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Development trends for monoclonal antibody cancer therapeutics

Abstract

Monoclonal antibodies are now established as a key therapeutic modality for a range of diseases. Owing to the ability of these agents to selectively target tumour cells, cancer has been a major focus of development programmes for monoclonal antibodies so far. Here, we overview trends in the clinical development and regulatory approval of monoclonal antibodies for cancer since 1980, with the aim of informing future research and development for this class of therapeutics.

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Figure 1: Categories of monoclonal antibody cancer therapeutics entering clinical study during 1980–1989, 1990–1999 and 2000–2005.
Figure 2: Modes of action for immunoconjugate cancer therapeutics in clinical study, 1980–2005.
Figure 3: Category of monoclonal antibody cancer therapeutics in three phases of clinical study.

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Acknowledgements

The authors thank C. Rosensweig for assistance with data collection, D. Glover for comments and suggestions throughout the project, P. Round, C. Smith, as well as colleagues at the Tufts Center for the Study of Drug Development and Cambridge Antibody Technology for reviewing the manuscript.

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Correspondence to Janice M. Reichert.

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Viia Valge-Archer is employed by Cambridge Antibody Technology.

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Tufts Center for the Study of Drug Development

Glossary

Antibodies

Complex protein-based molecules produced by B lymphocytes that bind to and help to eliminate foreign and infectious agents in the body. Antibodies are Yshaped, having two sets of branches attached to a single stem. The arms of the Y (Fab) are the socalled variable regions, the tips of the arms contain antigen-binding regions, and the stem (Fc) is a constant region. The constant regions trigger effector functions (phagocytosis, cytolysis or initiation of complement cascade followed by cell lysis) by linking the complex to other cells of the immune system.

Chimeric monoclonal antibody

A monoclonal antibody that is constructed from variable regions that are derived from murine source and constant regions derived from human source.

Human monoclonal antibody

A monoclonal antibody that is derived entirely from a human source, currently transgenic mice or phage display. Human mAbs can also be produced from human hybridomas or human Blymphocyte cell lines immortalized by EpsteinBarr virus. However, these cell lines are unstable and produce only small amounts of mAbs.

Humanized monoclonal antibody

A monoclonal antibody constructed with only antigen-binding regions (also called complementarity determining regions (CDRs)) that are derived from a mouse. The remainder of the variable regions and constant regions are derived from a human source.

Immunoconjugates

A hybrid molecule formed by covalently or chemically joining a therapeutic molecule to an antibody, or antibody fragment, with the aim of targeting the therapeutic to a specific antigen.

Isotypes

Antibody types defined according to their classes and subclasses of heavy and light chain constant domains, which are encoded by distinct genetic loci.

Monoclonal antibodies

Originally, mAbs were antibodies produced from a single B lymphocyte. Genetic manipulation now allows genes from multiple sources of B lymphocytes (for example, mouse and human) to be combined. mAbs of a defined peptide sequence have identical antigen-binding regions and bind to the same site (the epitope) of an antigen.

Murine monoclonal antibody

A monoclonal antibody that is derived entirely from mice; specifically mouse hybridomas generated from the fusion of mouse myeloma and mouse Blymphocyte cells.

Phage display

Expression and display of antibody fragments (or other proteins) on the surface of filamentous bacteriophage, which links the antibody DNA sequence with its function, such as binding to target antigen.

Primatized monoclonal antibody

A monoclonal antibody that is constructed from variable regions that are derived from Cynomolgus macaques and constant regions that are derived from a human source. Primatized is a registered US trademark of Biogen IDEC.

Transgenic mice

Mice carrying foreign genetic material in their germline DNA. Mice capable of producing human antibodies contain gene sequences for human antibody heavy and light chains.

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Reichert, J., Valge-Archer, V. Development trends for monoclonal antibody cancer therapeutics. Nat Rev Drug Discov 6, 349–356 (2007). https://doi.org/10.1038/nrd2241

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