A multi-institutional team of researchers has found that a new cancer treatment, which combines antibody fragments with molecularly engineered nanoparticles, permanently eradicates stomach cancer in treated mice.
Results of a ‘hit and run’ drug delivery system, published in the March issue of advanced treatmentswas the culmination of more than five years of collaboration between Cornell, Memorial Sloan Kettering Cancer Center (MSKCC) and biopharmaceutical company AstraZeneca.
“I’ve seen great results before, but I’ve never seen anything that eradicates a tumor like this,” said study co-author Michelle Bradbury, director of intraoperative imaging and professor of radiology at Weill Cornell Medicine.
Other lead authors are Ulrich Wiesner, Spencer T. Olin Professor in the Department of Materials Science and Engineering at Cornell University of Engineering. and J. Anand Subramony, Vice President of Protein Engineering Research and Development at AstraZeneca at the time of the study.
Targeted cancer therapies such as antibody and nanoparticle therapies have seen limited clinical use due to each therapy’s limitations, but the new treatment — an evolution of what researchers call Cornell key points, or C points — combines the best features of both in a very small device. , a powerfully efficient system.
Because silica nanoparticles are only 6 nanometers in size, C-dots are small enough to penetrate tumors and pass safely through organs once injected into the body. Wiesner first developed it more than 15 years ago and, in collaboration with Bradbury, published a 2018 study that found a fragmentation hybrid of nanoparticles to be particularly effective at finding tumors.
This collaborative work with AstraZeneca began the search for a new, molecularly engineered therapeutic version of this immune complex.
AstraZeneca has designed “site” fragments of the antibody so that they bind effectively to C-dots and target HER2 proteins associated with stomach cancer. The team optimized the C-point surface partial coupling, along with specialized inhibitory drugs developed by AstraZeneca. This enabled the nanoparticles to carry five times more drugs than most antibodies.
The final product was a version of C-dots, armed with cancer-targeting antibody fragments and a large drug payload, all packaged into a sub-7 nanometer antidrug conjugate—a first in this size class, according to the researchers.
We describe the mode of action as a ‘hit and run, because C-points’ either target the tumor microenvironment and kill tumor cells or are safely cleared from the body by renal filtration as a result of their small size, thus minimizing target accumulation and associated side effects and toxicity. “
Ulrich Wiesner, Spencer T. Olin Professor, Department of Materials Science and Engineering, Cornell Engineering
Mice with stomach cancer received three doses of the treatment. Not only did the disease eradicate in every mouse, but there was no evidence of tumor recurrence after approximately 200 days.
“You usually have to combine therapy with other therapies to see these kind of long-term results,” Bradbury said. “It has shown that this team’s extremely meticulous work — the years spent measuring elemental and surface chemical evolutions — has paid off.”
Bradbury emphasized the versatility of the C-point platform, and said she envisions using it not as a replacement for antibody therapies, but as a complementary tool that could be adapted to different types of cancers and other specific needs of patients.
“C-points have become extraordinarily effective and safe in the treatment of cancer. They completely eradicated the tumor, even at the cellular level,” Wisner said. “This is what we hoped for in the end and it supports our previous decision to bet on C’ dot therapeutic applications.”
Wiesner and Bradbury said the research behind the new C’ dot treatment will be continued by Elucida Oncology, a startup they founded to help bring the technology to market. They said that while Elucida is not using antibody fragments in its current C-point clinical trial, the work will help them build new consortia that could use such fragments in future trials.
Chang, L.; et al. (2022). Engineered Ultra-Small Nanoparticle Drug‐Coupled Immune System with “Hit and Run” Tumor Delivery to Eradicate Stomach Cancer. advanced treatments. doi.org/10.1002/adtp.202200209.