By David Bautz, PhD
NASDAQ:MDNA
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Business Update
Anti-Tumor Activity of MDNA11 in MC38 Model
On March 25, 2021, Medicenna Therapeutics Corp. (MDNA) announced an oral presentation by CEO Dr. Fahar Merchant at the Cytokine-Baed Cancer Immunotherapies Summit. The presentation featured new preclinical data for MDNA11, the company's lead IL-2 Superkine, along with an overview of the company's Bi-functional SuperKine ImmunoTherapies (BiSKITs™) program.
MDNA11 is a long-acting variant of IL-2 that is engineered to have enhanced binding to CD122 and no affinity for CD25. IL-2 is a 16 kDa protein that activates a wide range of leukocytes, including T cells and natural killer (NK) cells through binding IL-2 receptors (IL-2Rα [CD25], IL-2Rβ [CD122], and IL-2Rγ [CD132]), with the arrangement of these receptors dictating the response seen. Binding of IL-2 to a heterodimer consisting of CD122 and CD132 is of "intermediate affinity', whereas a heterotrimer consisting of all three IL-2Rs is a ‘high affinity' complex. The heterotrimer is typically found on activated T cells (including regulatory T cells) while naïve T cells and NK cells only express the heterodimer. Thus, modifying IL-2 signaling to enhance binding to the CD122/CD132 complex could enhance T cell activation while diminishing the effect of regulatory T cells.
The following table shows that MDNA11 (and MDNA19, the company's other long-acting IL-2 variant) binds to CD122 with enhanced affinity compared to native IL-2 (as shown by the lower KD value), and that neither compound binds to CD25, thus preferentially activating immune effector cells but not T regulatory cells.
The company presented new preclinical data on MDNA11 as a monotherapy and in combination with anti-PD-1 therapy in a MC38 mouse model. MC38 is a murine colon adenocarcinoma cell line. The following image shows that MDNA11 monotherapy results in tumor growth inhibition, while combination therapy of MDNA11 and anti-PD-1 therapy results in complete tumor regression. Anti-PD-1 monotherapy did not have an effect on tumor growth.
When examining each of the animals from the different treatment groups, the data shows that most of the animals treated with MDNA11, whether with or without PD-1 therapy, showed complete tumor regression.
BiSKITs
In addition to presenting data on MDNA11, Dr. Merchant's presentation included an overview of the company's Bi-Functional SuperKine ImmunoTherapies (BiSKITs™) platform, which includes multiple iterations of IL-2, IL-4, and IL-13 combination molecules.
STAb Cancer™ (Superkines Targeted with Antibodies): This technology is based on a superkine combined with a targeting antibody with a proof-of-concept molecule composed of an enhanced IL-2 (sumIL2 or MDNA109FA) and anti-human EGFR (Sun et al., 2019). The following image on the left shows that the EGFR-IL-2 molecule collects in a MC38 tumor that expresses human EGFR while the image on the right shows that the EGFR-IL-2 molecule results in complete tumor regression while an anti-mouse molecule, TA99-sumIL2, only slows tumor growth.
Interleukin-Directed Bi-Specific T Cell Engagers (iBITE™): MDNA132 is an engineered human IL-13 that targets a tumor specific antigen (IL-13Rα2). IL-13 signaling is mediated through binding of the Type 2 IL-4 receptor that consists of IL-4Rα and IL-13Rα1 (Suzuki et al., 2015). IL-13 also binds to a second IL-13 receptor (IL-13Rα2) with very high affinity (Caput et al., 1996). However, that receptor has no known function and acts as a "decoy receptor". IL-13Rα2 is also highly expressed on a number of different tumor types and is correlated with poor survival (Barderas et al., 2012).
A localized T cell engager was developed that consists of an anti-CD3 antibody and MDNA132, as shown in the following image. The anti-CD3 antibody is utilized to attach the molecule to an active T cell, while the MDNA132 molecule is used to bind to a tumor cell that overexpresses IL13Rα2, thus bringing the T cell in close proximity to the tumor cell.
This is a similar strategy to Bispecific T Cell Engager (BiTE®), which utilizes a molecule with one side being specific for CD3 and the other for a tumor associated antigen (e.g., CD19, BCMA, CD33). Blincyto (blinatumomab) is a BiTE molecule that is approved for the treatment of acute lymphoblastic leukemia (ALL) and had revenues of $433 million in 2020 (EvaluatePharma).
Dual Cytokines (DUCK Cancer™): MDNA413 is a super antagonist that blocks IL-4 and IL-13 signaling through binding of the Type 2 receptor (IL-4Rα/IL-13Rα1). It has higher affinity for IL-13Rα1 than native IL-13, blocks downstream signaling, and inhibits M2a polarization (Moraga et al., 2015). A dual cytokine compound was created that contains MDNA19 (IL-2 super agonist) and MDNA413. The purpose of this compound is to increase CD8+ T cell and natural killer (NK) cell counts (through binding of the MDNA19 moiety to the CD122/CD132 heterodimer) and decrease the number of immunosuppressive myeloid cells (though binding of the IL-13 Type 2 receptor). We anticipate preliminary data for the IL-2/IL-13 DUCK molecule to be presented at the 2021 AACR Annual Meeting.
Conclusion
We are very intrigued by the new superkine programs that Medicenna is developing and look forward to additional details about each one, including data from the IL-2/IL-13 combination molecule that will be presented next month. The ability to modulate multiple signaling pathways with enhanced cytokines offers a huge opportunity to target different oncogenic pathways as well as other diseases where immunomodulation could benefit patients, and the following figure shows that the company is busy building up a pipeline of many diverse compounds.
We anticipate Medicenna initiating a Phase 1/2a clinical trial of MDNA11 in the U.K. in mid-2021, and it is conceivable we could see initial data before the end of 2021. However, MDNA11 represents only the ‘tip of the iceberg' for the company's superkine platform and we anxiously await updates throughout the year on what programs the company will be prioritizing. With no changes to our model the valuation remains at $12 per share.
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