The Pharmaceutical Journal Vol 267 No 7169 p510-525
13 October 2001

BPC 2001 summary

Use of monoclonal antibodies to target cancer cells

Monoclonal antibodies (MAbs) are becoming standard therapy, especially for haematological cancers, and there is hope that they will eventually be used successfully for solid tissue tumours, said Dr Sally Waterman, vice-president of research and development at KSBiomedix.

In an overview of the various types of MAb, she said that over 80 are in development for use against cancer. Ideally, MAbs target antigens that are only expressed on tumour cells. However, this is not always the case.

MAbs were initially unsuccessful because they were derived from mice and caused allergic reactions. Chimeric MAbs, which are 60 to 70 per cent human, then became available, and now 90 per cent humanised MAbs are being produced. However, even the improved versions can cause reactions, so fully human MAbs are in development. These are not easy to manufacture, because humans rarely make antibodies to their own tumours.

Dr Waterman explained the generic names of MAbs. Names that end “momab” are derived from mice, those that ending “ximab” are chimeric antibodies and “zumab” indicates that the MAb is either humanised or human.

MAbs can be classified as anti-idiotypic, naked or conjugated. Anti-idiotypic MAbs provoke an inflammatory response to themselves. Naked MAbs, such as rituximab, induce a direct inflammatory response to tumour cells or block the receptors of molecules needed for growth or differentiation (eg, trastuzumab, Herceptin).

Conjugated MAbs can be used to deliver a “warhead”, such as a cytotoxic or radioactive molecule (eg, ⁹⁰Yttrium or ¹³¹Iodine). Cytotoxic molecules are inactive when conjugated to the MAb but become active when dissociated from it. The selection of the radionuclide used with MAbs is important, and depends on the size of the tumour and the half-life and path length of the isotope used. Alpha particles have a limited ability to penetrate tissue and have a short half-life but b emitters can penetrate several cells deep.

The advantage of delivering of radionuclides by conjugated MAbs is that it does not rely on the patient having a competent immune system. Healthy cells next to the tumour remain unharmed, providing they do not express the targeted antigen. However, this method is complicated and expensive.

MAbs can also be used to deliver immunotoxins, which enter cancer cells and induce apoptosis (cell death) by inactivating protein synthesis. This is extremely effective but is not always tumour-specific and healthy cells can be damaged. In addition, immune responses to the immunotoxin can develop, limiting repeat treatment.

Newer areas of research include antibody-directed enzyme prodrug therapy, which should allow delivery of greater doses of cytotoxic drugs to tumours, and bispecific MAbs.

Bispecific MAbs have specificity for two active conjugates, for example, an antigen and a cytotoxic or an antigen and a radionuclide.

Whichever method is used, there is still a lot of work to be done to improve treatment using monoclonal antibodies, Dr Waterman concluded.

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