24.03.5 Monoclonal Antibodies

Most anticancer drugs exert their therapeutic effects by targeting processes that are integral to cell proliferation, a key marker of malignancy. However, since these processes are also occurring in normal cells, non-cancer cells are also a target for these drugs. As discussed earlier, this lack of selectivity often results in the adverse effects associated with anticancer drugs. The use of monoclonal antibody (mAB) technologies has resulted in an active area of drug development for anticancer therapy and other non-cancerous diseases. The ability of these molecules to specifically identify targets that arise during cancer development provides powerful and selective anticancer treatments that often have fewer adverse effects than conventional treatments.

The basic premise of all antibody treatments is to produce a drug that reacts with an antigen that is specifically expressed on cancer cells. Interaction of the mAB with the antigen, which is usually a component of cell growth and proliferation, leads either to interruption of the normal cellular processes that occur, killing the target cell or activation of the host’s immune system resulting in the same conclusion.

mABs are produced from B-lymphocytes isolated from immunised mice or hamsters which have been infused with an immortalised B-lymphocyte tumour cell line. The resultant hybrid cells (or hybridomas) are individually cultured to produce a clonal cell that produces antibodies against a single antigen type. Recent advances in recombinant DNA technology has allowed for the creation of “humanised” antibodies that can overcome previously observed immunological problems associated with administration of animal-derived antibodies. Currently, there are several mABs that are indicated for the treatment of cancer. These exist in the “naked” form where the immunological properties of the antibody alone are enough to disrupt cell function, and the “conjugated” form where the mAB is associated with a cytotoxic element such as a toxin or radioactivity.

The first mAB approved as an anticancer therapy was rituximab. This antibody is directed against the CD20 surface antigen found in normal and malignant lymphocytes but absent in other bone marrow derived cells. CD20 plays an important role in the activation process for cell-cycle initiation and cell differentiation. Binding to CD20 by rituximab results in an autoimmune response culminating in complement-mediated and antibody-dependent cytotoxicity of the B cells. The antibody is commonly used in combination with other drug therapies. Severe adverse effects have been noted with administration of rituximab. These include hypotension, bronchospasm, angioedema (swelling below the skin surface), tumour lysis syndrome resulting in acute renal failure, and blood cell problems including leukopaenia, thrombocytopaenia and neutropaenia.

Trastuzumab (marketed as Herceptin) targets human epidermal growth factor receptor 2 (HER2) and is used in the treatment of early breast cancer and metastatic breast cancer. Activation of HER2 by mitogen agonists promotes cell proliferation. The HER2 gene is amplified in some 25-30% of early breast cancers leading to an overexpression of the receptor and subsequent increased sensitivity of the malignant tissue to the mitogen, an effect blocked by administration of trastuzumab. The most serious adverse effect associated with trastuzumab administration is congestive heart failure. Other adverse effects such as infusion-related fever and chills, headache, dizziness, vomiting, nausea and back pain are well tolerated.

Bevacizumab is the first in a new class of anticancer drugs known as anti-angiogenesis agents and is indicated for use in the treatment of metastatic colorectal cancer. This antibody binds to vascular endothelial growth factor A (VEGFA) neutralising its ability to stimulate the formation of new blood vessels thus depriving tumours of oxygen and nutrients essential for growth and proliferation. Among the rare serious side effects of bevacizumab are bowel perforation and stroke. A second mAB also used to treat metastatic colorectal cancer, cetuximab, exerts its anticancer effect by targeting the epidermal growth factor receptors on the surface of cancer cells and retarding their growth. Cetuximab has been reported to cause breathing difficulties during the first treatment and interstitial lung disease has been reported.

Other “naked” mABs used in the treatment of cancers are alemtuzumab (chronic lymphocytic leukaemia) and panitumumab (metastatic colorectal cancer). It is expected that many more will be developed over the next few years.

A second group of mAB therapies being developed are the “conjugated” mABs which comprise couopling the antibody to a cytotoxic element ,usually a toxin or a radioactive isotope. The most successful of these is ibritumomab tiuxetan which is an antibody directed against the CD20 antigen coupled with a molecule called tiuxetan which contains a radionucleotide (either yttrium-90 or indium 111). The antibody binds to the CD20 antigen found on the surface of normal and malignant B cells (but not B cell precursors), allowing radiation from the attached isotope (mostly beta emission) to kill it and some nearby cells. It is primarily used in the treatment of non-Hodgkin lymphoma. A second mAB directed against the CD20 antigen tagged with Iodine-131, tositumomab is also available as a therapy for non-Hodgkin lymphoma. However, gemtuzumab, an antibody directed against the CD33 surface antigen found in 80% of all patients with acute myelocytic leukaemia, and conjugated with the plant toxin, ozogamicin has recently been withdrawn from clinical use due to toxicity problems.