Interleukin-2 liposomal(University of Minnesota)

A key aspect of Parkinson’s disease (PD) pathophysiology is decreased systemic regulatory T cell (Treg) function with associated neuroinflammation in the nigrostriatal pathway of the brain, including the presence of reactive astrocytes and microglia that have an initiating and progressing role in PD; Subcutaneous injection of COYA 302, an anti-inflammatory, Treg-enhancing combination biologic (comprising low dose interleukin-2 and CTLA-4 Ig fusion protein), in an inflammatory mouse model of PD resulted in significant reductions in microglia and astrocyte activation in the nigrostriatal pathway in the brain; Importantly, study illustrates that peripheral administration of COYA 302 is directly immunomodulatory in the brain and associated with significant downregulation of neuroinflammation HOUSTON, TX, USA I September 16, 2024 I Coya Therapeutics, Inc. (NASDAQ: COYA) (“Coya” or the “Company”), a clinical-stage biotechnology company developing biologics intended to enhance regulatory T cell (Treg) function, announces the direct CNS anti-inflammatory effect of subcutaneously administered COYA 302 in a preclinical inflammatory associated mouse model of Parkinson’s Disease (PD). Coya’s Chief Business Officer and incoming Chief Executive Officer Arun Swaminathan, Ph.D. stated: “We believe that the ability of peripherally administered biologics (COYA 302) that potently and directly ameliorate the inflammatory milieu in the brain translates to strategies to suppress CNS neuro-inflammation beyond PD, including other inflammatory mediated neurodegenerative diseases such as Alzheimer’s disease (AD) and Frontotemporal Dementia (FTD).” Parkinson’s disease is characterized by the selective loss of dopaminergic neurons in brain regions responsible for motor control (nigrostriatal pathway), while inflammation and immune dysfunction from the associated loss of systemic Treg function are currently recognized as critical mediators of disease and subsequent progression of PD. Targeting the sustained proinflammatory mechanisms that progress the disease and enhance immunosuppressive cells, such as Tregs, may have the potential to provide disease-modifying benefits in patients with PD. In an inflammatory mouse model of PD, subcutaneous injections of COYA 302 significantly reduced inflammation and microglial activation in nigrostriatal brain regions responsible for motor control (dorsal striatum and substantia nigra). Microglial activation is an important mediator of PD and plays an important role in PD pathology and neurodegeneration. Microglial inhibition may hold promise as a therapeutic strategy to delay the progression of PD.Additionally, subcutaneous injections of COYA 302 resulted in reductions in astrocyte numbers and their activation (astrogliosis) in the nigrostriatal pathway. It is known that pathogenic astrocyte activation leads to neurodegeneration in PD, and mitigating its damage may be another therapeutic target. COYA 302’s direct effect in reducing neuroinflammatory constituents known to drive neurodegeneration is promising and warrants clinical translation into additional preclinical models and, ultimately, into patients. The Company anticipates presenting and/or publishing these data in a peer reviewing setting. About Parkinson’s Disease Parkinson’s disease (PD) is the most common movement disorder and the second most common neurodegenerative disease, affecting approximately 1% of individuals over the age of 60. Its prevalence increases significantly with age, and as the global population continues to age, the incidence of PD is expected to rise further. The hallmark of PD is the progressive degeneration of dopaminergic neurons, particularly in the substantia nigra, a region of the brain integral to the nigrostriatal pathway, which plays a crucial role in coordinating motor control. This neuronal loss leads to the characteristic motor symptoms of PD, such as bradykinesia, rigidity, and tremors, while patients also exhibit non-motor manifestations, such as cognitive decline, mood disturbances, and sleep disorders. While the exact cause of the dopaminergic neuron loss is not fully understood, growing evidence highlights chronic neuroinflammation and immune dysfunction as central drivers of PD pathogenesis and progression. A key aspect of PD pathophysiology is neuroinflammation in the nigrostriatal pathway, including the presence of reactive astrocytes. This neuroinflammation has long been considered a downstream response to the death of dopaminergic neurons. However, increased evidence suggests that astrocytes have an initiating role in PD pathophysiology. Regulatory T cells (Tregs), a subset of T cells responsible for maintaining immune homeostasis and preventing excessive immune responses, are decreased and impaired in PD patients and preclinical models. Subsequently, chronic pro-inflammatory immune cell activation, oxidative stress, and mitochondrial dysfunction all contribute to neuronal damage. The combination of targeting the chronic, proinflammatory activation and enhancing the Treg immunosuppressive function offers promising therapeutic potential for a disease-modifying therapy that could effectively alter the course of the disease, reduce neuronal loss, and improve patient outcomes. References 1. Kouli, Torsney, and Kuanl. Chapter 1 – Parkinson’s Disease: Etiology, Neuropathology, and Pathogenesis; Parkinson’s Disease: Pathogenesis and Clinical Aspects, Codon Publications, 2018 2. Booth, Hirst, and Wade-Martins. The Role of Astrocyte Dysfunction in Parkinson’s Disease Pathogenesis; Trends in Neuroscience , 2017 June, 40(6): 358-370 About COYA 302 COYA 302 is an investigational and proprietary biologic combination therapy with a dual immunomodulatory mechanism of action intended to enhance the anti-inflammatory function of regulatory T cells (Tregs) and suppress the inflammation produced by activated monocytes and macrophages. COYA 302 is comprised of proprietary low dose interleukin-2 (LD IL-2) and CTLA4-Ig fusion protein and is being developed for subcutaneous administration for the treatment of patients with ALS, AD, FTD, and PD. These mechanisms may have additive or synergistic effects. In February of 2023, Coya announced results from a proof-of-concept, open-label clinical study evaluating commercially available LD IL-2 and CTLA4-Ig fusion protein in a small cohort of patients with ALS conducted at the Houston Methodist Research Institute (Houston, Texas) by Stanley Appel, M.D., Jason Thonhoff, M.D., Ph.D., and David Beers, Ph.D. This study was the first-of-its-kind evaluating this dual-mechanism immunotherapy for the treatment of ALS. Patients in the study received investigational treatment for 48 consecutive weeks and were evaluated for safety and tolerability, Treg function, serum biomarkers of oxidative stress and inflammation, and clinical functioning as measured by the ALSFRS-R scale. During the 48-week treatment period, the therapy was well tolerated. The most common adverse event was mild injection-site reactions. No patient discontinued the study, and no deaths or other serious adverse events were reported. Patients’ disease progression was measured using the ALSFRS-R scale, a validated rating tool for monitoring the progression of disability in patients with ALS. The mean (±SD) ALSFRS-R scores at week 24 (33.75 ±3.3) and week 48 (32 ±7.8) after initiation of treatment were not statistically different compared to the ALSFRS-R score at baseline (33.5 ±5.9), suggesting significant amelioration in the progression of the disease over the 48-week treatment period. Treg suppressive function, expressed as percentage of inhibition of proinflammatory T cell proliferation, showed a statistically significant increase over the course of the treatment period and was significantly reduced at the end of the 8-week washout post-treatment period. Treg suppressive function at 24 weeks (79.9 ±9.6) and 48 weeks (89.5 ±4.1) were significantly higher compared to baseline (62.1 ±8.1) (p<0.01), suggesting enhanced and durable Treg suppressive function over the course of treatment. In contrast, Treg suppressive function (mean ±SD) was significantly decreased at the end of the 8-week washout period compared to end-of-treatment at week 48 (70.3 ±8.1 vs. 89.5 ±4.1, p <0.05). The study also evaluated serum biomarkers of inflammation, oxidative stress, and lipid peroxides. The available data up to 16 weeks after initiation of treatment suggest a decrease in these biomarker levels, which is consistent with the observed enhancement of Treg function. The evaluation of the full biomarker data is ongoing. COYA 302 is an investigational product not yet approved by the FDA or any other regulatory agency. About Coya Therapeutics, Inc. Headquartered in Houston, TX, Coya Therapeutics, Inc. (Nasdaq: COYA) is a clinical-stage biotechnology company developing proprietary treatments focused on the biology and potential therapeutic advantages of regulatory T cells (“Tregs”) to target systemic inflammation and neuroinflammation. Dysfunctional Tregs underlie numerous conditions, including neurodegenerative, metabolic, and autoimmune diseases, and this cellular dysfunction may lead to sustained inflammation and oxidative stress resulting in lack of homeostasis of the immune system. Coya’s investigational product candidate pipeline leverages multiple therapeutic modalities aimed at restoring the anti-inflammatory and immunomodulatory functions of Tregs. Coya’s therapeutic platforms include Treg-enhancing biologics, Treg-derived exosomes, and autologous Treg cell therapy. COYA 302 – the Company’s lead biologic investigational product or “Pipeline in a Product” – is a proprietary combination of COYA 301 (Coya’s proprietary LD IL-2) and CTLA4-Ig for subcutaneous administration with a unique dual mechanism of action that is now being developed for the treatment of Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Parkinson’s Disease, and Alzheimer’s Disease. Its multi-targeted approach enhances the number and anti-inflammatory function of Tregs and simultaneously lowers the expression of activated microglia and the secretion of pro-inflammatory mediators. This synergistic mechanism may lead to the re-establishment of immune balance and amelioration of inflammation in a sustained and durable manner that may not be achieved by either low-dose IL-2 or CTLA4-Ig alone. For more information about Coya, please visit www.coyatherapeutics.com SOURCE: Coya Therapeutics

MDNA209 is a first-in-class “beta-enhanced” IL-2 Super-antagonist being developed for the potential treatment of autoimmune diseases, a disorder attributed to an imbalance of the immune system and affecting 5 to 10% of the global population MDNA209 restores immune balance by selectively blocking IL-2Rβγc, a receptor highly expressed by effector CD8 T cells which are known to promote tissue damage in autoimmune diseases In an aggressive animal model of graft versus host disease (GvHD) MDNA209 was able to extend overall survival by 400 percent, reduce weight loss and improve clinical scores, highlighting its therapeutic potential for treating GvHD and autoimmune diseases MDNA113 is an IL-13Rα2 tumor-targeted BiSKIT (Bifunctional SuperKine for ImmunoTherapy) which delivers an anti-PD1-IL-2 Superkine (anti-PD1-IL-2SK) directly to the tumor microenvironment (TME) where it is conditionally activated by tumor-associated proteases MDNA113’s efficacy was significantly enhanced in mice harboring tumors engineered to overexpress IL-13Rα2, highlighting its potential to treat immunologically “cold tumors” such as pancreatic, prostate, ovarian, and breast cancers that globally affect over two million patients every year TORONTO and HOUSTON, Sept. 09, 2024 (GLOBE NEWSWIRE) -- Medicenna Therapeutics Corp. (“Medicenna” or the “Company”) (TSX: MDNA, OTCQB: MDNAF), a clinical-stage immunotherapy company focused on the development of Superkines, announced today that, as planned and previously announced, new data from two of its preclinical programs were presented orally at the Promise of Interleukin-2 Conference held in Paris, France from September 4-7, 2024. “Inspired by the promising Phase 1/2 clinical results from the ABILITY-1 clinical trial of MDNA11, we are leveraging the same IL-2 Superkine platform to advance our pipeline of transformative medicines to treat not only cancer but also autoimmune diseases,” said Fahar Merchant, Ph.D., President and CEO of Medicenna. “We are encouraged by these preclinical data, which validates the versatility of our IL-2 Superkines beyond cancer as we further evaluate MDNA209 in GvHD and other disease models. Additionally, our IL-13 Superkines enable us to precisely deliver and localize BiSKITs to the tumor site which could potentially benefit patients with cancers that have not responded to currently approved checkpoint inhibitors, thereby addressing a huge unmet need.” MDNA209 and MDNA113 are preclinical assets based on the MDNA109 platform also used to develop MDNA11, a long-acting IL-2 Super-agonist, currently being evaluated in the Phase 1/2 ABILITY-1 clinical trial for the treatment of solid tumors. The first presentation outlined the potential of MDNA209 to treat autoimmune diseases, including high grade GvHD which has a 1-year survival rate of only 40%. Transplant patients with GvHD experience significant morbidity and mortality with limited therapeutic options to prolong survival. The initial preclinical data presented on the MDNA209 platform highlight the potential of the Company’s long-acting, high-affinity IL-2β biased IL-2/IL-15 Super-antagonists to downregulate the immune system, with therapeutic potential for GvHD and autoimmune diseases.The second presentation focused on MDNA113, which is being developed as a novel, targeted and bifunctional version (anti-PD1-IL-2 Superkine fusion) of a class of blockbuster anti-PD1 therapies, with current annual sales of over $30 billion but lose patent protection from 2028 onwards. Although Anti-PD-1 checkpoint blockade has improved survival outcomes in many types of solid tumors, approximately 70% of cancer patients do not benefit. To further improve patient outcomes, Medicenna has designed an anti-PD1-IL-2SK BiSKIT that uses an IL-13 Superkine to simultaneously target and localize the BiSKIT to the TME while masking the IL-2 domain during peripheral circulation and reducing its toxicity. At the TME, tumor specific proteases cleave the IL-13 component, releasing the BiSKIT to engage with T-cells thereby stimulating T-cell activity via the IL-2 domain and preventing T-cell exhaustion via the anti-PD1 domain. Key highlights from the presentations are: MDNA209, a High Affinity IL-2β Biased IL-2/IL-15 Super-antagonist, for the Treatment of Autoimmune Diseases MDNA209 is an IL-2 Super-antagonist with enhanced affinity for IL-2Rβ but does not engage with the γc subunit, therefore acting as a receptor clamp to exclude native IL-2 as well as native IL-15.MDNA209 is fused to an Fc scaffold (MDNA209-Fc) to extend its in vivo half-life, reducing the need for frequent dosing.MDNA209-Fc inhibits both, IL-2 and IL-15 induced p-STAT5 signaling, reduces IFNγ release and slows immune cell proliferation without reducing Treg population.In an aggressive animal model of acute GvHD, MDNA209 was able to extend overall survival by 400 percent, reduce weight loss and improve clinical scores. MDNA113, an IL-13Rα2 Tumor Targeting and Conditionally Activatable anti-PD1-IL-2SK BiSKIT Shows Enhanced Safety and Potent Therapeutic Efficacy MDNA113 (masked version) showed reduced capacity to induce IL-2R mediated pSTAT5 signaling compared to anti-PD1-IL-2SK (non-mask version) in cell-based assay and human CD8+ T cells without impacting PD1/PDL1 blockade.Proteolytic cleavage of MDNA113 releases anti-PD1-IL-2SK and fully restores its capacity to activate IL-2R signaling.Mice treated with MDNA113 showed reduced peripheral lymphocyte expansion compared to anti-PD1-IL-2SK due to masking by the IL-13 Superkine.MDNA113 showed greater tolerability than anti-PD1-IL-2SK following repeat dose administration in mice.MDNA113, but not a non-cleavable version, demonstrated similar efficacy as anti-PD1-IL-2SK in MC38 colon tumor model despite these tumors lacking IL-13Rα2 expression.Efficacy of MDNA113 is substantially enhanced when tested in mice harboring MC38 tumors that have been engineered to overexpress IL-13Rα2, resulting in complete tumor regression in most animals.Variants of MDNA113 have also been designed with tunable masking of the IL-2 Superkine underscoring the versatility of the platform. Copies of the two presentations are available on the “Scientific Presentations” page of Medicenna’s website. About MDNA209 The Company’s MDNA209 platform consists of IL-2 muteins with targeted mutations enabling high-affinity IL-2 receptor antagonism. MDNA209 blocks the formation of the IL-2Rβγc complex, preventing downstream signaling and blocking effector T-cell functions. MDNA209 outcompetes IL-2 for IL-2Rβ and impedes γc engagement, blocking downstream signaling and restraining reactive effector immune cells, thereby offering therapeutic potential for treating inflammatory and autoimmune diseases. About MDNA113 MDNA113 is a novel, first-in-class tumor-targeted and tumor-activated bi-functional anti-PD1-IL2 Superkine with exceptionally high affinity for IL-13Rα2 without binding to the functional IL-13R⍺1. IL-13Rα2 is overexpressed in a wide range of solid tumors, including cold tumors with minimal to no expression in normal tissues. IL-13Rα2 expressing tumors also have abundant matrix metalloprotease in the tumor microenvironment that may efficiently activate MDNA113. IL-13Rα2 expression is associated with poor clinical outcome in multiple tumor types including prostate cancer, pancreatic cancer, ovarian cancer, liver cancer, breast cancer and brain cancer, with an annual world-wide incidence of over 2 million. About Medicenna Therapeutics Medicenna is a clinical-stage immunotherapy company focused on developing novel, highly selective versions of IL-2, IL-4 and IL-13 Superkines and first-in-class Empowered Superkines. Medicenna’s long-acting IL-2 Superkine, MDNA11, is a next-generation IL-2 with superior affinity toward CD122 (IL-2 receptor beta) and no CD25 (IL-2 receptor alpha) binding, thereby preferentially stimulating cancer-killing effector T cells and NK cells. Medicenna’s IL-4 Empowered Superkine, bizaxofusp (formerly MDNA55), has been studied in 5 clinical trials enrolling over 130 patients, including a Phase 2b trial for recurrent GBM, the most common and uniformly fatal form of brain cancer. Bizaxofusp has obtained FastTrack and Orphan Drug status from the FDA and FDA/EMA, respectively. Medicenna’s early-stage high-affinity IL-2β biased IL-2/IL-15 Super-antagonists, from its MDNA209 platform, are being evaluated as potential therapies for autoimmune and graft-versus host diseases. Medicenna’s early-stage BiSKITs™ (Bifunctional SuperKine ImmunoTherapies) and the T-MASK™ (Targeted Metalloprotease Activated SuperKine) programs are designed to enhance the ability of Superkines to treat immunologically “cold” tumors. For more information, please visit www.medicenna.com, and follow us on Twitter and LinkedIn. Forward-Looking Statements This news release contains forward-looking statements within the meaning of applicable securities laws. Forward-looking statements include, but are not limited to, express or implied statements regarding the future operations of the Company, estimates, plans, strategic ambitions, partnership activities and opportunities, objectives, expectations, opinions, forecasts, projections, guidance, outlook or other statements that are not historical facts, such as statements on the therapeutic potential and safety profile of MDNA209 and MDNA113. Drug development and commercialization involve a high degree of risk, and only a small number of research and development programs result in commercialization of a product. Results in early-stage pre-clinical or clinical studies may not be indicative of full results or results from later stage or larger scale clinical studies and do not ensure regulatory approval. You should not place undue reliance on these statements, or the scientific data presented. Forward-looking statements are often identified by terms such as “will”, “may”, “should”, “anticipate”, “expect”, “believe”, “seek”, “potentially” and similar expressions. and are subject to risks and uncertainties. There can be no assurance that such statements will prove to be accurate and actual results and future events could differ materially from those anticipated in such statements. Important factors that could cause actual results to differ materially from the Company’s expectations include the risks detailed in the latest annual information form of the Company and in other filings made by the Company with the applicable securities regulators from time to time in Canada. The reader is cautioned that assumptions used in the preparation of any forward-looking information may prove to be incorrect. Events or circumstances may cause actual results to differ materially from those predicted, as a result of numerous known and unknown risks, uncertainties, and other factors, many of which are beyond the control of the Company. The reader is cautioned not to place undue reliance on any forward-looking information. Such information, although considered reasonable by management, may prove to be incorrect and actual results may differ materially from those anticipated. Forward-looking statements contained in this news release are expressly qualified by this cautionary statement. The forward-looking statements contained in this news release are made as of the date hereof and except as required by law, we do not intend and do not assume any obligation to update or revise publicly any of the included forward-looking statements. This news release contains hyperlinks to information that is not deemed to be incorporated by reference in this new release. Investor/Media Contact: Christina CameronInvestor Relations, Medicenna Therapeutics(647) 953-0673ir@medicenna.com