Review Article | Published:

Building better monoclonal antibody-based therapeutics

Nature Reviews Cancer volume 15, pages 361370 (2015) | Download Citation

Abstract

For 20 years, monoclonal antibodies (mAbs) have been a standard component of cancer therapy, but there is still much room for improvement. Efforts continue to build better cancer therapeutics based on mAbs. Anticancer mAbs function through various mechanisms, including directly targeting the malignant cells, modifying the host response, delivering cytotoxic moieties and retargeting cellular immunity towards the malignant cells. Characteristics of mAbs that affect their efficacy include antigen specificity, overall structure, affinity for the target antigen and how a mAb component is incorporated into a construct that can trigger target cell death. This Review discusses the various approaches to using mAb-based therapeutics to treat cancer and the strategies used to take advantage of the unique potential of each approach, and provides examples of current mAb-based treatments.

Key points

  • Monoclonal antibody (mAb)-based therapeutics are now standard in the treatment of cancer, and the numbers and varieties of clinically applicable mAb-based approaches continue to grow.

  • Effective mAb-based treatments of cancer include directly targeting the cancer, altering the host response to the cancer, delivering cytotoxic moieties to the cancer and retargeting T cells towards the cancer.

  • mAb-based treatments that directly target the cancer mediate their effects through direct signalling, antibody-dependent cellular cytotoxicity and complement-mediated lysis. Differentiating which of these mechanisms is most important for a given mAb can be difficult but is important when working to identify better mAb-based treatments.

  • mAb-based treatments that alter the host response can alter tumour angiogenesis or the T cell response through T cell checkpoint blockade. Checkpoint-blockade mAbs are showing particular promise.

  • mAb-based treatments that deliver cytotoxic agents to the cancer include radioimmunotherapy and antibody–drug conjugates (ADCs). ADCs are complex because of the need to match the target cancer to the right mAb, linker and drug, but early results are promising and many new ADCs are in development.

  • mAb-based treatments that retarget T cells towards cancer include bispecific antibodies and chimeric antigen receptor T cells. Both approaches are logistically challenging but have demonstrated exciting early results, particularly in B cell malignancies.

  • Each of these approaches has advantages and disadvantages that need to be considered in their development and evaluation.

  • Rapid progress is taking place in the development of new agents and the testing of new approaches, both alone and in combination, in each of these areas.

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Acknowledgements

The author would like to acknowledge support from the US National Institutes of Health grants P30 CA86862 and P50 CA97274.

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  1. Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, 5970Z-JPP, Iowa City, Iowa 52242, USA.

    • George J. Weiner

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The author declares no competing financial interests.

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Correspondence to George J. Weiner.

Glossary

Cluster of differentiation numbers

Numbers assigned to cell surface molecules on the basis of immunophenotyping. They are often used to identify different monoclonal antibodies that bind to the same antigen.

Transmembrane signalling

The process by which an extracellular signal, mediated by a natural ligand or an alternative agent such as a monoclonal antibody, binds to a membrane receptor and generates an intracellular signal that can affect a broad range of cellular functions, including cell growth, cell differentiation and cell death.

Complement-mediated cytotoxicity

(CMC). Also known as complement-dependent cytotoxicity. Cell death resulting from the activation of the complement cascade by a monoclonal antibody that leads to the formation of a membrane attack complex on the surface of the cell.

Antibody-dependent cellular cytotoxicity

(ADCC). Lysis of a target cell by an immune effector cell (such as a natural killer cell, monocyte, macrophage or granulocyte) induced by the recognition of an antibody bound to the surface of the target cell.

Fc receptors

(FcRs). A family of protein receptors specific for an epitope on the constant region of an antibody. When FcRs on immune effector cells come into contact with an antibody-coated target cell, this can result in immune effector cell activation (FcRs with immunoreceptor tyrosine-based activation motifs (ITAMs)) or inhibition (FcRs with immunoreceptor tyrosine-based inhibitory motifs (ITIMs)).

Complement fixation

Initiation of the complement cascade by an antibody bound to an antigen. It can lead to complement-mediated cytotoxicity of the target cell, as well as other complex effects mediated by the activation of various complement components.

mAb isotype

The subtype of a monoclonal antibody (mAb) based on the amino acid sequence of the constant region. Isotypes (IgG1, IgG2, IgG3 and IgG4) vary in their ability to mediate antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity.

Glycosylation

The post-translational attachment of a carbohydrate moiety to a protein. The Fc region of immunoglobulin G includes carbohydrate moieties. Altering the enzymes responsible for glycosylation in a cell line that produces a monoclonal antibody (mAb) can alter the glycosylation of the mAb, thereby altering its ability to activate immune effector cells.

Opsonization

The process by which a target is marked for phagocytosis or for destruction by phagocytes. This term is often used to describe phagocytosis of microbial pathogens. In the case of monoclonal antibody therapy of cancer, the target is a cancer cell.

Checkpoint blockade

Inhibitory pathways limit T cell activation in order to maintain self-tolerance and prevent autoimmunity. Checkpoint blockade involves blocking these inhibitory pathways, and thereby allowing for to a more robust T cell response.

Breakthrough therapy designation

US Food and Drug Administration (FDA) designation if a new drug is intended to treat a serious or life-threatening disease and preliminary clinical evidence suggests that it provides a substantial improvement over existing therapies.

Bispecific antibody

(Also known as bifunctional antibody). An engineered monoclonal antibody (mAb) that is composed of fragments of two different mAbs that bind to two different antigens. In cancer therapy, it typically binds to an activating antigen on an immune effector cell with one arm and to a tumour-associated antigen on a cancer cell with the other arm, thereby retargeting the immune effector cell towards the target cancer cell.

Chimeric antigen receptor

(CAR). An engineered receptor that grafts an alternative specificity onto an immune effector cell, most often a T cell. Most of the current constructs for engineered receptors include a single-chain monoclonal antibody variable region that recognizes the target cell and is linked to activating transmembrane domains that activate the T cell when it comes into contact with a target cell.

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