fibroblasts from patients with Pompe disease. Proceedings of the National Academy of Sciences USA, 93, 65–70.CrossRefGoogle Scholar
  81. Velander, W. H., Johnson, J. L., Page, R. L., Russell, C. G., Subramanian, A., Wilkins, T. D., Gwazdauskas, F. C., Pittius, C.,&Drohan, W. N. (1992). High-level expression of a heterologous protein in the milk of transgenic swine using the cDNA encoding human protein C. Proceedings of the National Academy of Sciences USA, 89, 12003–12007.CrossRefGoogle Scholar
  82. Whitelaw, C. B. (2003). Transgenic livestock made easy. Trends in Biotechnology, 22, 157–159.CrossRefGoogle Scholar
  83. Whitelaw, C. B., Archibald, A. L., Harris, S., McClenaghan, M., Simons, J. P.,&Clark, A. J. (1991). Targeting expression to the mammary gland: Intronic sequences can enhance the efficiency of gene expression in transgenic mice. Transgenic Research, 1, 3–13.CrossRefGoogle Scholar
  84. Wilmut, I., Schnieke, A. E., McWhir, J., Kind, A. J.,&Campbell, K. H. (1997). Viable offspring derived from fetal and adult mammalian cells. Nature, 385, 810–813.CrossRefGoogle Scholar
  85. Wolf, E., Jehle, P. M., Weber, M. M., Sauerwein, H., Daxenberger, A., Breier, B. H., 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.CrossRefGoogle Scholar
  86. Wright, G., Carver, A., Cottom, D., Reeves, D., Scott, A., Simons, P., Wilmut, I., Garner, I.,&Colman, A. (1991). High level expression of active human α1-antitrypsin in the milk of transgenic sheep. Biotechnology (NY), 9, 830–834.CrossRefGoogle Scholar
  87. Zinovieva, N., Lassnig, C., Schams, D., Besenfelder, U., Wolf, E., Muller, S., Frenyo, L., Seregi, J., Muller, 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 Research, 7, 437–447.CrossRefGoogle Scholar
  88. Ziomek, C. A. (1998). Commercialization of proteins produced in the mammary gland. Theriogenology, 49, 139–144.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Zsuzsanna Bösze
    • 1
  • Mária Baranyi
  • C. Bruce
  • A. Whitelaw
  1. 1.Agricultural Biotechnology CenterHungary

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