ICOS

SEATTLE--(BUSINESS WIRE)--Nov. 10, 2017-- Alpine Immune Sciences, Inc. (NASDAQ:ALPN), a leading immunotherapy company focused on developing treatments for autoimmune/inflammatory diseases and cancer, today announced immuno-oncology preclinical data characterizing the functional activity of molecules Alpine successfully generated from its variant immunoglobulin domain (vIgD) platform. Several novel immuno-oncology molecules were functionally active via multiple mechanisms of action, including the demonstration of tumor suppression in an animal model. The findings will be presented on Friday, November 10, in a poster session titled “Immune Modulation, Cytokines, and Antibodies” [#P343] at the Society for Immunotherapy of Cancer’s (SITC) 32nd Annual Meeting in National Harbor, MD. “Our unique vIgD platform is capable of producing first-in-class immuno-oncology biologics with potentially unique mechanisms of action,” said Stanford Peng, M.D., Ph.D., Executive Vice President of Research and Development and Chief Medical Officer of Alpine. “This promising data highlights the versatility of the platform, showing vIgDs may be implemented in multiple therapeutic formats and may be tailored to modulate multiple molecular pathways according to the desired therapeutic application.” Preclinical Study Design and Results Alpine scientists used the vIgD directed evolution platform to engineer a number of vIgDs with unique binding profiles to proteins relevant to the immune synapse, including PD-1, PD-L1, CTLA-4, TIGIT, CD155, CD28, and/or ICOS. The poster describes the vIgD domains in multiple therapeutic formats, including tumor-localized Fc fusion proteins, multi-checkpoint inhibitors, and vIgDs fused with tumor-specific monoclonal antibodies (V-mAbs). Various in vitro and in vivo tests characterized the functional activity of these potentially novel therapeutics. Data include: Tri-specific vIgDs for treating cancer with a single domain capable of interacting with three different B7 family members. Depending on formatting, tri-specific vIgDs are potentiallycapable of agonizing CD28, blocking PD-L1, blocking CTLA-4, and/or depleting tumor cells and/or regulatory T cells. Initial formats investigated in an animal model of cancer demonstrated activity with tumor growth suppression.A dual ICOS/CD28 costimulatory vIgD fused with the HER2-targeting monoclonal antibody trastuzumab to provide immune stimulation in the tumor microenvironment. These V-mAbs demonstrated in vitroproof of principle for immune cell stimulation and proliferation in response to HER2-positive tumor cells.Multiple vIgD Fc fusions capable of targeting TIGIT and PD-1 while sparing CD226. These multi-checkpoint inhibitory molecules blocked checkpoint activity and improved IFN-γ production by “exhausted” T cells. “The SITC data suggest the versatile vIgD platform has the potential to contribute to the next generation of immuno-oncology therapeutics. Based on these and other encouraging preclinical data, we are continuing to identify and develop appropriate candidates from our vIgD platform for clinical trials for both oncology and inflammation,” said Mitchell H. Gold, M.D., Executive Chairman and Chief Executive Officer of Alpine. About Alpine Immune Sciences, Inc. Alpine Immune Sciences, Inc. is focused on developing novel protein-based immunotherapies using its proprietary Variant Ig Domain (vIgD) platform technology. The vIgD platform is designed to interact with multiple targets, including many present in the immune synapse. Alpine’s vIgDs are developed using a process known as directed evolution, which produces proteins capable of either enhancing or diminishing an immune response and thereby may potentially apply therapeutically to cancer, autoimmune and inflammatory diseases. Alpine has also developed Transmembrane Immunomodulatory Protein (TIP) technology, based on the vIgD platform, to potentially enhance engineered cellular therapies. For more information, visit www.alpineimmunesciences.com.

Checkpoint immunotherapy utilizing PD-1 blockade has become the standard of care for metastatic melanoma. While this treatment is effective in 40 percent of patients, the other 60 percent develop resistance, leading to tumor regrowth. A multidisciplinary research team has identified a new strategy that could enhance the therapeutic effectiveness of this therapy by targeting the communication between immune cells within the tumor. Checkpoint immunotherapy utilizing PD-1 blockade has become the standard of care for metastatic melanoma. While this treatment is effective in 40 percent of patients, the other 60 percent develop resistance, leading to tumor regrowth. A multidisciplinary research team led by the University of California, Irvine has identified a new strategy that could enhance the therapeutic effectiveness of this therapy by targeting the communication between immune cells within the tumor. In a study published online today in the journal Cancer Cell, researchers demonstrate that while PD-1 blockade activates a potent antitumor response in CD8+ T cells, it also promotes the accumulation of T regulatory cells, decreasing the immune response against the tumor. The activation of these competing signals -- one set combatting the tumor and the other restraining the immune system -- is likely a significant challenge in providing effective cancer treatment. "Our latest research reveals that CD8+ T cells, activated by PD-1 blockade to target melanoma, also interact with T regulatory cells, which subsequently dampen the immune response against the tumor," said corresponding author Francesco Marangoni, UC Irvine assistant professor of physiology & biophysics. "We analyzed the intricate dynamics of communication between CD8+ T and T regulatory cells, which are analogous to two telephone landlines connected by a cable. If we cut the cable, the CD8+ T cells won't be able to 'call' the T regulatory cells and instruct them to inhibit the immune response to the cancer." Team members focused on the mechanism of communication between CD8+ T and T regulatory cells in tumors and identified a pivotal role for a molecule called ICOS, which is required for T cell activation. They found that by neutralizing ICOS and PD-1, CD8+ T cells increased their activity against the tumor but could no longer stimulate T regulatory cells. "Our work helped identify a reason why some patients treated with checkpoint blockade develop resistance to it," said first author Shannon Geels, a UC Irvine graduate student researcher in the Department of Physiology & Biophysics. "We found that communication between cells can lead to immunotherapy failure and that we can improve efficacy by interrupting specific messages exchanged by immune cells." The next phase of this research involves understanding the complex communication network among various cell types in a tumor. "We do not think there is only one 'phone cable' to cut," Marangoni said. "Our findings provide a promising pathway to increasing our understanding of communication among all cell types within a tumor. This will enable us to identify the messages that block the full potential of CD8+ T cells stimulated by PD-1 blockade so that we can maximize the benefit to patients." Other UC Irvine team members included faculty and graduate students from the physiology & biophysics, biological chemistry, dermatology and developmental & cell biology departments; the Institute for Immunology; the Center for Complex Biological Systems; and the NSF-Simons Center for Multiscale Cell Fate Research; as well as faculty from Saint John's Cancer Institute in Santa Monica; the University of Alabama at Birmingham; and Massachusetts General Hospital and Harvard Medical School. This work was supported by pilot grants from the Chao Family Comprehensive Cancer Center, the National Science Foundation, the U.S. Department of Defense and the National Institutes of Health, among others.

Findings highlight the novel mechanism of action and potential for therapeutic activity in highly inflammatory autoimmune disease SEATTLE, May 3, 2024 /PRNewswire/ -- Mozart Therapeutics, the leading developer of CD8 Treg network modulators, today announce the release of new pre-clinical data for their second program, a KIR x ICOS bispecific antibody targeting CD8 regulatory T cells. The data will be presented during the Immunology 2024 meeting, May 3–7 in Chicago, Illinois. Presentation highlights demonstrate KIR x ICOS Modulator: Restores and potentiates CD8 Treg function through binding the inhibitory receptor KIR and the costimulatory receptor ICOS, both expressed on CD8 Treg Selectively activates CD8 Treg with dose-dependent increases in both their prevalence and capacity to eliminate pathogenic CD4 T cells Enhances ICOS signaling only in CD8 Treg and not other ICOS-expressing immune cells Reduces proinflammatory cytokines and improves survival in a highly inflammatory disease model Has acceptable tolerability in initial studies in humanized mice "Our preclinical data underscore the potential of our KIR x ICOS CD8 Treg Modulator as a selective therapeutic approach for highly inflammatory autoimmune diseases, including Crohn's disease and ulcerative colitis. Findings show that the Modulator is selective toward CD8 Treg, efficacious in models of disease, and has an encouraging safety profile," said Dr. Kristine Swiderek, Chief Scientific Officer at Mozart Therapeutics. "The data support further advancement of this promising molecule." Presentation Details: The poster can be accessed from the Mozart Therapeutics website following the May 6 presentation. About KIR x ICOS Modulator Inhibitory killer immunoglobulin-like receptors (KIR) are autoimmune checkpoints expressed on CD8 regulatory T cells, limiting their function of killing pathogenic CD4 T cells. The inducible T cell costimulator (ICOS) is upregulated on activated CD8 Treg and critical to CD8 Treg function. KIR x ICOS is a bispecific antibody targeting CD8 Treg. The molecule aims to restore CD8 Treg function through inhibition of KIR, while promoting ICOS-mediated CD8 Treg activation, in chronic and highly inflammatory autoimmune disease. About Mozart Therapeutics Mozart Therapeutics is focused on developing first-in-class disease-modifying therapies for autoimmune and inflammatory diseases, utilizing a novel approach to restoring immune system homeostasis by targeting the CD8 Treg network. The company is headquartered in Seattle, WA. For more information, visit and follow the company on LinkedIn @Mozart-tx. Media Contact: Julie Rathbun Rathbun Communications [email protected] 206-769-9219 SOURCE Mozart Therapeutics