Abstract 2066: In vitro and in vivo properties of MDK703: An Fc-peptide fusion IL-7Rαγc agonist unrelated in structure to IL-7

Abstract

Abstract Background: IL-7 receptor activation is essential for the proper development and homeostasis of T-cell subpopulations, and maintenance of the TCR clonal repertoire. Emerging evidence indicates potential clinical utility of IL-7 for immunotherapy of lymphopenia, oncology, and other indications. IL-7-based proteins that have been studied in humans show high propensity for anti-drug antibodies (ADAs), including those that are neutralizing. Here we report an Fc-peptide fusion (MDK-703), which exhibits biological properties similar to IL-7 in vitro and when administered to non-human primates. The peptide sequence is unrelated to IL-7 and is predicted to be devoid of Class II (HLA-DR) restricted HLA ligands and putative T cell epitopes. Methods: Peptide ligands were identified from phage libraries and further engineered to bind simultaneously to the Rα and γc subunits of the human IL-7 receptor. Peptides were tested for agonist activity and screened in silico for potential HLA binding (EpiVax). The lead peptide sequence (corresponding to synthetic peptide MDK1472) was fused to a native IgG2 Fc-domain via a flexible linker (MDK-703) and evaluated for in vitro IL-7R agonist activity in human and cynomolgus macaque (CM) blood cells. Tolerability and PK/PD were assessed in CM. Results: MDK1472 bound to human IL-7Rα and γc extracellular domains with KD’s of 300nM and 10nM, respectively. MDK-703 induced pSTAT5 and proliferation in human T-cells with maximum effects equivalent to that of IL-7. MDK-703 does not activate nor inhibit any other γc family receptors at concentrations 100-fold greater than required for maximal IL-7R activation. Predicted immunogenicity, as determined by EpiMatrix Protein Score (-98.16) and EpiMatrix Cluster Scores (-3.54 to -30.28), was very low, indicating minimal potential for induction of T-cell-mediated anti-drug immune response. Single doses of MDK703 administered to CMs (1mg/kg IV or SC) exhibited a half-life of ~46hr after IV dosing, with exposure after SC dosing similar to IV. MDK-703 caused an initial reduction (due to migration into tissues), followed by sustained elevation of peripheral lymphocytes and CD8 and CD4 T-cells, with no observed adverse effects. Conclusions: MDK-703 offers an attractive alternative to IL-7-based drug candidates currently in clinical development. The structural novelty of MDK-703 eliminates the risk of ADAs that neutralize endogenous IL-7. A first human trial of MDK703 is anticipated in 2022. Citation Format: Angie I. Park, Steven E. Cwirla, Alice V. Bakker, Blake M. Williams, Prarthana Joshi, Praechompoo Pongtornpipat, Sandra M. Wang, Bryan Baxter, Michael C. Needels, Ronald W. Barrett, William J. Dower. In vitro and in vivo properties of MDK703: An Fc-peptide fusion IL-7Rαγc agonist unrelated in structure to IL-7 [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 2066.