Protein therapeutics: a summary and pharmacological classification

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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.

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References

  1. 1

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

  2. 2

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

  3. 3

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

  4. 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).

  5. 5

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

  6. 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).

  7. 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. 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).

  9. 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).

  10. 10

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

  11. 11

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

  12. 12

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

  13. 13

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

  14. 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).

  15. 15

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

  16. 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).

  17. 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).

  18. 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).

  19. 19

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

  20. 20

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

  21. 21

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

  22. 22

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

  23. 23

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

  24. 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).

  25. 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).

  26. 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).

  27. 27

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

  28. 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).

  29. 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).

  30. 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).

  31. 31

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

  32. 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).

  33. 33

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

  34. 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).

  35. 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).

  36. 36

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

  37. 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).

  38. 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).

  39. 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).

  40. 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).

  41. 41

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

  42. 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. 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).

  44. 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).

  45. 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).

  46. 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).

  47. 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. 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. 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. 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. 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).

  52. 52

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

  53. 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).

  54. 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).

  55. 55

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

  56. 56

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

  57. 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).

  58. 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).

  59. 59

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

  60. 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).

  61. 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).

  62. 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).

  63. 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).

  64. 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).

  65. 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).

  66. 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. 67

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

  68. 68

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

  69. 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).

  70. 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).

  71. 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).

  72. 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).

  73. 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).

  74. 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. 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).

  76. 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).

  77. 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).

  78. 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).

  79. 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).

  80. 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).

  81. 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).

  82. 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).

  83. 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).

  84. 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).

  85. 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).

  86. 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).

  87. 87

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

  88. 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).

  89. 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).

  90. 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).

  91. 91

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

  92. 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).

  93. 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).

  94. 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).

  95. 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).

  96. 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).

  97. 97

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

  98. 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).

  99. 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).

  100. 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).

  101. 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).

  102. 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).

  103. 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).

  104. 104

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

  105. 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).

  106. 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).

  107. 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).

  108. 108

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

  109. 109

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

  110. 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).

  111. 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).

  112. 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).

  113. 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).

  114. 114

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

  115. 115

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

  116. 116

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

  117. 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).

  118. 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).

  119. 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).

  120. 120

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

  121. 121

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

  122. 122

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

  123. 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).

  124. 124

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

  125. 125

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

  126. 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).

  127. 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).

  128. 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).

  129. 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).

  130. 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).

  131. 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).

  132. 132

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

  133. 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).

  134. 134

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

  135. 135

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

  136. 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).

  137. 137

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

  138. 138

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

  139. 139

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

  140. 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).

  141. 141

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

  142. 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).

  143. 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).

  144. 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).

  145. 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).

  146. 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).

  147. 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).

  148. 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).

  149. 149

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

  150. 150

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

  151. 151

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

  152. 152

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

  153. 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).

  154. 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).

  155. 155

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

  156. 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).

  157. 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).

  158. 158

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

  159. 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).

  160. 160

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

  161. 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).

  162. 162

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

  163. 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).

  164. 164

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

  165. 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).

  166. 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).

  167. 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).

  168. 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).

  169. 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. 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).

  171. 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).

  172. 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).

  173. 173

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

  174. 174

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

  175. 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).

  176. 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).

  177. 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).

  178. 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).

  179. 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).

  180. 180

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

  181. 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).

  182. 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. 183

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

  184. 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).

  185. 185

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

  186. 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).

  187. 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).

  188. 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).

  189. 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).

  190. 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).

  191. 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).

  192. 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).

  193. 193

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

  194. 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).

  195. 195

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

  196. 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. 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).

  198. 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. 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).

  200. 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).

  201. 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).

  202. 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).

  203. 203

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

  204. 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).

  205. 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).

  206. 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).

  207. 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).

  208. 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).

  209. 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).

  210. 210

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

  211. 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).

  212. 212

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

  213. 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).

  214. 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).

  215. 215

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

  216. 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).

  217. 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).

  218. 218

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

  219. 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).

  220. 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).

  221. 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).

  222. 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).

  223. 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).

  224. 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).

  225. 225

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

  226. 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).

  227. 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).

  228. 228

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

  229. 229

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

  230. 230

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

  231. 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).

  232. 232

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

  233. 233

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

  234. 234

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

  235. 235

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

  236. 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).

  237. 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).

  238. 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).

  239. 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).

  240. 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. 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).

  242. 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).

  243. 243

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

  244. 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).

  245. 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).

  246. 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).

  247. 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).

  248. 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).

  249. 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).

  250. 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).

  251. 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).

  252. 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).

  253. 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).

  254. 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).

  255. 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).

  256. 256

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

  257. 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).

  258. 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).

  259. 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).

  260. 260

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

  261. 261

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

  262. 262

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

  263. 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).

  264. 264

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

  265. 265

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

  266. 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).

  267. 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).

  268. 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).

  269. 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).

  270. 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. 271

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

  272. 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).

  273. 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).

  274. 274

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

  275. 275

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

  276. 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. 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).

  278. 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).

  279. 279

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

  280. 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).

  281. 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).

  282. 282

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

  283. 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).

  284. 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).

  285. 285

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

  286. 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).

  287. 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).

  288. 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).

  289. 289

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

  290. 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).

  291. 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).

  292. 292

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

  293. 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).

  294. 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).

  295. 295

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

  296. 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).

  297. 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).

  298. 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).

  299. 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).

  300. 300

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

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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.

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Correspondence to David E. Golan.

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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

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

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