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  • Review Article
  • Published:

Improving the efficacy of antibody-based cancer therapies

Key Points

  • Five antibodies are now approved for cancer therapy with more approvals anticipated from among the 20 or so antibodies currently in oncology trials.

  • The pressing clinical need to enhance the efficacy of anticancer antibodies is being met by the exploration of a plethora of strategies. Combination treatment of antibodies with chemotherapy is already benefiting some oncology patients.

  • Chemically coupling antibodies to toxins or radionuclides is the most widely investigated means for increasing their antitumour activity. In Mylotarg, the anti-CD33–calicheamicin conjugate is already approved for cancer therapy, and two anti-CD20 radioimmunoconjugates, Bexxar (tositumomab; 131iodine) and Zevalin (ibritumomab tituxetan; 90yttrium), are poised for regulatory approval.

  • Interactions between antibody Fc regions and their Fcγ receptors are crucial to the in vivo antitumour activity of at least four antitumour antibodies, including trastuzumab (Herceptin) and rituximab (Rituxan). Tumour-cell killing in vitro has been enhanced by point mutations in Fc that improve binding to FcγRIII and, alternatively, by cellular engineering of antibody production hosts to manipulate antibody glycoforms.

  • Pre-targeting of radionuclides and prodrugs to tumours might greatly reduce the systemic toxicity of conventional radioimmunotherapy and cytotoxic chemotherapy, respectively. Pre-targeting strategies must overcome many remaining obstacles for them to provide significant new treatment options for cancer patients.

  • Targeting tumour neovasculature and angiogenic growth factors (e.g. VEGF) and receptors are promising alternative and potentially complementary strategies to direct tumour targeting. A humanized anti-VEGF antibody, bevacizumab (Avastin), is now in Phase III oncology trials.

  • Liposomal formulations of doxorubicin and daunorubicin have been approved in recent years for the treatment of Kaposi's sarcoma. Attaching antibody fragments to the surface of such liposomes allows them to be specifically targeted to tumours.

  • Antibody–cytokine fusion proteins (immunocytokines) create high intratumour concentrations of cytokines to stimulate the antitumour immune response. An IL-2-containing immunocytokine eliminated established metastases in a syngeneic mouse tumour model, boding well for ongoing clinical studies with two different immunocytokines.

  • Bispecific antibodies binding two different antigens might selectively deliver cytotoxic machinery, such as immune effector cells, radionuclides, drugs and toxins, to tumour cells in vivo. Any future clinical success with bispecific antibodies will probably require a deeper understanding of underwhelming clinical trial data combined with powerful new production technologies for these complex molecules.

Abstract

A quarter of a century after their advent, monoclonal antibodies have become the most rapidly expanding class of pharmaceuticals for treating a wide variety of human diseases, including cancer. Although antibodies have yet to achieve the ultimate goal of curing cancer, many innovative approaches stand poised to improve the efficacy of antibody-based therapies.

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Figure 1: Strategies for enhancing the potency of antitumour antibodies.
Figure 2: Antibody effector functions.

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Acknowledgements

The author thanks L. Weiner, D. Liebowitz and J. Smothers for critical review of this manuscript and G. Yarranton and M. Pegram for kindly sharing unpublished data.

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DATABASES

CancerNet:

breast cancer

colorectal cancer

gastric adenocarcinoma

Kaposi's sarcoma

acute myelogenous leukaemia

non-Hodgkin's lymphoma

ovarian cancer

 LocusLink:

angiogenin

CD3

CD16

CD20

CD25

CD33

CD46

CD55

CD59

CD64

CD89

cyclooxygenase-2

EGFR

ERBB2

fibronectin

β-glucuronidase

GM-CSF

IgG1

IgG3

IL-2

IL-12

VEGF

VEGFR2

 Medscape DrugInfo:

Campath

carboplatin

celecoxib

cisplatin

cyclophosphamide

daunorubicin

doxorubicin

etoposide

Herceptin

methotrexate

Mylotarg

prednisone

Rituxan

taxol

vincristine

FURTHER INFORMATION

Campath information site

Immunogen, Inc. web site

Information on HER2 and Herceptin

Rituxan information site

Glossary

PHAGE DISPLAY

Technology for displaying a protein (or peptide) on the surface of a bacteriophage, which contains the gene(s) that encodes the displayed protein(s), thereby physically linking the genotype and phenotype.

VALENCY

For antibody-derived molecules, this refers to the number of binding sites for the cognate antigen(s).

COMPLETE RESPONSE

No remaining tumour can be detected by visual inspection or by clinical imaging technologies. This does not mean that the disease has been cured.

PARTIAL RESPONSE

≥ 50% reduction in tumour with no new lesions or increase in size of an existing lesion.

RESPONSE DURATION

Time from the first response until disease progression or death.

OVERALL RESPONSE RATE

Sum of partial and complete responses.

TUMOUR XENOGRAFT

Commonly refers to the growth of human tumour cells as tumours in immuno-compromised mice.

RIBOSOME DISPLAY

Technology for displaying a nascent protein, which is physically linked to its encoding mRNA, that relies on in vitro transcription and translation.

DNA SHUFFLING

Process for creating molecular diversity by homologous recombination of DNA in vitro.

YEAST DISPLAY

Technology for displaying a protein on the surface of a yeast cell that contains the gene(s) that encodes the displayed protein(s).

EXTRAVASATION

Movement out of the vasculature compartment into interstitial spaces.

MINIMAL RESIDUAL DISEASE

Tumour remaining in patients following debulking by surgery and/or chemotherapy and/or radiotherapy.

MICROMETASTATIC DISEASE

Metastatic disease that can be detected by immuno-histochemistry of tissue biopsies, but involves too few tumour cells to be directly imaged in patients.

DUKE'S STAGE C COLORECTAL CANCER

Cancer that has spread from the colon to nearby lymph nodes, but not to other parts of the body.

FC REGION

For an IgG, this comprises the CH2 and CH3 domains (Box 1).

KABAT NUMBERING SCHEME

Immunoglobulin amino-acid residue numbering scheme, devised by the late Elvin Kabat, that accommodates sequence insertions and deletions.

BISECTED COMPLEX OLIGOSACCHARIDES

Branched carbohydrate that might include several different kinds of monosaccharides, including N-acetylglucosamine between main branches.

PANNING

Process of separating target-binding clones from nonbinding clones for phage display library.

CURE

Tumour does not reappear for a prolonged time period — deemed sufficient for regrowth of any residual tumour — following anticancer therapies.

VASCULAR LEAK SYNDROME

Involves damage to vascular endothelial cells, extravasation of fluids and proteins resulting in weight gain and, in its most severe form, kidney damage and pulmonary oedema.

PEGYLATION

Chemical modification of a protein with one or more molecules of polyethylene glycol.

BYSTANDER CELLS

Cells in the immediate vicinity of a cell that has a bound antibody-based targeting agent.

MYELOABLATIVE

Elimination of myeloid cells and their progenitors.

AUTOLOGOUS STEM-CELL SUPPORT

Harvesting of a patient's haematological stem cells before myeloablative anticancer therapy, followed by rescue by engraftment of the stem cells back into the patient.

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Carter, P. Improving the efficacy of antibody-based cancer therapies. Nat Rev Cancer 1, 118–129 (2001). https://doi.org/10.1038/35101072

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