Agatolimod

Researchers have created a DNA origami platform called DoriVac, whose core component is a self-assembling square block-shaped nanostructure. DoriVac vaccines enabled tumor-bearing mice to better control the growth of tumors and to survive significantly longer than control mice. Therapeutic cancer vaccines are a form of immunotherapy in the making that could not only destroy cancer cells in patients, but keep a cancer from coming back and spreading. Multiple therapeutic cancer vaccines are being studied in clinical trials, but despite their promise, they are not routinely used yet by clinical oncologists to treat their patients. The central ingredient of therapeutic cancer vaccines is antigens, which are preferentially produced or newly produced (neoantigens) by tumor cells and enable a patient's immune system to search and destroy the cancerous cells. In most cases, those antigens cannot act alone and need the help of adjuvant molecules that trigger a general alarm signal in immune cells known as antigen-presenting cells (APCs). APCs internalize both antigen and adjuvant molecules and present the antigens to different types of T cells. Those T cells then launch an immediate attack against the tumor, or preserve a longer-lasting memory of the tumor for future defense. A cancer vaccine's effectiveness depends on the level and duration of the "alarm" its adjuvants can ring in APCs. Previously, researchers found that delivering adjuvant and antigen molecules to APCs simultaneously using nanostructures like DNA origami can increase APC activation. However, none of these approaches systematically investigated how the number and nanoscale arrangement of adjuvant molecules affect downstream tumor-directed immunity. Now, a research team at the Wyss Institute at Harvard University, Dana-Farber Cancer Institute (DFCI), Harvard Medical School (HMS), and Korea Institute of Science and Technology (KIST) has created a DNA origami platform called DoriVac, whose core component is a self-assembling square block-shaped nanostructure. To one face of the square block, defined numbers of adjuvant molecules can be attached in highly tunable, nanoprecise patterns, while the opposite face can bind tumor antigens. The study found that molecules of an adjuvant known as CpG spaced exactly 3.5 nanometers apart from each other resulted in the most beneficial stimulation of APCs that induced a highly-desirable pro T cells, including those that kill cancer cells (cytotoxic T cells), those that cause beneficial inflammation (Th-1 polarized T cells), and those that provide a long-term immune memory of the tumor (memory T cells). DoriVac vaccines enabled tumor-bearing mice to better control the growth of tumors and to survive significantly longer than control mice. Importantly, the effects of DoriVac also synergized with those of immune checkpoint inhibitors, which are a highly successful immunotherapy that is already widely used in the clinic. The findings are published in Nature Nanotechnology. "DoriVac's DNA origami vaccine technology merges different nanotechnological capabilities that we have developed over the years with an ever-deepening knowledge about cancer-suppressing immune processes," said Wyss Core Faculty member William Shih, Ph.D., who led the Wyss Institute team together with first-author Yang (Claire) Zeng, M.D., Ph.D.. "We envision that in the future, antigens identified in patients with different types of tumors could be quickly loaded onto prefabricated, adjuvant-containing DNA origami to enable highly effective personalized cancer vaccines that can be paired with FDA-approved checkpoint inhibitors in combination therapies." Shih is also a Professor at HMS and DFCI's Department of Cancer Biology and, as some of the other authors, a member of the NIH-funded cross-institutional "Immuno-engineering to Improve Immunotherapy" (i3) Center based at the Wyss. DNA origami rationale The CpG adjuvant is a synthetic strand of DNA made up of repeated CpG nucleotide motifs that mimic the genetic material from immune cell-invading bacterial and viral pathogens. Like its natural counterparts, CpG adjuvants bind to a "danger receptor" called TLR9 in immune cells, which in turn induces an inflammatory (innate) immune response that works in concert with the antigen-induced (adaptive) immune response. "We knew from previous work that to trigger strong inflammatory responses, TLR9 receptors need to dimerize and aggregate into multimeric complexes binding to multiple CpG molecules. The nanoscale distances between the CpG-binding domains in effective TLR9 assemblies revealed by structural analysis fell right into the range of what we hypothesized we could mirror with DNA origami structures presenting precisely spaced CpG molecules," explained Zeng, who was an Instructor in Medicine at the time of the study and now is a senior scientist at DFCI and Harvard Medical School (HMS). In addition to Shih, Zeng was also mentored on the project by senior authors Ju Hee Ryu, Ph.D., a Principal Researcher at KIST, and Wyss Founding Core Faculty member David Mooney, Ph.D., who also is Professor at Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS), and one of the i3 Center's Principal Investigators. Zeng and the team fabricated DoriVac vaccines in which different numbers of CpG strands were spaced at 2.5, 3.5, 5, or 7 nanometers apart from each other on one face of the square block, and a model antigen was attached to the opposite face. They protected their structures from being degraded in the body using a chemical modification method that Shih's group had developed earlier. When internalized by different types of APCs, including dendritic cells (DCs), which orchestrate tumor-directed T cell responses, the DoriVac vaccines improved the uptake of antigens compared to controls consisting of free antigen molecules. A CpG spacing of 3.5 nanometers produced the strongest and most beneficial responses in APCs, and significantly outperformed a control vaccine containing only free CpG molecules. "We were excited to find that the DoriVac vaccine preferentially induced an immune activation state that supports anti-tumor immunity, which is what researchers generally want to see in a good vaccine," said Zeng. Besides spacing, the numbers of CpG molecules in DoriVac vaccines also mattered. The team tested vaccines containing between 12 to 63 optimally spaced CpG molecules and found that 18 CpG molecules provided the best APC activation. This meant that their approach can also help limit the dosage of CpG molecules and thus minimize commonly observed toxic side effects observed with adjuvants. Gained in (tumor) translation Importantly, these in vitro trends translated to in vivo mouse tumor models. When prophylactically injected under the skin of mice, DoriVac vaccines accumulated in the closest lymph nodes where they stimulated DCs. A vaccine loaded with a melanoma antigen prevented the growth of subsequently injected aggressive melanoma cells. While all control animals had succumbed to the cancer by day 42 of the experiment, DoriVac-protected animals all were alive. DoriVac vaccines also inhibited tumor growth in mice in which the formation of melanoma tumors was already underway, with a 3.5 nanometer spacing of 18 CpG molecules again providing maximum effects on DC and T cells, and the strongest reduction in tumor growth. Next, the team asked whether DoriVac vaccines could also boost immune responses produced by small "neoantigens" emerging in melanoma tumors. Neoantigens are ideal targets because they are exclusively made by tumor cells. However, they often are not very immunogenic themselves, which make highly effective adjuvants an important component in neoantigen vaccines. A DoriVac vaccine customized with four neoantigens enabled the researchers to significantly suppress growth of the tumor in mice that produced the neoantigens. Finally, the researchers asked whether DoriVac could synergize with immune checkpoint therapy, which reactivates T cells that have been silenced in tumors. In mice, the two therapies combined resulted in the total regression of melanoma tumors, and prevented them from growing back when the animals were exposed to the same tumor cells again four months later. The animals had built up an immune memory of the tumor. The team obtained a similar vaccination efficiency in a mouse lymphoma model. "We think that DoriVac's value for determining a sweet spot in adjuvant delivery and enhancing the delivery and effects of coupled antigens can pave the way to more effective clinical cancer vaccines for use in patients with a variety of cancers," said Zeng. The team is currently translating the DoriVac platform toward its clinical application, which is supported by the study's assessment of vaccine distribution and vaccine-directed antibodies in mice, as well as cytokines produced by immune cells in response to the vaccines in vivo. "The DoriVac platform is our first example of how our pursuit of what we call Molecular Robotics -- synthetic bioinspired molecules that have programmable shape and function -- can lead to entirely new and powerful therapeutics. This technology opens an entirely new path for development of designer vaccines with properties tailored to meet specific clinical challenges. We hope to see its rapid translation into the clinic," said Wyss Institute Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at HMS and Boston Children's Hospital, and the Hansjörg Wyss Professor of Bioinspired Engineering at SEAS. Other authors on the study are Olivia Young, Christopher Wintersinger, Frances Anastassacos, James MacDonald, Giorgia Isinelli, Maxence Dellacherie, Miguel Sobral, Haiqing Bai, Amanda Graveline, Andyna Vernet, Melinda Sanchez, Kathleen Mulligan, Youngjin Choi, Thomas Ferrante, Derin Keskin, Geoffrey Fell, Donna Neuberg, Cathrine Wu, and Ick Chan Kwon. The study was funded by the Wyss Institute's Validation Project and Institute Project programs, Claudia Adams Barr Program at DFCI, Korean Fund for Regenerative Medicine (award #21A0504L1), Intramural Research Program of KIST (award #2E30840), and National Institutes of Health (under the i3 Center supporting U54 grant (award #CA244726-01).

DUET-102 in Combination with PD-1 Blockade Demonstrates Significant Anti-Tumor Activity in Models of Malignant Glioma Data Suggests Benefits of Combinations of DUET-102 with Other T-Cell Based Immunotherapies, such as CAR-Ts NEW YORK, Nov. 07, 2023 (GLOBE NEWSWIRE) -- Scopus BioPharma Inc. (OTCQB: “SCPS”) and its majority-owned subsidiary, Duet BioTherapeutics Inc., presented compelling new data that DUET-102 in combination with PD-1 blockade demonstrates significant anti-tumor activity in models of malignant glioma. The new data was presented on November 4, 2023 at the 38th Annual Meeting of the Society for Immunotherapy of Cancer (“SITC”) by Marcin Kortylewski, Ph.D. Dr. Kortylewski, Professor of Immuno-Oncology at City of Hope, is the Co-Founder and Senior Scientific Advisor of Duet. Duet is developing novel immunotherapies to overcome treatment-resistant cancers. DUET-102 is a double-stranded antisense oligonucleotide (“ASO”) STAT3 inhibitor linked to a TLR9 immune activator being developed for the treatment of glioma. Glioma is a common type of tumor originating in the glial cells of the brain. Approximately 20,000 patients are diagnosed in the United States annually, with such patients having a 5-year survival rate of less than 7%, reflecting the need for new therapies to combat this disease. Dr. Kortylewski presented the data in a poster titled “Reprograming of Tumor-associated Myeloid Cells by TLR9-targeted STAT3 Antisense Oligonucleotides Sensitizes Malignant Glioma to PD1-specific Immunotherapy”. The featured data shows: Intracranially injected DUET-102 sensitizes malignant glioma to systemic PD-1 blockade, triggering complete rejection of both orthotopic GL261 and PD-1 refractory QPP8 tumors in the majority of treated mice.DUET-102 creates ideal conditions for PD-1 blockade to recruit cancer-killing effector CD8 positive T cells into the tumor by activating intratumoral dendritic cells, M1 macrophages, and microglia, while concurrently reducing immunosuppressive tumor-associated M2 macrophages, resting microglia, and regulatory T cells.DUET-102, as a monotherapy, inhibited tumor growth and extended survival of mice in U251, GL261, and QPP8 models of glioma.DUET-102 was well tolerated and demonstrated unique suitability for intracranial injection, with optimized activity and tolerability in the brain compared to single-stranded ASO designs. Dr. Kortylewski stated, “DUET-102’s unique ability to release immunosuppression around a tumor, creating an environment in which PD-1 blockade can more effectively recruit cancer-killing CD8 positive T cells into glioma without lymphocyte exhaustion, is critical to killing glioma tumor cells. These new data suggest there is compelling potential for significant anti-tumor activity in gliomas utilizing a combination of DUET-102 with PD-1 inhibitors, such as Keytruda (Merck), Opdivo (Bristol-Myers Squibb) and Libtayo (Regeneron). Furthermore, the effectiveness of DUET-102 in releasing immunosuppression may enhance the efficacy of other T-cell based immunotherapies in the context of glioma, including potential combinations of DUET-102 with adoptive cell transfer therapies, such as CAR T-cell therapies.” Alan Horsager, Ph.D., President and Chief Executive Officer of Duet, stated, “These new data clearly show the synergistic potential of combining DUET-102 and PD-1 blockade for the treatment of glioma. There is an acute need for new treatment options for glioma, which have seen no significant advances in the past decade. Our new data demonstrate potent anti-tumor activity in malignant glioma. We are extremely excited about the significant potential of DUET-102 to be a game-changing and much-needed new treatment option for glioma patients.” Dr. Kortylewski added, “DUET-102 is a novel CNS-specific modification of Duet’s lead drug candidate, DUET-101, which is a single-stranded, ASO-based STAT3 inhibitor linked to a TLR9 immune activator being developed for the treatment of advanced solid tumors.” Dr. Horsager further stated, “These new data for DUET-102, taken together with the existing data for DUET-101, further validate the scientific underpinnings and extensive range of opportunities for our proprietary bifunctional oligonucleotide therapeutics. DUET-101 has demonstrated significant activity in a broad array of difficult to treat and genetically distinct cancer models, including metastatic prostate cancer, renal cancer, bladder cancer, and head and neck cancers. We are enthusiastic about the compelling potential of our immuno-oncology pipeline.” About Scopus BioPharma Scopus BioPharma Inc. is a biotechnology company developing transformational therapeutics for serious diseases with significant unmet medical need. Scopus currently conducts substantially all of its development efforts through Duet BioTherapeutics, its majority owned and controlled subsidiary. The Company may also seek to identify additional compelling technologies for potential acquisition, in-licensing and/or other similar transactions. About Duet BioTherapeutics Duet BioTherapeutics Inc. is a biotechnology company developing novel immunotherapies to overcome treatment-resistant cancers. Duet’s therapeutic candidates selectively and simultaneously activate TLR9, which stimulates the body’s immune system, and inhibit STAT3, which counteracts critical tumor defense mechanisms. Duet is currently pursuing therapeutic candidates for the treatment of solid tumors and hematological malignancies using a distinct set of oligonucleotide inhibitors. These inhibitors include antisense, or ASO; small-interfering RNA, or siRNA; and decoy technologies. DUET-101, Duet’s IND-ready lead candidate, combines CpG with a STAT3-inhibiting ASO and is being developed for the treatment of advanced solid tumors. Forward-Looking Statements This press release may include forward-looking statements that involve risks and uncertainties. Forward-looking statements are statements that are not historical facts. Such forward-looking statements are subject to risks (including those set forth in the Company’s Form 10-K for the fiscal year ended December 31, 2022, as amended, filed with the U.S. Securities and Exchange Commission) and uncertainties which could cause actual results to differ from the forward-looking statements. The Company expressly disclaims any obligations or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in the Company’s expectations with respect thereto or any change in events, conditions or circumstances on which any statement is based. Investors should realize that if our underlying assumptions for the projections contained herein prove inaccurate or that known or unknown risks or uncertainties materialize, actual results could vary materially from our expectations and projections. Further, there can be no assurance that the Company will identify and/or consummate any transaction relating to any additional technologies. The Company’s capital resources are extremely limited and the Company has an immediate need for additional financing. Failure to obtain sufficient financing in the immediate future will have a material adverse effect on the Company, including possibly requiring the Company to substantially curtail or cease its operations. Contacts David WaldmanCrescendo Communications, LLCTel: (212) 671-1020Email: SCPS@crescendo-ir.com Hugh Burns/Delia Cannan/Nicholas LeasureReevemarkTel: (212) 433-4600Email: scopus@reevemark.com