April 20, 2018 | by City of Hope
In the early 1980s, geneticist Art Riggs, Ph.D., Samuel Rahbar Chair in Diabetes & Drug Discovery and chair of the Department of Diabetes and Metabolic Diseases Research, worked with his City of Hope colleague Shmuel Cabilly, Ph.D., to develop a method to humanize monoclonal antibodies, magic bullets that can specifically target any substance and have become an extremely important tool in medicine, in particular leading to the creation of cancer drugs such as Herceptin, Rituxan, Erbitux and Avastin.
Now, another team of City of Hope researchers is leading the way to use the precision of monoclonal antibodies by bolting different types of cargo to them for therapeutic purposes, to improve drug delivery and even to help image inside the body.
We have developed an entirely novel and straightforward approach to rapidly produce and test different cargo to treat different diseases — each of which has the possibility of turning into a clinical candidate,” said John Williams, Ph.D., professor of molecular medicine at City of Hope and corresponding author of a paper recently published about the new approach.
"Furthermore, our technique is applicable to any antibody that is being developed for any disease.”
The team’s method builds upon a serendipitous discovery by the Williams lab — an observation that could only be made using X-ray crystallography, a tool used to determine the atomic structure of molecules. They identified a unique interaction between a small peptide and a naturally occurring ‘hole’ that runs through the antibody, much like a key and a lock, and recognized that they could use this interaction to selectively deliver material to cancer cells.
Follow-up studies worked to find a way to ensure that the key carrying the material didn’t fall out before the antibody could target the cell. The team’s recent paper reveals the answer: They found that the tip of the ‘key’ could be seen from the other side of the hole, so they developed a way to add something to that tip so it wouldn’t rattle out.
“In a nutshell, we literally figured out how to bolt on toxins and imaging agents to monoclonal antibodies,” said Williams.
The concept is similar to how molecular machines, awarded a Nobel Prize in Chemistry in 2016, are made. The researchers responsible for that breakthrough science found ways to interlock small molecules together. Williams said that, to the best of his knowledge, his team is the first to do the same with biologics — a classification of drugs that are made using a living organism or products from one.
“More importantly, we’ve done it using an antibody, which is the most important class of biologics for cancer and other illnesses,” said Williams.
Furthermore, the technique has seemingly endless capabilities for combining treatments. For example, you can decorate 20 bolts with different functionalities and 20 nuts with different functionalities, which gives you 400 different combinations without any need to 're-engineer' the antibody to see if it works. In this analogy, said Williams, each bolt has precisely the same threads and each nut will thread onto the bolt. The difference is the toxin, imaging agent or other cargo that you chemically attach to “decorate” the bolt and nut.
Meditope enabling of the antibody is straightforward and we have had a 100 percent success rate for every antibody we’ve attempted — around 50 thus far,” said Williams.
But the road to success wasn’t easy and required patience and a rational approach through the use of X-ray crystallography, biophysics and crafty chemical synthesis, said Williams. He credits David Horne, Ph.D., vice provost and associate director of Beckman Research Institute of City of Hope, as well as the Dr. & Mrs. Allen Y. Chao Chair in Developmental Cancer Therapeutics, and his team as being “absolutely instrumental” in the work’s progress by generating compounds that never existed and producing the next round of molecules needed to test the team’s process. Williams also points out that this achievement would not have been possible without donor support of the research.
“Reviewers on previous study sections indicated that we could not improve binding affinity beyond approximately 10 times and gave us a nonfundable score several times,” recalled Williams. “Thankfully, City of Hope donors and the W. M. Keck Foundation had the vision and means to provided sufficient funds, allowing us to improve the affinity nearly a million-fold and ultimately the meditope bolt and nut, effectively making it infinite affinity.”
Now, Williams and his team are working with multiple principal investigators at City of Hope to arm their favorite antibodies for targeted therapies and to improve drug delivery. For example, they have already added new functionalities to meditopes so they can simultaneously target multiple signaling pathways as a way of improving antibody drug conjugates and are also collaborating with the lab of assistant professor Tijana Talisman, Ph.D., to develop new reagents for super-resolution microscopy.
Williams likens the meditope technology to the iPhone: The device itself has inherently utility, however, its ability to connect the internet lead to a wide array of new devices and applications. The team doesn’t know all the applications their technique will enable but publishing the technology will allow them and others to develop many new monoclonal antibody applications.
“For me personally, it is super gratifying as it feels like we are able to add a small piece to the legacy of Dr. Riggs and City of Hope,” said Williams. “Dr. Riggs humanized monoclonal antibodies and we're now bolting on new pieces to further improve their therapeutic efficacy.”
The paper that describes the work, “Mechanically-interlocked functionalization of monoclonal antibodies,” was published on April 20 in the journal Nature Communications. City of Hope researchers Krzysztof P. Bzymek, Ph.D., Cindy Zer, Ph.D., Jun Xie, Ph.D., Yuelong Ma, Ph.D., Jeremy D. King, Ph.D., Kendra N. Avery, David Colcher, Ph.D., Gagandeep Singh, M.D., and Horne were co-authors of the study.