Advances and challenges in developing cytokine fusion proteins as improved therapeutics

Expert Opinion on Drug Discovery

Volumn 4, Issue 2, 2009, Pages 181-194

  Chang, Chien Hsing ^a   Gupta, Pankaj ^a   Goldenberg, David M ^b  

^a IMMUNOMEDICS INC   (United States)

^b CENTER FOR MOLECULAR MEDICINE AND IMMUNOLOGY   (United States)

Author keywords

Dock and Lock; Fusion proteins; Monoclonal antibodies; Multimeric cytokines

Indexed keywords

ALPHAN1 INTERFERON; BETA1A INTERFERON; CONSENSUS INTERFERON; CYTOKINE; ENDOSTATIN; FC RECEPTOR; GAMMA1B INTERFERON; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; HYBRID PROTEIN; INTERFERON BETA SERINE; INTERLEUKIN 12; INTERLEUKIN 15; INTERLEUKIN 2; INTERLEUKIN 24; INTERLEUKIN 4; MONOCLONAL ANTIBODY; NOVEL ERYTHROPOIESIS STIMULATING PROTEIN; PEGINTERFERON ALPHA2A; PEGINTERFERON ALPHA2B; RECOMBINANT ALPHA2A INTERFERON; RECOMBINANT ALPHA2B INTERFERON; RECOMBINANT ERYTHROPOIETIN; RECOMBINANT GRANULOCYTE COLONY STIMULATING FACTOR; RECOMBINANT GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; RECOMBINANT INTERLEUKIN 11; RECOMBINANT INTERLEUKIN 2; SERUM ALBUMIN; TRANSFERRIN; TUMOR NECROSIS FACTOR ALPHA; UNINDEXED DRUG;

ALBERS SCHOENBERG DISEASE; ANEMIA; CHRONIC HEPATITIS; DRUG APPROVAL; DRUG CONJUGATION; DRUG RESEARCH; DRUG SYNTHESIS; DRUG TARGETING; FEBRILE NEUTROPENIA; FOLLICULAR LYMPHOMA; GRANULOMATOSIS; HAIRY CELL LEUKEMIA; HEPATITIS C; HEPATITIS NON A NON B; HUMAN; IMMUNOPHARMACOLOGY; IMMUNOTHERAPY; KAPOSI SARCOMA; KIDNEY CARCINOMA; MELANOMA; MULTIPLE SCLEROSIS; NEUTROPENIA; NONHUMAN; PRIORITY JOURNAL; REVIEW; THROMBOCYTOPENIA;

EID: 67649203468     PISSN: 17460441     EISSN: None     Source Type: Journal    
DOI: 10.1517/17460440802702023     Document Type: Review

References (103)

1. Dranoff G. Cytokines in cancer pathogenesis and cancer therapy. Nat Rev Cancer 2004;4:11-22 • An overview of cytokine-based cancer therapies and the roles played by the mixture of cytokines produced in the tumor microenvironment in cancer development.
2. Marshall E. Cancer trial of interleukin-12 halted. Science 1995;268:1555
3. Leonard JP, Sherman ML, Fisher GL, et al. Effects of single dose interleukin-12 exposure on interleukin-12 associated toxicity and interferon-γ production. Blood 1997;90:2541-2548 (Pubitemid 27413462)
4. Forni G, Giovarelli M, Santoni A. Lymphokine-activated tumor inhibition in vivo: 1. The local administration of interleukin 2 triggers nonreactive lymphocytes from tumor-bearing mice to inhibit tumor growth. J Immunol 1985;134:1305-1311
5. Chang CH, Rossi EA, Goldenberg DM. The dock and lock method: a novel platform technology for building multivalent, multifunctional structures of defined composition with retained bioactivity. Clin Cancer Res 2007;13(19 Suppl):5586s-91s •• A concise description of the Dock-and-Lock method. (Pubitemid 47510391)
6. Yeh P, Landais D, Lemaitre M, et al. Design of yeast-secreted albumin derivatives for human therapy: biological and antiviral properties of a serum albumin-CD4 genetic conjugate. Proc Natl Acad Sci USA 1992;89:1904-1908
7. Poznansky MJ, Halford J, Taylor D. Growth hormone-albumin conjugates. Reduced renal toxicity and altered plasma clearance. FEBS Lett 1988;239:18-22
8. Makrides SC, Nygren PA, Andrews B, et al. Extended in vivo half-life of human soluble complement receptor type 1 fused to a serum albumin binding receptor. J Pharmacol Exp Ther 1996;277:534-542 (Pubitemid 27169101)
9. Kurtzhals P, Havelund S, Jonassen I, et al. Albumin binding of insulins acylated with fatty acids: characterization of the ligand-protein interaction and correlation between binding affinity and timing of the insulin effect in vivo. Biochem J 1995;312:725-731 (Pubitemid 26005980)
10. Dennis MS, Zhang M, Meng G, et al. Albumin binding as a general strategy for improving the pharmacokinetics of proteins. J Biol Chem 2002;277:35035-35043 (Pubitemid 35052399)
11. Chaudhury C, Mehnaz S, Robinson JM, et al. The major histocompatibility complex-related Fc receptor for IgG (FcRn) binds albumin and prolongs its lifespan. J Exp Med 2003;197:315-22 • Provides the first experimental proof to confirm an earlier hypothesis that a mechanism identical to that proposed for protecting IgG from degradation could be applied to albumin as well. (Pubitemid 36184238)
12. Chaudhury C, Brooks CL, Carter DC, et al. Albumin binding to FcRn: distinct from the FcRn-IgG interaction. Biochemistry 2006;45:4983-4990
13. Halpern W, Riccobene TA, Agostini H, et al. Albugranin, a recombinant human granulocyte colony stimulating factor (G-CSF) genetically fused to recombinant human albumin induces prolonged myelopoietic effects in mice and monkeys. Pharm Res 2002;19:1720-1729 (Pubitemid 35305525)
14. Osborn BL, Sekut L, Corcoran M, et al. Albutropin: a growth hormone-albumin fusion with improved pharmacokinetics and pharmacodynamics in rats and monkeys. Eur J Pharmacol 2002;456:149-158 (Pubitemid 35351748)
15. Sung C, Nardelli B, LaFleur DW, et al. An IFN-beta-albumin fusion protein that displays improved pharmacokinetic and pharmacodynamic properties in nonhuman primates. J Interferon Cytokine Res 2003;23:25-36 (Pubitemid 36308059)
16. Yao Z, Dai W, Perry J, et al. Effect of albumin fusion on the biodistribution of interleukin-2. Cancer Immuno Immunother 2004;53:404-410 (Pubitemid 38657253)
17. Osborn BL, Olsen HS, Nardelli B, et al. Pharmacokinetic and pharmacodynamic studies of a human serum albumin-interferon-a fusion protein in cynomolgus monkeys. J Pharmacol Exp Ther 2002;303:540-548 (Pubitemid 35231224)
18. Duttaroy A, Kanakaraj P, Osborn BL, et al. Development of a long-acting insulin analog using albumin fusion technology. Diabetes 2005;54:251-258 (Pubitemid 40105120)
19. Syed S, Schuyler PD, Kulczycky M, Sheffiled WP. Potent antithrombin activity and delayed clearance from the circulation characterize recombinant hirudin genetically fused to albumin. Blood 1997;89:3243-3252 (Pubitemid 27229809)
20. Weimer T, Wormsbacher W, Kronthaler U, et al. Prolonged in-vivo half-life of factor VIIa by fusion to albumin. Thromb Haemost 2008;99:659-667 (Pubitemid 351694221)
21. Dou WF, Lei JY, Zhang LF, et al. Expression, purification, and characterization of recombinant human serum albumin fusion protein with two human glucagon-like peptide-1 mutants in Pichia pastoris. Protein Expr Purif 2008;61:45-49
22. Huang YJ, Lundy PM, Lazaris A, et al. Substantially improved pharmacokinetics of recombinant human butyrylcholinesterase by fusion to human serum albumin. BMC Biotechnol 2008;8:50 (Pubitemid 351796681)
23. Wang W, Qu Y, Shi Y. AlbuBNP, a recombinant B-type natriuretic peptide and human serum albumin fusion hormone, as long-term therapy of congestive heart failure. Pharm Res 2004;21:2105-2111 (Pubitemid 40941232)
24. Muller D, Karle A, Meibburger B, et al. Improved pharmacokinetics of recombinant bispecific antibody molecules by fusion to human serum albumin. J Biol Chem 2007;282:12650-12660 (Pubitemid 47100581)
25. Subramanian GM, Fiscella M, Lamouse A, et al. Albinterferon a-2b: a genetic fusion protein for the treatment of chronic hepatitis C. Nat Biotechnol 2007;25:1411-9 •• An informative update on the drug development for Alb-IFN.
26. Ponka P, Lok CN. The transferrin receptor: role in health and disease. Int J Biochem Cell Biol 1999;31:1111-1137 (Pubitemid 29454549)
27. Daniels TR, Delgado T, Rodriguez JA, et al. The transferrin receptor part I: biology and targeting with cytotoxic antibodies for the treatment of cancer. Clin Immunol 2006;121:144-158 (Pubitemid 44592578)
28. Daniels TR, Delgado T, Helguera G, Penichet ML. The transferrin receptor part II: targeted delivery of therapeutic agents into cancer cells. Clin Immunol 2006;121:159-176 (Pubitemid 44572972)
29. Qian ZM, Li H, Sun H, Ho K. Targeted delivery via the transferrin receptor-mediated endocytosis pathway. Pharmacol Rev 2002;54:561-587 (Pubitemid 35351196)
30. Zari PR, Feeney R. Resistance of metal complexes of conalbumin and transferrin to proteolysis and to thermal denaturation. J Biol Chem 1958;232:293-302
31. Banerjee D, Flanagan PR, Cluett J, et al. Transferrin receptors in the human gastrointestinal tract. Relationship to body iron stores. Gastroenterology 1986;91:861-869
32. Bai Y, Ann DK, Shen WC. Recombinant granulocyte colony-stimulating factor-transferrin fusion protein as an oral myelopoietic agent. Proc Natl Acad Sci USA 2005;102:7272-6 • Demonstrates the feasibility of giving G-CSF-Tf orally in mouse models.
33. Zak O, Trinder D, Aisen P. Primary receptor-recognition site of human transferrin is in the C-terminal lobe. J Biol Chem 1994;269:7110-7114 (Pubitemid 24217894)
34. Bai Y, Shen WC. Improving the oral efficacy of recombinant granulocyte colony-stimulating factor and transferrin fusion protein by spacer optimization. Pharm Res 2006;23:2116-2121
35. Shin SU, Friden P, Moran M, et al. Transferrin-antibody fusion proteins are effective in brain targeting. Proc Natl Acad Sci USA 1995;92:2820-2824
36. Park E, Starzyk RM, McGrath JP, et al. Production and characterization of fusion proteins containing transferrin and nerve growth factor. J Drug Target 1998;6:53-64 (Pubitemid 28499589)
37. Lo KM, Sudo Y, Chen J, et al. High level expression and secretion of Fc-X fusion proteins in mammalian cells. Protein Eng 1998;11:495-500 •• Explains the advantages of Fc-X fusion proteins.
38. O'reilly MS, Boehm T, Shing Y, et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 1997;88:277-85 • Seminal paper on the discovery and properties of endostatin.
39. Folkman J. Antiangiogenesis in cancer therapy-endostatin and its mechanisms of action. Exp Cell Res 2006;312:594-607 (Pubitemid 43290336)
40. Thomas JP, Arzoomanian RZ, Alberti D, et al. Phase I pharmacokinetic and pharmacodynamic study of recombinant human endostatin in patients with advanced solid tumors. J Clin Oncol 2003;21:223-231 (Pubitemid 46606150)
41. Sim BK. Angiostatin and endostatin: endothelial cell-specific endogenous inhibitors of angiogenesis and tumor growth. Angiogenesis 1998;2:37-48
42. Tjin Tham Sjin RM, Satchi-Fainaro R, Birsner AE, et al. A 27-amino-acid synthetic peptide corresponding to the NH2-terminal zinc-binding domain of endostatin is responsible for its antitumor activity. Cancer Res 2005;65:3656-3663 (Pubitemid 40616342)
43. Lee TY, Tjin Tham Sjin RM, Movahedi S, et al. Linking antibody Fc domain to endostatin significantly improves endostatin half-life and efficacy. Clin Cancer Res 2008;14:1487-1493
44. Celik I, Surucu O, Dietz C, et al. Therapeutic efficacy of endostatin exhibits a biphasic dose-response curve. Cancer Res 2005;65:11044-11050 (Pubitemid 41713375)
45. Glaspy J, Bukowski R, Steinberg D, et al. Impact of therapy with epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice. J Clin Oncol 1997;15:1218-1234 (Pubitemid 27106310)
46. Littlewood TJ, Bajetta E, Nortier JW, et al. Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, double-blind, placebo-controlled trial. J Clin Oncol 2001;19:2865-2874 (Pubitemid 32538196)
47. Egrie JC, Browne JK. Development and characterization of novel erythropoiesis stimulating protein (NESP). Nephrol Dial Transplant 2001;16:3-13 • Overview of NESP.
48. Way JC, Lauder S, Brunkhorst B, et al. Improvement of Fc-erythropoietin structure and pharmacokinetics by modification at a disulfide bond. Protein Eng Des Sel 2005;18:111-118 (Pubitemid 40638061)
49. Bitonti AJ, Dumont JA, Low SC, et al. Pulmonary delivery of an erythropoietin Fc fusion protein in non-human primates through an immunoglobulin transport pathway. Proc Natl Acad Sci USA 2004;101:9763-8 • Shows Epo fused to Fc could be delivered through the lungs.
50. Ortiz-Sánchez E, Helguera G, Daniels TR, et al. Antibody-cytokine fusion proteins: applications in cancer therapy. Expert Opin Biol Ther 2008;8:609-32 • A comprehensive and current review of mono- and bi-functional immunocytokines.
51. Shin SO, Morrison SL. Expression and characterization of an antibody binding specificity joined to insulin-like growth factor 1: potential applications for cellular targeting. Proc Natl Acad Sci USA 1990;87:5322-5326 (Pubitemid 20260171)
52. Gillies SD, Wesolowski JS, Lo KM. Targeting human cytotoxic T lymphocytes to kill heterologous epidermal growth factor receptor-bearing tumor cells. J Immunol 1991;146:1067-1071
53. Shin SO, Friden P, Moran M, Morrison SL. Functional properties of antibody insulin-like growth factor fusion proteins. J Biol Chem 1994;269:4979-4985 (Pubitemid 24239480)
54. Camemolla B, Borsi L, Blza E, et al. Enhancement of the antitumor properties of interleukin-2 by its targeted delivery to the tumor blood vessel extracellular matrix. Blood 2002;99:1659-1665 (Pubitemid 34533039)
55. Wagner K, Schulz P, Scholz A, et al. The targeted immunocytokine L19-IL2 efficiently inhibits the growth of orthotopic pancreatic cancer. Clin Cancer Res 2008;14:4951-4960
56. Gillies SD, Lan Y, Williams S, et al. An Anti-CD20-IL2 immunocytokine is highly efficacious in a SCID mouse model of established human B lymphoma. Blood 2005;105:3972-3978 (Pubitemid 40656145)
57. Neal ZC, Yang JC, Rakhmilevich AL, et al. Enhanced activity of hu14.18-IL2 immunocytokine against murine NXS2 neuroblastoma when combined with interleukin 2 therapy. Clin Cancer Res 2004;10:4839-4847 (Pubitemid 38955538)
58. Lode HN, Xiang R, Varki NM, et al. Targeted interleukin-2 therapy for spontaneous neuroblastoma metastases to bone marrow. J Natl Cancer Inst 1997;89:1586-1594 (Pubitemid 27479718)
59. Gillies SD, Young D, Lo KM, Roberts S. Biological activity and in vivo clearance of antitumor antibody/cytokine fusion proteins. Bioconj Chem 1993;4:230-5 • An early report noting the susceptibility of IgG-fused cytokines to proteases.
60. Gillies SD, Reilly EB, Lo KM, Reisfeld RA. Antibody-targeted interleukin 2 stimulates T-cell killing of autologous tumor cells. Proc Nat Acad Sci USA 1992;89:1428-1432
61. Hu P, Mizokami M, Ruoff G, et al. Generation of low-toxicity interleukin-2 fusion proteins devoid of vasopermeability activity. Blood 2003;101:4853-61 • Documents the attempt to reduce vasopermeability activity of IL-2 by selective mutations. (Pubitemid 36857747)
62. Dolman CS, Mueller BM, Lode HN, et al. Suppression of human prostate carcinoma metastases in severe combined immunodeficiency mice by interleukin 2 immunocytokine therapy. Clin Cancer Res 1998;4:2552-2557 (Pubitemid 28477924)
63. Xiang R, Lode HN, Dolman CS, et al. Elimination of established murine colon carcinoma metastases by antibody-interleukin 2 fusion protein therapy. Cancer Res 1997;57:4948-4955 (Pubitemid 27469007)
64. Gillies SD, Lan Y, Lo KM. Improving the efficacy of antibody-interleukin 2 fusion proteins by reducing their interaction with Fc receptors. Cancer Res 1999;59:2159-2166 (Pubitemid 29217680)
65. Xu X, Clarke P, Szalai G, et al. Targeting and therapy of carcinoembryonic antigen-expressing tumors in transgenic mice with an antibody-interleukin 2 fusion protein. Cancer Res 2000;60:4475-4484 (Pubitemid 32103628)
66. Hornick JL, Khawli LA, Hu P, et al. Chimeric CLL-1 antibody fusion proteins containing granulocyte-macrophage colony-stimulating factor or interleukin-2 with specificity for B-cell malignancies exhibit enhanced effector functions while retaining tumor targeting properties. Blood 1997;89:4437-4447 (Pubitemid 27260254)
67. Christ O, Seiter S, Matzku S, et al. Efficacy of local versus systematic applications of antibody-cytokine fusion proteins in tumor therapy. Clin Cancer Res 2001;7:985-998 (Pubitemid 32708738)
68. Penichet ML, Dela Cruz JS, Shin SU, Morrison SL. A recombinant IgG3-(IL-2) fusion protein for the treatment of human HER2/neu expressing tumors. Hum Antibodies 2001;10:43-49 (Pubitemid 32328605)
69. Lo KM, Lan Y, Lander S, et al. huBC1-IL12, an immunocytokine which targets EDB-containing oncofecal fibronectin in tumors and tumor vasculature, shows potent anti-tumor activity in human tumor models. Cancer Immunol Immunother 2007;56:447-457 (Pubitemid 46204531)
70. Gafner V, Trachsel E, Neri D. An engineered antibody-interleukin-12 fusion protein with enhanced tumor vascular targeting properties. Int J Cancer 2006;19:2205-2212 (Pubitemid 44423682)
71. Halin C, Gafner V, Villani ME, et al. Synergistic therapeutic effects of a tumor targeting antibody fragment, fused to interleukin 12 and to tumor necrosis factor α. Cancer Res 2003;63:3202-3210 (Pubitemid 36735873)
72. Halin C, Rondini S, Nilsson F, et al. Enhancement of the antitumor activity of interleukin-12 by targeted delivery to neovasculature. Nat Biotechnol 2002;20:264-269 (Pubitemid 34205419)
73. Heuser C, Diehl V, Abken H, Hombach A. Anti-CD30-IL-12 antibody-cytokine fusion protein that induces IFN-γ secretion of T cells and NK cell-mediated lysis of Hodgkin's lymphoma-derived tumor cells. Int J Cancer 2003;106:545-552 (Pubitemid 36966211)
74. Peng LS, Penichet ML, Morrison SL. A single-chain IL-12 IgG3 antibody fusion protein retains antibody specificity and IL-12 bioactivity and demonstrates antitumor activity. J Immunol 1999;163:250-258 (Pubitemid 29295848)
75. Gillies SD, Lan Y, Wesolowski JS, et al. Antibody-IL-12 fusion proteins are effective in SCID mouse models of prostate and colon carcinoma metastases. J Immunol 1998;160:6195-6203 (Pubitemid 28298086)
76. Kaspar M, Trachsel E, Neri D. The antibody-mediated targeted delivery of interleukin-15 and GM-CSF to the tumor neovasculature inhibits tumor growth and metastasis. Cancer Res 2007;67:4940-4948 (Pubitemid 46910202)
77. Batova A, Kamps A, Gillies SD, et al. The ch14.18-GM-CSF fusion protein is effective at mediating antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity in vitro. Clin Cancer Res 1999;5:4259-4263 (Pubitemid 30013813)
78. Metelitsa LS, Gillies SD, Super M, et al. Antidisialoganglioside/ granulocyte macrophage-colony-stimulating factor fusion protein facilitates neutrophil antibody-dependent cellular cytotoxicity and depends on FcγRII (CD32) and Mac-1 (CD11b/CD18) for enhanced effector cell adhesion and azuophil granule exocytosis. Blood 2002;99:4166-4173
79. Dela Cruz JS, Trinh KR, Morrison SL, Penichet ML. Recombinant anti-human HER2/neu IgG3-(GM-CSF) fusion protein retains antigen specificity and cytokine function and demonstrates antitumor activity. J Immunol 2000;165:5112-5121 (Pubitemid 30809441)
80. Gillies SD, Young D, Lo KM, Reisfeld R. Expression of genetically engineered immunoconjugates of lymphotoxin and a chimeric anti-ganglioside GD2 antibody. Hybridoma 1991;10:347-356
81. Cho HM, Rosenblatt JD, Kang YS, et al. Enhanced inhibition of murine tumor and human breast tumor xenografts using targeted delivery of an antibody-endostatin fusion protein. Mol Cancer Ther 2005;4:956-967 (Pubitemid 40909078)
82. Huang TH, Chintalacharuvu KR, Morrison SL. Targeting IFN-α to B cell lymphoma by a tumor-specific antibody elicits potent antitumor activities. J Immunol 2007;179:6881-6888
83. Chang CH, Rossi E, Loo M, et al. A modular method to prepare novel tetrameric cytokines, IFN, G-CSF, and EPO, with improved pharmacokinetics by the Dock-and-Lock (DNL) platform technology [abstract 4906]. Proc Am Assoc Cancer Res 2008;49:1168
84. Gillies SD, Lan Y, Brunkhorst B, et al. Bi-functional cytokine fusion proteins for gene therapy and antibody-targeted treatment of cancer. Cancer Immunol Immunother 2002;51:449-60 • The first paper describing the generation of various types of bifunctional immunocytokines and their comparison.
85. Helguera G, Rodriguez JA, Penichet ML. Cytokines fused to antibodies and their combinations as therapeutic agents against different peritoneal HER2/neu expressing tumors. Mol Cancer Ther 2006;5:1029-1040 (Pubitemid 43724604)
86. Schanzer JM, Baeuerle PA, Dreier T, Kufer P. A human cytokine/single- chain antibody fusion protein for simultaneous delivery of GM-CSF and IL-2 to Ep-CAM overexpressing tumor cells. Cancer Immun 2006;6:4-14 • First report of dual cytokine heterominibodies. (Pubitemid 43361516)
87. Schanzer JM, Fichtner I, Baeuerle PA, Kufer P. Antitumor activity of a dual cytokine/single-chain antibody fusion protein for simultaneous delivery of GM-CSF and IL-2 to Ep-CAM expressing tumor cells. I Immunother 2006;29:477-488 (Pubitemid 44403697)
88. Harvill ET, Morrison SL. An IgG3-IL2 fusion protein activates complement, binds Fc gamma RI, generates LAK activity and shows enhanced binding to the high affinity IL-2R. Immunotechnology 1995;1:95-105
89. Harvill ET, Morrison SL. An IgG3-IL-2 fusion protein has higher affinity than hrIL-2 for the IL-2R alpha subunit: real time measurement of ligand binding. Mol Immunol 1996;33:1007-1014 (Pubitemid 26396454)
90. Harvill ET, Fleming JM, Morrison SL. In vivo properties of an IgG3-IL-2 fusion protein: a general strategy for immune potentiation. J Immunol 1996;157:3165-3170
91. Penichet ML, Harvill ET, Morrison SL. An IgG3-IL-2 fusion protein recognizing a murine B cell lymphoma exhibits effective tumor imaging and antitumor activity. J Interferon Cytokine Res 1998;18:597-607 (Pubitemid 28391587)
92. H3 terminus and IL-2 with a hydrophobic residue such as alanine or leucine could confer resistance to proteases and improve circulating half-life.
93. Ko YJ, Bubley GJ, Weber R, et al. Safety, pharmacokinetics, and biological pharmacodynamics of the immunocytokine EMD 273066 (huKS-IL2): results of a phase I trial in patients with prostate cancer. J Immunother 2004;27:232-239 (Pubitemid 39118088)
94. King DM, Albertini MR, Schalch H, et al. Phase I clinical trial of the immunocytokine EMD 273063 in melanoma patients. J Clin Oncol 2004;22:4463-4473 (Pubitemid 41185112)
95. Osenga KL, Hank JA, Albertini MR, et al. A phase I clinical trial of the hu14.18-IL2 (EMD 273063) as a treatment for children with refractory or recurrent neuroblastoma and melanoma: a study of the children's oncology group. Clin Cancer Res 2006;12:1750-1759
96. Shusterman S, London WB, Gillies SD, et al. Anti-neuroblastoma activity of hu14.18-IL2 against minimal residual disease in a Children's Oncology Group (COG) phase II study [abstract 3002]. J Clin Oncol 2008;26(Suppl)
97. Newlon MG, Roy M, Morikis D, et al. The molecular basis for protein kinase A anchoring revealed by solution NMR. Nat Struct Biol 1999;6:222-227 (Pubitemid 29107224)
98. Colledge M, Scott JD. AKAPs: from structure to function. Trends Cell Biol 1999;6:216-222 (Pubitemid 29244132)
99. Rossi EA, Goldenberg DM, Cardillo TM, et al. Stably tethered multifunctional structures of defined composition made by the dock and lock method for use in cancer targeting. Proc Natl Acad Sci USA 2006;103:6841-6 •• Seminal paper demonstrating the utility of the Dock-and-Lock method for constructing multivalent complexes suitable for in vivo applications.
100. Hodneland CD, Lee YS, Min DH, Mrksich M. Selective immobilization of proteins to self-assembled monolayers presenting active site-directed capture ligands. Proc Natl Acad Sci USA 2003;99:5048-5052 (Pubitemid 34411501)
101. Deyev SM, Waibel R, Lebedenko EN, et al. A. Design of multivalent complexes using the barnase-barstar module. Nat Biotechnol 2003;21:1486-1492
102. Backer MV, Gaynutdinov TI, Patel V, et al. Adapter protein for site-specific conjugation of payloads for targeted drug delivery. Bioconj Chem 2004;15:1021-1029 (Pubitemid 39297823)
103. Rossi EA, Goldenberg DM, Cardillo TM, et al. Novel design of multivalent anti-CD20 humanized antibodies as improved lymphoma therapeutics. Cancer Res 2008;68:8384-92 • Further validation of the Dock-and-Lock method as an effective tool to generate multivalent antibodies.