Concordance of preclinical and clinical pharmacology and toxicology of therapeutic monoclonal antibodies and fusion proteins: Cell surface targets

British Journal of Pharmacology

Volumn 166, Issue 3, 2012, Pages 823-846

  Bugelski, Peter J ^a   Martin, Pauline L ^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

ABATACEPT; ABCIXIMAB; ALEFACEPT; ALEMTUZUMAB; ALPHA4 INTEGRIN; BASILIXIMAB; CD20 ANTIGEN; CD3 ANTIGEN; CD52 ANTIGEN; CETUXIMAB; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; DACLIZUMAB; EFALIZUMAB; EPIDERMAL GROWTH FACTOR RECEPTOR; EPIDERMAL GROWTH FACTOR RECEPTOR 2; FIBRINOGEN RECEPTOR; HYBRID PROTEIN; INTERLEUKIN 2 RECEPTOR ALPHA; INTERLEUKIN 6 RECEPTOR; IPILIMUMAB; LYMPHOCYTE FUNCTION ASSOCIATED ANTIGEN 1; LYMPHOCYTE FUNCTION ASSOCIATED ANTIGEN 3; MONOCLONAL ANTIBODY; NATALIZUMAB; OKT 3; ORTHOCLONE; PANITUMUMAB; RITUXIMAB; TOCILIZUMAB; TRASTUZUMAB; UNCLASSIFIED DRUG;

ACUTE GRAFT REJECTION; ANEMIA; ANTIGEN FUNCTION; ANTIGEN STRUCTURE; ARTHRALGIA; ARTHRITIS; ASEPTIC MENINGITIS; ASPERGILLOSIS; B LYMPHOCYTE; BACTERIAL ARTHRITIS; BACTERIAL INFECTION; BASAL CELL CARCINOMA; BLEEDING; BRAIN HEMORRHAGE; BREAST CANCER; CANDIDIASIS; CARDIOPULMONARY ARREST; CARDIOTOXICITY; CARDIOVASCULAR DISEASE; CD4 LYMPHOCYTE COUNT; CELL SURFACE; CELLULITIS; CHILL; CHRONIC LYMPHATIC LEUKEMIA; CLINICAL PHARMACOLOGY; CLINICAL TOXICOLOGY; COLITIS; COLORECTAL CARCINOMA; CONGESTIVE HEART FAILURE; CONSTIPATION; CREATININE BLOOD LEVEL; CROHN DISEASE; CRYPTOCOCCOSIS; CYTOKINE RELEASE SYNDROME; CYTOMEGALOVIRUS INFECTION; CYTOPENIA; DEMYELINATING DISEASE; DERMATITIS; DIARRHEA; DIGESTIVE SYSTEM PERFORATION; DIVERTICULITIS; DRUG FEVER; DRUG HYPERSENSITIVITY; DRUG INDUCED HEADACHE; DRUG RECEPTOR BINDING; DYSPNEA; ELECTROLYTE DISTURBANCE; ENDOCRINE DISEASE; EYE TOXICITY; FATIGUE; GASTROENTERITIS; GASTROINTESTINAL HEMORRHAGE; GENETIC DISORDER; GRAFT REJECTION; HEART PALPITATION; HEMOLYTIC ANEMIA; HEPATITIS; HEPATITIS C; HERPES ZOSTER; HUMAN; HYPERCHOLESTEROLEMIA; HYPERKALEMIA; HYPERTENSION; HYPOPHOSPHATEMIA; HYPOPHYSITIS; HYPOTENSION; IMMUNOPATHOLOGY; INFECTION; INFLUENZA; INFUSION RELATED REACTION; INTERSTITIAL PNEUMONIA; INTESTINE PERFORATION; KIDNEY DYSFUNCTION; LIVER INJURY; LUNG FIBROSIS; LUNG HYPOPLASIA; LUNG TOXICITY; LYMPHOPROLIFERATIVE DISEASE; MALIGNANT NEOPLASTIC DISEASE; METASTATIC MELANOMA; MICROSCOPIC POLYANGIITIS; MULTIPLE SCLEROSIS; MYALGIA; MYCOSIS; MYOSITIS; NAUSEA; NEPHRITIS; NEUROPATHY; NEUTROPENIA; NEUTROPHIL; NEWBORN DISEASE; NON MELANOMA SKIN CANCER; NONHODGKIN LYMPHOMA; NONHUMAN; OLIGOHYDRAMNIOS; OPPORTUNISTIC INFECTION; PAIN; PERIPHERAL EDEMA; PNEUMOCYSTOSIS; PNEUMONIA; POLYOMAVIRUS INFECTION; PREDICTIVE VALUE; PRIORITY JOURNAL; PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; PROTEIN EXPRESSION; PROTEIN TARGETING; PROTOZOAL INFECTION; PRURITUS; PSORIASIS; PSORIASIS VULGARIS; RESPIRATORY DISTRESS; REVIEW; RHEUMATOID ARTHRITIS; RHINOPHARYNGITIS; RIGOR; SCID MOUSE; SEIZURE; SEPSIS; SIDE EFFECT; SIGNAL TRANSDUCTION; SINGLE DRUG DOSE; SKIN MANIFESTATION; SKIN TOXICITY; STOMACH TUMOR; SYSTEMIC INFLAMMATORY RESPONSE SYNDROME; SYSTEMIC LUPUS ERYTHEMATOSUS; SYSTEMIC MYCOSIS; T LYMPHOCYTE; TACHYCARDIA; THROMBOCYTE; THROMBOCYTOPENIA; THROMBOSIS; THYROIDITIS; TOXIC EPIDERMAL NECROLYSIS; TOXICOLOGY; TUBERCULOSIS; TUMOR LYSIS SYNDROME; UPPER RESPIRATORY TRACT INFECTION; URINARY TRACT INFECTION; UVEITIS; VIRUS INFECTION; VIRUS MENINGITIS; VIRUS REACTIVATION; WEGENER GRANULOMATOSIS;

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

EID: 84860854354     PISSN: 00071188     EISSN: 14765381     Source Type: Journal    
DOI: 10.1111/j.1476-5381.2011.01811.x     Document Type: Review

References (283)

1. Abraham DJ, Bou-Gharios G, Beauchamp JR, Plater-Zyberk C, Maini RN, Olsen I, (1991). Function and regulation of the murine lymphocyte CD2 receptor. J Leukoc Biol 49: 329-341.
2. Actemra USPI (2011). Available at (accessed 15 February 2012).
3. Agus DB, Gordon MS, Taylor C, Natale RB, Karlan B, Mendelson DS, et al,. (2005). Phase I clinical study of pertuzumab, a novel HER dimerization inhibitor, in patients with advanced cancer. J Clin Oncol 23: 2534-2543.
4. Alcaide ML, Abbo L, Pano JR, Gaynor JJ, Tryphonopoulos P, Weppler D, et al,. (2008). Herpes zoster infection after liver transplantation in patients receiving induction therapy with alemtuzumab. Clin Transplant 22: 502-507.
5. Alegre ML, Vandenabeele P, Depierreux M, Florquin S, Deschodt-Lanckman M, Flamand V, et al,. (1991). Cytokine release syndrome induced by the 145-2C11 anti-CD3 monoclonal antibody in mice: prevention by high doses of methylprednisolone. J Immunol 146: 1184-1191.
6. Alinari L, Lapalombella R, Andritsos L, Baiocchi RA, Lin TS, Byrd JC, (2007). Alemtuzumab (Campath-1H) in the treatment of chronic lymphocytic leukemia. Oncogene 26: 3644-3653.
7. ® USPI (2011). Available at (accessed 15 February 2012).
8. Angelov GS, Guillaume P, Luescher IF, (2009). CD8beta knockout mice mount normal anti-viral CD8+ T cell responses-but why? Int Immunol 21: 123-135.
9. Ansell SM, Hurvitz SA, Koenig PA, LaPlant BR, Kabat BF, Fernando D, et al,. (2009). Phase I study of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with relapsed and refractory B-cell non-Hodgkin lymphoma. Clin Cancer Res 15: 6446-6453.
10. Ashraf-Benson S, Wall GC, Veach LA, (2009). Serum sickness-like reaction associated with efalizumab. Ann Pharmacother 43: 383-386.
11. Banerjee S, Wei BY, Hillman K, Luthra HS, David CS, (1988). Immunosuppression of collagen-induced arthritis in mice with an anti-IL-2 receptor antibody. J Immunol 141: 1150-1154.
12. Bannwarth B, Richez C, (2011). Clinical safety of tocilizumab in rheumatoid arthritis. Expert Opin Drug Saf 10: 123-131.
13. Bekar KW, Owen T, Dunn R, Ichikawa T, Wang W, Wang R, et al,. (2010). Prolonged effects of short-term anti-CD20 B cell depletion therapy in murine systemic lupus erythematosus. Arthritis Rheum 62: 2443-2457.
14. Berger JR, (2010). Progressive multifocal leukoencephalopathy and newer biological agents. Drug Saf 33: 969-983.
15. Bergman ML, Cilio CM, Penha-Goncalves C, Lamhamedi-Cherradi SE, Lofgren A, Colucci F, et al,. (2001). CTLA-4-/- mice display T cell-apoptosis resistance resembling that ascribed to autoimmune-prone non-obese diabetic (NOD) mice. J Autoimmun 16: 105-113.
16. Berlin PJ, Bacher JD, Sharrow SO, Gonzalez C, Gress RE, (1992). Monoclonal antibodies against human T cell adhesion molecules-modulation of immune function in nonhuman primates. Transplantation 53: 840-849.
17. Berman D, Parker SM, Siegel J, Chasalow SD, Weber J, Galbraith S, et al,. (2010). Blockade of cytotoxic T-lymphocyte antigen-4 by ipilimumab results in dysregulation of gastrointestinal immunity in patients with advanced melanoma. Cancer Immun 10: 11.
18. Bezabeh S, Flowers CM, Kortepeter C, Avigan M, (2010). Clinically significant liver injury in patients treated with natalizumab. Aliment Pharmacol Ther 31: 1028-1035.
19. Bierer BE, Hahn WC, (1993). T cell adhesion, avidity regulation and signaling: a molecular analysis of CD2. Semin Immunol 5: 249-261.
20. Bigbee CL, Gonchoroff DG, Vratsanos G, Nadler SG, Haggerty HG, Flynn JL, (2007). Abatacept treatment does not exacerbate chronic Mycobacterium tuberculosis infection in mice. Arthritis Rheum 56: 2557-2565.
21. Blazar BR, Taylor PA, Vallera DA, (1994). In vivo or in vitro anti-CD3 epsilon chain monoclonal antibody therapy for the prevention of lethal murine graft-versus-host disease across the major histocompatibility barrier in mice. J Immunol 152: 3665-3674.
22. Boasberg P, Hamid O, O'Day S, (2010). Ipilimumab: unleashing the power of the immune system through CTLA-4 blockade. Semin Oncol 37: 440-449.
23. Boden E, Tang Q, Bour-Jordan H, Bluestone JA, (2003). The role of CD28 and CTLA4 in the function and homeostasis of CD4+CD25+ regulatory T cells. Novartis Found Symp 252: 55-66.
24. Boggi U, Danesi R, Vistoli F, Del Chiaro M, Signori S, Marchetti P, et al,. (2004). A benefit-risk assessment of basiliximab in renal transplantation. Drug Saf 27: 91-106.
25. Boudousquie C, Pellaton C, Barbier N, Spertini F, (2009). CD4+CD25+ T cell depletion impairs tolerance induction in a murine model of asthma. Clin Exp Allergy 39: 1415-1426.
26. Brady JL, Yamashita K, Lew AM, (2001). Enhanced survival of grafts genetically endowed with the ability to block CD2 and B7. Cell Transplant 10: 175-181.
27. Brady JL, Mannering SI, Kireta S, Coates PT, Proietto AI, Cowan PJ, et al,. (2009). Monoclonal antibodies generated by DNA immunization recognize CD2 from a broad range of primates. Immunol Cell Biol 87: 413-418.
28. Brok HP, Tekoppele JM, Hakimi J, Kerwin JA, Nijenhuis EM, De Groot CW, et al,. (2001). Prophylactic and therapeutic effects of a humanized monoclonal antibody against the IL-2 receptor (DACLIZUMAB) on collagen-induced arthritis (CIA) in rhesus monkeys. Clin Exp Immunol 124: 134-141.
29. Bromberg JS, (1993). The biology of CD2: adhesion, transmembrane signal, and regulatory receptor of immunity. J Surg Res 54: 258-267.
30. Brown DL, (2003). Deaths associated with platelet glycoprotein IIb/IIIa inhibitor treatment. Heart 89: 535-537.
31. 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.
32. Calabresi PA, Giovannoni G, Confavreux C, Galetta SL, Havrdova E, Hutchinson M, et al,. (2007). The incidence and significance of anti-natalizumab antibodies: results from AFFIRM and SENTINEL. Neurology 69: 1391-1403.
33. Camacho-Halili M, George R, Gottesman M, Davis-Lorton M, (2011). An approach to natalizumab hypersensitivity: a case series of induction of tolerance. Mult Scler 17: 250-253.
34. Campath USPI (2009). Available at (accessed 15 February 2012).
35. Campbell L, Chen C, Bhagat SS, Parker RA, Ostor AJK, (2011). Risk of adverse events including serious infections in rheumatoid arthritis patients treated with tocilizumab: a systematic literature review and meta-analysis of randomized controlled trials. Rheumatology 50: 552-562.
36. Cannella B, Cross AH, Raine CS, (1993). Anti-adhesion molecule therapy in experimental autoimmune encephalomyelitis. J Neuroimmunol 46: 43-55.
37. Carrigan SO, Yang YJ, Issekutz T, Forward N, Hoskin D, Johnston B, et al,. (2009). Depletion of natural CD4+CD25+ T regulatory cells with anti-CD25 antibody does not change the course of Pseudomonas aeruginosa-induced acute lung infection in mice. Immunobiology 214: 211-222.
38. Cather JC, Cather JC, Menter A, (2003). Modulating T cell responses for the treatment of psoriasis: a focus on efalizumab. Expert Opin Biol Ther 3: 361-370.
39. Caudy AA, Reddy ST, Chatila T, Atkinson JP, Verbsky JW, (2007). CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes. J Allergy Clin Immunol 119: 482-487.
40. Cavagnaro J, (ed.) (2008). Preclinical Safety Evaluation of Biopharmaceuticals: A Science-Based Approach to Facilitating Clinical Trials. John A. Wiley and Sons: Hoboken, NJ.
41. Cecchinato V, Tryniszewska E, Ma ZM, Vaccari M, Boasso A, Tsai W-P, et al,. (2008). Immune activation driven by CTLA-4 blockade augments viral replication at mucosal sites in simian immunodeficiency virus infection. J Immunol 180: 5439-5447.
42. Chapman TM, Keating GM, (2003). Basiliximab: a review of its use as induction therapy in renal transplantation. Drugs 63: 2803-2835.
43. Chatenoud L, Bluestone JA, (2007). CD3-specific antibodies: a portal to the treatment of autoimmunity. Nat Rev Immunol 7: 622-632.
44. Chavin KD, Lau HT, Bromberg JS, (1992). Prolongation of allograft and xenograft survival in mice by anti-CD2 monoclonal antibodies. Transplantation 54: 286-291.
45. Chen Y, Bord E, Tompkins T, Miller J, Tan CS, Kinkel RP, et al,. (2009). Asymptomatic reactivation of JC virus in patients treated with natalizumab. NEJM 361: 1067-1074.
46. Cheson BD, (2010). Monoclonal antibody therapy of chronic lymphocytic leukaemia. Best Pract Res Clin Haematol 23: 133-143.
47. Chisholm PL, Williams CA, Jones WE, Majeau GR, Oleson FB, Burrus-Fischer B, et al,. (1994). The effects of an immunomodulatory LFA3-IgG1 fusion protein on nonhuman primates. Ther Immunol 1: 205-216.
48. Clarke J, Leach W, Pippig S, Joshi A, Wu B, House R, et al,. (2004). Evaluation of a surrogate antibody for preclinical safety testing of an anti-CD11a monoclonal antibody. Regul Toxicol Pharmacol 40: 219-226.
49. Cohen PR, Escudier SM, Kurzrock R, (2011). Cetuximab-associated elongation of the eyelashes: case report and review of eyelash trichomegaly secondary to epidermal growth factor receptor inhibitors. Am J Clin Dermatol 12: 63-67.
50. Coiffier B, (2007). Rituximab therapy in malignant lymphoma. Oncogene 26: 3603-3613.
51. Coller BS, Folts JD, Smith SR, Scudder LE, Jordan R, (1989). Abolition of in vivo platelet thrombus formation in primates with monoclonal antibodies to the platelet GPIIb/IIIa receptor. Correlation with bleeding time, platelet aggregation, and blockade of GPIIb/IIIa receptors. Circulation 80: 1766-1774.
52. Cosimi AB, Burton RC, Colvin RB, Goldstein G, Delmonico FL, LaQuaglia MP, et al,. (1981). Treatment of acute renal allograft rejection with OKT3 monoclonal antibody. Transplantation 32: 535-539.
53. Couper KN, Lanthier PA, Perona-Wright G, Kummer LW, Chen W, Smiley ST, et al,. (2009). Anti-CD25 antibody-mediated depletion of effector T cell populations enhances susceptibility of mice to acute but not chronic Toxoplasma gondii infection. J Immunol 182: 3985-3994.
54. Cragg MS, Walshe CA, Ivanov AO, Glennie MJ, (2005). The biology of CD20 and its potential as a target for mAb therapy. Curr Dir Autoimmun 8: 140-174.
55. Creelan B, Ferber A, (2008). A fatal case of alemtuzumab-associated interstitial pneumonitis. Am J Ther 15: 82-84.
56. Crofts F, Rohatagi S, Pino M, DeLise B, Zhang J, Nguyen M, et al,. (2004). Critical period for a teratogenic VLA-4 antagonist: developmental effects and comparison of embryo drug concentrations of teratogenic and non-teratogenic VLA-4 antagonists. Birth Defects Res B Dev Reprod Toxicol 71: 69-79.
57. Cunha MS, da Silva JCF, Nakamoto HA, Machado FA, Ferreira MC, (2009). Effect of IIb-IIIa glycoprotein inhibitors in a partial limb amputation model submitted to warm ischemia in rats. J Reconstr Microsurg 25: 283-288.
58. D'Elia R, Behnke JM, Bradley JE, Else KJ, (2009). Regulatory T cells: a role in the control of helminth-driven intestinal pathology and worm survival. J Immunol 182: 2340-2348.
59. Damaj G, Rubio MT, Audard V, Hermine O, (2002). Severe cardiac toxicity after monoclonal antibody therapy. Eur J Haematol 68: 324-329.
60. Dave VP, (2009). Hierarchical role of CD3 chains in thymocyte development. Immunol Rev 232: 22-33.
61. Dearden CE, Matutes E, (2006). Alemtuzumab in T-cell lymphoproliferative disorders. Best Pract Res Clin Haematol 19: 795-810.
62. Dedrick RL, Bodary S, Garovoy MR, (2003). Adhesion molecules as therapeutic targets for autoimmune diseases and transplant rejection. Expert Opin Biol Ther 3: 85-95.
63. Demko S, Summers J, Keegan P, Pazdur R, (2008). FDA drug approval summary: alemtuzumab as single-agent treatment for B-cell chronic lymphocytic leukemia. Oncologist 13: 167-174.
64. Dennis RF, Siemasko KF, Tang Q, Hendricks RL, Finnegan A, (1995). Involvement of LFA-1 and ICAM-1 in the herpetic disease resulting from HSV-1 corneal infection. Curr Eye Res 14: 55-62.
65. Di Giacomo AM, Biagioli M, Maio M, (2010). The emerging toxicity profiles of anti-CTLA-4 antibodies across clinical indications. Semin Oncol 37: 499-507.
66. Dimitrov DS, Marks JD, (2009). Therapeutic antibodies: current state and future trends-is a paradigm change coming soon? Methods Mol Biol 525: 1-27.
67. Ding ZM, Babensee JE, Simon SI, Lu H, Perrard JL, Bullard DC, et al,. (1999). Relative contribution of LFA-1 and Mac-1 to neutrophil adhesion and migration. J Immunol 163: 5029-5038.
68. Downey J, Smith A, Schneider H, Hogg N, Rudd CE, (2008). TCR/CD3 mediated stop-signal is decoupled in T-cells from Ctla4 deficient mice. Immunol Lett 115: 70-72.
69. Edula RG, Picco MF, (2009). An evidence-based review of natalizumab therapy in the management of Crohn's disease. Ther Clin Risk Manag 5: 935-942.
70. El Andaloussi A, Han Y, Lesniak MS, (2006). Prolongation of survival following depletion of CD4+CD25+ regulatory T cells in mice with experimental brain tumors. J Neurosurg 105: 430-437.
71. EMA (2004a). Erbitux (Cetuximab) Scientific Discussion. Available at (accessed 15 February 2012).
72. EMA (2004b). Raptiva (Efalizimab) Scientific Discussion. Available at (accessed 15 February 2012).
73. EMA (2005a). Herceptin (trastuzumab) Scientific Discussion. Available at (accessed 15 February 2012).
74. EMA (2005b). MabCampath (alemtuzumab) Scientific Discussion. Available at (accessed 15 February 2012).
75. EMA (2005c). MabThera (rituximab) Scientific Discussion, Vol. 2011. Available at (accessed 15 February 2012).
76. EMA (2005d). Simulect (basiliximab) Scientific Discussion, Vol. 2011. Available at (accessed 15 February 2012).
77. EMA (2005e). Zenapax (dacilizumab). Available at (accessed 15 February 2012).
78. EMA (2007). Orencia (Abatacept) Scientific Discussion, Vol. 2011. Available at (accessed 15 February 2012).
79. EMA (2009a). Roactemra (Tocilizumab) Assessment Report, Vol. 2011. Available at (accessed 15 February 2012).
80. EMA (2009b). RoActemra (tocilizumab) Assessment Report, Vol. 2011. Available at (accessed 15 February 2012).
81. EMA (2010a). Roactemra (Tocilizumab) Scientific Discussion, Vol. 2011. Available at (accessed 15 February 2012).
82. EMA (2010b). Vectabix: (Panitumumab) Summary of Product. Characteristics, Vol. 2011. Available at (accessed 15 February 2012).
83. EMA (2011). Yervoy (Ipilimumab). Available at (accessed 15 February 2012).
84. Erbitux USPI (2011). Available at (accessed 15 February 2012).
85. Evans CF, Rall GF, Killeen N, Littman D, Oldstone MB, (1993). CD2-deficient mice generate virus-specific cytotoxic T lymphocytes upon infection with lymphocytic choriomeningitis virus. J Immunol 151: 6259-6264.
86. Fang J, Hodivala-Dilke K, Johnson BD, Du LM, Hynes RO, White GC, et al,. (2005). Therapeutic expression of the platelet-specific integrin, alphaIIbbeta3, in a murine model for Glanzmann thrombasthenia. Blood 106: 2671-2679.
87. FDA (1997). Rituximab (Rituxan) Preclinical and Clinical Pharmacology Review, Vol. 2011. Available at (accessed 15 February 2012).
88. FDA (2005a). Orencia (abatacept) Pharmacology/Toxicology Review and Evaluation, Vol. 2011. Available at (accessed 15 February 2012).
89. FDA (2005b). Tysabri (natalizumab) Pharmacology/Toxicology Review and Evaluation, Parts 1, 2 and 3, Vol. 2011. Available at (accessed 15 February 2012).
90. FDA (2010). Actemra (Tocilizumab) Pharmacology Review(S), Vol. 2011. Available at (accessed 15 February 2012).
91. FDA (2011). Yervoy (Ipilimumab) Pharmacology Review. Available at (accessed 15 February 2012).
92. Fernandez MA, Puttur FK, Wang YM, Howden W, Alexander SI, Jones CA, (2008). T regulatory cells contribute to the attenuated primary CD8+ and CD4+ T cell responses to herpes simplex virus type 2 in neonatal mice. J Immunol 180: 1556-1564.
93. Fischer A, de Saint Basile G, Le Deist F, (2005). CD3 deficiencies. Curr Opin Allergy Clin Immunol 5: 491-495.
94. Fleischmann RM, (2009). Safety of biologic therapy in rheumatoid arthritis and other autoimmune diseases: focus on rituximab. Semin Arthritis Rheum 38: 265-280.
95. Foon KA, Yang X-D, Weiner LM, Belldegrun AS, Figlin RA, Crawford J, et al,. (2004). Preclinical and clinical evaluations of ABX-EGF, a fully human anti-epidermal growth factor receptor antibody. Int J Radiat Oncol Biol Phys 58: 984-990.
96. Fortner KA, Russell JQ, Budd RC, (1998). Down-modulation of CD2 delays deletion of superantigen-responsive T cells. Eur J Immunol 28: 70-79.
97. Fukushima A, Yamaguchi T, Sumi T, Fukuda K, Kumagai N, Nishida T, et al,. (2007). Roles of CD4+CD25+ T cells in the development of experimental murine allergic conjunctivitis. Graefes Arch Clin Exp Ophthalmol 245: 705-714.
98. Furtado GC, Curotto de Lafaille MA, Kutchukhidze N, Lafaille JJ, (2002). Interleukin 2 signaling is required for CD4(+) regulatory T cell function. J Exp Med 196: 851-857.
99. Gadri Z, Kukulansky T, Bar-Or E, Haimovich J, Hollander N, (2009). Synergistic effect of dendritic cell vaccination and anti-CD20 antibody treatment in the therapy of murine lymphoma. J Immunother 32: 333-340.
100. Garnock-Jones KP, Keating GM, Scott LJ, (2010). Trastuzumab: A review of its use as adjuvant treatment in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. Drugs 70: 215-239.
101. Gaufin T, Pattison M, Gautam R, Stoulig C, Dufour J, MacFarland J, et al,. (2009). Effect of B-cell depletion on viral replication and clinical outcome of simian immunodeficiency virus infection in a natural host. J Virol 83: 10347-10357.
102. Gerritsen WR, Wagemaker G, Jonker M, Kenter MJ, Wielenga JJ, Hale G, et al,. (1988). The repopulation capacity of bone marrow grafts following pretreatment with monoclonal antibodies against T lymphocytes in rhesus monkeys. Transplantation 45: 301-307.
103. de Giorgi L, Brent L, Linch D, Nicolaides K, Rodeck CH, (1987). The inheritance of a Macaca fascicularis red cell antigen detected by CAMPATH-1 antibody. Immunol Lett 15: 101-103.
104. Gisondi P, Prignano F, Grossi P, Lotti T, Girolomoni G, (2009). Treatment of psoriasis with efalizumab in patients with hepatitis C viral infection: report of five cases. Dermatology 219: 158-161.
105. Giusti RM, Cohen MH, Keegan P, Pazdur R, (2009). FDA review of a panitumumab (Vectibix) clinical trial for first-line treatment of metastatic colorectal cancer. Oncologist 14: 284-290.
106. Goffe B, Papp K, Gratton D, Krueger GG, Darif M, Lee S, et al,. (2005). An integrated analysis of thirteen trials summarizing the long-term safety of alefacept in psoriasis patients who have received up to nine courses of therapy. Clin Ther 27: 1912-1921.
107. Goldenberg DM, Morschhauser F, Wegener WA, (2010). Veltuzumab (humanized anti-CD20 monoclonal antibody): characterization, current clinical results, and future prospects. Leuk Lymphoma 51: 747-755.
108. Grazia TJ, Gill RG, Gelhaus HC Jr, Doan AN, Sleater ML, Pietra BA, (2005). Perturbation of leukocyte function-associated antigen-1/intercellular adhesion molecule-1 results in differential outcomes in cardiac vs islet allograft survival. J Heart Lung Transplant 24: 1410-1414.
109. Guerau-de-Arellano M, Alroy J, Bullard D, Huber BT, (2005). Aggravated Lyme carditis in CD11a-/- and CD11c-/- mice. Infect Immun 73: 7637-7643.
110. Guex-Crosier Y, Raber J, Chan CC, Kriete MS, Benichou J, Pilson RS, et al,. (1997). Humanized antibodies against the alpha-chain of the IL-2 receptor and against the beta-chain shared by the IL-2 and IL-15 receptors in a monkey uveitis model of autoimmune diseases. J Immunol 158: 452-458.
111. Hamel K, Doodes P, Cao Y, Wang Y, Martinson J, Dunn R, et al,. (2008). Suppression of proteoglycan-induced arthritis by anti-CD20 B Cell depletion therapy is mediated by reduction in autoantibodies and CD4+ T cell reactivity. J Immunol 180: 4994-5003.
112. Hansen RJ, Balthasar JP, (2001). Pharmacokinetics, pharmacodynamics, and platelet binding of an anti-glycoprotein IIb/IIIa monoclonal antibody (7E3) in the rat: a quantitative rat model of immune thrombocytopenic purpura. J Pharmacol Exp Ther 298: 165-171.
113. Hasegawa A, Takenobu T, Kasumi H, Komori S, Koyama K, (2008). CD52 is synthesized in cumulus cells and secreted into the cumulus matrix during ovulation. Am J Reprod Immunol 60: 187-191.
114. Hashizume M, Uchiyama Y, Horai N, Tomosugi N, Mihara M, (2010). Tocilizumab, a humanized anti-interleukin-6 receptor antibody, improved anemia in monkey arthritis by suppressing IL-6-induced hepcidin production. Rheumatol Int 30: 917-923.
115. Hausen B, Gummert J, Berry GJ, Christians U, Serkova N, Ikonen T, et al,. (2000). Prevention of acute allograft rejection in nonhuman primate lung transplant recipients: induction with chimeric anti-interleukin-2 receptor monoclonal antibody improves the tolerability and potentiates the immunosuppressive activity of a regimen using low doses of both microemulsion cyclosporine and 40-O-(2-hydroxyethyl)-rapamycin. Transplantation 69: 488-496.
116. Heinzel FP, Maier RA Jr, (1999). Interleukin-4-independent acceleration of cutaneous leishmaniasis in susceptible BALB/c mice following treatment with anti-CTLA4 antibody. Infect Immun 67: 6454-6460.
117. Helman EE, Newman JR, Dean NR, Zhang W, Zinn KR, Rosenthal EL, (2010). Optical imaging predicts tumor response to anti-EGFR therapy. Cancer Biol Ther 10: 166-171.
118. Henrickson M, Giannini EH, Hirsch R, (1994). Reduction of mortality and lymphadenopathy in MRL-lpr/lpr mice treated with nonmitogenic anti-CD3 monoclonal antibody. Arthritis Rheum 37: 587-594.
119. Herbst RS, Davies AM, Natale RB, Dang TP, Schiller JH, Garland LL, et al,. (2007). Efficacy and safety of single-agent pertuzumab, a human epidermal receptor dimerization inhibitor, in patients with non small cell lung cancer. Clin Cancer Res 13: 6175-6181.
120. Herceptin USPI (2010). Available at (accessed 15 February 2012)
121. Hernandez Garcia I, (2008). Severe erythroderma in a patient under intermittent therapy with efalizumab. J Drugs Dermatol 7: 987-989.
122. Hibberd PL, Tolkoff-Rubin NE, Cosimi AB, Schooley RT, Isaacson D, Doran M, et al,. (1992). Symptomatic cytomegalovirus disease in the cytomegalovirus antibody seropositive renal transplant recipient treated with OKT3. Transplantation 53: 68-72.
123. Hoag JB, Azizi A, Doherty TJ, Lu J, Willis RE, Lund ME, (2009). Association of cetuximab with adverse pulmonary events in cancer patients: a comprehensive review. J Exp Clin Cancer Res 28: 113.
124. Hoff H, Kolar P, Ambach A, Radbruch A, Brunner-Weinzierl MC, (2010). CTLA-4 (CD152) inhibits T cell function by activating the ubiquitin ligase Itch. Mol Immunol 47: 1875-1881.
125. Hokibara S, Takamoto M, Isobe M, Sugane K, (1998). Effects of monoclonal antibodies to adhesion molecules on eosinophilic myocarditis in Toxocara canis-infected CBA/J mice. Clin Exp Immunol 114: 236-244.
126. Holzmann B, Gosslar U, Bittner M, (1998). Alpha 4 integrins and tumor metastasis. Curr Top Microbiol Immunol 231: 125-141.
127. Hoos A, Ibrahim R, Korman A, Abdallah K, Berman D, Shahabi V, et al,. (2010). Development of ipilimumab: contribution to a new paradigm for cancer immunotherapy. Semin Oncol 37: 533-546.
128. Hsu WT, Suen JL, Chiang BL, (2006). The role of CD4CD25 T cells in autoantibody production in murine lupus. Clin Exp Immunol 145: 513-519.
129. Hu Y, Turner MJ, Shields J, Gale MS, Hutto E, Roberts BL, et al,. (2009). Investigation of the mechanism of action of alemtuzumab in a human CD52 transgenic mouse model. Immunology 128: 260-270.
130. Huang H, Benoist C, Mathis D, (2010). Rituximab specifically depletes short-lived autoreactive plasma cells in a mouse model of inflammatory arthritis. Proc Natl Acad Sci U S A 107: 4658-4663.
131. Hutto D, (2010). Opportunistic infections in non-human primates exposed to immunomodulatory biotherapeutics: considerations and case examples. J Immunotoxicol 7: 120-127.
132. Hynes RO, Hodivala-Dilke KM, (1999). Insights and questions arising from studies of a mouse model of Glanzmann thrombasthenia. Thromb Haemost 82: 481-485.
133. ICH (2011). S6 (R1). Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals, Vol. 2011. Available at (accessed 15 February 2012).
134. Imai Y, Shimaoka M, Kurokawa M, (2010). Essential roles of VLA-4 in the hematopoietic system. Int J Hematol 91: 569-575.
135. Jean GW, Shah SR, (2008). Epidermal growth factor receptor monoclonal antibodies for the treatment of metastatic colorectal cancer. Pharmacotherapy 28: 742-754.
136. Jenneck C, Novak N, (2007). The safety and efficacy of alefacept in the treatment of chronic plaque psoriasis. Ther Clin Risk Manag 3: 411-420.
137. Johnson BD, Jing W, Orentas RJ, (2007). CD25+ regulatory T cell inhibition enhances vaccine-induced immunity to neuroblastoma. J Immunother 30: 203-214.
138. Johnson P, Glennie M, (2003). The mechanisms of action of rituximab in the elimination of tumor cells. Semin Oncol 30: 3-8.
139. Jones E, Dahm-Vicker M, Simon AK, Green A, Powrie F, Cerundolo V, et al,. (2002). Depletion of CD25+ regulatory cells results in suppression of melanoma growth and induction of autoreactivity in mice. Cancer Immun 2: 1.
140. Kapic E, Becic F, Kusturica J, (2004). Basiliximab, mechanism of action and pharmacological properties. Med Arh 58: 373-376.
141. Katsume A, Saito H, Yamada Y, Yorozu K, Ueda O, Akamatsu K, et al,. (2002). Anti-interleukin 6 (IL-6) receptor antibody suppresses Castleman's disease like symptoms emerged in IL-6 transgenic mice. Cytokine 20: 304-311.
142. Keefe DL, (2002). Trastuzumab-associated cardiotoxicity. Cancer 95: 1592-1600.
143. Keeley KA, Rivey MP, Allington DR, (2005). Natalizumab for the treatment of multiple sclerosis and Crohn's disease. Ann Pharmacother 39: 1833-1843.
144. Khan SB, Allen AR, Bhangal G, Smith J, Lobb RR, Cook HT, et al,. (2003). Blocking VLA-4 prevents progression of experimental crescentic glomerulonephritis. Nephron Exp Nephrol 95: e100-e110.
145. Khraishi M, Russell A, Olszynski WP, (2010). Safety profile of abatacept in rheumatoid arthritis: a review. Clin Ther 32: 1855-1870.
146. Kim S, Fridlender ZG, Dunn R, Kehry MR, Kapoor V, Blouin A, et al,. (2008). B-cell depletion using an anti-CD20 antibody augments antitumor immune responses and immunotherapy in nonhematopoetic murine tumor models. J Immunother 31: 446-457.
147. Kimby E, (2005). Tolerability and safety of rituximab (MabThera). Cancer Treat Rev 31: 456-473.
148. Klos KS, Zhou X, Lee S, Zhang L, Yang W, Nagata Y, et al,. (2003). Combined trastuzumab and paclitaxel treatment better inhibits ErbB-2-mediated angiogenesis in breast carcinoma through a more effective inhibition of Akt than either treatment alone. Cancer 98: 1377-1385.
149. Kothary N, Diak I, Brinker A, Bezabeth S, Avigan M, Pan DG, (2011). Progressive multifocal leukoencephalopathy associated with efalizumab use in psoriasis patients. J Am Acad Dermatol 65: 546-551.
150. Kozawa E, Sugiura H, Wasa J, Kohyama K, Yamada K, Nishioka A, et al,. (2010). Suppression of tumour metastasis in a murine osteosarcoma model with anti-CD25 monoclonal antibody treatment. Anticancer Res 30: 5019-5022.
151. Kuijpers TW, Bende RJ, Baars PA, Grummels A, Derks IAM, Dolman KM, et al,. (2010). CD20 deficiency in humans results in impaired T cell-independent antibody responses. J Clin Invest 120: 214-222.
152. Kuo Y-R, Jeng S-F, Wang F-S, Huang H-C, Wei F-C, Yang KD, (2002). Platelet glycoprotein IIb/IIIa receptor antagonist (abciximab) inhibited platelet activation and promoted skin flap survival after ischemia/reperfusion injury. J Surg Res 107: 50-55.
153. Kyewski BA, Jenkinson EJ, Kingston R, Altevogt P, Owen MJ, Owen JJ, (1989). The effects of anti-CD2 antibodies on the differentiation of mouse thymocytes. Eur J Immunol 19: 951-954.
154. Laurenti L, Piccioni P, Cattani P, Cingolani A, Efremov D, Chiusolo P, et al,. (2004). Cytomegalovirus reactivation during alemtuzumab therapy for chronic lymphocytic leukemia: incidence and treatment with oral ganciclovir. Haematologica 89: 1248-1252.
155. Lee T-C, Threadgill DW, (2009). Generation and validation of mice carrying a conditional allele of the epidermal growth factor receptor. Genesis 47: 85-92.
156. LeMessurier K, Hacker H, Tuomanen E, Redecke V, (2010). Inhibition of T cells provides protection against early invasive pneumococcal disease. Infect Immun 78: 5287-5294.
157. Li T, Perez-Soler R, (2009). Skin toxicities associated with epidermal growth factor receptor inhibitors. Target Oncol 4: 107-119.
158. Li W, Zheng XX, Kuhr CS, Perkins JD, (2005). CTLA4 engagement is required for induction of murine liver transplant spontaneous tolerance. Am J Transplant 5: 978-986.
159. Li W, Carper K, Liang Y, Zheng XX, Kuhr CS, Reyes JD, et al,. (2006). Anti-CD25 mAb administration prevents spontaneous liver transplant tolerance. Transplant Proc 38: 3207-3208.
160. Lim SY, Constantinescu CS, (2010). Current and future disease-modifying therapies in multiple sclerosis. Int J Clin Pract 64: 637-650.
161. Lin W, Sanchez HB, Deerinck T, Morris JK, Ellisman M, Lee KF, (2000). Aberrant development of motor axons and neuromuscular synapses in erbB2-deficient mice. Proc Natl Acad Sci U S A 97: 1299-1304.
162. Liu F, Liu J, Weng D, Chen Y, Song L, He Q, et al,. (2010). CD4+CD25+Foxp3+ regulatory T cells depletion may attenuate the development of silica-induced lung fibrosis in mice. PLoS ONE 5: e15404.
163. Luo FR, Yang Z, Dong H, Camuso A, McGlinchey K, Fager K, et al,. (2005). Correlation of pharmacokinetics with the antitumor activity of Cetuximab in nude mice bearing the GEO human colon carcinoma xenograft. Cancer Chemother Pharmacol 56: 455-464.
164. Macdonald PS, Mundy J, Keogh AM, Chang VP, Spratt PM, (1993). A prospective randomized study of prophylactic OKT3 versus equine antithymocyte globulin after heart transplantation-increased morbidity with OKT3. Transplantation 55: 110-116.
165. Maeda A, Maeda T, Liang Y, Yenerel M, Saperstein DA, (2006). Effects of cytotoxic T lymphocyte antigen 4 (CTLA4) signaling and locally applied steroid on retinal dysfunction by recoverin, cancer-associated retinopathy antigen. Mol Vis 12: 885-891.
166. Mahajan TD, Hooker R, Maher L, Brown G, Reimold A, (2010). Abatacept therapy for rheumatoid arthritis in the setting of hepatitis C infection. J Clin Rheumatol 16: 332-334.
167. Mao Y, Brigham D, Chen D, (2004). Overexpression of a mutant CTLA4 inhibits T-cell activation and homeostasis-driven expansion. Exp Hematol 32: 735-747.
168. Mariano FS, Gutierrez FRS, Pavanelli WR, Milanezi CM, Cavassani KA, Moreira AP, et al,. (2008). The involvement of CD4+CD25+ T cells in the acute phase of Trypanosoma cruzi infection. Microbes Infect 10: 825-833.
169. Martin PL, Bugelski PJ, (2012). Concordance of preclinical and clinical pharmacology and toxicology of monoclonal antibodies and fusion proteins: soluble targets. Br J Pharmacol 166: 806-822.
170. Martinez C, Solano C, Ferra C, Sampol A, Valcarcel D, Perez-Simon JA, et al,. (2009). Alemtuzumab as treatment of steroid-refractory acute graft-versus-host disease: results of a phase II study. Biol of Blood Marrow Transplant 15: 639-642.
171. Maxwell LJ, Singh JA, (2010). Abatacept for rheumatoid arthritis: a Cochrane systematic review. J Rheumatol 37: 234-245.
172. McFarland-Mancini MM, Funk HM, Paluch AM, Zhou M, Giridhar PV, Mercer CA, et al,. (2010). Differences in wound healing in mice with deficiency of IL-6 versus IL-6 receptor. J Immunol 184: 7219-7228.
173. McKeage K, McCormack PL, (2010). Basiliximab: a review of its use as induction therapy in renal transplantation. Biodrugs 24: 55-76.
174. Mendelsohn J, Baselga J, (2000). The EGF receptor family as targets for cancer therapy. Oncogene 19: 6550-6565.
175. Mihara M, Takagi N, Takeda Y, Ohsugi Y, (1998). IL-6 receptor blockage inhibits the onset of autoimmune kidney disease in NZB/W F1 mice. Clin Exp Immunol 112: 397-402.
176. Mihara M, Nishimoto N, Yoshizaki K, Suzuki T, (2002). Influences of anti-mouse interleukin-6 receptor antibody on immune response in mice. Immunol Lett 84: 223-229.
177. Mihara M, Kasutani K, Okazaki M, Nakamura A, Kawai S, Sugimoto M, et al,. (2005). Tocilizumab inhibits signal transduction mediated by both mIL-6R and sIL-6R, but not by the receptors of other members of IL-6 cytokine family. Int Immunopharmacol 5: 1731-1740.
178. Miller CJ, Genesca M, Abel K, Montefiori D, Forthal D, Bost K, et al,. (2007). Antiviral antibodies are necessary for control of simian immunodeficiency virus replication. J Virol 81: 5024-5035.
179. Mineo J-F, Scheffer A, Karkoutly C, Nouvel L, Kerdraon O, Trauet J, et al,. (2008). Using human CD20-transfected murine lymphomatous B cells to
180. Monostori E, Lang G, Kioussis D, Cantrell DA, Zamoyska R, Brown MH, et al,. (1991). Human CD2 is functional in CD2 transgenic mice. Immunology 74: 369-372.
181. Montgomery SP, Mog SR, Xu H, Tadaki DK, Hirshberg B, Berning JD, et al,. (2002). Efficacy and toxicity of a protocol using sirolimus, tacrolimus and daclizumab in a nonhuman primate renal allotransplant model. Am J Transplant 2: 381-385.
182. Mqadmi A, Zheng X, Yazdanbakhsh K, (2005). CD4+CD25+ regulatory T cells control induction of autoimmune hemolytic anemia. Blood 105: 3746-3748.
183. Murakami M, Sakamoto A, Bender J, Kappler J, Marrack P, (2002). CD25+CD4+ T cells contribute to the control of memory CD8+ T cells. Proc Natl Acad Sci U S A 99: 8832-8837.
184. Najafian N, Sayegh MH, (2000). CTLA4-Ig: a novel immunosuppressive agent. Expert Opin Investig Drugs 9: 2147-2157.
185. Nakada MT, Montgomery MO, Nedelman MA, Guerrero JL, Cohen SA, Barnathan ES, et al,. (2004). Clot lysis in a primate model of peripheral arterial occlusive disease with use of systemic or intraarterial reteplase: addition of abciximab results in improved vessel reperfusion. J Vasc Interv Radiol 15: 169-176.
186. Nakajima T, Suarez CJ, Lin K-W, Jen KY, Schnitzer JE, Makani SS, et al,. (2010). T cell pathways involving CTLA4 contribute to a model of acute lung injury. J Immunol 184: 5835-5841.
187. Negro A, Brar BK, Lee K-F, (2004). Essential roles of Her2/erbB2 in cardiac development and function. Recent Prog Horm Res 59: 1-12.
188. Nieswandt B, Echtenacher B, Wachs FP, Schroder J, Gessner JE, Schmidt RE, et al,. (1999). Acute systemic reaction and lung alterations induced by an antiplatelet integrin gpIIb/IIIa antibody in mice. Blood 94: 684-693.
189. Oldfield V, Dhillon S, Plosker GL, (2009). Tocilizumab: a review of its use in the management of rheumatoid arthritis. Drugs 69: 609-632.
190. Orencia USPI (2011). Available at (accessed 15 February 2012)
191. Ortega S, Arima A, Chihaya Y, Allison D, Braen A, Lauriault V, et al,. (2009). Embryo-fetal development study of pertuzumab administered by intravenous injection to pregnant cynomolgus monkeys. Int J Toxicol 29: 89-90.
192. Orthoclone OKT3 USPI (2011). Available at (accessed 15 February 2012)
193. Osterborg A, Karlsson C, Lundin J, Kimby E, Mellstedt H, (2006). Strategies in the management of alemtuzumab-related side effects. Semin Oncol 33 (Suppl. 5): S29-S35.
194. Ouwerkerk J, Boers-Doets C, (2010). Best practices in the management of toxicities related to anti-EGFR agents for metastatic colorectal cancer. Eur J Oncol Nurs 14: 337-349.
195. Pan Q, Brodeur J-F, Drbal K, Dave VP, (2006). Different role for mouse and human CD3delta/epsilon heterodimer in preT cell receptor (preTCR) function: human CD3delta/epsilon heterodimer restores the defective preTCR function in CD3gamma- and CD3gammadelta-deficient mice. Mol Immunol 43: 1741-1750.
196. Parlevliet KJ, Bemelman FJ, Yong SL, Hack CE, Surachno J, Wilmink JM, et al,. (1995). Toxicity of OKT3 increases with dosage: a controlled study in renal transplant recipients. Transpl Int 8: 141-146.
197. Patel D, Bassi R, Hooper A, Prewett M, Hicklin DJ, Kang X, (2009). Anti-epidermal growth factor receptor monoclonal antibody cetuximab inhibits EGFR/HER-2 heterodimerization and activation. Int J Oncol 34: 25-32.
198. Pawlowski N-N, Struck D, Grollich K, Kuhl A-A, Zeitz M, Liesenfeld O, et al,. (2007). CD2 deficiency partially prevents small bowel inflammation and improves parasite control in murine Toxoplasma gondii infection. World J Gastroenterol 13: 4207-4213.
199. Peerzada MM, Spiro TP, Daw HA, (2010). Pulmonary toxicities of biologics: a review. Anticancer Drugs 21: 131-139.
200. Peeters M, Balfour J, Arnold D, (2008). Review article: panitumumab-a fully human anti-EGFR monoclonal antibody for treatment of metastatic colorectal cancer. Aliment Pharmacol Ther 28: 269-281.
201. Perez EA, (2008). Cardiac toxicity of ErbB2-targeted therapies: what do we know? Clin Breast Cancer 8 (Suppl. 3): S114-S120.
202. Pescovitz MD, (2005). Daclizumab: humanized monoclonal antibody to the interleukin-2 receptor. Expert Rev Clin Immunol 1: 337-344.
203. Phan DT, Barta E, Gidali J, Feher I, Harsanyi V, Petranyi GG, et al,. (1987). T-cell depletion of Cercopithecus aethiops monkey bone marrow with Campath-1 monoclonal antibody and complement. Haematologia 20: 155-163.
204. Piehl F, Holmen C, Hillert J, Olsson T, (2011). Swedish natalizumab (Tysabri) multiple sclerosis surveillance study. Neurol Sci 31 (Suppl. 3): 289-293.
205. Platt AM, Gibson VB, Patakas A, Benson RA, Nadler SG, Brewer JM, et al,. (2010). Abatacept limits breach of self-tolerance in a murine model of arthritis via effects on the generation of T follicular helper cells. J Immunol 185: 1558-1567.
206. Podolsky DK, Lobb R, King N, Benjamin CD, Pepinsky B, Sehgal P, et al,. (1993). Attenuation of colitis in the cotton-top tamarin by anti-alpha 4 integrin monoclonla antibody. J Clin Invest 92: 372-380.
207. Portoles P, Rojo JM, (2009). The TCR/CD3 complex: opening the gate to successful vaccination. Curr Pharm Des 15: 3290-3300.
208. Prignano F, Zanieri F, Mokhtarzadeh S, Lotti T, (2008). Efalizumab-induced severe thrombocytopenia can be resolved. Biologics 2: 923-927.
209. Pugashetti R, Koo J, (2009). Efalizumab discontinuation: a practical strategy. J Dermatolog Treat 20: 132-136.
210. Qu L, Li Q, Jiang H, Gu L, Zhang Q, Wang C, et al,. (2009). Effect of anti-mouse CD52 monoclonal antibody on mouse intestinal intraepithelial lymphocytes. Transplantation 88: 766-772.
211. Ram R, Ben-Bassat I, Shpilberg O, Polliack A, Raanani P, (2009). The late adverse events of rituximab therapy-rare but there! Leuk Lymphoma 50: 1083-1095.
212. Raychaudhuri A, Chou M, Weetall M, Jeng AY, (2003). Blockade of integrin VLA-4 prevents inflammation and matrix metalloproteinase expression in a murine model of accelerated collagen-induced arthritis. Inflammation 27: 107-113.
213. Reff ME, Carner K, Chambers KS, Chinn PC, Leonard JE, Raab R, et al,. (1994). Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 83: 435-445.
214. Reopro USPI (2005). Available at (accessed 15 February 2012)
215. Riccio G, Esposito G, Leoncini E, Contu R, Condorelli G, Chiariello M, et al,. (2009). Cardiotoxic effects, or lack thereof, of anti-ErbB2 immunoagents. FASEB J 23: 3171-3178.
216. Rinaldi L, Rinaldi F, Perini P, Calabrese M, Seppi D, Grossi P, et al,. (2010). No evidence of JC virus reactivation in natalizumab treated multiple sclerosis patients: an 18 month follow-up study. J Neurol Neurosurg Psychiatry 81: 1345-1350.
217. Rituxan USPI (2011). Available at (accessed 15 February 2012)
218. Rose-John S, Waetzig GH, Scheller J, Grotzinger J, Seegert D, (2007). The IL-6/sIL-6R complex as a novel target for therapeutic approaches. Expert Opin Ther Targets 11: 613-624.
219. Rudd CE, (2008). The reverse stop-signal model for CTLA4 function. Nat Rev Immunol 8: 153-160.
220. Rudick RA, Panzara MA, (2008). Natalizumab for the treatment of relapsing multiple sclerosis. Biologics 2: 189-199.
221. Rueff-Juy D, Liberman I, Drapier AM, Guillon JC, Leclerc C, Cazenave PA, (1991). Cellular basis of the resistance of newborn mice to the pathogenic effects of anti-CD3 treatment. Int Immunol 3: 683-690.
222. Sachdeva A, Matuschak GM, (2008). Diffuse alveolar hemorrhage following alemtuzumab. Chest 133: 1476-1478.
223. Sassoli PM, Emmell EL, Tam SH, Trikha M, Zhou Z, Jordan RE, et al,. (2001). 7E3 F(ab')2, an effective antagonist of rat alphaIIbbeta3 and alphavbeta3, blocks in vivo thrombus formation and in vitro angiogenesis. Thromb Haemost 85: 896-902.
224. Scheinfeld N, (2005). Alefacept: a safety profile. Expert Opin Drug Saf 4: 975-985.
225. Scheinfeld N, (2007). Alefacept: its safety profile, off-label uses, and potential as part of combination therapies for psoriasis. J Dermatolog Treat 18: 197-208.
226. Scholl S, Beuzeboc P, Pouillart P, (2001). Targeting HER2 in other tumor types. Ann Oncol 12 (Suppl. 1): S81-S87.
227. Sharma R, Zheng L, Deshmukh US, Jarjour WN, Sung S-SJ, Fu SM, et al,. (2007). A regulatory T cell-dependent novel function of CD25 (IL-2Ralpha) controlling memory CD8(+) T cell homeostasis. J Immunol 178: 1251-1255.
228. Shinriki S, Jono H, Ota K, Ueda M, Kudo M, Ota T, et al,. (2009). Humanized anti-interleukin-6 receptor antibody suppresses tumor angiogenesis and in vivo growth of human oral squamous cell carcinoma. Clin Cancer Res 15: 5426-5434.
229. Sibilia J, Westhovens R, (2007). Safety of T-cell co-stimulation modulation with abatacept in patients with rheumatoid arthritis. Clin Exp Rheumatol 25 (Suppl. 46): S46-S56.
230. Siders WM, Shields J, Garron C, Hu Y, Boutin P, Shankara S, et al,. (2010). Involvement of neutrophils and natural killer cells in the anti-tumor activity of alemtuzumab in xenograft tumor models. Leuk Lymphoma 51: 1293-1304.
231. Sido B, Otto G, Zimmermann R, Muller P, Meuer SC, Dengler TJ, (1997). Modulation of the CD2 receptor and not disruption of the CD2/CD48 interaction is the principal action of CD2-mediated immunosuppression in the rat. Cell Immunol 182: 57-67.
232. Silva HM, Vieira PMMM, Costa PLN, Pimentel BMS, Moro AM, Kalil J, et al,. (2009). Novel humanized anti-CD3 antibodies induce a predominantly immunoregulatory profile in human peripheral blood mononuclear cells. Immunol Lett 125: 129-136.
233. Simmons DL, (2005). Anti-adhesion therapies. Curr Opin Pharmacol 5: 398-404.
234. Simulect SPC (2011). Available at (accessed 15 February 2012)
235. Simulect USPI (2005). Available at (accessed 15 February 2012)
236. Smith JP, Morris-Downes M, Brennan FR, Wallace GJ, Amor S, (2000). A role for alpha4-integrin in the pathology following Semliki Forest virus infection. J Neuroimmunol 106: 60-68.
237. Smyth SS, Tsakiris DA, Scudder LE, Coller BS, (2000). Structure and function of murine alphaIIbbeta3 (GPIIb/IIIa): studies using monoclonal antibodies and beta3-null mice. Thromb Haemost 84: 1103-1108.
238. Stagg J, Sharkey J, Pommey S, Young R, Takeda K, Yagita H, et al,. (2008). Antibodies targeted to TRAIL receptor-2 and ErbB-2 synergize in vivo and induce an antitumor immune response. Proc Natl Acad Sci U S A 105: 16254-16259.
239. Steinhoff G, Jonker M, Gubernatis G, Wonigeit K, Lauchart W, Bornscheuer A, et al,. (1990). The course of untreated acute rejection and effect of repeated anti-CD3 monoclonal antibody treatment in rhesus monkey liver transplantation. Transplantation 49: 669-674.
240. Stohl W, Jacob N, Quinn WJ 3rd, Cancro MP, Gao H, Putterman C, et al,. (2008). Global T cell dysregulation in non-autoimmune-prone mice promotes rapid development of BAFF-independent, systemic lupus erythematosus-like autoimmunity. J Immunol 181: 833-841.
241. Storage SS, Agrawal H, Furst DE, (2010). Description of the efficacy and safety of three new biologics in the treatment of rheumatoid arthritis. Korean J Intern Med 25: 1-17.
242. Takagi N, Mihara M, Moriya Y, Nishimoto N, Yoshizaki K, Kishimoto T, et al,. (1998). Blockage of interleukin-6 receptor ameliorates joint disease in murine collagen-induced arthritis. Arthritis Rheum 41: 2117-2121.
243. Tamhane UU, Gurm HS, (2008). The chimeric monoclonal antibody abciximab: a systematic review of its safety in contemporary practice. Expert Opin Drug Saf 7: 809-819.
244. Tanaka T, Ogata A, Narazaki M, (2010). Tocilizumab for the treatment of rheumatoid arthritis. Expert Rev Clin Immunol 6: 843-854.
245. Tarhini A, Lo E, Minor DR, (2010). Releasing the brake on the immune system: ipilimumab in melanoma and other tumors. Cancer Biother Radiopharm 25: 601-613.
246. Thistlethwaite JR Jr, Stuart JK, Mayes JT, Gaber AO, Woodle S, Buckingham MR, et al,. (1988). Complications and monitoring of OKT3 therapy. Am J Kidney Dis 11: 112-119.
247. Thomas JM, Neville DM, Contreras JL, Eckhoff DE, Meng G, Lobashevsky AL, et al,. (1997). Preclinical studies of allograft tolerance in rhesus monkeys: a novel anti-CD3-immunotoxin given peritransplant with donor bone marrow induces operational tolerance to kidney allografts. Transplantation 64: 124-135.
248. Tomiyama Y, (2000). Glanzmann thrombasthenia: integrin alpha IIb beta 3 deficiency. Int J Hematol 72: 448-454.
249. Tomiyama-Hanayama M, Rakugi H, Kohara M, Mima T, Adachi Y, Ohishi M, et al,. (2009). Effect of interleukin-6 receptor blockage on renal injury in apolipoprotein E-deficient mice. Am J Physiol Renal Physiol 297: F679-F684.
250. 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 Toxciol 19: 226-228.
251. Trikha M, Zhou Z, Timar J, Raso E, Kennel M, Emmell E, et al,. (2002). Multiple roles for platelet GPIIb/IIIa and alphavbeta3 integrins in tumor growth, angiogenesis, and metastasis. Cancer Res 62: 2824-2833.
252. Trivedi SM, Shani J, Hollander G, (2002). Bleeding complications of platelet glycoprotein IIb/IIIa inhibitor abciximab (ReoPro). J Invasive Cardiol 14: 423-425.
253. Tsunenari T, Akamatsu K, Kaiho S, Sato K, Tsuchiya M, Koishihara Y, et al,. (1996). Therapeutic potential of humanized anti-interleukin-6 receptor antibody: antitumor activity in xenograft model of multiple myeloma. Anticancer Res 16: 2537-2544.
254. Tysabri USPI (2011). Available at (accessed 15 February 2012)
255. Uchida J, Lee Y, Hasegawa M, Liang Y, Bradney A, Oliver JA, et al,. (2004). Mouse CD20 expression and function. Int Immunol 16: 119-129.
256. Uchiyama Y, Yorozu K, Hashizume M, Moriya Y, Mihara M, (2008). Tocilizumab, a humanized anti-interleukin-6 receptor antibody, ameliorates joint swelling in established monkey collagen-induced arthritis. Biol Pharm Bull 31: 1159-1163.
257. Untch B, Ahmad S, Messmore HL, Schultz CL, Ma Q, Hoppensteadt DA, et al,. (2002). Development of a non-human primate sub-clinical model of heparin-induced thrombocytopenia: platelet responses to human anti-heparin-platelet factor 4 antibodies. Thromb Res 106: 149-156.
258. Vaidyanathan A, McKeever K, Anand B, Eppler S, Weinbauer GF, Beyer JC, (2011). Developmental immunotoxicology assessment of rituximab in cynomolgus monkeys. Toxicol Sci 119: 116-125.
259. Van Buren G 2nd, Yang AD, Dallas NA, Gray MJ, Lim SJ, Xia L, et al,. (2008). Effect of molecular therapeutics on liver regeneration in a murine model. J Clin Oncol 26: 1836-1842.
260. Vectibix USPI (2011). Available at (accessed 15 February 2012)
261. Vinet E, Pineau C, Gordon C, Clarke AE, Bernatsky S, (2009). Biologic therapy and pregnancy outcomes in women with rheumatic diseases. Arthritis Rheum 61: 587-592.
262. Walther A, Czabanka M, Gebhard MM, Martin E, (2004). Glycoprotein IIB/IIIA-inhibition and microcirculatory alterations during experimental endotoxemia-an intravital microscopic study in the rat. Microcirculation 11: 79-88.
263. Wasson S, Zafar MN, Best J, Reddy HK, (2006). Post-transplantation lymphoproliferative disorder in heart and kidney transplant patients: a single-center experience. J Cardiovasc Pharmacol Ther 11: 77-83.
264. Watanabe T, J-i M, Sohma Y, Inazawa H, Horie K, Kojima K, et al,. (2006). CD52 is a novel costimulatory molecule for induction of CD4+ regulatory T cells. Clin Immunol 120: 247-259.
265. Weaver TA, Charafeddine AH, Agarwal A, Turner AP, Russell M, Leopardi FV, et al,. (2009). Alefacept promotes co-stimulation blockade based allograft survival in nonhuman primates. Nat Med 15: 746-749.
266. Weber J, (2010). Immune checkpoint proteins: a new therapeutic paradigm for cancer-preclinical background: CTLA-4 and PD-1 blockade. Semin Oncol 37: 430-439.
267. Wehner NG, Gasper C, Shopp G, Nelson J, Draper K, Parker S, et al,. (2009a). Immunotoxicity profile of natalizumab. J Immunotoxicol 6: 115-129.
268. Wehner NG, Shopp G, Oneda S, Clarke J, (2009b). Embryo/fetal development in cynomolgus monkeys exposed to natalizumab, an alpha4 integrin inhibitor. Birth Defects Res B Dev Reprod Toxicol 86: 117-130.
269. Wehner NG, Shopp G, Osterburg I, Fuchs A, Buse E, Clarke J, (2009c). Postnatal development in cynomolgus monkeys following prenatal exposure to natalizumab, an alpha4 integrin inhibitor. Birth Defects Res B Dev Reprod Toxicol 86: 144-156.
270. Wehner NG, Shopp G, Roccca MS, (2009d). Effects of natalizumab, an α4 integrin inhibitor, on the development of Hartley guinea pigs. Birth Defects Res B Dev Reprod Toxicol 86: 98-107.
271. Wehner NG, Skov M, Shopp G, Rocca MS, Clarke J, (2009e). Effects of natalizumab, an alpha4 integrin inhibiutor, on fertility in male and female guinae pigs. Birth Defects Res B Dev Reprod Toxicol 86: 108-116.
272. Wijkstrom M, Kenyon NS, Kirchhof N, Kenyon NM, Mullon C, Lake P, et al,. (2004). Islet allograft survival in nonhuman primates immunosuppressed with basiliximab, RAD, and FTY720. Transplantation 77: 827-835.
273. Wilkins AL, Yang W, Yang JJ, (2003). Structural biology of the cell adhesion protein CD2: from molecular recognition to protein folding and design. Curr Protein Pept Sci 4: 367-373.
274. van der Windt DJ, Smetanka C, Macedo C, He J, Lakomy R, Bottino R, et al,. (2010). Investigation of lymphocyte depletion and repopulation using alemtuzumab (Campath-1H) in cynomolgus monkeys. Am J Transplant 10: 773-783.
275. Yamaguchi K, Itoh Y, Yokomizo C, Nishimura T, Niimi T, Umemura A, et al,. (2011). Blockade of IL-6 signaling exacerbates liver injury and suppresses antiapoptotic gene expression in methionine choline-deficient diet-Fed db/db mice. Lab Invest 91: 609-618.
276. Yamaguchi R, Yamagata K, Hasuwa H, Inano E, Ikawa M, Okabe M, (2008). Cd52, known as a major maturation-associated sperm membrane antigen secreted from the epididymis, is not required for fertilization in the mouse. Genes Cells 13: 851-861.
277. Yang XD, Jia XC, Corvalan JR, Wang P, Davis CG, (2001). Development of ABX-EGF, a fully human anti-EGF receptor monoclonal antibody, for cancer therapy. Crit Rev Oncol Hematol 38: 17-23.
278. Yao K, Gagnon S, Akhyani N, Williams E, Fotheringham J, Frohman E, et al,. (2008). Reactivation of human herpesvirus-6 in natalizumab treated multiple sclerosis patients. PLoS ONE 3: e2028.
279. Yeon CH, Pegram MD, (2005). Anti-erbB-2 antibody trastuzumab in the treatment of HER2-amplified breast cancer. Invest New Drugs 23: 391-409.
280. Yervoy USPI (2011). Available at (accessed 15 February 2012).
281. Yusuf-Makagiansar H, Anderson ME, Yakovleva TV, Murray JS, Siahaan TJ, (2002). Inhibition of LFA-1/ICAM-1 and VLA-4/VCAM-1 as a therapeutic approach to inflammation and autoimmune diseases. Med Res Rev 22: 146-167.
282. Zenapax USPI (2005). Available at (accessed 15 February 2012)
283. Zhang Z, Pascuet E, Hueber P-A, Chu L, Bichet DG, Lee T-C, et al,. (2010). Targeted inactivation of EGF receptor inhibits renal collecting duct development and function. J Am Soc Nephrol 21: 573-578.