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Study shores up Medicenna’s Superkine platform
TORONTO—Medicenna Therapeutics Corp. announced today the publication of a peer-reviewed article in Nature Communications that provides independent third-party validation of Medicenna’s IL-2 Superkine platform, MDNA109.
The article, entitled “A next-generation tumor-targeting IL-2 preferentially promotes tumor infiltrating CD8+ T-cell response and effective tumor control,” describes the safety, efficacy, pharmacokinetics, immunogenicity and efficacy profile in different tumor models of long-acting variants of MDNA109, including fusions to antibodies to create tumor targeted immunocytokines.
While native IL-2 (Proleukin) has been approved for the treatment of metastatic melanoma and kidney cancer, its short in vivo half-life, severe toxicity and propensity to amplify tumor protecting Treg cells are major barriers that prevent Proleukin from being widely used for cancer therapy.
MDNA109 is an engineered version of IL-2 that binds up to 200 times more effectively to IL-2Rβ (CD122), greatly increasing its ability to activate and proliferate the immune cells needed to fight cancer. MDNA109 — an IL-2 Superkine which preferentially drives the expansion and responses of effector T cells and natural killer (NK) cells over Treg cells — is the only IL-2 in development with a distinct mechanism. Its high affinity towards CD122 allows it to effectively combat NK cell anergy, which frequently occurs after cancer immunotherapy.
“A publication in the prestigious journal Nature Communications has now independently validated the strategy undertaken by Medicenna to develop MDNA109 as a next-generation IL-2 superkine to treat cancers,” said Dr. Moutih Rafei, associate professor in the department of Pharmacology and Physiology at the Université de Montreal and head of Discovery at Medicenna. “These independent findings provide strong confirmation that Medicenna’s MDNA109 superkine represents a potential breakthrough in cytokine-based cancer therapy with broad therapeutic implications.”
According to some of the findings in the Nature Communications paper regarding the MDNA109 platform, it has increased half-life and preferentially boosts tumor killing CD8+ T cells instead of tumor protecting regulatory T cells (Tregs). The platform has reduced CD25 binding, a better safety profile, and it’s not immunogenic; in combination with anti-PD-L1 antibodies, it significantly enhances antitumor effects in advanced cancers by overcoming tumor resistance to checkpoint blockade. Pre-treatment prior to surgical resection of the tumor in an aggressive metastatic breast cancer model significantly reduced tumor spread.
“The publication confirms our expectation of IL-2 superkine being a versatile platform for multiple uses in immuno-oncology and making it accessible to a much larger pool of cancer patients. Unlike other efforts to develop better versions of IL-2, our approach to genetically create IL-2 superkines using rational drug design avoids the manufacturing issues associated with polymer based conjugation techniques and their limited ability to be developed as antibody targeted immunocytokines. Based on these data and other preclinical data in hand, we continue with confidence to advance this program towards clinical development next year,” added Fahar Merchant, president & CEO of Medicenna Therapeutics.
When combined with tyrosine kinase inhibitors (TKI), which are currently used to treat various cancers in a first line setting, the anti-tumor effect was synergistic and generated a strong memory response when re-challenged, limiting cancer relapse and the ability to overcome resistance commonly observed with TKI therapies.
“In the clinic, TKI is the first-line therapy for treating EGFR mutant positive cancer since most of the patients have fewer TILs [tumor-infiltrating lymphocytes] and do not respond to immunotherapy,” the article points out. “After standard TKI therapy, most patients have initial responses including impressive complete responses but undergo relapse or develop metastasis. Consequently, creating an appropriate regimen for tumor therapy that can reduce tumor burden while increasing TILs is of utmost importance.”
“We propose that besides direct tumor killing, TKI therapy may have two advantages for combination therapy. TKI treatment can not only reduce tumor burden, but tumor immunogenicity can also be enhanced after TKI therapy; both outcomes may set a platform and promote the function of immunotherapy. Conversely, immunotherapy could further promote the therapeutic effects of TKI by facilitating tumor killing, including TKI resistant clones, thus overcoming resistance,” the article continues. “We found that the ratio of CD3+ T cell/tumor cells indeed increased after TKI therapy.”
The platform functions as an immune accelerator to enhance the therapeutic effects of checkpoint blockades and synergizes with targeted therapy to control “cold” tumors, which generally do not respond to checkpoint blockade. Intra-tumoral treatment is not only sufficient for local-tumor control but is able to also control untreated distal-tumors.
“Overall, our study revealed the therapeutic potential of tumor-targeting sumIL-2, a next-generation IL-2, for not only increasing half-life and reducing toxicity but also enhancing treatment effect by efficiently targeting CD8+ T cells inside tumor tissues. SumIL-2 can overcome the resistance to TKI treatment and TILs are critical for the responsiveness to sumIL-2 therapy,” the article states. “Preoperative sumIL-2 treatment could induce robust antitumor immune responses for eradicating the metastatic disease. Furthermore, sumIL-2 can function as an ‘immune accelerator’ to enhance the therapeutic effects of checkpoint blockades. Altogether, our study has provided a novel, combinatory therapeutic strategy for effectively treating patients with EGFR-driven cancer.”