Concordance of preclinical and clinical pharmacology and toxicology of monoclonal antibodies and fusion proteins: Soluble targets

British Journal of Pharmacology

Volumn 166, Issue 3, 2012, Pages 806-822

  Martin, Pauline L ^a   Bugelski, Peter J ^a  

^a JANSSEN RESEARCH AND DEVELOPMENT   (Belgium)

Author keywords

adverse effects; biopharmaceutical; clinical safety; cynomolgus monkey; genetically deficient mice; monoclonal antibody; non clinical safety; rodent; surrogate; toxicology

Indexed keywords

ADALIMUMAB; BEVACIZUMAB; BRIAKINUMAB; CANAKINUMAB; CERTOLIZUMAB PEGOL; COMPLEMENT COMPONENT C5; COMPLEMENT COMPONENT C5B; DENOSUMAB; ECULIZUMAB; ETANERCEPT; GOLIMUMAB; HYBRID PROTEIN; IMMUNOGLOBULIN E; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INFLIXIMAB; INTERLEUKIN 12; INTERLEUKIN 12P40; INTERLEUKIN 1ALPHA; INTERLEUKIN 1BETA; INTERLEUKIN 23; MONOCLONAL ANTIBODY; OMALIZUMAB; PLACEBO; RANIBIZUMAB; RECOMBINANT INTERLEUKIN 1 RECEPTOR BLOCKING AGENT; RILONACEPT; TUMOR NECROSIS FACTOR ALPHA; TUMOR NECROSIS FACTOR ALPHA ANTIBODY; USTEKINUMAB;

ANAPHYLAXIS; ARM PAIN; ARTERIAL THROMBOEMBOLISM; ARTHRALGIA; ASTHMA; BACKACHE; BLEEDING; BONE MARROW SUPPRESSION; CINCA SYNDROME; CLINICAL PHARMACOLOGY; CLINICAL TOXICOLOGY; CONJUNCTIVAL HYPEREMIA; CYSTITIS; CYTOPENIA; DEMYELINATING DISEASE; DERMATITIS; DIARRHEA; DIGESTIVE SYSTEM PERFORATION; DIZZINESS; DRUG ERUPTION; DRUG FEVER; DRUG HYPERSENSITIVITY; DRUG INDUCED HEADACHE; DRUG MEGADOSE; DRUG RECEPTOR BINDING; DRUG SAFETY; DRUG STRUCTURE; DRY SKIN; ECZEMA; ENDOPHTHALMITIS; EOSINOPHILIA; EPISTAXIS; EXFOLIATIVE DERMATITIS; EYE INFLAMMATION; EYE PAIN; FATIGUE; FISTULA; FRACTURE; GENETIC DISORDER; GOOD LABORATORY PRACTICE; HEART DISEASE; HEART FAILURE; HELMINTHIASIS; HISTOPLASMOSIS; HUMAN; HYPERCHOLESTEROLEMIA; HYPERTENSION; HYPOCALCEMIA; IMMUNOPATHOLOGY; IMMUNOTOXICITY; INFECTION; INFLUENZA; INFUSION RELATED REACTION; INJECTION SITE REACTION; INNATE IMMUNITY; INTRAOCULAR HYPERTENSION; JAW OSTEONECROSIS; LACRIMATION DISORDER; LEG PAIN; LOADING DRUG DOSE; LUNG DISEASE; LUPUS LIKE SYNDROME; MAINTENANCE DRUG DOSE; MALIGNANT NEOPLASTIC DISEASE; MENINGOCOCCOSIS; MUCKLE WELLS SYNDROME; MUSCULOSKELETAL PAIN; NAUSEA; NEUROPATHY; NONHUMAN; OSTEOPOROSIS; OTALGIA; PAIN; PANCREATITIS; PAROXYSMAL NOCTURNAL HEMOGLOBINURIA; POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME; PREDICTIVE VALUE; PRIMATE; PRIORITY JOURNAL; PROTEIN CLEAVAGE; PROTEIN FUNCTION; PROTEIN STRUCTURE; PROTEIN TARGETING; PROTEINURIA; PRURITUS; PSORIASIS VULGARIS; RECTUM HEMORRHAGE; RETINA DETACHMENT; RETINA MACULA AGE RELATED DEGENERATION; REVIEW; RHEUMATOID ARTHRITIS; RHINITIS; RHINOPHARYNGITIS; SEPSIS; SKIN INFECTION; SYSTEMIC MYCOSIS; TASTE DISORDER; TOXICOLOGY; TUBERCULOSIS; UPPER RESPIRATORY TRACT INFECTION; VITREOUS FLOATERS; WOUND HEALING IMPAIRMENT;

ANIMALS; ANTIBODIES, MONOCLONAL; DRUG EVALUATION, PRECLINICAL; HUMANS; MAXIMUM TOLERATED DOSE; NO-OBSERVED-ADVERSE-EFFECT LEVEL; PHARMACOLOGY, CLINICAL; PREDICTIVE VALUE OF TESTS; RECOMBINANT FUSION PROTEINS; SOLUBILITY; SPECIES SPECIFICITY;

EID: 84860866781     PISSN: 00071188     EISSN: 14765381     Source Type: Journal    
DOI: 10.1111/j.1476-5381.2011.01812.x     Document Type: Review

References (188)

1. Amari W, Zeringue A, McDonald J, Caplan L, Eisen S, Ranganathan P, (2011). Risk of non-melanoma skin cancer in a national cohort of veterans with rheumatoid arthritis. Rheumatology (Oxford) 50: 1431-1439.
2. Anastasilakis AD, Toulis KA, Goulis DG, Polyzos SA, Delaroudis S, Giomisi A, et al,. (2009). Efficacy and safety of denosumab in postmenopausal women with osteopenia or osteoporosis: a systematic review and a meta-analysis. Horm Metab Res 41: 721-729.
3. Apostolaki M, Armaka M, Victoratos P, Kollias G, (2010). Cellular mechanisms of TNF function in models of inflammation and autoimmunity. Curr Dir Autoimmun 11: 1-26.
4. Arcalyst USPI, (2010). Arcalyst (Rilonocept). Available at (accessed 13 February 2012).
5. Arseneau K, Stukenborg G, Connors A, Cominelli F, (2001). The incidence of lymphoid and myeloid malignancies among hospitalized Crohn's disease patients. Inflamm Bowel Dis 7: 106-112.
6. Avastin USPI, (2011). Avastin (bevacizumab). Available at (accessed 13 February 2012).
7. Balkwill F, (2009). Tumor necrosis factor and cancer. Nat Rev Cancer 9: 361-371.
8. Banda N, Kraus D, Vondracek A, Huynh L, Bendele A, Holers V, et al,. (2002). Mechanisms of effects of complement inhibition in murine collagen-induced arthritis. Arthritis Rheum 46: 3065-3075.
9. Becher B, Durell B, Noelle R, (2002). Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12. J Clin Invest 110: 493-497.
10. Bekker P, Holloway D, Nakanishi A, Arrighi M, Leese P, Dunstan C, (2001). The effect of a single dose of osteoprotegerin in postmenopausal women. J Bone Miner Res 16: 348-360.
11. Bendele A, Mcabee T, Sennello G, Frazier J, Chlipala E, McCabe D, (1999). Efficacy of sustained blood levels of interleukin-1 receptor antagonist in animal models of arthritis. Arthritis Rheum 42: 498-506.
12. Bertazza L, Mocellin S, (2010). The dual role of tumor necrosis factor (TNF) in cancer biology. Curr Med Chem 17: 3337-3352.
13. Body J, Greipp P, Coleman R, Facon T, Geurs F, Fermand J, et al,. (2003). A phase I study of AMGN-0007, a recombinant osteoprotegerin construct, in patients with multiple myeloma or breast carcinoma related bone metastases. Cancer 97: 887-892.
14. Bowman E, Chackerian A, Cua D, (2006). Rationale and safety of anti-interleukin-23 and anti-interleukin-17A therapy. Curr Opin Infect Dis 19: 245-252.
15. Bracken W, Learn D, Blaich G, Veldman G, (2011). Subcutaneous administration study to determine the influence of an anti-mouse IL-12/IL-23p40 antibody on photocarcinogenesis in hairless mice. Toxicologist 120 (Suppl. 2): 172.
16. Brodmerkel C, Zhu Y, Jiao Q, Cornacoff J, Treacy G, Mascelli M, et al,. (2010). Effects of ustekinumab administration on primate/human antigen-recall and humoral immune response functions. J Drugs Dermatol 9: 677-683.
17. Bugelski P, Treacy G, (2004). Predictive power of preclinical studies in animals for the immunogenicity of recombinant therapeutic proteins in humans. Curr Opin Mol Ther 6: 10-16.
18. Bugelski P, Volk A, Walker M, Krayer J, Martin P, Descotes J, (2010). Critical review of preclinical approaches to evaluate the potential for immunosuppressive drugs to influence human neoplasia. Int J Toxicol 29: 435-466.
19. Burasa J, Ricea L, Orlowa D, Pavlidesa S, Reenstraa W, Ceonzob K, et al,. (2004). Inhibition of C5 or absence of C6 protects from sepsis mortality. Immunobiology 209: 629-635.
20. Burkiewicz JS, Scarpace SL, Bruce SP, (2009). Denosumab in osteoporosis and oncology. Ann Pharmacother 43: 1445-1455.
21. Bussiere J, (2008). Species selection considerations for preclinical toxicology studies for biotherapeutics. Expert Opin Drug Metab Toxicol 4: 871-877.
22. Bussiere J, Martin P, Horner M, Couch J, Flaherty M, Andrews L, et al,. (2009). Alternative strategies for toxicity testing of species-specific biopharmaceuticals. Int J Toxicol 28: 230-253.
23. Campa C, Kasman I, Ye W, Lee W, Fuh G, Ferrara N, (2008). Effects of an anti-VEGF-A monoclonal antibody on laser-induced choroidal neovascularization in mice: optimizing methods to quantify vascular changes. Invest Ophthalmol Vis Sci 49: 1178-1183.
24. Campbell J, Lowe D, Sleeman MA, (2011). Develoeping the next generation of monoclonal antibodies for the treatmnet of rheumatoid arthritis. Br J Pharmacol 162: 1470-1484.
25. Caprioli F, Caruso R, Sarra M, Pallone F, Monteleone G, (2011). Distruption of inflammatory signals by cytokine-targeted therapies for inflammatory bowel diseases. Br J Pharmacol 165: 820-828.
26. Cerquetti M, Sordelli D, Bellanti J, Hooke A, (1986). Lung defenses against Pseudomonas aeruginosa in C5-deficient mice with different genetic backgrounds. Infect Immun 52: 853-857.
27. Chatzidakis I, Mamalaki C, (2010). T cells as sources and targets of TNF: implications for immunity and autoimmunity. Curr Dir Autoimmun 11: 105-118.
28. Cimzia USPI, (2011). Cimzia (certolizumab pegol). Available at (accessed 13 February 2012).
29. Connor V, (2011). Anti-TNF therapies: a comprehensive analysis of adverse effects associated with immunosuppression. Rheumatol Int 31: 327-337.
30. Cooper P, Ayre G, Martin C, Rizzo J, Ponte E, Cruz A, (2008). Geohelminth infections: a review of the role of IgE and assessment of potential risks of anti-IgE treatment. Allergy 63: 409-417.
31. Cornacoff J, Howk K, Pikounis B, Mendenhall V, Martin P, (2008). Development of a method for the evaluation of wound tensile strength in cynomolgus macaques. J Pharmacol Toxicol Methods 57: 74-79.
32. Deepe G, Gibbons R, (2006). T cells require tumor necrosis factor-alpha to provide protective immunity in mice infected with Histoplasma capsulatum. J Infect Dis 193: 322-330.
33. Delgado-Cervino E, Fontan G, Lopez-Trascasa M, (2005). C5 complement deficiency in a Spanish family. Molecular characterization of the double mutation responsible for the defect. Mol Immunol 42: 105-111.
34. Dessein A, Parker W, James S, David J, (1981). IgE antibody and resistance to infection. I. Selective suppression of the IgE antibody response in rats diminishes the resistance and the eosinophil response to Trichinella spiralis infection. J Exp Med 153: 423-436.
35. Diao H, Kohanawa M, Nakajima H, Sato Y, Minagawa T, Nakane A, (2002). Lipopolysaccharide triggers invasive streptococcal disease in mice through a tumour necrosis factor-alpha-dependent mechanism. Immunology 105: 344-349.
36. Dinarello C, (2003). Anti-cytokine therapeutics and infections. Vaccine 21: S24-S34.
37. Dinarello C, (2005). The many worlds of reducing interleukin-1. Arthritis Rheum 53: 1960-1967.
38. Ding C, Xu J, Li J, (2008). ABT-874, a fully human monoclonal anti-IL-12/IL-23 antibody for the potential treatment of autoimmune diseases. Curr Opin Investig Drugs 9: 515-522.
39. Dmytrijuk A, Robie-Suh K, Cohen MH, Rieves D, Weiss K, Pazdur R, (2008). FDA report: eculizumab (Soliris) for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Oncologist 13: 993-1000.
40. Douni E, Sfikakis P, Haralambous S, Fernandes P, Kollias G, (2004). Attenuation of inflammatory polyarthritis in TNF transgenic mice by diacerein: comparative analysis with dexamethasone, methotrexate and anti-TNF protocols. Arthritis Res Ther 6: R65-R72.
41. El Ridi R, Ozaki T, Kamiya H, (1998). Schistosoma mansoni infection in IgE-producing and IgE-deficient mice. J Parasitol 84: 171-174.
42. EMA (2003). Anakinra (Kineret). Available at (accessed 13 February 2012).
43. EMA (2004a). Etanercept (Enbrel). Available at (accessed 13 February 2012).
44. EMA (2004b). Infliximab (Remicade). Available at (accessed 13 February 2012).
45. EMA (2005a). Adalimumab (Humira). Available at (accessed 13 February 2012).
46. EMA (2005b). Bevacizumab (Avastin). Available at (accessed 13 February 2012).
47. EMA (2005c). Omalizumab (Xolair). Available at (accessed 13 February 2012).
48. EMA (2007). Eculizumab (Soliris). Available at (accessed 13 February 2012).
49. EMA (2009a). Canakinumab (Ilaris). Available at (accessed 13 February 2012).
50. EMA (2009b). Golimumab (Simponi). Available at (accessed 13 February 2012).
51. EMA (2009c). Rilonacept (Arcalyst). Available at (accessed 13 February 2012).
52. EMA (2010). Denosumab (Prolia). Available at (accessed 13 February 2012).
53. Enbrel USPI, (2011). Enbrel (etanercept). Available at (accessed 13 February 2012).
54. Fata J, Kong Y, Li J, Sasaki T, Irie-Sasaki J, Moorehead R, et al,. (2000). The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell 103: 41-50.
55. FDA (1998a). Etancercept (Enbrel). Availabe at (accessed 13 February 2012).
56. FDA (1998b). Remicade (infliximab). Available at (accessed 13 February 2012).
57. FDA (1999). Remicade (infliximab). Available at (accessed 13 February 2012).
58. FDA (2001). Anakinra (Kineret). Available at (accessed 13 February 2012).
59. FDA (2002). Adalimumab (Humira). Available at (accessed 13 February 2012).
60. FDA (2004a). Bevacizumab (Avastin). Available at (accessed 13 February 2012).
61. FDA (2004b). Ranibizumab (Lucentis). Available at (accessed 13 February 2012).
62. FDA (2007). Eculizumab (Soliris). Available at (accessed 13 February 2012).
63. FDA (2008a). Certolizumab Pegol (Cimzia). Available at; (accessed 13 February 2012).
64. FDA (2008b). Rilonacept (Arcalyst). Available at;; (accessed 13 February 2012).
65. FDA (2009a). Canakinumab (Ilaris). Available at;; (accessed 13 February 2012).
66. FDA (2009b). Golimumab (Simponi). Available at; (accessed 13 February 2012).
67. FDA (2009c). Ustekinumab (Stelara). Available at (accessed 13 February 2012).
68. FDA (2010a). Denosumab (Prolia). Available at (accessed 13 February 2012).
69. FDA (2010b). Good Laboratory Practice for Nonclinical Laboratory Studies. Available at (accessed 13 February 2012).
70. Ferrara N, Bunting S, (1996). Vascular endothelial growth factor, a specific regulator of angiogenesis. Curr Opin Nephrol Hypertens 5: 35-44.
71. Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, O'Shea K, et al,. (1996). Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380: 439-442.
72. Ferrari-Lacraz S, Ferrari S, (2011). Do RANKL inhibitors (denosumab) affect inflammation and immunity? Osteoporos Int 22: 435-446.
73. Fiedler V, Loof I, Sander E, Voehringer V, Galanos C, Fournel M, (1992). Monoclonal antibody to tumor necrosis factor-alpha prevents lethal endotoxin sepsis in adult rhesus monkeys. J Lab Clin Med 120: 574-588.
74. Filipe-Santos O, Bustamante J, Chapgier A, Vogt G, de Beaucoudrey L, Feinberg J, et al,. (2006). Inborn errors of IL-12/23- and IFN-gamma-mediated immunity: molecular, cellular, and clinical features. Semin Immunol 18: 347-361.
75. Flynn J, Goldstein M, Chan J, Triebold K, Pfeffer K, Lowenstein C, et al,. (1995). Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice. Immunity 2: 561-572.
76. Fraser H, Wilson H, Silvestri A, Morris K, Wiegand S, (2008). The role of vascular endothelial growth factor and estradiol in the regulation of endometrial angiogenesis and cell proliferation in the marmoset. Endocrinology 149: 4413-4420.
77. Gabay C, Lamacchia C, Palmer G, (2010). IL-1 pathways in inflammation and human diseases. Nat Rev Rheumatol 6: 232-241.
78. Gee K, Guzzo C, Che Mat NF, Ma W, Kumar A, (2009). The IL-12 family of cytokines in infection, inflammation and autoimmune disorders. Inflamm Allergy Drug Targets 8: 40-52.
79. Geiger T, Towbin H, Cosenti-Vargas A, Zingel O, Arnold J, Rordorf C, et al,. (1993). Neutralization of interleukin-1 beta activity in vivo with a monoclonal antibody alleviates collagen-induced arthritis in DBA/1 mice and prevents the associated acute-phase response. Clin Exp Rheumatol 11: 515-522.
80. Geiger-Gritsch S, Stollenwerk B, Miksad R, Guba B, Wild C, Siebert U, (2010). Safety of bevacizumab in patients with advanced cancer: a meta-analysis of randomized controlled trials. Oncologist 15: 1179-1191.
81. Gerber H, Ferrara N, (2005). Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in preclinical studies. Cancer Res 665: 671-680.
82. Ghosh D, Sengupta J, (2005). Target-oriented anti-implantation approaches for pregnancy interception: experiences in the rhesus monkey model. Contraception 71: 294-301.
83. Guengerich F, (2011). Mechanisms of drug toxicity and relevance to pharmaceutical development. Drug Metab Pharmacokinet 26: 3-14.
84. Gurish M, Bryce P, Tao H, Kisselgof A, Thornton E, Miller H, et al,. (2004). IgE enhances parasite clearance and regulates mast cell responses in mice infected with Trichinella spiralis. J Immunol 172: 1139-1145.
85. Haak-Frendscho M, Robbins K, Lyon R, Shields R, Hooley J, Schoenhoff M, et al,. (1994). Administration of an anti-IgE antibody inhibits CD23 expression and IgE production in vivo. Immunology 82: 306-313.
86. Hamilton RG, MacGlashan DW Jr, Saini SS, (2010). IgE antibody-specific activity in human allergic disease. Immunol Res 47: 273-284.
87. Hart B, Brok H, Remarque E, Benson J, Treacy G, Amor S, et al,. (2005). Suppression of ongoing disease in a nonhuman primate model of multiple sclerosis by a human-anti-human IL-12p40 antibody. J Immunol 175: 4761-4768.
88. Hatta M, Yamamoto N, Miyazato A, Ishii N, Nakamura K, Inden K, et al,. (2010). Early production of tumor necrosis factor-alpha by Gr-1 cells and its role in the host defense to pneumococcal infection in lungs. FEMS Immunol Med Microbiol 58: 182-192.
89. Herring A, Falkowski N, Chen G, McDonald R, Toews G, Huffnagle G, (2005). Transient neutralization of tumor necrosis factor alpha can produce a chronic fungal infection in an immunocompetent host: potential role of immature dendritic cells. Infect Immun 73: 39-49.
90. Humira USPI, (2011). Humira (adalimumab). Available at (accessed 13 February 2012).
91. ICH M3 (R2) (2009). Non-Clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals. Available at (accessed 13 February 2012).
92. ICH S6 (R1) (1997). Preclinical safety assessment of biotechnology derived pharmaceuticals. Addendum (2011). Available at (accessed 13 February 2012).
93. Ilaris USPI, (2009). Ilaris (canakinumab). Available at (accessed 13 February 2012).
94. Kanakura Y, Ohyashiki K, Shichishima T, Okamoto S, Ando K, Ninomiya H, et al,. (2011). Safety and efficacy of the terminal complement inhibitor eculizumab in Japanese patients with paroxysmal nocturnal hemoglobinuria: the AEGIS clinical trial. Int J Hematol 93: 36-46.
95. Keefe D, Bowen J, Gibson R, Tan T, Okera M, Stringer A, (2011). Noncardiac vascular toxicities of vascular endothelial growth factor inhibitors in advanced cancer: a review. Oncologist 16: 432-444.
96. Khosla S, (2001). The OPG/RANKL/RANK system. Endocrinology 142: 5050-5055.
97. Kim T, Chung J, Hong J, Min K, Seo K, Kim E, (2009). Bevacizumab application delays epithelial healing in rabbit cornea. Invest Ophthalmol Vis Sci 50: 4653-4659.
98. Kineret USPI, (2009). Kineret (anakinra). Available at (accessed 13 February 2012).
99. King C, Xianli J, Malhotra I, Liu S, Mahmoud A, Oettgen H, (1997). Mice with a targeted deletion of the IgE gene have increased worm burdens and reduced granulomatous inflammation following primary infection with Schistosoma mansoni. J Immunol 158: 294-300.
100. Kisselgof A, Oettgen H, (1998). The expression of murine B cell CD23, in vivo, is regulated by its ligand, IgE. Int Immunol 10: 1377-1384.
101. Kong Y-Y, Yoshida H, Sarosi I, Tan H, Timms E, Capparelli C, et al,. (1999). OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397: 315-323.
102. Kontoyiannis D, Kollias G, (2000). Accelerated autoimmunity and lupus nephritis in NZB mice with an engineered heterozygous deficiency in tumor necrosis factor. Eur J Immunol 30: 2038-2047.
103. Korner H, Cook M, Riminton D, Lemckert F, Hoek R, Ledermann B, et al,. (1997). Distinct roles for lymphotoxin-alpha and tumor necrosis factor in organogenesis and spatial organization of lymphoid tissue. Eur J Immunol 27: 2600-2609.
104. Korner H, McMorran B, Schluter D, Fromm P, (2010). The role of TNF in parasitic diseases: still more questions than answers. Int J Parasitol 40: 879-888.
105. Krzystolik M, Afshari M, Adamis A, Gaudreault J, Gragoudas E, Michaud N, et al,. (2002). Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody fragment. Arch Ophthalmol 120: 338-346.
106. Kurzeja M, Rudnicka L, Olszewska M, (2011). New interleukin-23 pathway inhibitors in dermatology: ustekinumab, briakinumab, and secukinumab. Am J Clin Dermatol 12: 113-125.
107. Langowski J, Zhang X, Wu L, Mattson J, Chen T, Smith K, et al,. (2006). IL-23 promotes tumor incidence and growth. Nature 442: 461-465.
108. Lawrence D, Schell R, (1978). Susceptibility of C5-deficient mice to listeriosis: modulation by concanavalin A. Cell Immunol 39: 336-344.
109. Levin TA, Ownby DR, Smith PH, Peterson EL, Williams LK, Ford J, et al,. (2006). Relationship between extremely low total serum IgE levels and rhinosinusitis. Ann Allergy Asthma Immunol 97: 650-652.
110. Lin P, Myers A, Smith L, Bigbee C, Bigbee M, Fuhrman C, et al,. (2010). Tumor necrosis factor neutralization results in disseminated disease in acute and latent Mycobacterium tuberculosis infection with normal granuloma structure in a cynomolgus macaque model. Arthritis Rheum 62: 340-350.
111. Lucentis USPI, (2010). Lucentis (ranibizumab). Available at (accessed 13 February 2012).
112. Lundberg P, Welander P, Edwards C, van Rooijen N, Cantin E, (2007). Tumor necrosis factor (TNF) protects resistant C57BL/6 mice against herpes simplex virus-induced encephalitis independently of signaling via TNF receptor 1 or 2. J Virol 81: 1451-1460.
113. Maeda A, Schneider S, Kojima M, Beissert S, Schwarz T, Schwarz A, (2006). Enhanced photocarcinogenesis in interleukin-12-deficient mice. Cancer Res 66: 2962-2069.
114. Magnano M, Robinson W, Genovese M, (2004). Demyelination and inhibition of tumor necrosis factor (TNF). Clin Exp Rheumatol 22 (Suppl. 35): S134-S140.
115. Magram J, Connaughton S, Warrier R, Carvajal D, Wu C, Ferrante J, et al,. (1996). IL-12-deficient mice are defective in IFN gamma production and type 1 cytokine responses. Immunity 4: 471-481.
116. Mariette X, Matucci-Cerinic M, Pavelka K, Taylor P, van Vollenhoven R, Heatley R, et al,. (2011). Malignacies assicaiated with tumor necrosis factor inhibitors in registries and prospective observational studies: a systematic review and meta-analysis. Ann Rheum Dis 70: 1895-1904.
117. Marino M, Dunn A, Grail D, Inglese M, Noguchy Y, Richards E, et al,. (1997). Characterization of tumor necrosis factor-deficient mice. Proc Natl Acad Sci U S A 94: 8093-8098.
118. Martin P, Oneda S, Treacy G, (2007). Effects of an anti-TNFα monoclonal antibody, administered throughout pregnancy and lactation, on the development of the macaque immune system. Am J Reprod Immunol 58: 138-149.
119. Martin P, Cornacoff J, Treacy G, Eirikas E, Marini J, White K, et al,. (2008). Effects of administration of monoclonal antibody against tumor necrosis factor alpha during pregnancy and lactation on the pre- and postnatal development of the mouse immune system. Int J Toxicol 27: 341-347.
120. Martin P, Sachs C, Imai N, Tsusaki H, Oneda S, Jiao Q, et al,. (2010). Development in the cynomolgus macaque following administration of ustekinumab, a human anti-IL-12/23p40 monoclonal antibody, during pregnancy and lactation. Birth Defects Res B Dev Reprod Toxicol 89: 351-363.
121. Mathias C, Freyschmidt E, Oettgen H, (2009). Immunoglobulin E antibodies enhance pulmonary inflammation induced by inhalation of a chemical hapten. Clin Exp Allergy 39: 417-425.
122. Mease PJ, (2011). Certolizumab pegol in the treatment of rheumatoid arthritis: a comprehensive review of its clinical efficacy and safety. Rheumatology (Oxford) 50: 261-270.
123. Mehlhop P, van de Rijn M, Goldberg A, Brewer J, Kurup V, Martin T, et al,. (1997). Allergen-induced bronchial hyperreactivity and eosinophilic inflammation occur in the absence of IgE in a mouse model of asthma. Proc Natl Acad Sci U S A 94: 1344-1349.
124. Mewar D, Wilson AG, (2011). Treatmnet of rheumatoid arthritis with tumour necrosis factor inhibitors. Br J Pharmacol 162: 785-791.
125. Miura T, Nishikawa S, Sasaki S, Yamada K, Hasegawa S, Mizuki D, et al,. (2000). Roles of endogenous cytokines in liver apoptosis of mice in lethal Listeria monocytogenes infection. FEMS Immunol Med Microbiol 28: 335-341.
126. Mordenti J, Thomsen K, Licko V, Chen H, Meng Y, Ferrara N, (1999). Efficacy and concentration-response of murine anti-VEGF monoclonal antibody in tumor-bearing mice and extrapolation to humans. Toxicol Pathol 27: 14-21.
127. Mullick A, Leon Z, Min-Oo G, Berghout J, Lo R, Daniels E, et al,. (2006). Cardiac failure in C5-deficient A/J mice after Candida albicans infection. Infect Immun 74: 4439-4451.
128. Nakajima K, Kanda T, Takaishi M, Shiga T, Miyoshi K, Nakajima H, et al,. (2011). Distinct roles of IL-23 and IL-17 in th development of psoriasis-like lesions in a mouse model. J Immunol 186: 4481-4489.
129. Nauciel C, Espinasse-Maes F, (1992). Role of gamma interferon and tumor necrosis factor alpha in resistance to Salmonella typhimurium infection. Infect Immun 60: 450-454.
130. O'Neill C, Miller P, Christian B, Beyer J, Bentley E, Ver Hoeve J, et al,. (2003). 26-week intravitreal injection toxicity study with rhuFab VEGF in cynomolgus monkeys with an 8-week recovery. Invest Ophthalmol Vis Sci 44: Astract # 3929.
131. OECD (1998). OECD Principles on Good Laboratory Practice. Available at (accessed 13 February 2012).
132. Ominsky M, Kostenuik P, Cranmer P, Smith S, Atkinson J, (2007). The RANKL inhibitor OPG-Fc increases cortical and trabecular bone mass in young gonad-intact cynomolgus monkeys. Osteoporos Int 18: 1073-1082.
133. Pasparakis M, Alexopoulou L, Episkopou V, Kollias G, (1996). Immune and inflammatory responses in TNF alpha-deficient mice: a critical requirement for TNF alpha in the formation of primary B cell follicles, follicular dendritic cell networks and germinal centers, and in the maturation of the humoral immune response. J Exp Med 184: 1397-1411.
134. Picard C, Puel A, Bonnet M, Ku C, Bustamante J, Yang K, et al,. (2003). Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science 299: 2076-2079.
135. Pickering M, Warren J, Rose K, Carlucci F, Wang Y, Walport M, et al,. (2006). Prevention of C5 activation ameliorates spontaneous and experimental glomerulonephritis in factor H-deficient mice. Proc Natl Acad Sci U S A 103: 9649-9654.
136. Ponce R, Abad L, Amaravadi L, Gelzleichter T, Gore E, Green J, et al,. (2009). Immunogenicity of biologically-derived theraeutics: assessment and interpretation of nonclinical safety stduies. Regul Toxicol Pharmacol 54: 164-182.
137. Prolia USPI, (2011). Prolia (denosumab). Available at (accessed 13 February 2012).
138. Quesniaux VFJ, Jacobs M, Allie N, Grivennikov S, Nedospasov SA, Garcia I, et al,. (2010). TNF in host resistance to tuberculosis infection. Curr Dir Autoimmun 11: 157-179.
139. Radin A, Marbury T, Osgood G, Belomestnov P, (2010). Safety and pharmacokinetics of subcutaneously administered rilonacept in patients with well-controlled end-stage renal disease (ESRD). J Clin Pharmacol 50: 835-841.
140. Remicade USPI, (2011). Remicade (infliximab). Available at (accessed 13 February 2012).
141. van de Rijn M, Mehlhop P, Judkins A, Rothenberg M, Luster A, Oettgen H, (1998). A murine model of allergic rhinitis: studies on the role of IgE in pathogenesis and analysis of the eosinophil influx elicited by allergen and eotaxin. J Allergy Clin Immunol 102: 65-74.
142. Rojko J, Price-Schiavi S, (2008). Physiologic IgG biodostribution, transport, and clearance: implication for monoclonal antibody products. In:, Cavagnaro J, (ed.). Preclinical Safety Evaluation of Biopharmaceuticals. John Wiley and Sons: New York, pp. 241-276.
143. Ryan A, Eppler D, Hagler K, Bruner R, Thomford P, Hall R, et al,. (1999). Preclinical safety evaluation of rhuMAbVEGF, an antiangiogenic humanized monoclonal antibody. Toxicol Pathol 27: 78-86.
144. Sahdev I, O'Reilly R, Hoffman MK, (1989). Correlation between interleukin-1 production and engraftment of transplanted bone marrow stem cells in patients with lethal immunodeficiencies. Blood 73: 1712-1719.
145. Saijo S, Asano M, Horai R, Yamamoto H, Iwakura Y, (2002). Suppression of autoimmune arthritis in interleukin-1-deficient mice in which T cell activation is impaired due to low levels of CD40 ligand and OX40 expression on T cells. Arthritis Rheum 46: 533-544.
146. Salmon-Ceron D, Tubach F, Lortholary O, Chosidow O, Bretagne S, Nicolas N, et al,. (2010). Drug-specific risk of non-tuberculosis opportunistic infections in patients receiving anti-TNF therapy reported to the 3-year prospective French RATIO registry. Ann Rheum Dis 70: 613-623.
147. Sarma JV, Ward PA, (2011). The complement system. Cell Tissue Res 343: 227-235.
148. Scherl EJ, Kumar S, Warren RU, (2010). Review of the safety and efficacy of ustekinumab. Therap Adv Gastroenterol 3: 321-328.
149. Schmucker C, Loke YK, Ehlken C, Agostini HT, Hansen LL, Antes G, et al,. (2011). Intravitreal bevacizumab (Avastin) versus ranibizumab (Lucentis) for the treatment of age-related macular degeneration: a safety review. Br J Ophthalmol 95: 308-317.
150. Schonthaler H, Huggenberger R, Wculek S, Detmar M, Wagner E, (2009). Systemic anti-VEGF treatment strongly reduces skin inflammation in a mouse model of psoriasis. Proc Natl Acad Sci U S A 106: 21264-21269.
151. Scott K, Moore R, Arnott C, East N, Thompson R, Scallon B, et al,. (2003). An anti-tumor necrosis factor-α antibody inhibits the development of experimental skin tumors. Mol Cancer Ther 2: 445-451.
152. Segal BM, Constantinescu CS, Raychaudhuri A, Kim L, Fidelus-Gort R, Kasper LH, et al,. (2008). Repeated subcutaneous injections of IL 12/23 p40 neutralizing antibody, ustekinumab, in patinets with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomized, dose-ranging study. Lancet Neurol 7: 796-804.
153. Shen C, de Hertogh G, Bullens D, Van Assche G, Geboes K, Rutgeerts P, et al,. (2007). Remission-inducing effect of anti-TNF monoclonal antibody in TNBS colitis: mechanisms beyond neutralization? Inflamm Bowel Dis 13: 308-316.
154. Shrestha B, Zhang B, Purtha W, Klein R, Diamond M, (2008). Tumor necrosis factor alpha protects against lethal West Nile virus infection by promoting trafficking of mononuclear leukocytes into the central nervous system. J Virol 82: 8956-8964.
155. Silva J, Vespa G, Cardoso M, Aliberti J, Cunha F, (1995). Tumor necrosis factor alpha mediates resistance to Trypanosoma cruzi infection in mice by inducing nitric oxide production in infected gamma interferon-activated macrophages. Infect Immun 63: 4862-4867.
156. Simponi USPI, (2011). Simponi (golimumab). Available at (accessed 13 February 2012).
157. Smith B, Cosenza M, Mancini A, Dunstan C, Gregson R, Martin S, et al,. (2003). A toxicity profile of osteoprotegerin in the cynomolgus monkey. Int J Toxicol 22: 403-412.
158. Smitten A, Simon T, Hochberg M, Suissa S, (2008). A meta-analysis of the incidence of malignancy in adult patients with rheumatoid arthritis. Arthritis Res Ther 10: R45.
159. Solaris USPI, (2011). Solaris (eculizumab). Available at (accessed 13 February 2012).
160. Steinshamn S, Waage A, (1992). Tumor necrosis factor and interleukin-6 in Candida albicans infection in normal and granulocytopenic mice. Infect Immun 60: 4003-4008.
161. Stelara USPI, (2011). Stelara (ustekinumab). Available at (accessed 13 February 2012).
162. Stolina M, Kostenuik P, Dougall W, Fitzpatrick L, Zack D, (2007). RANKL inhibition: from mice to men (and women). Adv Exp Med Biol 602: 143-150.
163. Street S, Trapani J, MacGregor D, Smyth M, (2002). Suppression of lymphoma and epithelial malignancies effected by interferon γ. J Exp Med 196: 129-134.
164. Swann J, Vesely M, Silva A, Sharkey J, Akira S, Schreiber R, et al,. (2008). Demonstration of inflammation-induced cancer and cancer immunoediting during primary tumorigenesis. Proc Natl Acad Sci U S A 105: 652-656.
165. Tan RA, Corren J, (2011). Safety of omalizumab in asthma. Expert Opin Drug Saf 10: 463-471.
166. Tarrant T, Silver P, Chan C, Wiggert B, Caspi R, (1998). Endogenous IL-12 is required for induction and expression of experimental autoimmune uveitis. J Immunol 161: 122-127.
167. Thaler K, Chandiramani DV, Hansen RA, Gartlehner G, (2009). Efficacy and safety of anakinra for the treatment of rheumatoid arthritis: an update of the Oregon Drug Effectiveness Review Project. Biologics 3: 485-498.
168. Toker O, Hashkes PJ, (2010). Critical appraisal of canakinumab in the treatment of adults and children with cryopyrin-associated periodic syndrome (CAPS). Biologics 4: 131-138.
169. Torres R, Macdonald L, Croll S, Reinhardt J, Dore A, Stevens S, et al,. (2009). Hyperalgesia, synovitis and multiple biomarkers of inflammation are suppressed by interleukin 1 inhibition in a novel animal model of gouty arthritis. Ann Rheum Dis 68: 1602-1608.
170. Torti D, Feldman S, (2007). Interleukin-12, interleukin-23, and psoriasis: current prospects. J Am Acad Dermatol 57: 1059-1068.
171. Treacy G, (2000). Using and analogous monoclonal antibody to evalaute the reproductive and chronic toxicity potential for a humanized anti-TNFalpha monoclonal anatibody. Hum Exp Toxicol 19: 226-228.
172. Trendelenburg M, (2007). Complement inhibition by anti-C5 antibodies- from bench to bedside and back again. Swiss Med Wkly 137: 413-417.
173. Vakeva A, Agah A, Rollins S, Matis L, Li L, Stahl G, (1998). Myocardial infarction and apoptosis after myocardial ischemia and reperfusion. Role of the terminal complement components and inhibition by anti-C5 therapy. Circulation 97: 2259-2267.
174. Voronov E, Dayan M, Zinger H, Gayvoronsky L, Lin J, Iwakura Y, et al,. (2006). IL-1 beta-deficient mice are resistant to induction of experimental SLE. Eur Cytokine Netw 17: 109-116.
175. Wakefield I, Stephens S, Foulkes R, Nesbitt A, Bourne T, (2011). The use of surrogate antibodies to evaluate the developmental and reproductive toxicity potential of an anti-TNFα PEGylated Fab' monoclonal antibody. Toxicol Sci 122: 170-176.
176. Walsh G, (2010). Biopharmaceutical benchmarks. Nat Biotechnol 28: 917-924.
177. Watanabe N, Ishiwata K, Kaneko S, Oku Y, Kamiya M, Katakura K, (1993). Immune defense and eosinophilia in congenitally IgE-deficient SJA/9 mice infected with Angiostrongylus costaricensis. Parasitol Res 79: 431-434.
178. Watanabe N, Nawa Y, Okamoto K, Kobayashi A, (1994). Expulsion of Hymenolepis nana from mice with congenital deficiencies of IgE production or of mast cell development. Parasite Immunol 16: 137-144.
179. Webster R, Elliott V, Park BK, Walker D, Hankin M, Taupin P, (2009). PEG and PEG conjugates toxcity: towards and understanding of the toxcity of PEG and its relevance to PEGylated biologicals. In:, Veronese FM, (ed.). Pegyated Protein Drugs: Basic and Clinical Applications. Birkhausen Verlag: Basel, Switzerland, pp. 127-147.
180. Weger W, (2010). Current status and new developments in the traetment of psoriasis and psoriatic arthritis with biological agents. Br J Pharmacol 160: 810-820.
181. Wolfe F, Michaud K, (2007). Biologic treatment of rheumatoid arthritis and the risk of malignancy: analyses from a large US observational study. Arthritis Rheum 56: 2886-2895.
182. Woolard J, Bevan HS, Harper SJ, Bates DO, (2009). Molecular diversity of VEGF-A as a regulator of its biological activity. Microcirculation 16: 572-592.
183. Wu G, Hu W, Shahsafaei A, Song W, Dobarro M, Sukhova G, et al,. (2009). Complement regulator CD59 protects against atherosclerosis by restricting the formation of complement membrane attack complex. Circ Res 104: 550-559.
184. Wulff C, Wilson H, Wiegand S, Rudge J, Fraser H, (2002). Prevention of thecal angiogenesis, antral follicular growth, and ovulation in the primate by treatment with vascular endothelial growth factor Trap R1R2. Endocrinology 143: 2797-2807.
185. Xolair USPI, (2011). Xolair (omalizumab). Available at (accessed 13 February 2012).
186. Yamaguchi M, Lantz C, Oettgen H, Katona I, Fleming T, Miyajima I, et al,. (1997). IgE enhances mouse mast cell Fc(epsilon)RI expression in vitro and in vivo: evidence for a novel amplification mechanism in IgE-dependent reactions. J Exp Med 185: 663-672.
187. Zhou Y, Gong B, Lin F, Rother R, Edward M, Kaminski H, (2007). Anti-C5 antibody treatment ameliorates weakness in experimentally acquired myasthenia gravis. J Immunol 179: 8562-8567.
188. Zhu L-J, Yang X, Yu X-Q, (2010). Anti-TNF-α therapies in systemic lupus erythematosus. J Biomed Biotechnol 2010: Article ID 465898.