Journal Article

Comparing antibody and small-molecule therapies for cancer

Takaoka, Akinori, Imai, Kohzoh

2006

Overview

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. Several small-molecule inhibitors and monoclonal antibodies are now approved for the therapy of various cancers. Focusing on the example of the epidermal growth factor receptor inhibitors, this Review compares and contrasts these two classes of agents. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Antibodies, Monoclonal - therapeutic use / Antineoplastic Agents - therapeutic use / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer Research / Care and treatment / Cellular signal transduction / Dosage and administration / Drugs, Investigational - therapeutic use / Health aspects / Humans / Methods / Monoclonal antibodies / Neoplasms - drug therapy / Neoplasms - metabolism / Physiological aspects / review-article