Monoclonal Antibodies: Therapeutic Uses

Abstract

Monoclonal antibodies are protein molecules made in the laboratory from hybridoma cells (stable cell lines derived by fusing antibody‐producing cells from immunised animals with cells that confer immortality and high‐yield antibody production) or by recombinant deoxyribonucleic acid (DNA) technology. They are originally derived from the immune system and have a number of unique properties that have stimulated their use in medicine, including the ability to bind specifically and with high affinity to almost any molecular structure. They can be made in various expression systems such as bacteria or mammalian cells and modified for enhanced affinity, immune function or half‐life in blood. They are made in a homogeneous and reproducible form that allows comparisons across laboratories for diagnosis as well as therapeutics. Current major therapeutic applications of monoclonal antibodies include cancer, chronic inflammatory disease, and infection and they constitute the largest and fastest growing sector of the biological pharmaceutical industry.

Key Concepts:

  • Monoclonal antibodies are proteins with high specificity towards targets.

  • Monoclonal antibodies have multiple utilities in therapy as they can recognise specific structures in targets such as bacteria, viruses, cancer cells, etc.

  • Monoclonal antibodies can be produced in large amounts in homogeneous and reproducible form for diagnostic and therapeutic purposes.

  • Monoclonal antibodies have a clear regulatory path for their approval as therapeutics.

  • Monoclonal antibodies can be derived from B‐cells from immunised animals, humans with autoimmune diseases and de novo by phage display.

  • Therapeutic monoclonal antibodies can be engineered to be more human‐like proteins, to increase their affinity, reduce their immunogenicity and increase their half‐life in the circulation, and can be conjugated with toxin for better lytic effect.

  • Monoclonal antibodies can mediate antibody‐mediated cytotoxicity by linking the target cells to cytotoxic cells through their binding sites and Fc sites.

Keywords: antibody; monoclonal; therapy; immunoconjugate; cancer; transplantation

Figure 1.

Whole antibody and fragments retaining the antigen‐binding site.

Figure 2.

(a) Murine antibody; (b) chimaeric antibody (human C domains and murine V domains); (c) humanised antibody (murine complementarity‐determining regions on a human framework) and (d) completely human antibody.

close

References

Abraham E, Anzueto A, Gutierrez G et al. (1998) Double‐blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock. NORASEPT II Study Group. Lancet 351(9107): 929–933.

AIDS Clinical Trials Group (1997) MSL‐109 adjuvant therapy for cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome: the monoclonal antibody cytomegalovirus retinitis trial. The studies of ocular complications of AIDS Research Group. Archives of Ophthalmology 115(12): 1528–1536.

Amado RG, Wolf M, Peeters M et al. (2008) Wild‐type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. Journal of Clinical Oncology 26(10): 1626–1634.

Amos SM, Duong CPM, Westwood JA et al. (2011) Autoimmunity associated with immunotherapy of cancer. Blood 118: 499–509.

Blumenthal RD (2004) Technology evaluation: cT84.66, City of Hope. Current Opinion in Molecular Therapeutics 1: 90–95.

Bonnet D and Dick JE (1997) Human acute myeloid leukemia is organised as a hierarchy that originates from a primitive hematopoietic cell. Nature Medicine 3(7): 730–737.

Burnett AK, Hills RK, Milligan D et al. (2011) Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. Journal of Clinical Oncology 29(4): 369–377.

Ceesay MM, Matutes E, Taylor GP et al. (2012) Phase II study on combination therapy with CHOP-Zenapax for HTLV‐I associated adult T-cell leukaemia/lymphoma (ATLL). Leukemia Research 36(7): 857–861.

Chapman TM and Keating GM (2003) Basiliximab: a review of its use as induction therapy in renal transplantation. Drugs 63(24): 2803–2835.

Coleman M, Goldenberg DM, Siegel AB et al. (2003) Epratuzumab: targeting B‐cell malignancies through CD22. Clinical Cancer Research 9(10 Pt 2): 3991S–3994S.

Eddleston M and Persson H (2003) Acute plant poisoning and antitoxin antibodies. Journal of Toxicology and Clinical Toxicology 41: 309–315.

Ferrara N, Hillan KJ, Gerber HP and Novotny W (2004) Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nature Reviews Drug Discovery 3(5): 391–400.

Fischer N and Léger O (2007) Bispecific antibodies: molecules that enable novel therapeutic strategies. Pathobiology 74: 3–14.

Gambill BD (2001) Edrecolomab (Panorex) as adjuvant therapy for stage II colon cancer. Clinical Colorectal Cancer 1: 16–17.

Grossbard ML, Multani PS, Freedman AS et al. (1999) A Phase II study of adjuvant therapy with anti‐B4‐blocked ricin after autologous bone marrow transplantation for patients with relapsed B‐cell non‐Hodgkin's lymphoma. Clinical Cancer Research 5(9): 2392–2398.

Hagenbeek A (2003) Radioimmunotherapy for NHL: experience of 90Y‐ibritumomab tiuxetan. Leukemia and Lymphoma 44(Suppl. 4): S37–S47.

Hercus TR, Thomas D, Guthridge MA et al. (2009) The GM–CSF receptor: linking its structure to cell signaling and its role in disease. Blood 114: 1289–1298.

Hodi FS, O'Day SJ, McDermott DF et al. (2010) Improved survival with ipilimumab in patients with metastatic melanoma. New England Journal of Medicine 363(8): 711–723.

Jin L, Lee EM, Ramshaw HS et al. (2009) Monoclonal antibody-mediated targeting of CD123, IL-3 receptor alpha chain, eliminates human acute myeloid leukemic stem cells. Cell Stem Cell 5(1): 31–42.

Keating M, Coutré S, Rai K et al. (2004) Management guidelines for use of alemtuzumab in B‐cell chronic lymphocytic leukemia. Clinical Lymphoma 4(4): 220–227.

Khalil MY, Grandis JR, Shin DM (2003) Targeting epidermal growth factor receptor: novel therapeutics in the management of cancer. Expert Review of Anticancer Therapy 3(3): 367–380.

Kochendorfer JN, Wilson WH, Janik JE et al. (2010) Eradication of B‐lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognise CD19. Blood 116 (20): 4099–4102.

3Kohler G and Milstein C (1975) Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256: 495–497.

Lincoff AM, Tcheng JE, Califf RM et al. (1999) Sustained suppression of ischemic complications of coronary intervention by platelet GpIIb/IIIa blockade with abciximab: one‐year outcome in the EPILOG trial. Evaluation in PCTA to improve long‐term outcome with abciximab GpIIb/IIIa blockade. Circulation 99(15): 1951–1958.

Majeti R (2011) Monoclonal antibody therapy directed against human acute myeloid leukemia stem cells. Oncogene 30: 1009–1019.

Maloney D (2012) Anti‐CD20 antibody therapy for B‐cell lymphomas. New England Journal of Medicine 366(21): 2008–2016.

Nashan B, Light S, Hardie IR, Lin A and Johnson JR (1999) Reduction of acute renal allograft rejection by daclizumab. Daclizumab Double Therapy Study Group. Transplantation 67(1): 110–115.

Nashan B, Moore R, Amlot P et al. (1997) Randomised trial of basiliximab versus placebo for control of acute cellular rejection in renal allograft recipients. CHIB 201 International Study Group. Lancet 350(9096): 1193–1198.

Pegram MD, Lipton A, Hayes DF et al. (1998) Phase II study of receptor‐enhanced chemosensitivity using recombinant humanised anti‐p185HER2/neu monoclonal antibody plus cisplatin in patients with Her2/neu‐overexpressing metastatic breast cancer refractory to chemotherapy treatment. Journal of Clinical Oncology 16(8): 2659–2671.

Pegram MD, Pienkowski T, Northfelt DW et al. (2004) Results of two open‐label, multicenter phase II studies of docetaxel, platinum salts, and trastuzumab in HER2‐positive advanced breast cancer. Journal of the National Cancer Institute 96(10): 759–769.

Perkins DJ, St Clair EW, Misukonis MA and Weinberg JB (1998) Reduction of NOS2 overexpression in rheumatoid arthritis patients treated with anti‐tumor necrosis factor alpha monoclonal antibody (cA2). Arthritis and Rheumatism 41(12): 2205–2210.

Rastetter W, Molina A and White CA (2004) Rituximab: expanding role in therapy for lymphomas and autoimmune diseases. Annual Review of Medicine 55: 477–503.

Robak T and Robak E (2011). New anti‐CD20 antibodies for the treatment of B‐cell lymphoid malignancies. Biodrugs 25: 13–25.

Senter PD and Sievers EL (2012) The discovery and development of brentuximab vedotin for use in relapsed Hodgkin's disease and systemic anaplastic large cell lymphoma. Nature Biotechnology 30(7): 631–637.

Shi JD, Bullock C, Hall WC et al. 2002 In vivo pharmacodynamic effects of Hu1D10 (remitogen), a humanized antibody reactive against a polymorphic determinant of HLA‐DR expressed on B cells. Leukemia and Lymphoma 43(6): 1303–1312.

Sun Q, Woodcock JM, Rapoport A et al. (1996). Monoclonal antibody 7G3 recognizes the N‐terminal domain of the human interleukin‐3 (IL‐3) receptor alpha‐chain and functions as a specific IL‐3 receptor antagonist. Blood 87: 83–92.

Thiel MA, Coster DJ, Standfield SD et al. (2002) Penetration of engineered antibody fragments into the eye. Clinical and Experimental Immunology 128: 67–74.

Vanneman M and Dranoff G (2012) Combining immunotherapy and targeted therapies in cancer treatment. Nature Reviews Cancer 12(4): 237–251.

Vermorken JB, Herbst RS, Leon X et al. (2008) Overview of the efficacy of cetuximab in recurrent and/or metastatic squamous cell carcinoma of the head and neck in patients who previously failed platinum‐based therapies. Cancer 112(12): 2710–2719.

Vose JM (2004) Bexxar: novel radioimmunotherapy for the treatment of low‐grade and transformed low‐grade non‐Hodgkin's lymphoma. Oncologist 9(2): 160–172.

Williams LE, Wu AM, Yazaki PJ et al. (2001) Numerical selection of optimal tumor imaging agents with application to engineered antibodies. Cancer Biotherapy and Radiopharmaceuticals 16: 25–35.

Zhang J, Liu YF, Yang SJ et al. (2004) Primary targeting of recombinant Fv‐immunotoxin hscFv(25)‐mTNFalpha against hepatocellular carcinoma. World Journal of Gastroenterology 10(13): 1872–1875.

Further Reading

Hansel TT, Kropshofer H, Singer T et al. (2010) The safety and side effects of monoclonal antibodies. Nature Reviews Drug Discovery 9: 325–338.

Hudson PJ (2003) Engineered antibodies. Nature Medicine 9: 129–134.

Landon J and Chard T (1995) Therapeutic Antibodies. London: Springer.

McCafferty J, Hoogenboom H and Chiswell D (eds) (1996) Antibody Engineering: A Practical Approach. Oxford: Oxford University Press.

Reichert J and Valge‐Archer VE (2007) Development trends for monoclonal antibody cancer therapeutics. Nature Reviews Drug Discovery 6: 349–356.

Souriau C and Hudson PJ (2003) Recombinant antibodies for cancer diagnosis and therapy. Expert Opinion in Biological Therapy 3: 305–318.

Waldmann TA and O'Shea J (1998) The use of antibodies against the IL‐2 receptor in transplantation. Current Opinion in Immunology 10: 507–512.

Winter G and Milstein C (1991) Man‐made antibodies. Nature 349: 293–299.

Winter G, Grifiths AD, Hawkins RE and Hoogenboom HR (1994) Making antibodies by phage display. Annual Reviews in Immunology 12: 433–455.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Zola, Heddy, Thomas, Daniel, and Lopez, Angel(Sep 2013) Monoclonal Antibodies: Therapeutic Uses. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0002176.pub3]