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  • Review Article
  • Published:

Ligand-targeted therapeutics in anticancer therapy

Key Points

Summary

  • Ligand-targeted therapeutics (LTTs) are a successful means of improving the selective toxicity of anticancer therapeutics. A radioimmunotherapy, an immunotoxin and an immunoconjugate have received clinical approval and over 100 ligand-targeted therapeutics are currently in clinical trials.

  • Recent advances in antibody engineering have allowed humanized or fully human antibody fragments to be made, which will reduce problems with immune responses against mouse antibodies. Phage-display techniques allow the selection of new targeting moieties that have high affinity for the selected target.

  • The choice of targeting ligand can be crucial to the success of targeting applications. Variables that must be considered include the degree of receptor expression; whether the ligand is internalized or not; choice of antibody, antibody fragments or non-antibody ligands; and binding affinity of the ligand.

  • New approaches to LTTs include the use of crosslinked antibody fragments, bispecific antibodies and fusion proteins that carry both the targeting moiety and the therapeutic moiety in the same molecule.

  • The principles of LTTs can also be applied to microreservoir systems such as liposomes and polymers. Targeting of microreservoir systems can significantly increase the number of therapeutic molecules that can be delivered per targeting molecule and can allow sustained release of the therapy over time.

  • More basic research needs to be done to understand how to optimize factors such as drug-release rates and pharmacokinetics and biodistribution, and also to understand the mechanisms behind some of the side effects that are caused by some classes of LTTs.

  • Important issues that need to be addressed include what are the best ways to test LTTs in the clinic, given that they might have their best responses in an adjuvant setting, and how to resolve non-clinical considerations that surround the complex intellectual-property rights in this field.

  • The principles of LTTs can also be applied to the targeted delivery of gene medicines such as antisense oligonucleotides.

Abstract

Cytotoxic chemotherapy or radiotherapy of cancer is limited by serious, sometimes life-threatening, side effects that arise from toxicities to sensitive normal cells because the therapies are not selective for malignant cells. So how can selectivity be improved? One strategy is to couple the therapeutics to antibodies or other ligands that recognize tumour-associated antigens. This increases the exposure of the malignant cells, and reduces the exposure of normal cells, to the ligand-targeted therapeutics.

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Figure 1: Internalization of LTTs and the 'bystander effect'.
Figure 2: Antibodies and antibody fragments.
Figure 3: Examples of the main classes of LTT.

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Acknowledgements

T. Allen's research into targeted therapeutics is supported by the Canadian Institutes for Health Research and by ALZA Corporation, Mountain View, California, USA.

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DATABASES

Cancer.gov

acute myeloid leukaemia

breast cancer

chronic myelogenous leukaemia

colorectal cancer

lung cancer

lymphoma

melanoma

non-Hodgkin's lymphoma

ovarian cancer

LocusLink

ABL

BCR

β-lactamase

cathepsin B

CD19

CD20

CD22

CD25

CD33

CPG2

ERBB2

GM-CSF

IL-2

MUC1

tenascin

transferrin

FURTHER INFORMATION

Cancer.gov Clinical Trials Database

Protein Reviews on the Web (PROW)

Glossary

ANTHRACYCLINE

Any of a class of antineoplastic antibiotics, including doxorubicin, daunorubicin and epirubicin.

LIPOSOME

A spherical particle that is formed by a lipid bilayer that encloses an aqueous compartment.

POLYMER

A macromolecule that is made up of many monomers that are linked by covalent bonds.

BYSTANDER EFFECT

Cells that are killed because they are in close proximity to the actual target, rather than being targets themselves.

PHAGE DISPLAY

A technique that is used for displaying a peptide (or protein) on the surface of a bacteriophage that contains the gene(s) encoding the displayed peptide(s).

ANTI-IDIOTYPIC ANTIBODY

An antibody that binds selectively to a specific antigen determinant on a variable domain of an immunoglobulin molecule. As these antibodies can mimic the original antigen, they might compete with the targeting antibody for binding to its epitope.

IMMUNOGLOBULIN

Any of the structurally related glycoproteins that function as antibodies. They are divided into five classes (IgG, IgM, IgA, IgD and IgE) on the basis of structure and biological activity.

FC DOMAIN

The antibody fragment that does not contain antigen-combining sites. The Fc domain mediates complement activation and binds to Fc cell-surface receptors — for example, on macrophages.

ANTIBODY-DEPENDENT CELLULAR CYTOTOXICITY

The lysis of target cells coated with antibody by means of direct cell–cell contact with effector cells bearing Fc receptors — for example, macrophages.

COMPLEMENT-DEPENDENT CYTOTOXICITY

The lysis of antibody-coated cells by the complement cascade. Cell–cell contact is not required.

MULTIVALENCY

The ability of an antibody or array of antibodies to bind to several antigen determinants at the same time, which increases the strength of binding between the antibody and its target.

TIGHT JUNCTIONS

Zones of contact between two adjacent cells that are impermeable to all but the very smallest molecules.

EXTRAVASATION

Escape of a particle or macromolecule from the bloodstream into the surrounding tissues.

TUMOUR WINDOW MODELS

A chamber that is attached to the back of an animal — for example, a mouse — that allows the characteristics of an implanted tumour to be observed.

LINEAR-ENERGY TRANSFER

Measurement of the number of ionizations that radiation causes per unit distance as it traverses the living cell or tissue.

MYELOSUPPRESSION

Causing toxicity against the cells of the bone marrow.

BISPECIFIC ANTIBODIES

Hybrid, artificially produced antibodies in which each of two antigen-binding sites is specific for separate antigenic determinants.

HAPTEN

A small molecule, not antigenic by itself, that reacts with antibodies and elicits the formation of antibodies when conjugated to a larger, antigenic molecule.

HYPOTENSION

Low blood pressure.

OEDEMA

The presence of abnormally large amounts of fluid in the intercellular tissue spaces of the body.

HYPOALBUMINAEMIA

An abnormally low albumin content of the blood.

PHARMACOKINETICS

The study of the fate of drugs in the body over a period of time, including the processes of absorption, distribution, localization in tissues (biodistribution), metabolism and excretion.

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Allen, T. Ligand-targeted therapeutics in anticancer therapy. Nat Rev Cancer 2, 750–763 (2002). https://doi.org/10.1038/nrc903

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