City of Hope researchers have announced game-changing technology to chemically modify antibodies (Abs) so that they can cross cell membranes to disable disease-causing proteins inside cells, a feat long-sought by researchers worldwide. The new technology is expected to lead to never-before-imagined targeted treatments for some of the most intractable diseases.
To date, drug companies had been reluctant to put effort into developing therapies that target intracellular factors, simply because they couldn’t get them inside cells. That is, the targets were “undruggable.” The new technology allows for such targeting and has already been licensed to San Diego-based Sorrento Therapeutics, which with City of Hope has created a new company, LA Cell Inc., to pioneer this new class of antibodies.
The technology was invented by Andreas Herrmann, Ph.D., associate research professor, and Hua Eleanor Yu, Ph.D., the Billy and Audrey L. Wilder Professor in Tumor Immunotherapy at City of Hope and co-leader of the Cancer Immunotherapeutics Program. “This novel technology has the potential to revolutionize medicine,” Yu said. “Antibodies that can penetrate the cell could be used to treat what up until now have been incurable diseases, including deadly malignancies like pancreatic cancer and even infectious diseases like HIV.”
Yu and Herrmann discovered that Abs could be chemically modified to allow passage into a cell’s interior, or cytoplasm, without compromising their ability to recognize specific targets. They have tested the technology to modify a number of Abs to recognize several critical cancer-causing oncoproteins, including STAT3, which is activated in a majority of human cancers.
“Treatment with the modified STAT3 antibodies significantly slowed tumor growth in animal models of cancer and prevented STAT from binding DNA,” said Herrmann. “The unmodified antibodies didn’t even penetrate cultured tumor cells.”
The new technology puts STAT3 and other previously undruggable targets within reach of therapeutics. Among those is Myc, the “granddaddy” of all oncoproteins (characterized in lymphoma 25 years ago, Myc is a subject of more than 23,000 scientific papers). High levels of Myc, which like STAT3 is a transcription factor, likely keep cells uncontrollably dividing in half of all cancers, including breast, prostate and gastrointestinal tumors, in addition to lymphoma.
City of Hope’s cell-penetrating antibody technology and Sorrento’s track record of producing fully humanized antibodies puts that brass ring within reach. “This new method to harness the inherent specificity of antibodies against antigens inside cells could transform the field of biomedical research and benefit patients worldwide who are in need of new and effective immunotherapies,” said Steven T. Rosen, provost and chief scientific officer at City of Hope.