Overview of therapeutic monoclonal antibodies
- John P Manis, MD
John P Manis, MD
- Assistant Professor of Pathology
- Harvard Medical School
- Joint Program in Transfusion Medicine, Dep
- Section Editor
- Daniel E Furst, MD
Daniel E Furst, MD
- Section Editor — Treatment Issues in Rheumatology
- Clinical professor, University of Washington, Seattle
- Clinical professor, University of Florence, Florence, Italy
- Professor of Rheumatology, University of California in Los Angeles (Emeritus)
- Director of Research, Pacific Arthritis Associates
Immunoglobulin molecules (antibodies) are multifunctional components of the immune system. Antibodies facilitate numerous cellular and humoral reactions to a variety of antigens, including those of the host (self) and foreign substances.
Most antibodies produced as part of the normal immune response are polyclonal, meaning that they are produced by a number of distinct B lymphocytes, and, as a result, they each have a slightly different specificity for the target antigen (eg, by binding different epitopes or binding the same epitope with different affinities). However, it is possible to produce large quantities of an antibody from a single B-cell clone.
Since 1985, approximately 100 independent monoclonal antibodies (mAbs) have been designated as drugs. Available mAbs are directed against a large number of antigens and used for the treatment of immunologic diseases, reversal of drug effects, and cancer therapy. The World Health Organization (WHO), which is responsible for therapeutic mAb nomenclature, reported in 2017 that over 500 mAb names have been provided. (See 'Naming convention for therapeutic mAbs' below.)
This topic will provide an overview of therapeutic mAbs, including their mechanisms of action, production, modifications, nomenclature, administration, and adverse effects.
Separate topic reviews discuss clinical uses of polyclonal antibodies, including subcutaneous, intramuscular, and intravenous immune globulin products (SCIG, IMIG, and IVIG, respectively):To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- http://www.who.int/medicines/services/inn/BioRev2014.pdf (Accessed on July 25, 2017).
- Kopp-Kubel S. International Nonproprietary Names (INN) for pharmaceutical substances. Bull World Health Organ 1995; 73:275.
- http://www.who.int/medicines/services/inn/Revised_mAb_nomenclature_scheme.pdf?ua=1 (Accessed on July 25, 2017).
- Parren PWHI, Carter PJ, Plückthun A. Changes to International Nonproprietary Names for antibody therapeutics 2017 and beyond: of mice, men and more. MAbs 2017; 9:898.
- Jones TD, Carter PJ, Plückthun A, et al. The INNs and outs of antibody nonproprietary names. MAbs 2016; 8:1.
- Kunert R, Reinhart D. Advances in recombinant antibody manufacturing. Appl Microbiol Biotechnol 2016; 100:3451.
- Catapano AL, Papadopoulos N. The safety of therapeutic monoclonal antibodies: implications for cardiovascular disease and targeting the PCSK9 pathway. Atherosclerosis 2013; 228:18.
- Glassy MC, Gupta R. Technical and ethical limitations in making human monoclonal antibodies (an overview). Methods Mol Biol 2014; 1060:9.
- Flego M, Ascione A, Cianfriglia M, Vella S. Clinical development of monoclonal antibody-based drugs in HIV and HCV diseases. BMC Med 2013; 11:4.
- Zhao A, Tohidkia MR, Siegel DL, et al. Phage antibody display libraries: a powerful antibody discovery platform for immunotherapy. Crit Rev Biotechnol 2016; 36:276.
- Köhler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 1975; 256:495.
- Fan G, Wang Z, Hao M, Li J. Bispecific antibodies and their applications. J Hematol Oncol 2015; 8:130.
- Kontermann RE, Brinkmann U. Bispecific antibodies. Drug Discov Today 2015; 20:838.
- Bakhtiar R. Antibody drug conjugates. Biotechnol Lett 2016; 38:1655.
- Zaghouani H, Steinman R, Nonacs R, et al. Presentation of a viral T cell epitope expressed in the CDR3 region of a self immunoglobulin molecule. Science 1993; 259:224.
- Pasman Y, Soliman C, Ramsland PA, Kaushik AK. Exceptionally long CDR3H of bovine scFv antigenized with BoHV-1 B-epitope generates specific immune response against the targeted epitope. Mol Immunol 2016; 77:113.
- Macdonald JC, Hartman H, Jacobs IA. Regulatory considerations in oncologic biosimilar drug development. MAbs 2015; 7:653.
- https://www.fda.gov/downloads/drugs/guidances/ucm459987.pdf (Accessed on December 01, 2017).
- Goldberg ME, Djavadi-Ohaniance L. Methods for measurement of antibody/antigen affinity based on ELISA and RIA. Curr Opin Immunol 1993; 5:278.
- Ludwig DL, Pereira DS, Zhu Z, et al. Monoclonal antibody therapeutics and apoptosis. Oncogene 2003; 22:9097.
- Cartron G, Watier H. Obinutuzumab: what is there to learn from clinical trials? Blood 2017; 130:581.
- Cragg MS, Morgan SM, Chan HT, et al. Complement-mediated lysis by anti-CD20 mAb correlates with segregation into lipid rafts. Blood 2003; 101:1045.
- Bruhns P. Properties of mouse and human IgG receptors and their contribution to disease models. Blood 2012; 119:5640.
- Choi DK, Bae J, Shin SM, et al. A general strategy for generating intact, full-length IgG antibodies that penetrate into the cytosol of living cells. MAbs 2014; 6:1402.
- Tabrizi MA, Tseng CM, Roskos LK. Elimination mechanisms of therapeutic monoclonal antibodies. Drug Discov Today 2006; 11:81.
- Newsome BW, Ernstoff MS. The clinical pharmacology of therapeutic monoclonal antibodies in the treatment of malignancy; have the magic bullets arrived? Br J Clin Pharmacol 2008; 66:6.
- Dempke WCM, Fenchel K, Uciechowski P, Dale SP. Second- and third-generation drugs for immuno-oncology treatment-The more the better? Eur J Cancer 2017; 74:55.
- McDonald V, Manns K, Mackie IJ, et al. Rituximab pharmacokinetics during the management of acute idiopathic thrombotic thrombocytopenic purpura. J Thromb Haemost 2010; 8:1201.
- Khatri BO, Man S, Giovannoni G, et al. Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function. Neurology 2009; 72:402.
- Demlova R, Valík D, Obermannova R, ZdraŽilová-Dubská L. The safety of therapeutic monoclonal antibodies: implications for cancer therapy including immuno-checkpoint inhibitors. Physiol Res 2016; 65:S455.
- Topp MS, Gökbuget N, Stein AS, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol 2015; 16:57.
- Foran AE, Nadel HR, Lee AF, et al. Nivolumab in the Treatment of Refractory Pediatric Hodgkin Lymphoma. J Pediatr Hematol Oncol 2017; 39:e263.
- Williams M, Khalid T, Hughes S, et al. Rituximab-induced Cytokine Storm in the Absence of Overt Lymphoproliferative Disease. J Pediatr Hematol Oncol 2016; 38:e29.
- Frey NV, Porter DL. Cytokine release syndrome with novel therapeutics for acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program 2016; 2016:567.
- NAMING CONVENTION FOR THERAPEUTIC mAbs
- PRODUCTION METHODS AND SPECIAL MODIFICATIONS
- Initial antibody selection
- Mass production
- - Fab fragments and single-chain antibodies
- - Humanized and chimeric mAbs
- - Bifunctional antibodies
- - Drug or toxin conjugation
- - Antigenized antibodies
- BIOSIMILAR mAbs
- IgG1 FUSION PROTEINS
- MECHANISM OF ACTION
- General principles of mAb activity
- Target is a cell surface antigen
- Target is a plasma protein or drug
- Dose, route, and pharmacokinetics
- Co-administration of more than one mAb
- Timing related to plasmapheresis or plasma exchange
- ADVERSE EVENTS
- Infusion reactions
- Other immune-related AEs
- Undesired effects related to the target antigen
- Cytokine release syndrome