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BackgroundRecombinant human interleukin-2 (rhIL-2, aldesleukin) is Food and Drug Administration approved for the treatment of metastatic melanoma and renal cell carcinoma and has achieved durable response in a subset of patients. However, its utility as an immunotherapeutic drug is limited by undesirable activation of immune suppressive regulatory T cells (Tregs) and a short half-life requiring frequent high dose administration, leading to unacceptable toxicities. We have engineered MDNA11, a long-acting IL-2 superkine, to overcome these limitations by (1) modifying receptor selectivity in favor of anti-cancer immune cells to increase therapeutic efficacy and (2) fusion to human albumin to extend the pharmacokinetic (PK) profile, circumventing the need for frequent dosing.MethodsMDNA11 was evaluated using in vitro and in vivo studies including: binding analyses to measure receptor affinity, IL-2 pathway signaling, PK studies in mice, and efficacy studies in syngeneic tumor models as single agent and in combination with immune checkpoint inhibitors. Finally, the safety and pharmacodynamic profile of MDNA11 was assessed in non-human primate (NHP).ResultsBinding studies with MDNA11 demonstrated increased affinity for IL-2Rβ (CD122) and no binding to IL-2Rα (CD25). As a result, MDNA11 exhibits reduced/limited Treg stimulation while triggering an enhanced activation of natural killer and naïve CD8 T cells compared with rhIL-2. When administered to animals with pre-established tumors, MDNA11 controlled tumor growth in a monotherapy setting and in combination with anti-PD1 or anti-CTLA4 to induce durable tumor clearance with a once weekly dosing regimen. In a NHP model, MDNA11 was well tolerated while triggering durable and potent immune responses including expansion of lymphocytes without significant effect on Tregs and eosinophils, the latter been linked to an increased risk of vascular leak syndrome.ConclusionMDNA11 is a next generation long-acting IL-2 immunotherapeutic with a highly favorable pharmacodynamic profile that translates to a strong therapeutic efficacy in preclinical tumor models and a strong and durable immune response in NHP.

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Introduction: Regulation of Th1/Th2 balance in the tumor microenvironment (TME) plays an important role in both tumor progression and response to immunotherapy. The IL-4/IL-13 pathway induces an anti-inflammatory (Th2) response by stimulating M2 skewing of tumor associated macrophage (TAM) and myeloid derived suppressor cells (MDSCs), thereby supporting tumor growth by suppressing Th1 response. Therefore, inhibition of the IL-4/IL-13 pathway has the potential to inhibit tumor growth by shifting the TME towards a pro-inflammatory response. To achieve this, we engineered a long-acting IL-13 super-antagonist (i.e., Fc-MDNA413) to target the IL-13Rα1 component of type II IL-4 receptor (IL-4Rα/IL-13α1) expressed on TAMs and MDSCs to inhibit their differentiation and expansion for immuno-oncological applications. Experimental Procedure: Studies conducted include binding analyses by Biacore/SPR, signaling analyses in IL-4/IL-13 cell reporters, in vitro cell proliferation, in vitro M1/M2 macrophage polarization and in vivo efficacy in syngeneic tumor models. Summary of Data: IL-13Rα1 and IL-4Rα constitute the type II IL-4R that drives a Th2 response upon activation by IL-4 and IL-13. Binding studies showed that in comparison to wild-type Fc-IL13, Fc-MDNA413 has higher affinity for IL-13Rα1 but lower affinity for the decoy IL-13Rα2 receptor, indicating a more favorable receptor selectivity. In a cell-based reporter assay, Fc-MDNA413 inhibits both IL-4 and IL-13 induced p-STAT6 signaling, a pathway that drives towards a Th2 response. The antagonism of Fc-MDNA413 was also observed in an IL-13 dependent TF-1 proliferation assay where dose-dependent inhibition of cell proliferation was demonstrated. In a macrophage polarization assay with human primary myeloid cells, Fc-MDNA413 inhibited both IL-4 and IL-13 induced M2 polarization in a dose-dependent manner, consistent with an inhibitory effect on IL-4/IL-13 signaling. Treatment of tumor bearing mice with Fc-MDNA413 inhibited tumor growth in multiple syngeneic tumor models (e.g., EMT6 breast cancer and KLN205 lung cancer) known to have higher percentage of TAMs and MDSCs in TME, hence demonstrating the therapeutic potential of this long-acting IL-4/IL-13 super-antagonist. Conclusion: Fc-MDNA413 is a long-acting IL-4/IL-13 super-antagonist that inhibits IL-4 and IL-13 induced signaling and M2 skewing of macrophages, resulting in tumor growth inhibition in vivo. Ongoing studies include testing in additional syngeneic tumor models, deciphering in vivo mechanism of action and investigating potential synergy with other therapies. Next generation multifunctional superkines that incorporate IL-4/IL-13 antagonism are under development to target immunologically challenging tumors. Citation Format: Aanchal Sharma, Manjunatha Ankathatti Munegowda, Fahar Merchant, Minh D. To. Characterization of a long-acting IL-13 super-antagonist engineered to target tumor associated macrophages and myeloid cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5542.