Stat, Myc, Myb, Fos, Ras and Fox: Those bland monosyllables, unfamiliar to most of us, command the respect and fear of oncologists and cancer researchers worldwide. Why? Because they name proteins that drive uncontrollable cell division, metastasis and/or drug resistance in numerous cancers.
Worsening their reputation is the fact that all of these proteins are sequestered inside cells, many in the nucleus, where they’ve proved largely out of reach to therapies based on antibodies (Abs) — a most effective and precise drug modality.
That could be about to change.
City of Hope researchers, Hua Eleanor Yu
, Ph.D., and Andreas Herrmann
, Ph.D., have devised game-changing technology to chemically modify Abs so that they cross cell membranes to disable disease-causing proteins inside cells. City of Hope has licensed this technology to San Diego-based Sorrento Therapeutics
, and last month the two entities announced the creation of LA Cell Inc., a company that will develop a new class of antibodies based on the breakthrough. That deal sets the stage for never-before-imagined targeted treatments for some of the most intractable diseases, including cancer.
Sharpening the aim of targeted treatment
Because therapies using antibodies have been effective only against proteins on the outside of cells, drug companies had been reluctant to put equivalent effort into developing Abs against intracellular factors.
“This novel technology has the potential to revolutionize medicine,” says Yu, the Billy and Audrey L. Wilder Professor in Tumor Immunotherapy at City of Hope, and co-leader of the Cancer Immunotherapeutics Program. “Antibodies that can penetrate the cell could be used to treat what, up to now, have been incurable diseases, including deadly malignancies like pancreatic cancer and even infectious diseases like HIV.”
Herrmann and Yu 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. Their results show that modified Abs recognize and potently inhibit several cancer-causing oncoproteins, including STAT3 and Kras mutant, leading to effective inhibition of tumor growth.
“Treatment with the modified STAT3 antibodies significantly slowed tumor growth in animal models of cancer and prevented STAT from binding DNA,” says Herrmann, a City of Hope associate research professor. “The unmodified antibodies didn’t even penetrate cultured tumor cells.”
Learning to turn off cancer’s ‘on’ switch
STAT3 is what molecular biologists call a transcription factor, meaning it binds DNA in a cell’s nucleus and switches genes on. Herrmann says further studies suggested that the modified antibodies trapped STAT3 inside cell’s cytoplasm before it reached its nuclear destination, restraining it from activating oncogenic gene expression.
STAT3 activity in the context of cancer has long been a focus of Yu’s research. Her team has been a key pioneer in the field. Numerous studies have shown that activated STAT3 revs up cell division in tumors as diverse as prostate, pancreatic, blood and brain cancers. Over the last decade, she and her team have also published groundbreaking studies identifying STAT3 as a major player in subverting a patient’s immune response, and making tumors invisible to cell-killing T cells. The good news is they also have helped pioneer molecules that block STAT3 and hence awaken that immune response.
This puts potential STAT3 inhibitors center stage as candidate “immunotherapies,” that is, drugs that stimulate a patient’s immune system to eradicate tumors, in contrast to cytotoxic therapies that directly kill malignant cells. Nonetheless, STAT3’s intracellular locale presented a barrier to realizing that potential.
The new technology is a game-changer because it puts STAT3 and the other monosyllabic troublemakers within reach of antibody drugs that silence them. Among the latter 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.
Clinical tests of a game-changing technology are coming soon
City of Hope’s cell-penetrating expertise and Sorrento’s track record of developing human antibodies puts that brass ring within reach. “Once antibodies become available, we will be working to test their ability to block disease progression in cancer models,” says Yu. “Given our close collaborations with scientists at LA Cell, we envision possible clinical testing of one or two antibody drugs targeting cancer within 18 to 30 months.”
The new development builds on City of Hope’s rich history of developing revolutionary biopharmaceutical approaches, says Steven T. Rosen
, M.D., City of Hope provost and chief scientific officer.
“Those achievements include – for starters -- the fundamental technology required for mammalian cell-based antibody production, as captured in the Cabilly patent,” says Rosen, referring to former City of Hope scientists Shmuel Cabilly, Ph.D., and Art Riggs
, Ph.D., who invented the recombinant, or human-made, antibodies in the 1980s. “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.”
The total value of the partnership deal reached with Sorrento Therapeutics reportedly exceeds $170 million for development of modified monoclonal Abs and includes an equity provision and upfront and milestone payments to City of Hope.
The research was supported by grants from National Institutes of Health/National Cancer Institute and by City of Hope.
Research reported in this release was supported by the National Cancer Institute of the National Institutes of Health under grant number R01 CA122976. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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