Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

Protein therapeutics: a summary and pharmacological classification

Abstract

Once a rarely used subset of medical treatments, protein therapeutics have increased dramatically in number and frequency of use since the introduction of the first recombinant protein therapeutic — human insulin — 25 years ago. Protein therapeutics already have a significant role in almost every field of medicine, but this role is still only in its infancy. This article overviews some of the key characteristics of protein therapeutics, summarizes the more than 130 protein therapeutics used currently and suggests a new classification of these proteins according to their pharmacological action.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Pennisi, E. Bioinformatics. Gene counters struggle to get the right answer. Science 301, 1040–1041 (2003).

    Article  CAS  PubMed  Google Scholar 

  2. Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Venter, J. C. et al. The sequence of the human genome. Science 291, 1304–1351 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Reichert, J. M. Trends in development and approval times for new therapeutics in the United States. Nature Rev. Drug Discov. 2, 695–702 (2003).

    Article  CAS  Google Scholar 

  5. Slaff, J., Jacobson, D., Tillman, C. R., Curington, C. & Toskes, P. Protease-specific suppression of pancreatic exocrine secretion. Gastroenterology 87, 44–52 (1984).

    Article  CAS  PubMed  Google Scholar 

  6. Brown, A., Hughes, M., Tenner, S. & Banks, P. A. Does pancreatic enzyme supplementation reduce pain in patients with chronic pancreatitis: a meta-analysis. Am. J. Gastroenterol. 92, 2032–2035 (1997).

    CAS  PubMed  Google Scholar 

  7. American Thoracic Society. Guidelines for the approach to the patient with severe hereditary α-1-antitrypsin deficiency. Am. Rev. Respir. Dis. 140, 1494–1497 (1989).

  8. Dirksen, A. et al. A randomized clinical trial of α(1)-antitrypsin augmentation therapy. Am. J. Respir. Crit. Care Med. 160, 1468–1472 (1999).

    Article  CAS  PubMed  Google Scholar 

  9. Mason, H. S., Warzecha, H., Mor, T. & Arntzen, C. J. Edible plant vaccines: applications for prophylactic and therapeutic molecular medicine. Trends Mol. Med. 8, 324–329 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Wurm, F. & Bernard, A. Large-scale transient expression in mammalian cells for recombinant protein production. Curr. Opin. Biotechnol. 10, 156–159 (1999).

    Article  CAS  PubMed  Google Scholar 

  11. Zoller, M. J. New molecular biology methods for protein engineering. Curr. Opin. Biotechnol. 2, 526–531 (1991).

    Article  CAS  PubMed  Google Scholar 

  12. Brannigan, J. A. & Wilkinson, A. J. Protein engineering 20 years on. Nature Rev. Mol. Cell Biol. 3, 964–970 (2002).

    Article  CAS  Google Scholar 

  13. Watson, J. D., Gilman, M., Witkowksi, J. & Zoller, M. in Recombinant DNA 453–470 (Scientific American Books, New York, 1992).

    Google Scholar 

  14. Egrie, J. C. & Browne, J. K. Development and characterization of novel erythropoiesis stimulating protein (NESP). Br. J. Cancer 84 (Suppl. 1), 3–10 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Golan, D. E. et al. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy 2nd edn (Lippincott Williams & Wilkins, Philadelphia, 2007).

    Google Scholar 

  16. Banting, F. G., Best, C. H., Collip, J. B., Campbell, W. R. & Fletcher, A. A. Pancreatic extracts in the treatment of diabetes mellitus: preliminary report. 1922. CMAJ 145, 1281–1286 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Goeddel, D. V. et al. Expression in Escherichia coli of chemically synthesized genes for human insulin. Proc. Natl Acad. Sci. USA 76, 106–110 (1979).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Clark, A. J. et al. Biosynthetic human insulin in the treatment of diabetes. A double-blind crossover trial in established diabetic patients. Lancet 2, 354–357 (1982).

    Article  CAS  PubMed  Google Scholar 

  19. Keen, H. et al. Human insulin produced by recombinant DNA technology: safety and hypoglycaemic potency in healthy men. Lancet 2, 398–401 (1980).

    Article  CAS  PubMed  Google Scholar 

  20. Richter, B. & Neises, G. 'Human' insulin versus animal insulin in people with diabetes mellitus. Cochrane Database Syst. Rev. 1, CD003816 (2003).

    Google Scholar 

  21. Morales, L. E. Gaucher's disease: a review. Ann. Pharmacother. 30, 381–388 (1996).

    Article  CAS  PubMed  Google Scholar 

  22. Niederau, C. & Haussinger, D. Gaucher's disease: a review for the internist and hepatologist. Hepatogastroenterology 47, 984–997 (2000).

    CAS  PubMed  Google Scholar 

  23. Whittington, R. & Goa, K. L. Alglucerase. A review of its therapeutic use in Gaucher's disease. Drugs 44, 72–93 (1992).

    Article  CAS  PubMed  Google Scholar 

  24. Grabowski, G. A. et al. Enzyme therapy in type 1 Gaucher disease: comparative efficacy of mannose-terminated glucocerebrosidase from natural and recombinant sources. Ann. Intern. Med. 122, 33–39 (1995).

    Article  CAS  PubMed  Google Scholar 

  25. Barton, N. W. et al. Replacement therapy for inherited enzyme deficiency — macrophage-targeted glucocerebrosidase for Gaucher's disease. N. Engl. J. Med. 324, 1464–1470 (1991).

    Article  CAS  PubMed  Google Scholar 

  26. Rosado, J. L., Solomons, N. W., Lisker, R. & Bourges, H. Enzyme replacement therapy for primary adult lactase deficiency. Effective reduction of lactose malabsorption and milk intolerance by direct addition of β-galactosidase to milk at mealtime. Gastroenterology 87, 1072–1082 (1984).

    Article  CAS  PubMed  Google Scholar 

  27. Abildgaard, C. F. et al. Treatment of hemophilia with glycine-precipitated factor 8. N. Engl. J. Med. 275, 471–475 (1966).

    Article  CAS  PubMed  Google Scholar 

  28. Bray, G. L. et al. A multicenter study of recombinant factor VIII (recombinate): safety, efficacy, and inhibitor risk in previously untreated patients with hemophilia A. The Recombinate Study Group. Blood 83, 2428–2435 (1994).

    CAS  PubMed  Google Scholar 

  29. Roth, D. A. et al. Human recombinant factor IX: safety and efficacy studies in hemophilia B patients previously treated with plasma-derived factor IX concentrates. Blood 98, 3600–3606 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Haase, M. Human recombinant factor IX: safety and efficacy studies in hemophilia B patients previously treated with plasma-derived factor IX concentrates. Blood 100, 4242 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Kasper, D. K. et al. Harrison's Principles of Internal Medicine 16th edn (McGraw-Hill Professional, New York, 2004).

    Google Scholar 

  32. Benz, R. L., Pressman, M. R., Hovick, E. T. & Peterson, D. D. A preliminary study of the effects of correction of anemia with recombinant human erythropoietin therapy on sleep, sleep disorders, and daytime sleepiness in hemodialysis patients (The SLEEPO study). Am. J. Kidney Dis. 34, 1089–1095 (1999).

    Article  CAS  PubMed  Google Scholar 

  33. Corwin, H. L. et al. Efficacy of recombinant human erythropoietin in critically ill patients: a randomized controlled trial. JAMA 288, 2827–2835 (2002).

    Article  CAS  PubMed  Google Scholar 

  34. Evans, R. W., Rader, B. & Manninen, D. L. The quality of life of hemodialysis recipients treated with recombinant human erythropoietin. Cooperative Multicenter EPO Clinical Trial Group. JAMA 263, 825–830 (1990).

    Article  CAS  PubMed  Google Scholar 

  35. Levin, N. W., Lazarus, J. M. & Nissenson, A. R. National Cooperative rHu erythropoietin study in patients with chronic renal failure — an interim report. The National Cooperative rHu Erythropoietin Study Group. Am. J. Kidney Dis. 22, 3–12 (1993).

    Article  CAS  PubMed  Google Scholar 

  36. Miles, S. The use of hematopoietic growth factors in treating HIV infection. Curr. Opin. Hematol. 2, 227–233 (1995).

    Article  CAS  PubMed  Google Scholar 

  37. Lieschke, G. J. & Burgess, A. W. Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor (2). N. Engl. J. Med. 327, 99–106 (1992).

    Article  CAS  PubMed  Google Scholar 

  38. Tepler, I. et al. A randomized placebo-controlled trial of recombinant human interleukin-11 in cancer patients with severe thrombocytopenia due to chemotherapy. Blood 87, 3607–3614 (1996).

    CAS  PubMed  Google Scholar 

  39. Out, H. J., Driessen, S. G., Mannaerts, B. M. & Coelingh Bennink, H. J. Recombinant follicle-stimulating hormone (follitropin beta, Puregon) yields higher pregnancy rates in in vitro fertilization than urinary gonadotropins. Fertil. Steril. 68, 138–142 (1997).

    Article  CAS  PubMed  Google Scholar 

  40. Van Wely, M., Westergaard, L. G., Bossuyt, P. M. & Van der Veen, F. Human menopausal gonadotropin versus recombinant follicle stimulation hormone for ovarian stimulation in assisted reproductive cycles. Cochrane Database Syst. Rev. 1, CD003973 (2003).

    Google Scholar 

  41. Ludwig, M., Doody, K. J. & Doody, K. M. Use of recombinant human chorionic gonadotropin in ovulation induction. Fertil. Steril. 79, 1051–1059 (2003).

    Article  PubMed  Google Scholar 

  42. A comparison of continuous infusion of alteplase with double-bolus administration for acute myocardial infarction. The Continuous Infusion versus Double-Bolus Administration of Alteplase (COBALT) Investigators. N. Engl. J. Med. 337, 1124–1130 (1997).

  43. Clark, W. M. et al. Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: a randomized controlled trial. alteplase thrombolysis for acute noninterventional therapy in ischemic stroke. JAMA 282, 2019–2026 (1999).

    Article  CAS  PubMed  Google Scholar 

  44. Goldhaber, S. Z. et al. Alteplase versus heparin in acute pulmonary embolism: randomised trial assessing right-ventricular function and pulmonary perfusion. Lancet 341, 507–511 (1993).

    Article  CAS  PubMed  Google Scholar 

  45. Albers, G. W. et al. Intravenous tissue-type plasminogen activator for treatment of acute stroke: the Standard Treatment with Alteplase to Reverse Stroke (STARS) study. JAMA 283, 1145–1150 (2000).

    Article  CAS  PubMed  Google Scholar 

  46. Katzan, I. L. et al. Use of tissue-type plasminogen activator for acute ischemic stroke: the Cleveland area experience. JAMA 283, 1151–1158 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. No authors listed. Randomised, double-blind comparison of reteplase double-bolus administration with streptokinase in acute myocardial infarction (INJECT): trial to investigate equivalence. International Joint Efficacy Comparison of Thrombolytics. Lancet 346, 329–336 (1995).

  48. No authors listed. A comparison of reteplase with alteplase for acute myocardial infarction. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) Investigators. N. Engl. J. Med. 337, 1118–1123 (1997).

  49. No authors listed. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial. Assessment of the Safety and Efficacy of a New Thrombolytic Investigators. Lancet 354, 716–722 (1999).

  50. No authors listed. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial infarction. Lancet 358, 605–613 (2001).

  51. Shapiro, A. D., Gilchrist, G. S., Hoots, W. K., Cooper, H. A. & Gastineau, D. A. Prospective, randomised trial of two doses of rFVIIa (NovoSeven) in haemophilia patients with inhibitors undergoing surgery. Thromb. Haemost. 80, 773–778 (1998).

    Article  CAS  PubMed  Google Scholar 

  52. Hedner, U. Dosing with recombinant factor VIIa based on current evidence. Semin. Hematol. 41, 35–39 (2004).

    Article  CAS  PubMed  Google Scholar 

  53. Bernard, G. R. et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N. Engl. J. Med. 344, 699–709 (2001).

    Article  CAS  PubMed  Google Scholar 

  54. Dhainaut, J. F., Yan, S. B. & Claessens, Y. E. Protein C/activated protein C pathway: overview of clinical trial results in severe sepsis. Crit. Care Med. 32, S194–S201 (2004).

    Article  CAS  PubMed  Google Scholar 

  55. Burke, J. F. & Golden, T. A clinical evaluation of enzymatic debridement with papain-urea-chlorophyllin ointment. Am. J. Surg. 95, 828–842 (1958).

    Article  CAS  PubMed  Google Scholar 

  56. Boxer, A. M., Gottesman, N., Bernstein, H. & Mandl, I. Debridement of dermal ulcers and decubiti with collagenase. Geriatrics 24, 75–86 (1969).

    CAS  PubMed  Google Scholar 

  57. Rao, D. B., Sane, P. G. & Georgiev, E. L. Collagenase in the treatment of dermal and decubitus ulcers. J. Am. Geriatr. Soc. 23, 22–30 (1975).

    Article  CAS  PubMed  Google Scholar 

  58. Fuchs, H. J. et al. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group. N. Engl. J. Med. 331, 637–642 (1994).

    Article  CAS  PubMed  Google Scholar 

  59. Holle, L. M. Pegaspargase: an alternative? Ann. Pharmacother. 31, 616–624 (1997).

    Article  CAS  PubMed  Google Scholar 

  60. Clavell, L. A. et al. Four-agent induction and intensive asparaginase therapy for treatment of childhood acute lymphoblastic leukemia. N. Engl. J. Med. 315, 657–663 (1986).

    Article  CAS  PubMed  Google Scholar 

  61. Greinacher, A. et al. Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia: a prospective study. Circulation 99, 73–80 (1999).

    Article  CAS  PubMed  Google Scholar 

  62. Eriksson, B. I. et al. A comparison of recombinant hirudin with a low-molecular-weight heparin to prevent thromboembolic complications after total hip replacement. N. Engl. J. Med. 337, 1329–1335 (1997).

    Article  CAS  PubMed  Google Scholar 

  63. Rogers, L. Q. & Lutcher, C. L. Streptokinase therapy for deep vein thrombosis: a comprehensive review of the English literature. Am. J. Med. 88, 389–395 (1990).

    Article  CAS  PubMed  Google Scholar 

  64. Kennedy, J. W., Ritchie, J. L., Davis, K. B. & Fritz, J. K. Western Washington randomized trial of intracoronary streptokinase in acute myocardial infarction. N. Engl. J. Med. 309, 1477–1482 (1983).

    Article  CAS  PubMed  Google Scholar 

  65. Anderson, J. L. et al. A randomized trial of intracoronary streptokinase in the treatment of acute myocardial infarction. N. Engl. J. Med. 308, 1312–1318 (1983).

    Article  CAS  PubMed  Google Scholar 

  66. No authors listed. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. The GUSTO investigators. N. Engl. J. Med. 329, 673–682 (1993).

  67. Clark, M. Antibody humanization: a case of the 'Emperor's new clothes'? Immunol. Today 21, 397–402 (2000).

    Article  CAS  PubMed  Google Scholar 

  68. Mease, P. J. et al. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet 356, 385–390 (2000).

    Article  CAS  PubMed  Google Scholar 

  69. Weinblatt, M. E. et al. A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N. Engl. J. Med. 340, 253–259 (1999).

    Article  CAS  PubMed  Google Scholar 

  70. Gorman, J. D., Sack, K. E. & Davis, J. C. Jr. Treatment of ankylosing spondylitis by inhibition of tumor necrosis factor α. N. Engl. J. Med. 346, 1349–1356 (2002).

    Article  CAS  PubMed  Google Scholar 

  71. Lipsky, P. E. et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N. Engl. J. Med. 343, 1594–1602 (2000).

    Article  CAS  PubMed  Google Scholar 

  72. Maini, R. et al. Infliximab (chimeric anti-tumour necrosis factor α monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet 354, 1932–1939 (1999).

    Article  CAS  PubMed  Google Scholar 

  73. Present, D. H. et al. Infliximab for the treatment of fistulas in patients with Crohn's disease. N. Engl. J. Med. 340, 1398–1405 (1999).

    Article  CAS  PubMed  Google Scholar 

  74. No authors listed. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. The IMpact-RSV Study Group. Pediatrics 102, 531–537 (1998).

  75. Meissner, H. C. & Long, S. S. Revised indications for the use of palivizumab and respiratory syncytial virus immune globulin intravenous for the prevention of respiratory syncytial virus infections. Pediatrics 112, 1447–1452 (2003).

    Article  PubMed  Google Scholar 

  76. Matthews, T. et al. Enfuvirtide: the first therapy to inhibit the entry of HIV-1 into host CD4 lymphocytes. Nature Rev. Drug Discov. 3, 215–225 (2004).

    Article  CAS  Google Scholar 

  77. Lazzarin, A. et al. Efficacy of enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia. N. Engl. J. Med. 348, 2186–2195 (2003).

    Article  CAS  PubMed  Google Scholar 

  78. Lalezari, J. P. et al. Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. N. Engl. J. Med. 348, 2175–2185 (2003).

    Article  CAS  PubMed  Google Scholar 

  79. McLaughlin, P. et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J. Clin. Oncol. 16, 2825–2833 (1998).

    Article  CAS  PubMed  Google Scholar 

  80. Maloney, D. G. et al. IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma. Blood 90, 2188–2195 (1997).

    Article  CAS  PubMed  Google Scholar 

  81. Coiffier, B. et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N. Engl. J. Med. 346, 235–242 (2002).

    Article  CAS  PubMed  Google Scholar 

  82. Cunningham, D. et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N. Engl. J. Med. 351, 337–345 (2004).

    Article  CAS  PubMed  Google Scholar 

  83. Slamon, D. J. et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344, 783–792 (2001).

    Article  CAS  PubMed  Google Scholar 

  84. Vogel, C. L. et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J. Clin. Oncol. 20, 719–726 (2002).

    Article  CAS  PubMed  Google Scholar 

  85. Valabrega, G. M., Montemurro, F. & Aglietta, M. Trastuzumab: mechanism of action, resistance and future perspectives in HER2-overexpressing breast cancer. Ann. Oncol. 18, 977–984 (2007).

    Article  CAS  PubMed  Google Scholar 

  86. Sievers, E. L. et al. Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J. Clin. Oncol. 19, 3244–3254 (2001).

    Article  CAS  PubMed  Google Scholar 

  87. Giles, F., Estey, E. & O'Brien, S. Gemtuzumab ozogamicin in the treatment of acute myeloid leukemia. Cancer 98, 2095–2104 (2003).

    Article  CAS  PubMed  Google Scholar 

  88. Witzig, T. E. et al. Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. J. Clin. Oncol. 20, 2453–2463 (2002).

    Article  CAS  PubMed  Google Scholar 

  89. Ho, V. T. et al. Safety and efficacy of denileukin diftitox in patients with steroid-refractory acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Blood 104, 1224–1226 (2004).

    Article  CAS  PubMed  Google Scholar 

  90. Olsen, E. et al. Pivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma. J. Clin. Oncol. 19, 376–388 (2001).

    Article  CAS  PubMed  Google Scholar 

  91. Phelan, A., Elliott, G. & O'Hare, P. Intercellular delivery of functional p53 by the herpesvirus protein VP22. Nature Biotechnol. 16, 440–443 (1998).

    Article  CAS  Google Scholar 

  92. Francis, J. W., Hosler, B. A., Brown, R. H. Jr & Fishman, P. S. CuZn superoxide dismutase (SOD-1):tetanus toxin fragment C hybrid protein for targeted delivery of SOD-1 to neuronal cells. J. Biol. Chem. 270, 15434–15442 (1995).

    Article  CAS  PubMed  Google Scholar 

  93. Szmuness, W. et al. Hepatitis B vaccine: demonstration of efficacy in a controlled clinical trial in a high-risk population in the United States. N. Engl. J. Med. 303, 833–841 (1980).

    Article  CAS  PubMed  Google Scholar 

  94. Crosnier, J. et al. Randomised placebo-controlled trial of hepatitis B surface antigen vaccine in French haemodialysis units: I, Medical staff. Lancet 1, 455–459 (1981).

    Article  CAS  PubMed  Google Scholar 

  95. Sigal, L. H. et al. A vaccine consisting of recombinant Borrelia burgdorferi outer-surface protein A to prevent Lyme disease. Recombinant Outer-Surface Protein A Lyme Disease Vaccine Study Consortium. N. Engl. J. Med. 339, 216–222 (1998).

    Article  CAS  PubMed  Google Scholar 

  96. Steere, A. C. et al. Vaccination against Lyme disease with recombinant Borrelia burgdorferi outer-surface lipoprotein A with adjuvant. Lyme Disease Vaccine Study Group. N. Engl. J. Med. 339, 209–215 (1998).

    Article  CAS  PubMed  Google Scholar 

  97. Shi, L. et al. Gardasil: prophylactic human papillomavirus vaccine development — from bench top to bed-side. Clin. Pharm. Ther. 81, 259–264 (2007).

    Article  CAS  Google Scholar 

  98. MacKenzie, I. Z. et al. Efficacy and safety of a new, chromatographically purified rhesus (D) immunoglobulin. Eur. J. Obstet. Gynecol. Reprod. Biol. 117, 154–161 (2004).

    Article  CAS  PubMed  Google Scholar 

  99. McCormick, A. A. et al. Rapid production of specific vaccines for lymphoma by expression of the tumor-derived single-chain Fv epitopes in tobacco plants. Proc. Natl Acad. Sci. USA 96, 703–708 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Campos-Neto, A. et al. Evaluation of DPPD, a single recombinant Mycobacterium tuberculosis protein as an alternative antigen for the Mantoux test. Tuberculosis (Edinb.) 81, 353–358 (2001).

    Article  CAS  Google Scholar 

  101. Coler, R. N. et al. Cloning of a Mycobacterium tuberculosis gene encoding a purifed protein derivative protein that elicits strong tuberculosis-specific delayed-type hypersensitivity. J. Infect. Dis. 182, 224–233 (2000).

    Article  CAS  PubMed  Google Scholar 

  102. Duchin, J. S., Jereb, J. A., Nolan, C. M., Smith, P. & Onorato, I. M. Comparison of sensitivities to two commercially available tuberculin skin test reagents in persons with recent tuberculosis. Clin. Infect. Dis. 25, 661–663 (1997).

    Article  CAS  PubMed  Google Scholar 

  103. Ranke, M. B. et al. Testing with growth hormone-releasing factor (GRF(1–29)NH2) and somatomedin C measurements for the evaluation of growth hormone deficiency. Eur. J. Pediatr. 145, 485–492 (1986).

    Article  CAS  PubMed  Google Scholar 

  104. Ghigo, E. et al. New approach to the diagnosis of growth hormone deficiency in adults. Eur. J. Endocrinol. 134, 352–356 (1996).

    Article  CAS  PubMed  Google Scholar 

  105. Ladenson, P. W. et al. Comparison of administration of recombinant human thyrotropin with withdrawal of thyroid hormone for radioactive iodine scanning in patients with thyroid carcinoma. N. Engl. J. Med. 337, 888–896 (1997).

    Article  CAS  PubMed  Google Scholar 

  106. Meier, C. A. et al. Diagnostic use of recombinant human thyrotropin in patients with thyroid carcinoma (phase I/II study). J. Clin. Endocrinol. Metab. 78, 188–196 (1994).

    CAS  PubMed  Google Scholar 

  107. Taillefer, R., Edell, S., Innes, G. & Lister-James, J. Acute thromboscintigraphy with Tc-99m-apcitide: results of the phase 3 multicenter clinical trial comparing Tc-99m-apcitide scintigraphy with contrast venography for imaging acute DVT. J. Nucl. Med. 41, 1214–1223 (2000).

    CAS  PubMed  Google Scholar 

  108. Sodee, D. B. et al. Multicenter ProstaScint imaging findings in 2154 patients with prostate cancer. Urology 56, 988–993 (2000).

    Article  CAS  PubMed  Google Scholar 

  109. Urnovitz, H. B., Sturge, J. C. & Gottfried, T. D. Increased sensitivity of HIV-1 antibody detection. Nature Med. 3, 1258 (1997).

    Article  CAS  PubMed  Google Scholar 

  110. Van de Perre, P. et al. Postnatal transmission of human immunodeficiency virus type 1 from mother to infant. A prospective cohort study in Kigali, Rwanda. N. Engl. J. Med. 325, 593–598 (1991).

    Article  CAS  PubMed  Google Scholar 

  111. Busch, M. P. et al. Evaluation of screened blood donations for human immunodeficiency virus type 1 infection by culture and DNA amplification of pooled cells. N. Engl. J. Med. 325, 1–5 (1991).

    Article  CAS  PubMed  Google Scholar 

  112. Van der Poel, C. L. et al. Confirmation of hepatitis C virus infection by new four-antigen recombinant immunoblot assay. Lancet 337, 317–319 (1991).

    Article  CAS  PubMed  Google Scholar 

  113. Soffredini, R. et al. Increased detection of antibody to hepatitis C virus in renal transplant patients by third-generation assays. Am. J. Kidney Dis. 28, 437–440 (1996).

    Article  CAS  PubMed  Google Scholar 

  114. Putney, S. D. & Burke, P. A. Improving protein therapeutics with sustained-release formulations. Nature Biotech. 16, 153–157 (1998).

    Article  CAS  Google Scholar 

  115. Mahmood, I. & Green, M. D. Pharmacokinetic and pharmacodynamic considerations in the development of therapeutic proteins. Clin. Pharmacokinet. 44, 331–347 (2005).

    Article  CAS  PubMed  Google Scholar 

  116. Schellekens, H. Bioequivalence and the immunogenicity of biopharmaceuticals. Nature Rev. Drug Discov. 1, 457–462 (2002).

    Article  CAS  Google Scholar 

  117. Peerlinck, K., Arnout, J., Gilles, J. G., Saintremy, J. M. & Vermylen, J. A higher than expected incidence of factor-VIII inhibitors in multitransfused hemophilia-A patients treated with an intermediate purity pasteurized factor-VIII concentrate. Thromb. Haemost. 69, 115–118 (1993).

    Article  CAS  PubMed  Google Scholar 

  118. Gilles, J. G., Arnout, J., Vermylen, J. & Saint-Remy, J. M. Anti-factor VIII antibodies of hemophiliac patients are frequently directed towards nonfunctional determinants and do not exhibit isotypic restriction. Blood 82, 2452–2461 (1993).

    Article  CAS  PubMed  Google Scholar 

  119. Mascelli, M. A. et al. Molecular, biologic, and pharmacokinetic properties of monoclonal antibodies: impact of these parameters on early clinical development. J. Clin. Pharm. 47, 553–565 (2007).

    Article  CAS  Google Scholar 

  120. Reichert, J. M. & Valge-Archer, V. E. Development trends for monoclonal antibody cancer therapeutics. Nature Rev. Drug Discov. 6, 349–356 (2007).

    Article  CAS  Google Scholar 

  121. Bussel, J. B. et al. AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP. N. Engl. J. Med. 355, 1672–1681 (2006).

    Article  CAS  PubMed  Google Scholar 

  122. Li, J. Z. et al. Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood 98, 3241–3248 (2001).

    Article  CAS  PubMed  Google Scholar 

  123. Basser, R. L. et al. Development of pancytopenia with neutralizing antibodies to thrombopoietin after multicycle chemotherapy supported by megakaryocyte growth and development factor. Blood 99, 2599–2602 (2002).

    Article  CAS  PubMed  Google Scholar 

  124. Walsh, C. T. Posttranslational Modification of Proteins: Expanding Nature's Inventory (Roberts & Company, Colorado, 2005).

    Google Scholar 

  125. Frokjaer, S. & Otzen, D. E. Protein drug stability: a formulation challenge. Nature Rev. Drug Discov. 4, 298–306 (2005).

    Article  CAS  Google Scholar 

  126. Fowler, S. B. et al. Rational design of aggregation-resistant bioactive peptides: reengineering human calcitonin. Proc. Natl Acad. Sci. USA 102, 10105–10110 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Dinnis, D. M. & James, D. C. Engineering mammalian cell factories for improved recombinant monoclonal antibody production: lessons from nature? Biotechnol. Bioeng. 91, 180–189 (2005).

    Article  CAS  Google Scholar 

  128. Datar, R. V., Cartwright, T. & Rosen, C. G. Process economics of animal cell and bacterial fermentations: a case study analysis of tissue plasminogen activator. Biotechnology (NY) 11, 349–357 (1993).

    Article  CAS  Google Scholar 

  129. Lillico, S. G., McGrew, M. J., Sherman, A. & Sang, H. M. Transgenic chickens as bioreactors for protein-based drugs. Drug Discov. Today 10, 191–196 (2005).

    Article  CAS  PubMed  Google Scholar 

  130. Pogue, G. P., Lindbo, J. A., Garger, S. J. & Fitzmaurice, W. P. Making an ally from an enemy: plant virology and the new agriculture. Annu. Rev. Phytopathol. 40, 45–74 (2002).

    Article  CAS  PubMed  Google Scholar 

  131. Micheletti, M. et al. Fluid mixing in shaken bioreactors: implications for scale-up predictions for microlitre-scale microbial and mammalian cell cultures. Chem. Eng. Sci. 61 (2006).

    Article  CAS  Google Scholar 

  132. Gross, M. L. Ethics, policy, and rare genetic disorders: the case of Gaucher disease in Israel. Theor. Med. Bioeth. 23, 151–170 (2002).

    Article  PubMed  Google Scholar 

  133. Finkelstein, B. S. et al. Effect of growth hormone therapy on height in children with idiopathic short stature: a meta-analysis. Arch. Pediatr. Adolesc. Med. 156, 230–240 (2002).

    Article  PubMed  Google Scholar 

  134. Hokken-Koelega, A. C. et al. Growth hormone treatment in growth-retarded adolescents after renal transplant. Lancet 343, 1313–1317 (1994).

    Article  CAS  PubMed  Google Scholar 

  135. Howrie, D. L. Growth hormone for the treatment of growth failure in children. Clin. Pharm. 6, 283–291 (1987).

    CAS  PubMed  Google Scholar 

  136. Salomon, F., Cuneo, R. C., Hesp, R. & Sonksen, P. H. The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. N. Engl. J. Med. 321, 1797–1803 (1989).

    Article  CAS  PubMed  Google Scholar 

  137. Thorner, M. O. et al. The diagnosis of growth hormone deficiency (GHD) in adults. J. Clin. Endocrinol. Metab. 80, 3097–3098 (1995).

    CAS  PubMed  Google Scholar 

  138. Graham, J., Muhsin, M. & Kirkpatrick, P. Cetuximab. Nature Rev. Drug Discov. 3, 549–550 (2004).

    Article  Google Scholar 

  139. Goldberg, R. M. & Kirkpatrick, P. Cetuximab. Nature Rev. Drug Discov. 4 (Suppl. 1) S10–S11 (2005).

    Article  Google Scholar 

  140. Saltz, L. B. et al. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J. Clin. Oncol. 22, 1201–1208 (2004).

    Article  CAS  PubMed  Google Scholar 

  141. Warrier, I. et al. Factor IX inhibitors and anaphylaxis in hemophilia B. J. Pediatr. Hematol. Oncol. 19, 23–27 (1997).

    Article  CAS  PubMed  Google Scholar 

  142. Thorland, E. C. et al. Anaphylactic response to factor IX replacement therapy in haemophilia B patients: complete gene deletions confer the highest risk. Haemophilia 5, 101–105 (1999).

    Article  CAS  PubMed  Google Scholar 

  143. Rosenberg, R. D., Goldman, P., Bing, D. & Glass, J. Actions and interactions of antithrombin and heparin. N. Engl. J. Med. 292, 146–151 (1975).

    Article  CAS  PubMed  Google Scholar 

  144. Mannucci, P. M., Boyer, C., Wolf, M., Tripodi, A. & Larrieu, M. J. Treatment of congenital antithrombin-III deficiency with concentrates. Br. J. Haematol. 50, 531–535 (1982).

    Article  CAS  PubMed  Google Scholar 

  145. Moritz, B. et al. The efficacy and safety of protein C concentrate (Human) vapor-heated in the treatment of severe congenital protein C deficiency with or without pupura fulminans. Blood 96, 53A–53A (2000).

    Google Scholar 

  146. Quattrin, T., Belanger, A., Bohannon, N. J. V. & Schwartz, S. L. Efficacy and safety of inhaled insulin (Exubera) compared with subcutaneous insulin therapy in patients with type 1 diabetes — results of a 6-month, randomized, comparative trial. Diabetes Care 27, 2622–2627 (2004).

    Article  CAS  PubMed  Google Scholar 

  147. Hollander, P. A. et al. Efficacy and safety of inhaled insulin (Exubera) compared with subcutaneous insulin therapy in patients with type 2 diabetes — results of a 6-month, randomized, comparative trial. Diabetes Care 27, 2356–2362 (2004).

    Article  CAS  PubMed  Google Scholar 

  148. Skyler, J. S. et al. Efficacy of inhaled human insulin in type 1 diabetes mellitus: a randomised proof-of-concept study. Lancet 357, 331–335 (2001).

    Article  CAS  PubMed  Google Scholar 

  149. Edwards, D. A. et al. Large porous particles for pulmonary drug delivery. Science 276, 1868–1871 (1997).

    Article  CAS  PubMed  Google Scholar 

  150. Hirsch, I. B. Drug therapy: Insulin analogues. N. Engl. J. Med. 352, 174–183 (2005).

    Article  CAS  PubMed  Google Scholar 

  151. Dreyer, M. et al. Efficacy and safety of insulin glulisine in patients with type 1 diabetes. Horm. Metab. Res. 37, 702–707 (2005).

    Article  CAS  PubMed  Google Scholar 

  152. Soran, H. & Younis, N. Insulin detemir: a new basal insulin analogue. Diabetes Obes. Metab. 8, 26–30 (2006).

    Article  CAS  PubMed  Google Scholar 

  153. Thompson, R. G., Peterson, J., Gottlieb, A. & Mullane, J. Effects of pramlintide, an analog of human amylin, on plasma glucose profiles in patients with IDDM — results of a multicenter trial. Diabetes 46, 632–636 (1997).

    Article  CAS  PubMed  Google Scholar 

  154. Backeljauw, P. F. & Underwood, L. E. Therapy for 6.5–7.5 years with recombinant insulin-like growth factor I in children with growth hormone insensitivity syndrome: a clinical research center study. J. Clin. Endocrinol. Metab. 86, 1504–1510 (2001).

    CAS  PubMed  Google Scholar 

  155. Kemp, S. F., Fowlkes, J. L. & Thrailkill, K. M. Efficacy and safety of mecasermin rinfabate. Expert Opin. Biol. Ther. 6, 533–538 (2006).

    CAS  Google Scholar 

  156. Ho, M. W. & O'Brien, J. S. Gaucher's disease: deficiency of 'acid' -glucosidase and reconstitution of enzyme activity in vitro. Proc. Natl Acad. Sci. USA 68, 2810–2813 (1971).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Klinge, L. et al. Safety and efficacy of recombinant acid α-glucosidase (rhGAA) in patients with classical infantile Pompe disease: results of a phase II clinical trial. Neuromuscul. Disord. 15, 24–31 (2005).

    Article  CAS  PubMed  Google Scholar 

  158. Scott, H. S. et al. Human α-L-iduronidase: cDNA isolation and expression. Proc. Natl Acad. Sci. USA 88, 9695–9699 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Bach, G., Friedman, R., Weissmann, B. & Neufeld, E. F. The defect in the Hurler and Scheie syndromes: deficiency of α-L-iduronidase. Proc. Natl Acad. Sci. USA 69, 2048–2051 (1972).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Kakkis, E. D. et al. Enzyme-replacement therapy in mucopolysaccharidosis I. N. Engl. J. Med. 344, 182–188 (2001).

    Article  CAS  PubMed  Google Scholar 

  161. Muenzer, J. et al. A phase II/III clinical study of enzyme replacement therapy with idursulfase in mucopolysaccharidosis II (Hunter syndrome). Genet. Med. 8, 465–473 (2006).

    Article  CAS  PubMed  Google Scholar 

  162. Hopwood, J. J., Bate, G. & Kirkpatrick, P. Galsulfase. Nature Rev. Drug Discov. 5, 101–102 (2006).

    Article  CAS  Google Scholar 

  163. Eng., C. M. et al. Safety and efficacy of recombinant human α-galactosidase A — replacement therapy in Fabry's disease. N. Engl. J. Med. 345, 9–16 (2001).

    Article  CAS  PubMed  Google Scholar 

  164. Schiffmann, R. et al. Enzyme replacement therapy in Fabry disease: a randomized controlled trial. JAMA 285, 2743–2749 (2001).

    Article  CAS  PubMed  Google Scholar 

  165. Society, A. T. Guidelines for the approach to the patient with severe hereditary a-1-antitrypsin deficiency. Am. Rev. Respir. Dis. 140, 1494–1497 (1989).

    Article  Google Scholar 

  166. Hershfield, M. S. et al. Treatment of adenosine deaminase deficiency with polyethylene glycol-modified adenosine deaminase. N. Engl. J. Med. 316, 589–596 (1987).

    Article  CAS  PubMed  Google Scholar 

  167. Ochs, H. D. & Pinciaro, P. J. Octagam 5%, an intravenous IgG product, is efficacious and well tolerated in subjects with primary immunodeficiency diseases. J. Clin. Immunol. 24, 309–314 (2004).

    Article  CAS  PubMed  Google Scholar 

  168. Finfer, S. et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N. Engl. J. Med. 350, 2247–2256 (2004).

    Article  CAS  PubMed  Google Scholar 

  169. No authors listed. Association between recombinant human erythropoietin and quality of life and exercise capacity of patients receiving haemodialysis. Canadian Erythropoietin Study Group. BMJ 300, 573–578 (1990).

  170. Laupacis, A. Changes in quality of life and functional capacity in hemodialysis patients treated with recombinant human erythropoietin. The Canadian Erythropoietin Study Group. Semin. Nephrol. 10, 11–19 (1990).

    CAS  PubMed  Google Scholar 

  171. Heil, G. et al. A randomized, double-blind, placebo-controlled, phase III study of filgrastim in remission induction and consolidation therapy for adults with de novo acute myeloid leukemia. Blood 90, 4710–4718 (1997).

    Article  CAS  PubMed  Google Scholar 

  172. Tarlatzis, B. et al. The use of recombinant human LH (lutropin alfa) in the late stimulation phase of assisted reproduction cycles: a double-blind, randomized, prospective study. Hum. Reprod. 21, 90–94 (2006).

    Article  CAS  PubMed  Google Scholar 

  173. Cirelli, R. & Tyring, S. K. Interferons in human papillomavirus infections. Antiviral Res. 24, 191–204 (1994).

    Article  CAS  PubMed  Google Scholar 

  174. Lindsay, K. L. Therapy of hepatitis C: overview. Hepatology 26, 71S–77S (1997).

    Article  CAS  PubMed  Google Scholar 

  175. Tong, M. J. et al. Treatment of chronic hepatitis C with consensus interferon: a multicenter, randomized, controlled trial. Consensus Interferon Study Group. Hepatology 26, 747–754 (1997).

    Article  CAS  PubMed  Google Scholar 

  176. Suzuki, H. & Tango, T. A multicenter, randomized, controlled clinical trial of interferon alfacon-1 in comparison with lymphoblastoid interferon-α in patients with high-titer chronic hepatitis C virus infection. Hepatol. Res. 22, 1–12 (2002).

    Article  CAS  PubMed  Google Scholar 

  177. van Zonneveld, M. et al. Long-term follow-up of α-interferon treatment of patients with chronic hepatitis B. Hepatology 39, 804–810 (2004).

    Article  CAS  PubMed  Google Scholar 

  178. Giannini, E. et al. Long-term follow up of chronic hepatitis C patients after α-interferon treatment: a functional study. J. Gastroenterol. Hepatol. 16, 399–405 (2001).

    Article  CAS  PubMed  Google Scholar 

  179. Smalley, R. V. et al. Interferon α combined with cytotoxic chemotherapy for patients with non-Hodgkin's lymphoma. N. Engl. J. Med. 327, 1336–1341 (1992).

    Article  CAS  PubMed  Google Scholar 

  180. Quesada, J. R. et al. Treatment of hairy cell leukemia with recombinant α-interferon. Blood 68, 493–497 (1986).

    Article  CAS  PubMed  Google Scholar 

  181. Allan, N. C., Richards, S. M. & Shepherd, P. C. UK Medical Research Council randomised, multicentre trial of interferon-α n1 for chronic myeloid leukaemia: improved survival irrespective of cytogenetic response. The UK Medical Research Council's Working Parties for Therapeutic Trials in Adult Leukaemia. Lancet 345, 1392–1397 (1995).

    Article  CAS  PubMed  Google Scholar 

  182. No authors listed. Interferon α-2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia. The Italian Cooperative Study Group on Chronic Myeloid Leukemia. N. Engl. J. Med. 330, 820–825 (1994).

  183. Misiani, R. et al. Interferon α-2a therapy in cryoglobulinemia associated with hepatitis C virus. N. Engl. J. Med. 330, 751–756 (1994).

    Article  CAS  PubMed  Google Scholar 

  184. Fried, M. W. et al. Peginterferon α-2a plus ribavirin for chronic hepatitis C virus infection. N. Engl. J. Med. 347, 975–982 (2002).

    Article  CAS  PubMed  Google Scholar 

  185. Zeuzem, S. et al. Peginterferon α-2a in patients with chronic hepatitis C. N. Engl. J. Med. 343, 1666–1672 (2000).

    Article  CAS  PubMed  Google Scholar 

  186. Heathcote, E. J. et al. Peginterferon α-2a in patients with chronic hepatitis C and cirrhosis. N. Engl. J. Med. 343, 1673–1680 (2000).

    Article  CAS  PubMed  Google Scholar 

  187. Mandelli, F. et al. Maintenance treatment with recombinant interferon α-2b in patients with multiple myeloma responding to conventional induction chemotherapy. N. Engl. J. Med. 322, 1430–1434 (1990).

    Article  CAS  PubMed  Google Scholar 

  188. Perrillo, R. P. et al. A randomized, controlled trial of interferon α-2b alone and after prednisone withdrawal for the treatment of chronic hepatitis B. The Hepatitis Interventional Therapy Group. N. Engl. J. Med. 323, 295–301 (1990).

    Article  CAS  PubMed  Google Scholar 

  189. Solal-Celigny, P. et al. Recombinant interferon α-2b combined with a regimen containing doxorubicin in patients with advanced follicular lymphoma. Groupe d'Etude des Lymphomes de l'Adulte. N. Engl. J. Med. 329, 1608–1614 (1993).

    Article  CAS  PubMed  Google Scholar 

  190. Manns, M. P. et al. Peginterferon α-2b plus ribavirin compared with interferon α-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 358, 958–965 (2001).

    Article  CAS  PubMed  Google Scholar 

  191. Simon, D. M. et al. Treatment of chronic hepatitis C with interferon α-n3: a multicenter, randomized, open-label trial. Hepatology 25, 445–448 (1997).

    Article  CAS  PubMed  Google Scholar 

  192. Friedmankien, A. Management of condylomata acuminata with Alferon-N injection, interferon α-n3 (human-leukocyte derived). Am. J. Obstet. Gynecol. 172, 1359–1368 (1995).

    Article  CAS  Google Scholar 

  193. Panitch, H. et al. Randomized, comparative study of interferon β-1a treatment regimens in MS: the EVIDENCE trial. Neurology 59, 1496–1506 (2002).

    Article  CAS  PubMed  Google Scholar 

  194. Jacobs, L. D. et al. Intramuscular interferon β-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N. Engl. J. Med. 343, 898–904 (2000).

    Article  CAS  PubMed  Google Scholar 

  195. Byrne, E. Randomized, comparative study of interferon β-1a treatment regimens in MS: the EVIDENCE trial. Neurology 60, 1872–1873 (2003).

    Article  PubMed  Google Scholar 

  196. No authors listed. Randomised double-blind placebo-controlled study of interferon β-1a in relapsing/remitting multiple sclerosis. PRISMS (Prevention of Relapses and Disability by Interferon β-1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet 352, 1498–1504 (1998).

  197. Paty, D. W. & Li, D. K. Interferon β-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. UBC MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group. Neurology 43, 662–667 (1993).

    Article  CAS  PubMed  Google Scholar 

  198. No authors listed. Interferon β-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. The IFNB Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. Neurology 45, 1277–1285 (1995).

  199. Durelli, L. et al. Every-other-day interferon β-1b versus once-weekly interferon β-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). Lancet 359, 1453–1460 (2002).

    Article  CAS  PubMed  Google Scholar 

  200. Raghu, G. et al. A placebo-controlled trial of interferon γ-1b in patients with idiopathic pulmonary fibrosis. N. Engl. J. Med. 350, 125–133 (2004).

    Article  CAS  PubMed  Google Scholar 

  201. Key, L. L. Jr et al. Long-term treatment of osteopetrosis with recombinant human interferon γ. N. Engl. J. Med. 332, 1594–1599 (1995).

    Article  PubMed  Google Scholar 

  202. Ezekowitz, R. A., Dinauer, M. C., Jaffe, H. S., Orkin, S. H. & Newburger, P. E. Partial correction of the phagocyte defect in patients with X-linked chronic granulomatous disease by subcutaneous interferon γ. N. Engl. J. Med. 319, 146–151 (1988).

    Article  CAS  PubMed  Google Scholar 

  203. Baron, S. et al. The interferons. Mechanisms of action and clinical applications. JAMA 266, 1375–1383 (1991).

    Article  CAS  PubMed  Google Scholar 

  204. Key, L. L. Jr, Ries, W. L., Rodriguiz, R. M. & Hatcher, H. C. Recombinant human interferon γ therapy for osteopetrosis. J. Pediatr. 121, 119–124 (1992).

    Article  PubMed  Google Scholar 

  205. Negrier, S. et al. Recombinant human interleukin-2, recombinant human interferon α-2a, or both in metastatic renal-cell carcinoma. Groupe Francais d'Immunotherapie. N. Engl. J. Med. 338, 1272–1278 (1998).

    Article  CAS  PubMed  Google Scholar 

  206. Atkins, M. B. et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J. Clin. Oncol. 17, 2105–2116 (1999).

    Article  CAS  PubMed  Google Scholar 

  207. Rosenberg, S. A. et al. Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2. J. Natl Cancer Inst. 86, 1159–1166 (1994).

    Article  CAS  PubMed  Google Scholar 

  208. Atkins, M. B., Kunkel, L., Sznol, M. & Rosenberg, S. A. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J. Sci. Am. 6 (Suppl. 1), 11–14 (2000).

    Google Scholar 

  209. Goldhaber, S. Z. et al. Randomized controlled trial of recombinant tissue plasminogen-activator versus urokinase in the treatment of acute pulmonary-embolism. Lancet 2, 293–298 (1988).

    Article  CAS  PubMed  Google Scholar 

  210. Tow, D. E., Wagner, H. N. & Holmes, R. A. Urokinase in pulmonary embolism. N. Engl. J. Med. 277, 1161–1167 (1967).

    Article  CAS  PubMed  Google Scholar 

  211. Chesnut, C. H. et al. A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurrence of osteoporotic fractures study. Am. J. Med. 109, 267–276 (2000).

    Article  CAS  PubMed  Google Scholar 

  212. Colman, E., Hedin, R., Swann, J. & Orloff, D. A brief history of calcitonin. Lancet 359, 885–886 (2002).

    Article  PubMed  Google Scholar 

  213. Body, J. J. et al. A randomized double-blind trial to compare the efficacy of teriparatide [recombinant human parathyroid hormone (1–34)] with alendronate in postmenopausal women with osteoporosis. J. Clin. Endocrinol. Metab. 87, 4528–4535 (2002).

    Article  CAS  PubMed  Google Scholar 

  214. Neer, R. M. et al. Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N. Engl. J. Med. 344, 1434–1441 (2001).

    Article  CAS  PubMed  Google Scholar 

  215. Reeve, J. Recombinant human parathyroid hormone. BMJ 324, 435–436 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  216. Tashjian, A. H. Jr. & Gagel, R. F. Teriparatide [human PTH(1–34)]: 2.5 years of experience on the use and safety of the drug for the treatment of osteoporosis. J. Bone Miner. Res. 21, 354–365 (2006).

    Article  CAS  Google Scholar 

  217. Heine, R. J. et al. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann. Intern. Med. 143, 559–569 (2005).

    Article  CAS  PubMed  Google Scholar 

  218. Tomassetti, P. et al. Treatment of type II gastric carcinoid tumors with somatostatin analogues. N. Engl. J. Med. 343, 551–554 (2000).

    Article  CAS  PubMed  Google Scholar 

  219. Lamberts, S. W. J., van der Lely, A-. J., de Herder, W. W. & Hofland, L. J. Drug therapy — Octreotide. N. Engl. J. Med. 334, 246–254 (1996).

    Article  CAS  PubMed  Google Scholar 

  220. Govender, S., Csimma, C., Genant, H. K. & Valentin-Opran, A. Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures. A prospective, controlled, randomized study of four hundred and fifty patients. J. Bone Joint Surg. Am. 84, 2123–2134 (2002).

    Article  PubMed  Google Scholar 

  221. Boden, S. D., Zdeblick, T. A., Sandhu, H. S. & Heim, S. E. The use of rhBMP-2 in interbody fusion cages. Definitive evidence of osteoinduction in humans: a preliminary report. Spine 25, 376–381 (2000).

    Article  CAS  PubMed  Google Scholar 

  222. Friedlaender, G. E. et al. Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions. A prospective, randomized clinical trial comparing rhOP-1 with fresh bone autograft. J. Bone Joint Surg. Am. 83, S151–S158 (2001).

    Article  PubMed  Google Scholar 

  223. Feuillan, P. P., Jones, J. V., Barnes, K., Oerter-Klein, K. & Cutler, G. B. Reproductive axis after discontinuation of gonadotropin-releasing hormone analog treatment of girls with precocious puberty: long term follow-up comparing girls with hypothalamic hamartoma to those with idiopathic precocious puberty. J. Clin. Endocrinol. Metab. 84, 44–49 (1999).

    Article  CAS  PubMed  Google Scholar 

  224. Jay, N. et al. Ovulation and menstrual function of adolescent girls with central precocious puberty after therapy with gonadotropin-releasing-hormone agonists. J. Clin. Endocrinol. Metab. 75, 890–894 (1992).

    CAS  PubMed  Google Scholar 

  225. Spielberger, R. et al. Palifermin for oral mucositis after intensive therapy for hematologic cancers. N. Engl. J. Med. 351, 2590–2598 (2004).

    Article  CAS  PubMed  Google Scholar 

  226. Smiell, J. M. et al. Efficacy and safety of becaplermin (recombinant human platelet-derived growth factor-BB) in patients with nonhealing, lower extremity diabetic ulcers: a combined analysis of four randomized studies. Wound Repair Regen. 7, 335–346 (1999).

    Article  CAS  PubMed  Google Scholar 

  227. Embil, J. M. et al. Recombinant human platelet-derived growth factor-BB (becaplermin) for healing chronic lower extremity diabetic ulcers: an open-label clinical evaluation of efficacy. Wound Repair Regen. 8, 162–168 (2000).

    Article  CAS  PubMed  Google Scholar 

  228. Wieman, T. J. Clinical efficacy of becaplermin (rhPDGF-BB) gel. Becaplermin Gel Studies Group. Am. J. Surg. 176, 74S–79S (1998).

    Article  CAS  PubMed  Google Scholar 

  229. Hellgren, L. Cleansing properties of stabilized trypsin and streptokinase-streptodornase in necrotic leg ulcers. Eur. J. Clin. Pharmacol. 24, 623–628 (1983).

    Article  CAS  PubMed  Google Scholar 

  230. Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA 287, 1531–1540 (2002).

  231. Colucci, W. S. et al. Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. Nesiritide Study Group. N. Engl. J. Med. 343, 246–253 (2000).

    Article  CAS  PubMed  Google Scholar 

  232. Blasi, J. et al. Botulinum neurotoxin-a selectively cleaves the synaptic protein snap-25. Nature 365, 160–163 (1993).

    Article  CAS  PubMed  Google Scholar 

  233. Jankovic, J. & Brin, M. F. Therapeutic uses of botulinum toxin. N. Engl. J. Med. 324, 1186–1194 (1991).

    Article  CAS  PubMed  Google Scholar 

  234. Schiavo, G. et al. Tetanus and botulinum-b neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin. Nature 359, 832–835 (1992).

    Article  CAS  PubMed  Google Scholar 

  235. Patel, B. C. K. et al. A comparison of topical and retrobulbar anesthesia for cataract surgery. Ophthalmology 103, 1196–1203 (1996).

    Article  CAS  PubMed  Google Scholar 

  236. Aslam, S. et al. Effect of hyaluronidase on ocular motility and eyelid function in sub-Tenon's anaesthesia: randomised controlled trial. Eye 20, 579–582 (2006).

    Article  CAS  PubMed  Google Scholar 

  237. Goldman, S. C. et al. A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis. Blood 97, 2998–3003 (2001).

    Article  CAS  PubMed  Google Scholar 

  238. Lincoff, A. M. et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention — REPLACE-2 Randomized Trial. JAMA 289, 853–863 (2003).

    Article  CAS  PubMed  Google Scholar 

  239. Bittl, J. A. et al. Treatment with bivalirudin (hirulog) as compared with heparin during coronary angioplasty for unstable or postinfarction angina. N. Engl. J. Med. 333, 764–769 (1995).

    Article  CAS  PubMed  Google Scholar 

  240. The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N. Engl. J. Med. 329, 673–682 (1993).

  241. Hunt, D. et al. Isis-3 — a randomized comparison of streptokinase vs tissue plasminogen-activator vs anistreplase and of aspirin plus heparin vs aspirin alone among 41,299 cases of suspected acute myocardial-infarction. Lancet 339, 753–770 (1992).

    Article  Google Scholar 

  242. Anderson, J. L. et al. Multicenter reperfusion trial of intravenous anisoylated plasminogen streptokinase activator complex (APSAC) in acute myocardial-infarction — controlled comparison with intracoronary streptokinase. J. Am. Coll. Cardiol. 11, 1153–1163 (1988).

    Article  CAS  PubMed  Google Scholar 

  243. Hurwitz, H. et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med. 350, 2335–2342 (2004).

    Article  CAS  PubMed  Google Scholar 

  244. Ferrara, N., Hillan, K. J., Gerber, H. P. & Novotny, W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nature Rev. Drug Discov. 3, 391–400 (2004).

    Article  CAS  Google Scholar 

  245. Yang, J. C. et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N. Engl. J. Med. 349, 427–434 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Kabbinavar, F. et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J. Clin. Oncol. 21, 60–65 (2003).

    Article  CAS  PubMed  Google Scholar 

  247. Wainberg, Z. & Hecht, J. R. A phase III randomized, open-label, controlled trial of chemotherapy and bevacizumab with or without panitumumab in the first-line treatment of patients with metastatic colorectal cancer. Clin. Colorectal Cancer 5, 363–367 (2006).

    Article  CAS  PubMed  Google Scholar 

  248. Keating, M. J. et al. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood 99, 3554–3561 (2002).

    Article  CAS  PubMed  Google Scholar 

  249. Keating, M. J. et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J. Clin. Oncol. 23, 4079–4088 (2005).

    Article  CAS  PubMed  Google Scholar 

  250. Di Gaetano, N. et al. Synergism between fludarabine and rituximab revealed in a follicular lymphoma cell line resistant to the, cytotoxic activity of either drug alone. Br. J. Haematology 114, 800–809 (2001).

    Article  CAS  Google Scholar 

  251. Jazirehi, A. R., Huerta-Yepez, S., Cheng, G. H. & Bonavida, B. Rituximab (chimeric anti-CD20 monoclonal antibody) inhibits the constitutive nuclear factor-k B signaling pathway in non-Hodgkin's lymphoma B-cell lines: role in sensitization to chemotherapeutic drug-induced apoptosis. Cancer Res. 65, 264–276 (2005).

    CAS  PubMed  Google Scholar 

  252. Genovese, M. C. et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor α inhibition. N. Engl. J. Med. 353, 1114–1123 (2005).

    Article  CAS  PubMed  Google Scholar 

  253. Cohen, S. B. et al. A multicenter double-blind randomized placebo-controlled trial of Kineret (anakinra), a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis treated with background methotrexate therapy. Ann. Rheum. Dis. 63, 1062–1068 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Fleischmann, R. M. et al. Anakinra, a recombinant human interleukin-1 receptor antagonist (r-metHuIL-1ra), in patients with rheumatoid arthritis: a large, international, multicenter, placebo-controlled trial. Arthritis Rheum. 48, 927–934 (2003).

    Article  CAS  PubMed  Google Scholar 

  255. Tesser, J. et al. Concomitant medication use in a large, international, multicenter, placebo controlled trial of anakinra, a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis. J. Rheumatol. 31, 649–654 (2004).

    CAS  PubMed  Google Scholar 

  256. Olsen, N. J. & Stein, C. M. Drug therapy — new drugs for rheumatoid arthritis. N. Engl. J. Med. 350, 2167–2179 (2004).

    Article  CAS  PubMed  Google Scholar 

  257. Weinblatt, M. E. et al. Adalimumab, a fully human anti-tumor necrosis factor a monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate — The ARMADA trial. Arthritis Rheum. 48, 35–45 (2003).

    Article  CAS  PubMed  Google Scholar 

  258. Ellis, C. N. & Krueger, G. G. Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. N. Engl. J. Med. 345, 248–255 (2001).

    Article  CAS  PubMed  Google Scholar 

  259. Krueger, G. G. et al. A randomized, double-blind, placebo-controlled phase III study evaluating efficacy and tolerability of 2 courses of alefacept in patients with chronic plaque psoriasis. J. Am. Acad. Dermatol. 47, 821–833 (2002).

    Article  PubMed  Google Scholar 

  260. Lebwohl, M. et al. A novel targeted T-cell modulator, efalizumab, for plaque psoriasis. N. Engl. J. Med. 349, 2004–2013 (2003).

    Article  CAS  PubMed  Google Scholar 

  261. Gordon, K. B. et al. Efalizumab for patients with moderate to severe plaque psoriasis: a randomized controlled trial. JAMA 290, 3073–3080 (2003).

    Article  CAS  PubMed  Google Scholar 

  262. Miller, D. H. et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med. 348, 15–23 (2003).

    Article  CAS  PubMed  Google Scholar 

  263. Hillmen, P. et al. Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. N. Engl. J. Med. 350, 552–559 (2004).

    Article  CAS  PubMed  Google Scholar 

  264. Hillmen, P. et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N. Engl. J. Med. 355, 1233–1243 (2006).

    Article  CAS  PubMed  Google Scholar 

  265. Denton, M. D., Magee, C. C. & Sayegh, M. H. Immunosuppressive strategies in transplantation. Lancet 353, 1083–1091 (1999).

    Article  CAS  PubMed  Google Scholar 

  266. Frickhofen, N. et al. Treatment of aplastic-anemia with antilymphocyte globulin and methylprednisolone with or without cyclosporine. N. Engl. J. Med. 324, 1297–1304 (1991).

    Article  CAS  PubMed  Google Scholar 

  267. Soulillou, J. P. et al. Randomized controlled trial of a monoclonal-antibody against the interleukin-2 receptor (33b3.1) as compared with rabbit antithymocyte globulin for prophylaxis against rejection of renal-allografts. N. Engl. J. Med. 322, 1175–1182 (1990).

    Article  CAS  PubMed  Google Scholar 

  268. Nashan, B. et al. Randomised trial of basiliximab versus placebo for control of acute cellular rejection in renal allograft recipients. CHIB 201 International Study Group. Lancet 350, 1193–1198 (1997).

    Article  CAS  PubMed  Google Scholar 

  269. Vincenti, F. et al. Interleukin-2-receptor blockade with daclizumab to prevent acute rejection in renal transplantation. Daclizumab Triple Therapy Study Group. N. Engl. J. Med. 338, 161–165 (1998).

    Article  CAS  PubMed  Google Scholar 

  270. No authors listed. A comparison of tacrolimus (FK 506) and cyclosporine for immunosuppression in liver transplantation. The U.S. Multicenter FK506 Liver Study Group. N. Engl. J. Med. 331, 1110–1115 (1994).

  271. Cosimi, A. B. et al. Treatment of acute renal allograft rejection with OKT3 monoclonal antibody. Transplantation 32, 535–539 (1981).

    Article  CAS  PubMed  Google Scholar 

  272. Cosimi, A. B. et al. A randomized clinical trial comparing OKT3 and steroids for treatment of hepatic allograft rejection. Transplantation 43, 91–95 (1987).

    Article  CAS  PubMed  Google Scholar 

  273. Busse, W. et al. Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J. Allergy Clin. Immunol. 108, 184–190 (2001).

    Article  CAS  PubMed  Google Scholar 

  274. Casale, T. B. et al. Effect of omalizumab on symptoms of seasonal allergic rhinitis: a randomized controlled trial. JAMA 286, 2956–2967 (2001).

    Article  CAS  PubMed  Google Scholar 

  275. Milgrom, H. et al. Treatment of childhood asthma with anti-immunoglobulin E antibody (omalizumab). Pediatrics 108, e36 (2001).

    Article  CAS  PubMed  Google Scholar 

  276. No authors listed. Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE Study. Lancet 349, 1429–1435 (1997).

  277. Antman, E. M. et al. Abciximab facilitates the rate and extent of thrombolysis: results of the thrombolysis in myocardial infarction (TIMI) 14 trial. The TIMI 14 Investigators. Circulation 99, 2720–2732 (1999).

    Article  CAS  PubMed  Google Scholar 

  278. Ibbotson, T., McGavin, J. K. & Goa, K. L. Abciximab: an updated review of its therapeutic use in patients with ischaemic heart disease undergoing percutaneous coronary revascularisation. Drugs 63, 1121–1163 (2003).

    Article  CAS  PubMed  Google Scholar 

  279. Trainer, P. J. et al. Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant. N. Engl. J. Med. 342, 1171–1177 (2000).

    Article  CAS  PubMed  Google Scholar 

  280. van der Lely, A. J. et al. Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist. Lancet 358, 1754–1759 (2001).

    Article  CAS  PubMed  Google Scholar 

  281. Ruha, A. M. et al. Initial postmarketing experience with Crotalidae polyvalent immune Fab for treatment of rattlesnake envenomation. Ann. Emerg. Med. 39, 609–615 (2002).

    Article  PubMed  Google Scholar 

  282. Dart, R. C. & McNally, J. Efficacy, safety, and use of snake antivenoms in the United States. Ann. Emerg. Med. 37, 181–188 (2001).

    Article  CAS  PubMed  Google Scholar 

  283. Smith, T. W., Haber, E., Yeatman, L. & Butler, V. P. Jr. Reversal of advanced digoxin intoxication with Fab fragments of digoxin-specific antibodies. N. Engl. J. Med. 294, 797–800 (1976).

    Article  CAS  PubMed  Google Scholar 

  284. Antman, E. M., Wenger, T. L., Butler, V. P. Jr, Haber, E. & Smith, T. W. Treatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments. Final report of a multicenter study. Circulation 81, 1744–1752 (1990).

    Article  CAS  PubMed  Google Scholar 

  285. Brown, D. M. et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N. Engl. J. Med. 355, 1432–1444 (2006).

    Article  CAS  PubMed  Google Scholar 

  286. Kaminski, M. S. et al. Radioimmunotherapy with iodine (131)I tositumomab for relapsed or refractory B-cell non-Hodgkin lymphoma: updated results and long-term follow-up of the University of Michigan experience. Blood 96, 1259–1266 (2000).

    Article  CAS  PubMed  Google Scholar 

  287. Press, O. W. et al. A phase 2 trial of CHOP chemotherapy followed by tositumomab/iodine I 131 tositumomab for previously untreated follicular non-Hodgkin lymphoma: Southwest Oncology Group Protocol S9911. Blood 102, 1606–1612 (2003).

    Article  CAS  PubMed  Google Scholar 

  288. Aman, J. & Wranne, L. Hypoglycaemia in childhood diabetes. II. Effect of subcutaneous or intramuscular injection of different doses of glucagon. Acta Paediatr. Scand. 77, 548–553 (1988).

    Article  CAS  PubMed  Google Scholar 

  289. Carson, M. J. & Koch, R. Clinical studies with glucagon in children. J. Pediatr. 47, 161–170 (1955).

    Article  CAS  PubMed  Google Scholar 

  290. Jowell, P. S. et al. A double-blind, randomized, dose response study testing the pharmacological efficacy of synthetic porcine secretin. Aliment. Pharmacol. Ther. 14, 1679–1684 (2000).

    Article  CAS  PubMed  Google Scholar 

  291. Somogyi, L., Ross, S. O., Cintron, M. & Toskes, P. P. Comparison of biologic porcine secretin, synthetic porcine secretin, and synthetic human secretin in pancreatic function testing. Pancreas 27, 230–234 (2003).

    Article  CAS  PubMed  Google Scholar 

  292. Oberg, K. Neuroendocrine gastrointestinal tumours. Ann. Oncol. 7, 453–463 (1996).

    Article  CAS  PubMed  Google Scholar 

  293. Maguire, R. T., Pascucci, V. L., Maroli, A. N. & Gulfo, J. V. Immunoscintigraphy in patients with colorectal, ovarian, and prostate-cancer — results with site-specific immunoconjugates. Cancer 72, 3453–3462 (1993).

    Article  CAS  PubMed  Google Scholar 

  294. Hughes, K. et al. Use of carcinoembryonic antigen radioimmunodetection and computed tomography for predicting the resectability of recurrent colorectal cancer. Ann. Surg. 226, 621–631 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  295. Goldenberg, D. M. et al. Carcinoembryonic antigen immunoscintigraphy complements mammography in the diagnosis of breast carcinoma. Cancer 89, 104–115 (2000).

    Article  CAS  PubMed  Google Scholar 

  296. Balaban, E. P. et al. Detection and staging of small-cell lung-carcinoma with a technetium-labeled monoclonal-antibody: a comparison with standard staging methods. Clin. Nucl. Med. 17, 439–445 (1992).

    Article  CAS  PubMed  Google Scholar 

  297. Johnson, L. L. et al. Antimyosin imaging in acute transmural myocardial infarctions — results of a multicenter clinical trial. J. Am. Coll. Cardiol. 13, 27–35 (1989).

    Article  CAS  PubMed  Google Scholar 

  298. Kipper, S. L. et al. Neutrophil-specific Tc-99m-labeled anti-CD15 monoclonal antibody imaging for diagnosis of equivocal appendicitis. J. Nucl. Med. 41, 449–455 (2000).

    CAS  PubMed  Google Scholar 

  299. Chapman, W. C., et al. A phase 3, randomized, double-blind comparative study of the efficacy and safety of topical recombinant human thrombin and bovine thrombin in surgical hemostasis. J. Am. Coll. Surg. 205, 256–265 (2007).

    Article  PubMed  Google Scholar 

  300. Food and Drug Administration (FDA). Product Approval Information: Thrombin, Topical (Human), Updated October 23, 2007. FDA web site [online], (2007).

Download references

Acknowledgements

We thank A. H. Tashjian Jr for many helpful discussions and expert review of the manuscript. D.E.G. is supported by NIH grants R37HL032854 and U54HL070819. Q.J.B. is supported by NIH grant T32GM07753. Portions of this article have been published in abbreviated form (Golan, D. E. et al. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy (Lippincott Williams & Wilkins, 2004); Golan, D.E. et al. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 2nd edn (Lippincott Williams & Wilkins, 2007)), and are adapted with permission.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to David E. Golan.

Related links

Related links

DATABASES

OMIM

Amyotrophic lateral sclerosis

cervical cancer

colorectal cancer

cystic fibrosis

diabetes mellitus type I

diabetes mellitus type II

Fabry disease

haemophilia A

haemophilia B

hepatitis B

hepatitis C

inflammatory bowel disease

Kaposi's sarcoma

prostate cancer

psoriasis

rheumatoid arthritis

Rights and permissions

Reprints and permissions

About this article

Cite this article

Leader, B., Baca, Q. & Golan, D. Protein therapeutics: a summary and pharmacological classification. Nat Rev Drug Discov 7, 21–39 (2008). https://doi.org/10.1038/nrd2399

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd2399

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing