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  • Review Article
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Comparing antibody and small-molecule therapies for cancer

Nature Reviews Cancer volume 6, pages 714–727 (2006)Cite this article

Key Points

  • The concept of specific molecular targeting has been applied to the development of innovative cancer-treatment strategies. At present, two main approaches are available for use in clinical practice: therapeutic monoclonal antibodies (mAbs) and small-molecule agents.

  • We focus on the ErbB receptor family, particularly epidermal growth factor receptor (EGFR, also known as ERBB1) as an example of a target in our comparison of mAbs and small-molecule inhibitors. Cetuximab, a mAb, and gefitinib and erlotinib, which are small-molecule inhibitors, differ markedly in their basic properties and their underlying mechanisms of action.

  • The presence of activating mutations within the ATP-binding cleft of the EGFR kinase domain is associated with the sensitivity of non-small-cell lung cancer (NSCLC) to gefitinib, but not to cetuximab. By contrast, cetuximab shows a clinical benefit for colorectal cancers that overexpress EGFR in a manner independent of EGFR mutations. In malignant glioma, the sensitivity to gefitinib is closely related to deletions within the ectodomain of EGFR. In contrast to these drug-sensitivity mutations, the appearance of the T790M mutation confers resistance to gefitinib in NSCLC.

  • There are unique immune-effector mechanisms that are only triggered by therapeutic mAbs, such as antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity and complement-dependent cell-mediated cytotoxicity. By contrast, the effects of small-molecule agents are not directly linked to the activation of an immune response against tumour cells.

  • In general, mild adverse effects such as dermatological complications are commonly observed with these two classes of EGFR inhibitors. Although interstitial lung diseases or diarrhoea are more commonly associated with small-molecule therapies, therapeutic murine mAbs or chimeric mAbs can cause immunogenicity, leading to the production of human anti-mouse antibodies or human antichimeric antibodies, respectively.

  • It has been shown that mAbs such as trastuzumab and cetuximab exert synergistic anti-tumour effects in combination with chemotherapeutic agents more frequently than small-molecule inhibitors.

  • The combination of distinct classes of EGFR inhibitors could not only increase their efficacy, but also contribute to overcoming resistance to one class of EGFR inhibitor.

  • Further investigation into the distinct properties of these two classes of targeted agents should not only contribute to the development of new targeted agents but also provide an optimal therapeutic strategy for cancer treatment, thereby leading to the improvement of dual-targeted or multi-targeted therapy.

Abstract

The 'magic bullet' concept of specifically targeting cancer cells at the same time as sparing normal tissues is now proven, as several monoclonal antibodies and targeted small-molecule compounds have been approved for cancer treatment. Both antibodies and small-molecule compounds are therefore promising tools for target-protein-based cancer therapy. We discuss and compare the distinctive properties of these two therapeutic strategies so as to provide a better view for the development of new drugs and the future direction of cancer therapy.

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Figure 1: The classification of therapeutic monoclonal antibodies (mAbs) by the different antibody types — murine, chimeric, humanized and human.
Figure 2: Schematic model of antibody action by immune mechanisms.
Figure 3: Distinct mechanisms of small-molecule inhibitors and monoclonal antibodies for targeting receptor tyrosine kinases in cancer cells.
Figure 4: EGFR mutations correlated with clinical response to EGFR inhibitors.

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Acknowledgements

We would like to thank T. Ishida for his continuous support of the work in our laboratory described in this Review. The work in our laboratory was supported in part by a grant for Advanced Research on Cancer from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. We also thank Z. Wang for his assistance with this manuscript.

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Authors and Affiliations

  1. Sapporo Medical University, South 1, West 17, Chuo-ku, Sapporo, 060-8556, Japan

    Kohzoh Imai

  2. Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, 113-0033, Japan

    Akinori Takaoka

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  1. Kohzoh Imai
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Correspondence to Kohzoh Imai.

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DATABASES

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colorectal

HNSCC

non-Hodgkin lymphoma

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Glossary

Bacteriophage display

A display method for identifying proteins or peptides that recognize and bind to a target molecule(s). Bacteriophages that display the antibody of interest are selected by antigen binding and are propagated in bacteria. This helps identify therapeutic antibodies with high binding affinity.

Shedding

The release of the extracellular domain of a cell-membrane protein, such as a growth-factor receptor, from the cell surface. ERBB2 is proteolytically cleaved, possibly by a matrix metalloproteinase activator, although this proteolysis does not seem to be mediated by a general shedding system that can be activated by protein kinase C. ERBB2 cleavage generates a membrane-associated receptor fragment with potentially increased tyrosine kinase activity.

Complement-dependent cytotoxicity

This is one of the antigen-elimination processes that is mediated by immunoglobulins (Ig). When IgM and certain IgG subclasses (IgG1 and IgG3) bind to an antigen, one of the complement factors is strongly activated. Then, a sequence of cleavage reactions of other complement factors (classical pathway of complement activation) is triggered to activate their cytotoxic function, which leads to the destruction of the target cells.

Antibody-dependent cellular cytotoxicity

This reaction can be initiated by the Fc portion of immunoglobulins (Ig). Phagocytes such as monocytes/macrophages, dendritic cells, natural killer cells and neutrophils take up IgG-coated target cells through binding with Fcγ-receptors on the surface of the phagocytes. This is eventually followed by the elimination of target cells.

ATP mimetics

These small-molecule inhibitors competitively bind to the ATP-binding cleft at the activation loop of target kinases, thereby inhibiting their kinase activity.

Chymotryptic protease in the 26S proteasome

The 26S proteasome is a multicatalytic complex, which is composed of the 20S catalytic core subunit and the 19S regulatory subunit that recognize and degrade ubiquitylated proteins. A chymotrypsin-like proteolytic activity is one of the catalytic activities of this core subunit for the hydrolysis of peptide substrates.

Complement-dependent cellular cytotoxicity

This is a cell-mediated effector mechanism for target cell killing. As similarly observed in CDC, complement activation is triggered in CDCC by the interaction of C1 q to the Fc regions of antibodies bound to target antigens. During this process, several complement components, such as C3b, are generated and recognized by effector immune cells through their complementary receptors, which leads to phagocytosis and cytotoxicity.

Opsonins

Opsonins are any molecules with which antigens are coated, such as IgG and components of complement factors (C1 q, C3b, iC3b, and C4b), to become more susceptible to phagocytosis by macrophages or neutrophils.These phagocytes bind opsonin molecules through Fcγ receptors or complement receptors that are expressed on their surface membrane.

Cancer stem cells

A small subpopulation of quiescent tumour cells within a tumour that have properties similar to normal stem cells, such as the capability to undergo self-renewal and to maintain tumour growth and heterogeneity. According to the stem-cell-based model, conventional therapies typically target actively proliferating cells but spare drug-resistant cancer stem cells, which might contribute to therapeutic failure and eventual relapses.

Pruritus

A dermatological symptom (itching) that is often observed in cutaneous lesions caused by allergy and infections.

Asthenia

A general feeling of weakness or lack of vigour, which can be associated with various diseases.

Anaphylactoid reactions

Systemic immunological hyper-responses that mimic anaphylaxis. In contrast to IgE-mediated anaphylactic reactions, these are triggered by an IgE-independent mechanism, frequently appear as allergic reactions to drugs, foods and exercise, and manifest as potentially life-threatening symptoms such as hypotension, bronchospasm and laryngeal oedema.

Urticaria

A cutaneous symptom that primarily manifests as a rash and pruritus. This manifestation is caused by IgE- or non-IgE hypersensitivity with histamine and other vasoactive chemicals released from mast cells as a result of exposure to drugs and foods.

Interstitial pneumonitis

A form of pneumonia that is characterized by non-infectious inflammation and fibrosis in the space between the epithelial and endothelial basement membranes of the lower respiratory tract. This is caused by unknown and known factors such as drugs (gefitinib, lefluomide or irinotecan) or environmental factors, and can be observed in association with other diseases (for example, connective tissue diseases). Patients with this disorder typically present with cough and shortness of breath.

Human anti-mouse antibodies

HAMAs are antibodies that are produced by the human immune system against therapeutic murine monoclonal antibodies (mAbs)

Human anti-chimeric antibodies

HACAs are antibodies that are produced against murine components of chimeric or humanized mAbs. HAMAs and HACAs are often related to immunogenicity problems associated with a lack of efficacy and rapid clearance during mAb therapy.

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Imai, K., Takaoka, A. Comparing antibody and small-molecule therapies for cancer. Nat Rev Cancer 6, 714–727 (2006). https://doi.org/10.1038/nrc1913

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