The new study, which was published July 5 in an advanced, online edition of the Proceedings of the National Academy of Sciences, achieved a significant enhancement of the treatment of metastatic breast cancer in animal models. The study showed the new hybrid compound remained in circulation for a week. In comparison, the small molecule drug was cleared in a matter of minutes.
"Although the study focused specifically on breast cancer, these new findings could have broad application in the treatment of a number of other cancers, potentially increasing the efficacy of a number of existing or undeveloped small molecule therapies," said Subhash C. Sinha, Ph.D., associate professor in the Scripps Research Department of Molecular Biology and the Skaggs Institute for Chemical Biology, who led the research with Scripps Research President Richard A. Lerner, M.D., Lita Annenberg Hazen Professor of Immunochemistry, Cecil H. and Ida M. Green Chair in Chemistry, and a member of the Skaggs Institute for Chemical Biology.
In the study, the scientists created what is known as a "chemically programmed antibody" by using small cell-targeting molecules and a non-targeting catalytic monoclonal aldolase antibody in a novel self-assembly strategy. Antibodies are proteins produced by immune cells that are designed to recognize foreign pathogens harmful to the body; monoclonal antibodies are produced in the laboratory from a single cloned B-cell, the immune system cell that makes antibodies.
"By bringing together chemistry and biology, our approach provides a way to break the traditional one antibody-one target axiom of immunochemistry," said Lerner. "This new hybrid technology offers great possibilities for the enhanced treatment and diagnosis of a variety of diseases, including cancer."
Preventing Breast Cancer Metastasis
In the study, the researchers used the unique assembly strategy to create a novel compound to combat metastatic breast cancer.
Breast cancer can be a treatable disease, but only if diagnosed early. Since the prognosis grows considerably worse once the cancer has spread to other organs, the prevention of metastasis-the phenomenon in which cancer cells separate from a tumor mass, move through the bloodstream, anchor down in a distant tissue or organ to begin a new cancer-remains a critically important goal. The most recent figures from the Centers for Disease Control and Prevention indicate that more than 200,000 U.S. women are diagnosed with new cases of invasive breast cancer each year and that more than 40,000 of these women will die of the disease-usually the end result of metastasis.
The therapeutic use of monoclonal antibodies has expanded rapidly over the last several years precisely because of their long half-life, combined with their overall lack of toxicity and the fact that they can be easily designed and produced. For cancer treatment, the ability of antibodies to direct immune system responses to specific tumor types is one of the factors that have led to their increased use.
Until recently, it had been widely accepted that while antibodies possess a number of therapeutically advantageous traits, treatment with monoclonals required a different antibody for each specific target. However, the paper's authors have been showing that scientists can use different small molecule targeting agents-called programming agents or adapters-to selectively direct the same antibody to different sites for different uses so that only a single antibody is required for multiple tasks.
Recent research led by Scripps Research Professor Carlos F. Barbas III, for example, used the chemically programmed antibody approach in a melanoma model, dramatically enhancing the effectiveness of a small molecule drug (International Journal of Cancer 119 (5), 1194-1207, March 28, 2006).
In the new study, the researchers used a self-assembly process to link small synthetic molecules and a well-known catalytic monoclonal antibody, mAb38C2, through chemical bonding, a modification that resulted in the reprogramming of the specificity of the antibody to match the binding specificity of the small molecule. In this way, the antibodies were directed to the target avb3 integrin-a cell membrane protein expressed on a variety of cancers and the vasculatures they produce.
"Key to this unique approach is the ability of the small molecule targeting agents-called programming agents or adapters-to selectively react in the antibody binding sites without compromising the targeting property of the adapters," notes Sinha.
The results showed those mice treated with the new compound developed significantly fewer metastases than those treated with other similar compounds or the antibody alone. These results, the study noted, were a "significant enhancement in the therapeutic efficacy" of the integrin antagonist directly attributable to the chemically programmed antibody approach.
Moreover, the study indicated that this approach allows for the effective assembly of chemically programmed antibodies in vivo or in vitro, widening the possibilities for their therapeutic application. The compound could be created in vitro and delivered as a conventional single therapy. Alternately, the small molecule and antibody could be injected separately, with the new complex formed in vivo. The authors note that even though the administration of two separate compounds might complicate regulatory approval, the regimen could have advantages-for example, an imaging agent could be attached to the small molecule, allowing a physician to monitor localization of a drug before arming the agent with the antibody molecule.
Keith McKeown | EurekAlert!
How brains surrender to sleep
23.06.2017 | IMP - Forschungsinstitut für Molekulare Pathologie GmbH
A new technique isolates neuronal activity during memory consolidation
22.06.2017 | Spanish National Research Council (CSIC)
An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.
Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...
Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.
Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...
Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.
As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...
Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.
With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...
Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine
Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...
19.06.2017 | Event News
13.06.2017 | Event News
13.06.2017 | Event News
23.06.2017 | Physics and Astronomy
23.06.2017 | Physics and Astronomy
23.06.2017 | Information Technology