On September 6, 2022 NaNotics LLC, a biopharmaceutical company developing NaNots, novel subtractive nanoparticles that treat disease by capturing and clearing pathogenic molecules from blood, reported a research collaboration with Mass General Cancer Center, a program of Massachusetts General Hospital (MGH) in Boston, to develop NaNots that target the soluble forms of Tumor Necrosis Factor Receptors, which are tumor-generated immune inhibitors, with the goal of initiating human trials by mid-2024 (Press release, NaNotics, SEP 6, 2022, View Source [SID1234619088]).
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Tumor necrosis factor-alpha (TNF-α) is an essential immune signaling molecule which, as the name implies, is toxic to cancer and other abnormal cells. Immune cells kill bad cells by delivering TNF-α to TNF receptors on the target cell membrane, inducing apoptosis (cell death). However, most if not all malignant tumors inhibit TNF-α by cleaving off the extracellular domains of their TNF receptors, producing a soluble receptor form called "sTNF-Rs". sTNF-Rs neutralize TNF-α molecules secreted by immune cells, preventing them from inducing apoptosis in cancer cells, thereby enabling immune evasion. This bioanimation by the Company illustrates the process.
sTNF-Rs have been undruggable targets. Functional membrane TNF receptors (mTNF-Rs) are essential for a broad range of normal immune functions. A drug that neutralizes sTNF-Rs would also block mTNF-Rs, given that the binding sites of both forms are identical. Instead, NaNots deplete soluble targets – in this case sTNF-Rs – without blocking membrane forms of the same target – in this case mTNF-Rs. NaNots represent a novel form of immunotherapy, targeting an important new immunosuppressive pathway. NaNots have been tested for safety in rodents at up to 100x the planned human dose, with no observed toxicity.
The MGCC team is led by Keith Flaherty, M.D., Director of Clinical Research and a Professor of Medicine at Harvard Medical School. Dr. Flaherty is also a co-founder of multiple cancer therapeutics companies, including Loxo Oncology. Dr. Flaherty’s team includes Justin Gainor, MD, Director of Targeted Immunotherapy at MGCC.
"Despite the profound benefits of PD-1/PD-L1 antibody-based immunotherapy for approximately 10% of cancer patients, it is clear that we have not yet overcome the primary basis for immune evasion in the vast majority of cancer patients," said Dr. Flaherty. "TNF-α has been on the very short list of desired mechanisms to leverage for decades, but has been largely forgotten because there has been no feasible way of selectively delivering TNF-α to tumor cells. The NaNotics approach overcomes this barrier by depleting the molecules that tumor cells produce and shed in order to intercept TNF-α produced by immune cells."
"NaNotics is delighted to be collaborating with the Mass General Cancer Center in the study of NaNots against sTNF-Rs," said Lou Hawthorne, CEO of NaNotics and the inventor of NaNots. "We’re especially excited to be working with Dr. Flaherty – a brilliant scientist and clinician with a record of innovation and success – and his colleagues at MGCC, including Dr. Gainor, an expert in immunotherapy. They bring deep scientific insight and a wealth of clinical trial experience to our collaboration, enabling translation of the NaNot platform from novel science into therapeutics of potential benefit to millions of patients suffering deadly cancers."
As part of the collaboration, NaNotics will produce pre-clinical and then clinical NaNots against sTNF-Rs. MGCC will provide patient samples for preclinical validation of NaNots, following which the teams will work together on clinical trial design, leading to a study of NaNots against sTNF-Rs in cancer patients, centered at MGCC in 2024.