Dr. Fahar Merchant reports

MEDICENNA PRESENTS PRECLINICAL RESULTS FROM ITS IL-2 SUPER-ANTAGONIST AND ANTI-PD1-IL-2 BISKIT PROGRAMS AT THE PROMISE OF INTERLEUKIN-2 THERAPY CONFERENCE

As planned and previously announced, new data from two of Medicenna Therapeutics Corp.'s preclinical programs were presented orally at the Promise of Interleukin-2 Conference held in Paris, France, from Sept. 4 to Sept. 7, 2024.

• 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 per cent of the global population.
• MDNA209 restores immune balance by selectively blocking IL-2Rbetagamma c, 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 per cent, reduce weight loss and improve clinical scores, highlighting its therapeutic potential for treating GvHD and autoimmune diseases.
• MDNA113 is an IL-13Ralpha2 tumour-targeted BiSKIT (bifunctional superkine for immunotherapy) which delivers an anti-PD1-IL-2 superkine (anti-PD1-IL-2 SK) directly to the tumour microenvironment (TME) where it is conditionally activated by tumour-associated proteases.
• MDNA113's efficacy was significantly enhanced in mice harboring tumours engineered to overexpress IL-13Ralpha2, highlighting its potential to treat immunologically "cold tumours" such as pancreatic, prostate, ovarian and breast cancers that globally affect over two million patients every year.

"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 Dr. Fahar Merchant, PhD, president and chief executive officer 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 tumour 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-antagonist, currently being evaluated in the phase 1/2 Ability-1 clinical trial for the treatment of solid tumours.

• The first presentation outlined the potential of MDNA209 to treat autoimmune diseases, including high-grade GvHD which has a one-year survival rate of only 40 per cent. 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-2beta biased IL-2/IL-15 super-antagonists to down-regulate 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 tumours, approximately 70 per cent 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, tumour-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-2beta 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-2Rbeta but does not engage with the gammac 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 signalling, reduces IFNgamma 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 per cent, reduce weight loss and improve clinical scores.

MDNA113, an IL-13Ralpha2 tumour targeting and conditionally activatable anti-PD1-IL-2 SK BiSKIT shows enhanced safety and potent therapeutic efficacy

• MDNA113 (masked version) showed reduced capacity to induce IL-2R-mediated pSTAT5 signalling compared with 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 signalling.
• Mice treated with MDNA113 showed reduced peripheral lymphocyte expansion compared with 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 tumour model despite these tumours lacking IL-13Ralpha2 expression.
• Efficacy of MDNA113 is substantially enhanced when tested in mice harboring MC38 tumours that have been engineered to overexpress IL-13Ralpha2, resulting in complete tumour 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-2Rbetagammac complex, preventing downstream signalling and blocking effector T-cell functions. MDNA209 outcompetes IL-2 for IL-2Rbeta and impedes gammac 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 tumour-targeted and tumour-activated bifunctional anti-PD1-IL2 superkine with exceptionally high affinity for IL-13Ralpha2 without binding to the functional IL-13Ralpha1. IL-13Ralpha2 is overexpressed in a wide range of solid tumours, including cold tumours with minimal to no expression in normal tissues. IL-13Ralpha2 expressing tumours also have abundant matrix metalloprotease in the tumour microenvironment that may efficiently activate MDNA113. IL-13Ralpha2 expression is associated with poor clinical outcome in multiple tumour types including prostate cancer, pancreatic cancer, ovarian cancer, liver cancer, breast cancer and brain cancer, with an annual worldwide incidence of over two million.

About Medicenna Therapeutics Corp.

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 five 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 fast-track and orphan drug status from the U.S. Food and Drug Administration (FDA) and FDA/EMA (European Medicines Agency), respectively. Medicenna's early-stage BiSkits (bifunctional superkine immunotherapies) and the T-Mask(TM) (targeted metalloprotease activated superkine) programs are designed to enhance the ability of superkines to treat immunologically cold tumours.