BIOTECHNOLOGY IN PHARMACEUTICAL MANUFACTURING
4. Monoclonal antibodies
4.2. Conditions potentially treatable by monoclonal antibodies
Autoimmune diseases
Monoclonal antibodies are used in different fields of immunology:
1) anti-TNF α antibodies as adalimumab and infliximab are used in rheumatoid arthritis, Crohn‘s disease and ulcerative colitis [Rang 2003];
2) daclizumab and basilixumab inhibits IL-2 production of activated T-cells thus are suitable to prevent rejection of organ transplants;
3) omalizumab, an anti human immunoglobulin E (IgE) can help in the treatment of moderate to severe allergic asthma.
Cancer
Anti-cancer monoclonal antibodies can exert their effects through several mechanisms (Fig. 13):
1. In radioimmunotherapy, antibodies against a cell surface marker of cancerous cells are conjugated to radioactive isotopes (e.g. tositumomab in the treatment of radio-sensitive lymphomas). Because this type of monoclonal antibodies is produced in rodents, their immunogenicity is higher but promotes clearance from the body.
2. In antibody-directed enzyme prodrug therapy, monoclonal antibodies are attached to drug-activating non-toxic enzymes. This enzyme will transform a prodrug into a cytotoxic drug only in the targeted cells. The clinical success of this approach has been limited till now but holds great promise in future oncological treatments [Phrancis 2002].
3. Drug molecules or therapeutic agents can be linked to immunoliposomes and targeted directly against malignant cells. Tissue-specific gene delivery using immunoliposomes has been achieved in brain, and breast cancer tissue [Krauss 2000] but it has not been used routinely in the clinic, yet.
Figure 13. Antibody-based cancer therapy.
1. Naked monoclonal antibody 2. Monoclonal antibody conjugated to radionuclide, cytokine, toxin or liposome 3.Complex monoclonal antibody conjugated to biotinylated radioactive ligand
through streptavidin [Carter 2001].
Table 9. Monoclonal antibodies approved by the American Food and Drug Administration (FDA) (List based on year of approval) Generic name Brand name Year of first
approval
1986 Mouse Targeted at the CD3 membrane protein on the surface of T cells
Acute, glucocorticoid resistant rejection of allogeneic renal, heart and liver transplants
Intravenous injection Abciximab ReoPro 1994 Chimeric Glycoprotein IIb/IIIa receptor
antagonist, platelet aggregation inhibitor
During and after high risk coronary artery procedures
Intravenous injection
Rituximab Rituxan 1997 Chimeric Against CD20 on the surface of B-cells
Humanized Against the alpha subunit of the IL-2 receptor (CD25) of T cells
Rejection in organ transplantation Intravenous injection
Basilixumab Simulect 1998 Chimeric Against CD25 Rejection in organ transplantation Intravenous
injectionor infusion Infliximab Remicade 1998 Chimeric Against TNF-α Psoriasis, Crohn's disease, ankylosis spondylitis,
psoriatic arthritis, rheumatoid arthritis, ulcerative colitis
Intravenous injection
Palivizumab Synagis 1998 Humanized Directed against an epitope in the A antigenic site of the F protein of RSV
Respiratory syncytial virus infection Intramuscular injection
Gemtuzumab ozogamicin
Mylotarg 2000
(withdrawn in 2010)
Humanized Anti-CD33 linked to a cytotoxic agent from the class of
calicheamicins
Acute myelogenous leukemia Intravenous infusion
Alemtuzumab Campath-1H 2001 Humanized Against cell surface protein CD52 on matured lymphocytes
Adalimumab Humira 2002 Human TNF-α inhibitor Rheumatoid arthritis, psoriatic arthritis,
ankylosing spondylitis, Crohn's disease,
Zevalin 2002 Mouse B-lymphocyte specific anti-CD20
antibody conjugated to a
Omalizumab Xolair 2003 Humanized Selectively binds to human
immunoglobulin E
Bexxar 2003 Mouse Anti-CD20; I 131 same antibody
covalently bound to the
Cetuximab Erbitux 2004 Chimera EGFR inhibitor Colorectal cancer, head and neck cancer Intravenous
infusion
Natalizumab Tsabri 2004 Humanized Against cellular adhesion molecule α4-integrin
Sclerosis multiplex Intravenous
infusion
Bevacizumab Avastin 2004
(withdrawn for breast cancer indication in 2010)
Humanized Anti-VEGF-A, anti-angiogenesis Metastatic colorectal cancer, non-small cell lung cancer, metastatic renal cell carcinoma
Intravenous infusion
Ranibizumab Lucentis 2006 Humanized Binds to VEGF-A, anti-angiogenic Macular degeneration Intravitreal
injection Eculizumab Soliris 2007 Humanized Directed against complement
protein C5
Paroxysmal nocturnal hemoglobinuria Intravenous infusion Certolizumab
pegol
Cimzia 2008 Humanized Anti-TNF-α Chron's disease, rheumatoid arthritis Subcutaneous
injection
Golimumab Simponi 2009 Human Anti-TNF-α Rheumatoid and psoriatic arthritis, active
spondylitis ankylopoetica
Subcutaneous injection
References
Ali O, Wyatt D. Therapy of growth disorders. Curr Opin Endocrinol Diabetes Obes. 18(1):3-8. 2011.
Antonia S, Mulé JJ, Weber JS. Current developments of immunotherapy in the clinic. Curr Opin Immunol. 16(2):130-6. 2004.
Avidor Y, Mabjeesh N, Matzkin H. Biotechnology and Drug Discovery From Bench to Bedside. South Med J. 96(12):1174-86. 2003.
Bhatti Z, Berenson CS. Adult systemic cat scratch disease associated with therapy for hepatitis B. BMC Infect Dis. 23;7:8. 2007.
Boyle JJ. Macrophage activation in atherosclerosis: pathogenesis and pharmacology of plaque rupture. Curr Vasc Pharmacol. 3(1), 63-68. 2005.
Davami F, Sardari S, Majidzadeh-A K, Hemayatkar M, Barkhrdari F, Omidi M, Azami M, Adeli A, Davoudi N, Mahboudi F. Expression of a Novel Chimeric Truncated t-PA in CHO Cells Based on in Silico Experiments. J Biomed Biotechnol. 108159. Epub 2010. Sep 22.
Ellis R.W. New technologies for making vaccines. Vaccine 17:1596–1604. 1999.
Fernández-Montequín JI, Valenzuela-Silva CM, Díaz OG, Savigne W, Sancho-Soutelo N, Rivero-Fernández F, Sánchez-Penton P, Morejón-Vega L, Artaza-Sanz H, García-Herrera A, González-Benavides C, Hernández-Cañete CM, Vázquez-Proenza A, Berlanga-Acosta J, López-Saura PA; Cuban Diabetic Foot Study Group Intra-lesional injections of recombinant human epidermal growth factor promote granulation and healing in advanced diabetic foot ulcers: multicenter, randomised, placebo-controlled, double-blind study. Int Wound J.
6(6):432-43. 2009.
Genentech News Release. First Successful Laboratory Production of Human Insulin Announced.1978-09-06.http://www.gene.com/gene/news/press
releases/display.do?method=detail&id=4160. Retrieved 2011. 03. 28.
Hershfield MS. PEG-ADA: an alternative to haploidentical bone marrow transplantation and an adjunct to gene therapy for adenosine deaminase deficiency. Hum Mutat. 5(2):107-12.
1995.
J Lalezari, R Mitsuyasu, S Deeks, and others. Successful and Persistent Engraftment of ZFN-M-R5-D Autologous CD4 T Cells (SB-728-T) in Aviremic HIV-infected Subjects on HAART. 18th Conference on Retroviruses and Opportunistic Infections (CROI 2011).
Boston. February 27-March 2, 2011. Abstract 46.
Lapchak PA. Development of thrombolytic therapy for stroke: a perspective. Expert Opin Investig Drugs. 11(11):1623-32. 2002.
Lowy DR, Schiller JT. Prophylactic human papillomavirus vaccines. J. Clin. Invest. 116 (5):
1167–73. 2006.
Marcial GG. SemBiosys: A New Kind Of Insulin inside wall street. 2007.
Online 'Mendelian Inheritance in Man' (OMIM): http://www.ncbi.nlm.nih.gov/omim/102700.
Retrieved 2011. 04. 01.
Pharmaceutical biotechnology, Drug Discovery and Clinical Applications. Editor: Kayser O, Müller RH. Wiley-VCH Verlag GmBH and CO. KGaA, Weinheim. 2004.
Pipe SW. Recombinant clotting factors. Thromb Haemost. 99(5):840-50. 2008.
Robertson I, Kessel DO, Berridge DC. Fibrinolytic agents for peripheral arterial occlusion.
Cochrane Database Syst Rev. 17;(3):CD001099. 2010.
Rogers D. Biotechnology and Pharmacogenomics. APhA‘s Complete Review for Pharmac, C.C. Graduate Medical Publishing, Pharmacists Assoc. Editor: D.R. Gourley, J. C. Eoff. 135-143. 2004.
Rosen PS. Using recombinant platelet-derived growth factor to facilitate wound healing.
Compend Contin Educ Dent.27 (9):520-5. 2006.
United Nations. The Convention on Biological Diversity (Article 2. Use of Terms). 1992.
Retrieved 2008. 02. 6.
US Department of Health and Human Services - Ricky Ray Hemophilia Relief Fund; Federal Register.70:188,2005.