Breast cancer is a complex and devastating disease that affects thousands of women every year; occurring when cells acquire mutations causing them to behave differently from healthy cells. The mutated cells proliferate uncontrollably, dedifferentiate, or regress to a simpler form, avoid apoptosis (the time a cell is supposed to die) and can spread and invade other tissues – we call this process metastasis.
Currently many chemotherapy drugs for breast cancer lack selectivity, resulting in damage to healthy tissue. This causes a number of side effects including emesis (nausea), myelosuppression (decrease in bone marrow activity), alopecia (hair loss), impaired wound healing, and sterility.
One strategy to try and reduce these distressing side effects, as well as improve the outcome of treatment, is to target the cancer cells without harming the healthy cells. Due to their specificity, antibodies are able to bind to antigens that are unique to or overexpressed on cancer cells. ‘This means they can help deliver a cytotoxic drug directly to the cancer cell. We call these new anti cancer agents antibody drug conjugates.
Trastuzumab Emtansaine: an Overview
In February 2013, the FDA approved the antibody drug conjugate Trastuzumab Emtansaine (Kadcyla) to treat HER2-positive breast cancer. This conjugate is the third antibody drug conjugate to gain approval. The humanised antibody Trastuzmab, which targets the human epidermal growth factor receptor on breast cancer cells, makes up part of Trastuzumab Emtansaine.
Gene amplifications and protein overexpression of this antigen occur in around 15% to 25% of breast cancer patients. Trastuzmab joins a noncleavable thioether linker to the cytotoxic agent DM1, a derivative of maytansine first isolated from the Ethiopian shrub Maytenus ovatus. After binding to the HER2 target, Trastuzumab Emtansaine internalizes. Proteolytic digestion then occurs, freeing the drug – this results in inhibition of microtubule assembly. The process ends with mitotic arrest and death of the cancerous cell.
What Do the Clinical Studies Say?
Trastuzumab Emtansaine gained approval based on data from the phase III EMILIA trial. During this trial, 991 patients were randomly assigned to taking Trastuzumab Emtansaine or lapatinib plus capecitabine. The results showed that Trastuzumab Emtansaine increased median progression-free survival from 6.4 months for the patients on lapatinib plus capecitabine to 9.6 months for patients on Trastuzumab Emtansaine. The overall survival was increased by 5.8 months and it was shown that Trastuzumab Emtansaine had fewer side effects than lapatinib plus capecitabine.
Promising Anti-Cancer Agent
Trastuzumab Emtansaine looks like a promising anti-cancer agent that meets the requirements for a successful antibody drug conjugate. It has an antibody that targets an antigen that is over-expressed in cancer cells but only present in low amounts on healthy cells. The cytotoxic agent is potent and conjugated to the antibody via a non-cleavable linker which is stable in systemic circulation. The cancer cell internalizes the agent, which results in cell death. So far clinical trials have shown that patients tolerate the agent well, and that it is effective at improving treatment outcomes.
Burris, H.A., Tibbitts, J., Holdon, S.N., Sliwkowski, M.X. & Lewis Phillips, G.D. Trastuzumab Emtansine (T-DM1): A Novel Agent for Targeting HER2+ Breast Cancer. (2011). Clinical breast cancer. Accessed November 3, 2013.
Genetech. FDA Approves Genentech’s Kadcyla (Ado-Trastuzumab Emtansine), the First Antibody-Drug Conjugate for Treating Her2-Positive Metastatic Breast Cancer. (2013). Accessed November 3, 2013.
LoRusso, P.M., Weiss, D., Guardino, E., Girish, S. & Sliwkowski, M.X. Trastuzumab Emtansine: A Unique Antibody-Drug Conjugate in Development for Human Epidermal Growth Factor Receptor 2-Positive Cancer. (2011). Clinical Cancer Research. Accessed November 3, 2013.
Verma, S., Miles, D., Gianni, L., Krop, I.E., Welslau, M., Baselga, J., Pegram, M., Oh, D., Diéras, V., Guardino, E., Fang, L., Lu, M.W., Olsen, S. & Blackwell, K. Trastuzumab Emtansine for HER2-Positive Advanced Breast Cancer. (2012). North England Journal Medicine. Accessed November 3, 2013.