Using Conjugated Monoclonal Antibodies to Decrease the Toxicity of Chemotherapy
For many cancer patients, coping with the consequences of chemotherapy treatment can be as much of a challenge as living with the disease itself. Some potentially useful chemotherapeutic agents are so toxic to healthy cells that they cannot be directly administered to patients. By conjugating these drugs to monoclonal antibodies that bind specifically to cancer cell surface receptors, it is possible to selectively deliver them to cancer cells in order to decrease the toxicity of chemotherapy.
Conjugated monoclonal antibodies open the door for fighting cancer with much stronger cytotoxic drugs while significantly improving a patient’s quality of life. For patients with particularly aggressive forms of cancer, low doses of chemotherapy aren’t enough to combat the disease, but increasing the dose or using a stronger cytotoxic agent is too risky. Killing a patient’s healthy cells not only triggers immediate side effects, but it can also have long-term medical consequences even after a patient is in remission. Conjugated monoclonal antibodies could improve patient outcomes by decreasing the toxicity of chemotherapy. Currently, two monoclonal antibodies have received approval from the FDA: Trastuzumab emtansine (Kadcyla) can effectively treat certain forms of breast cancer, and Brentuximab vedotin (Adcetris) can improve outcomes for patients with relapsed or refractory Hodgkin’s lymphoma and relapsed or refractory anaplastic large cell lymphoma.
However, like most cancer treatments, conjugated monoclonal antibodies aren’t a “silver bullet” cure for the disease. Not all early efforts have been successful. One such case is that of gemtuzumab ozogamicin, which consists of a toxic calicheamicin linked to monoclonal antibody that targets the CD33 receptor on cancer cells.1 It was used to treat acute myelogenous leukemia from 2000 to 2010, but it was withdrawn from the market because studies found that it provided no benefit over traditional chemotherapy treatment and was even associated with an increase in patient mortality.2 Another drug-antibody conjugate, inotuzumab ozogamicin, hasn’t fared much better. The monoclonal antibody targets the CD22 protein on cancer cells and was considered a potential treatment for non-Hodgkin lymphoma, but Phase 3 drug trials were abandoned for “futility.”3 Inexplicably, the treatment just didn’t seem to work.
Finding Ways to Increase the Effectiveness of Monoclonal Antibodies
To improve the effectiveness of monoclonal antibody treatment, scientists have started tethering chemotherapy drugs to monoclonal antibodies that themselves prevent cancer cell proliferation. Treatment with “naked” monoclonal antibodies has long been used to supplement treatment with chemotherapy. Naked monoclonal antibodies bind to cancer cell surface receptors involved in the activation of cell proliferation pathways.4 Researchers hope that by linking chemotherapy drugs to monoclonal antibodies that themselves block proliferation pathways, they can develop monoclonal antibody treatments that are more effective than gemtuzumab ozogamicin and inotuzumab ozogamicin.
This has certainly been true in the case of trastuzumab emtansine. Trastuzumab is a monoclonal antibody that binds to the HER2 protein on the surface of breast and stomach cancer cells, thereby blocking two major cell proliferation pathways. At the same time, trastuzumab delivers the toxin emtansine directly to a cancer cell.5 Targeting cancer cells in two different ways makes the conjugated monoclonal antibody doubly effective, and trastuzumab emtansine has been shown to improve outcomes for many breast cancer patients.
How Researchers Can Harness Technology to Develop Conjugated Monoclonal Antibodies That Work
Although the example of trastuzumab emtansine demonstrates the potential for conjugated monoclonal antibodies to effectively treat cancer, researchers still face a daunting task. For many types of cancer, monoclonal antibodies have not yet been identified. In the past, searching for antibodies that could target cancer cells was slow going, but modern software has the potential to significantly speed up the discovery process. This technology provides tools that process enormous amounts of antibody sequence and cancer cell line data, which will allow scientists to screen more antibodies than ever before, in the context of more types of cancer. Because of this unprecedented access to such high volumes of data, scientists will be able to find more antibody matches for more cancers.
Still, even when researchers do find a monoclonal antibody that targets a specific surface receptor on a cancer cell, there’s a chance that the treatment will be ineffective, as it was in the case of gemtuzumab ozogamicin and inotuzumab ozogamicin. Once again, researchers are turning to software that makes it easier to determine which conjugated monoclonal antibodies to target for development. Appropriate software tools efficiently integrate and analyze data, which reduces errors so that ineffective and dangerous drugs never make it to clinical trials. By streamlining the development process, new technology makes it possible for researchers to focus all of their efforts on developing the conjugated monoclonal antibodies that will really work.
Improving the workflow of conjugated monoclonal antibody development has the potential to significantly increase the speed of the overall development cycle. Once a conjugated monoclonal antibody has been developed for one form of cancer, researchers can start the search for an antibody that targets another form of the disease. In the field of cancer research, where time is of the essence, technology that speeds development while reducing errors will be revolutionary.
BIOVIA Biologics is an innovative software solution that provides the tools that life sciences organizations need to defeat cancer once and for all. The software makes it easy to process and analyze high volumes of antibody sequence data in the early identification stage, and its data management and analysis platforms make the overall workflow more efficient. Contact us today to learn how this software can help your research laboratory develop superior cancer treatment options.
- “Approval summary: gemtuzamab ozogamicin in relapsed acute myeloid leukemia,” June 2001, https://www.ncbi.nlm.nih.gov/pubmed/11410481 ↩
- “Pfizer pulls leukemia drug from US market,” June 21, 2010, http://www.reuters.com/article/us-pfizer-mylotarg-idUSTRE65K5QG20100621 ↩
- “Pfizer Discontinues Phase 3 Study of Inotuzumab Ozogamicin in Relapsed or Refractory Aggressive Non-Hodgkin Lymphoma (NHL) Due to Futility,” May 20, 2013, http://pfizer.newshq.businesswire.com/press-release/pfizer-discontinues-phase-3-study-inotuzumab-ozogamicin-relapsed-or-refractory-aggress ↩
- “Monoclonal antibodies to treat cancer,” July 23, 2015, http://bit.ly/1RqdIGx ↩
- “Trastuzumab emtansine for HER2-positive advanced breast cancer,” June 20, 2013, https://www.ncbi.nlm.nih.gov/pubmed/23020162 ↩