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  • Review Article
  • Published:

Monoclonal antibodies: versatile platforms for cancer immunotherapy

Nature Reviews Immunology volume 10, pages 317–327 (2010)Cite this article

Subjects

Key Points

  • The past century has witnessed the evolution of the 'magic bullet' from concept to clinical reality. Therapeutic antibodies have been established as 'standard of care' agents for several human cancers.

  • Therapeutic antibodies possess unique and multiple clinically relevant antitumour mechanisms: these include antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity and the induction of T cell immunity through cross-presentation.

  • Antibodies directed against elements of the tumour microenvironment might synergize with antibodies targeting tumour antigens and provide enhanced therapeutic benefit.

  • Fc receptors for IgG (FcγRs) provide a key link between therapeutic antibodies and the cellular immune system and enable monoclonal antibodies to induce adaptive immune responses. Antibody-induced antitumour adaptive immunity against tumour-specific antigens might already contribute to the patterns of delayed and prolonged antitumour responses seen when antibodies are used alone or in combination with chemotherapy.

  • Monoclonal antibodies can exert synergistic antitumour effects in combination with other immunomodulatory approaches such as chemotherapy, radiotherapy, targeted therapy agents, vaccines or other immunomodulators.

  • Advances in protein engineering have provided platforms for the development of novel antibody constructs, such as bispecific T cell engager (BiTE) molecules, as well as engineered protein scaffolds, such as designed ankyrin repeat domains (DARPins) and adnectins.

Abstract

Antibodies are important therapeutic agents for cancer. Recently, it has become clear that antibodies possess several clinically relevant mechanisms of action. Many clinically useful antibodies can manipulate tumour-related signalling. In addition, antibodies exhibit various immunomodulatory properties and, by directly activating or inhibiting molecules of the immune system, antibodies can promote the induction of antitumour immune responses. These immunomodulatory properties can form the basis for new cancer treatment strategies.

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Figure 1: IgG structure and function.
Figure 2: Antitumour mechanisms mediated by IgG–FcγR interactions.

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Acknowledgements

L.M.W. and S.W. are supported by the US National Institutes of Health (grants CA51008, CA50633 and CA121033).

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  1. Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, 20057, DC, USA

    Louis M. Weiner, Rishi Surana & Shangzi Wang

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  1. Louis M. Weiner
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Glossary

Monoclonal antibodies

Antibodies containing uniform variable regions and thus specific for a single epitope. Originally, monoclonal antibodies were derived from a single B lymphocyte clone. Genetic manipulation now allows genes from multiple sources of B lymphocytes (for example, mouse and human) to be combined.

Chimeric antibody

An antibody encoded by genes from more than one species, usually with antigen-binding regions from mouse genes and constant regions from human genes. The aim of this process is to prevent a mouse-specific antibody response in humans treated with the antibody.

Humanized antibody

A genetically engineered mouse antibody in which the protein sequence has been modified to increase the similarity of the antibody to human antibodies. This is to prevent a mouse-specific antibody response in humans treated with the antibody.

Human epidermal growth factor receptor 2

(HER2; also known as ERBB2). A type I membrane glycoprotein that is a member of the ERBB family of tyrosine kinase receptors. This tumour-associated antigen is overexpressed in 10–40% of breast cancer and other carcinomas.

Complement-dependent cytotoxicity

(CDC). A mechanism of killing cells in which antibody, bound to the target cell surface, fixes complement, which results in assembly of the membrane attack complex that punches holes in the target cell membrane resulting in subsequent cell lysis.

Immunoreceptor tyrosine-based activation motif

(ITAM). A sequence that is present in the cytoplasmic domains of the invariant chains of various cell-surface immune receptors. Following phosphorylation of their tyrosine residues, ITAMs function as docking sites for SRC homology 2 (SH2)-domain-containing tyrosine kinases and adaptor molecules, thereby facilitating intracellular-signalling cascades.

Immunoreceptor tyrosine-based inhibitory motif

(ITIM). A motif that is present in the cytoplasmic domain of several inhibitory receptors. After ligand binding, ITIMs are tyrosine phosphorylated and recruit inhibitory phosphatases.

Antibody-dependent cell-mediated cytotoxicity

(ADCC). A mechanism by which NK cells kill other cells; for example, virus-infected target cells that are coated with antibodies. The Fc portions of the coating antibodies interact with Fc receptors that are expressed by NK cells, thereby initiating signalling cascades that result in the release of cytotoxic granules (containing perforin and granzyme B), which induce apoptosis of the antibody-coated cell.

Cross-presentation

The ability of certain antigen-presenting cells to load peptides that are derived from exogenous antigens onto MHC class I molecules and present these at the cell surface. This property is atypical, as most cells exclusively present peptides derived from endogenous proteins on MHC class I molecules.

Angiogenesis

The process of developing new blood vessels. Angiogenesis is important in the normal development of the embryo and fetus. It is also important for tumour growth.

FOLFIRI chemotherapy

A chemotherapy regimen for the treatment of colorectal cancer, made up of the drug folinic acid (Leucovorin), fluorouracil (5-FU) and irinotecan (Camptosar).

Heregulin

A family of ligands known to bind the HER3 and HER4 receptors, also capable of inducing phosphorylation of HER2.

Regulatory T (TReg) cell

A type of CD4+ T cell that is characterized by its expression of forkhead box P3 (FOXP3) and high levels of CD25. TReg cells can suppress many types of immune responses.

Tumour-associated antigens

Antigens that are expressed by tumour cells. These belong to three main categories: tissue-differentiation antigens (which are also expressed by non-malignant cells), mutated or aberrantly expressed molecules and cancer testis antigens, which are normally expressed only by spermatocytes and occasionally in the placenta.

Bispecific antibody

Antibodies engineered to express two distinct antigen binding sites. They are most often used therapeutically to physically cross-link a tumour cell and an immune effector cell.

Co-stimulation

Receptor-mediated signals required in addition to antigen-receptor engagement to achieve complete lymphocyte activation.

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Weiner, L., Surana, R. & Wang, S. Monoclonal antibodies: versatile platforms for cancer immunotherapy. Nat Rev Immunol 10, 317–327 (2010). https://doi.org/10.1038/nri2744

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