Metalloproteases

MDNA113 is targeted to the tumor site where it is activated to simultaneously deliver two immunotherapies, an IL-2 superkine and anti-PD1 antibody, to the same cancer fighting immune cells in the tumor micro-environment (TME) to maximize efficacy and minimize systemic toxicity MDNA113 is our most advanced pre-clinical candidate that targets IL-13Rα2, a tumor associated antigen, which is overexpressed by immunologically “cold” tumors with high unmet needs in pancreatic, prostate, ovarian, breast and brain cancer affecting over two million patients every year TORONTO and HOUSTON, April 09, 2024 (GLOBE NEWSWIRE) -- Medicenna Therapeutics Corp. (“Medicenna” or the “Company”) (TSX: MDNA), a clinical-stage immunotherapy company focused on the development of Superkines, today announced new preclinical data on MDNA113, the Company’s novel T-MASK (Targeted Metallo/protease Activated SuperKine) candidate, an IL-13R⍺2 (Interleukin-13 receptor alpha2) specific superkine featuring unique masking and tumor targeting characteristics, were presented at the 2024 Annual Meeting of the American Association for Cancer Research (AACR) held in San Diego, CA, on April 9th, 2024. “We are pleased to show preclinical data demonstrating the ability of Medicenna’s first T-MASK candidate, MDNA113 to enhance tumor accumulation and tolerability of our potent bi-functional immune modulator, anti-PD1-IL-2SK,” said Fahar Merchant, Ph.D., President and Chief Executive Officer of Medicenna. “MDNA113 has novel features, including the tunable blockade of the IL-2R agonism to reduce peripheral immune stimulation for enhanced tolerability, and tumor targeting to IL-13R⍺2 which is linked to aggressive cancers that annually affect over 2 million patients world-wide. The cleavage and release of the IL-13 tumor-targeting/masking domain by matrix metalloproteases restores IL-2R signaling within the tumor microenvironment, thereby benefiting from the simultaneous and synergistic activity of IL-2R agonism and immune checkpoint blockade at the tumor site.” The Company selected MDNA113, a novel, first-in-class tumor-targeted and tumor-activated bi-functional anti-PD1-IL-2 superkine with high selectivity and affinity for IL-13Rα2, a tumor associated antigen expressed in many aggressive solid tumors. The IL-13 Superkine (MDNA213) is a highly specific tumor-targeting/masking domain which is fused via a protease sensitive linker to a bi-functional immunotherapy domain (MDNA223) containing an IL-2 Superkine fused to an anti-PD1 antibody. Key findings presented at the conference include: When not activated, MDNA113 shows reduced IL-2R agonism with no change to PD-1/PDL-1 blockade activity.Cleavage and activation of MDNA113 by cancer specific enzymes (metalloproteases) releases the T-MASK domain (MDNA213), restoring activity of the IL-2 Superkine at the tumor site.MDNA113 shows attenuated systemic lymphocyte expansion compared to non-masked version (MDNA223), consistent with design of MDNA113.MDNA113 is better tolerated than non-masked counterpart (MDNA223), supporting higher and more efficacious dosing schedule.MDNA113 selectively binds IL-13R⍺2 positive tumor cells in vitro, and durably accumulates (>7 days) in IL-13R⍺2 positive tumors in mice.Cleavable MDNA113 shows similar efficacy as non-masked MDNA223 in mouse tumor models by either localized (intra-tumoral) or systemic (intra-peritoneal) delivery, consistent with proteolytic activation within TME.Single neoadjuvant treatment with MDNA113 in a highly invasive orthotopic 4T1.2 breast cancer model significantly increases survival by preventing metastasis.In summary, the T-MASK platform exemplified by MDNA113, facilitates tumor targeting and minimizes systemic toxicity while maximizing therapeutic activity at the tumor site. The poster, “Characterization of MDNA113, a Tumor-Targeting Anti-PD1-IL-2SK Immunocytokine with Conditional Activation to Increase Tolerability and Maximize Efficacy” can be found on the AACR website for conference registrants. It will be also available on the Scientific Presentations page of Medicenna’s website following the conclusion of the 2024 Annual Meeting of AACR. About the T-MASK Platform Medicenna’s novel T-MASK (Targeted Metallo/protease Activated SuperKine) platform involves fusion of a dual tumor-targeting/masking domain to an immune modulator (such as a Superkine or a BiSKIT) via a matrix metalloprotease (MMP) sensitive linker to (i) reduce and fine-tune the potency of the immune modulator, (ii) increase its systemic tolerability (iii) prolong its retention in the TME and (iv) to maximize and restore full potency at the intended target site. The T-MASK platform offers opportunity to target and fine-tune immune cell stimulation in the TME to improve the therapeutic index of Medicenna’s Superkine and BiSKIT platforms. About MDNA113 MDNA113 is a novel, first-in-class tumor-targeted and tumor-activated bi-functional anti-PD1-IL-2 Superkine with 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. IL-13Rα2 is a tumor-associated antigen with minimal to no expression in normal tissues but is highly expressed by a wide range of tumors including “cold” tumors. IL-13Rα2 expressing tumors also have abundant MMPs in the TME that may efficiently activate MDNA113. IL-13Rα2 expression is associated with poor clinical outcome in multiple tumor types with an annual world-wide incidence of over 2 million in different tumor types including prostate cancer, pancreatic cancer, ovarian cancer, liver cancer, breast cancer and brain cancer, and among others. About Medicenna 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 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 may contain 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 Company’s cash runway, preclinical and clinical development activities and the potential benefits of its Superkine platform, clinical trial designs and results, clinical potential, expectations and beliefs around safety profiles and upcoming milestones and data reporting, including with respect to MDNA11, the ABILITY study and its expansion, bizaxofusp (MDNA55), MDNA113 and MDNA223. 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 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. Forward-looking statements are based on a number of assumptions believed by the Company to be reasonable at the date of this news release. Although the Company believes that the expectations reflected in such forward-looking statements are reasonable, there can be no assurance that such statements will prove to be accurate. These statements are subject to certain risks and uncertainties and may be based on assumptions that could cause actual results and future events to differ materially from those anticipated or implied 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 Report on Form 20-F 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 or implied in forward-looking statements. 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 news release. Investor and Media Contact: Christina CameronInvestor Relations, Medicenna Therapeuticsir@medicenna.com (647) 953-0673

A new analysis sheds light on the molecular processes involved when a carnivorous species of fungus known as Arthrobotrys oligospora senses, traps and consumes a worm. A new analysis sheds light on the molecular processes involved when a carnivorous species of fungus known as Arthrobotrys oligospora senses, traps and consumes a worm. Hung-Che Lin of Academia Sinica in Taipei, Taiwan, and colleagues present these findings November 21 in the open access journal PLOS Biology. A. oligospora usually derives its nutrients from decaying organic matter, but starvation and the presence of nearby worms can prompt it to form traps to capture and consume worms. A. oligospora is just one of many species of fungi that can trap and eat very small animals. Prior research has illuminated some of the biology behind this predator-prey relationship (such as certain genes involved in A. oligospora trap formation) but for the most part, the molecular details of the process have remained unclear. To boost understanding, Lin and colleagues performed a series of lab experiments investigating the genes and processes involved at various stages of A. oligospora predation on a nematode worm species called Caenorhabditis elegans. Much of this analysis relied on a technique known as RNAseq, which provided information on the level of activity of different A. oligospora genes at different points in time. This research surfaced several biological processes that appear to play key roles in A. oligospora predation. When A. oligospora first senses a worm, the findings suggest, DNA replication and the production of ribosomes (structures that build proteins in a cell) both increase. Next, the activity increases of many genes that encode proteins that appear to assist in the formation and function of traps, such as secreted worm-adhesive proteins and a newly identified family of proteins dubbed "trap enriched proteins" (TEP). Finally, after A. oligospora has extended filamentous structures known as hyphae into a worm to digest it, the activity is boosted of genes coding for a variety of enzymes known as proteases -- in particular, a group known as metalloproteases. Proteases break down other proteins, so these findings suggest that A. oligospora uses proteases to aid in worm digestion. These findings could serve as a foundation for future research into the molecular mechanisms involved in A. oligospora predation and other fungal predator-prey interactions. The authors add, "Our comprehensive transcriptomics and functional analyses highlight the role of increased DNA replication, translation, and secretion in trap development and efficacy. Furthermore, a gene family that is largely expanded in the genomes of nematode-trapping fungi were found to be enriched in traps and critical for trap adhesion to nematodes. These results furthered our understanding of the key processes required for fungal carnivory."

Company’s T-MASK platform demonstrates ability to maximize anti-tumor efficacy and minimize systemic toxicity, and opportunities to explore broad range of cytokines and other potent therapeutics MDNA113 is a first-in-class IL-13R⍺2 targeted therapy that delivers a masked bi-specific IL-2-AntiPD1 Superkine to the tumor micro-environment where it is activated by cancer specific enzymes IL-13Rα2 is overexpressed by some of the most immunologically “cold” tumors with high unmet needs in pancreatic, liver, brain, breast and prostate cancer that annually affect over 2 million patients TORONTO and HOUSTON, Nov. 03, 2023 (GLOBE NEWSWIRE) -- Medicenna Therapeutics Corp. (“Medicenna” or the “Company”) (TSX: MDNA), a clinical-stage immunotherapy company focused on the development of Superkines, today announced new preclinical data demonstrating proof of concept for the Company’s novel T-MASK (Targeted Metallo/protease Activated SuperKine) platform technology with the Company’s development candidate, MDNA113, at the 38th Annual Meeting of the Society for Immunotherapy of Cancer (“SITC”) held in San Diego, CA, from November 1-5, 2023. “We are pleased to show preclinical data demonstrating the ability of our T-MASK platform to enhance tumor specific accumulation, increased anti-tumor activity while improving the safety profile of potent immune modulators such as Medicenna’s bispecific IL-2-AntiPD1 Superkine,” said Fahar Merchant, Ph.D., President and Chief Executive Officer of Medicenna. “The results presented today demonstrates proof of concept with MDNA113, our first T-MASK candidate specifically designed to deliver bispecific IL-2-antiPD1 Superkine to cancers that express the tumor associate antigen, IL-13R⍺2. This is an important advance for cancer immunotherapy as the IL13Ra2 target is linked to aggressive cancers that annually affect over 2 million patients world-wide.” The Company selected MDNA113, a novel, first-in-class tumor-targeted and tumor-activated bi-specific antiPD1-IL-2 Superkine as its first development candidate using the T-MASK platform. MDNA113 has high selectivity and affinity for the IL-13 decoy receptor IL-13Rα2, a tumor associated antigen expressed by many aggressive solid tumors. MDNA113 is fused via a protease sensitive linker (“PSL”) to MDNA223, containing a not-alpha, beta-enhanced IL-2 Superkine fused to anti-PD1 antibody. Key findings include: T-MASK platform integrates tumor targeting and prolonged tumor retention with conditional activation to maximize anti-tumor efficacy and minimize systemic toxicityMDNA113 shows reduced IL-2R agonism with no change to PD1/PDL-1 blockadeMDNA113 reduces systemic lymphocyte expansion showing dampening of systemic activityCleavage of MDNA113 by tumor associated metalloproteases restores IL-2R signaling.MDNA113 is as effective as non-masked MDNA223 (a bispecific antiPD1-IL-2 superkine) in tumor models. Unlike other conditionally activated immunotherapies, the T-MASK platform has the following unique features: The IL-13 Superkine, engineered to bind with high affinity to the tumor associated antigen IL-13R⍺2, is used both as a tumor targeting component and a masking agent.The level of masking is tunable and avoids complete blockade of the immune-modulator thereby retaining good tolerability while achieving adequate systemic activity during its transit to the tumor micro-environment (TME)Upon delivery to the TME, the IL-13 Superkine traps the immune-modulator within the tumor for a prolonged period, allowing adequate time for metalloproteases to cleave the protease sensitive linker (“PSL”) and activate the long-acting immune-modulatorCombining modest systemic immune simulation with potent immune activation within the TME, could provide better outcomes for patients with immunosuppressive tumors. A copy of the poster will be posted to the “Events and Presentations” page of Medicenna’s website following the conclusion of the meeting. Details on the in-person poster presentation are shown below. Title: Characterization of a tumor-targeting and activatable T-MASK platform to enhance tumor accumulation and tolerability of potent immune modulatorsPoster Number: 1071Presentation Date: Friday, November 3, 2023, 9:00 am to 7:00 pm PDT About Medicenna 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 class-empowered superkines. Medicenna’s long-acting IL-2 Superkine, MDNA11, is a next-generation IL-2 with superior CD122 (IL-2 receptor beta) binding without CD25 (IL-2 receptor alpha) affinity 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, including a Phase 2b trial for recurrent GBM, the most common and uniformly fatal form of brain cancer. Bizaxofusp has FastTrack and Orphan Drug status from the FDA and FDA/EMA, respectively. Medicenna’s BiSKITs™ (Bifunctional SuperKine ImmunoTherapies) and T-MASK (Targeted Metalloprotease Activated SuperKines) programs are in pre-clinical development designed to enhance the ability of Superkines to treat immunologically “cold” tumors. Forward-Looking Statements This news release contains forward-looking statements within the meaning of applicable securities laws that relate to the future operations of the Company, plans and projections and other statements that are not historical facts, including, without limitation, statements on the clinical development and potential of MDNA113 and the Company’s T-MASK platform. 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 Report on Form 20-F of the Company and in other filings made by the Company with the applicable securities regulators from time to time in Canada and the United States.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. Investor ContactArgot PartnersPhone: 212-600-1902medicenna@argotpartners.com