A mechanistically novel peptide agonist of the IL-7 receptor that addresses limitations of IL-7 cytokine therapy

Interleukin (IL)-7 is broadly active on T-cell populations, and modified versions have been clinically evaluated for a variety of therapeutic applications, including cancer, lymphopenia and infectious diseases; and found to be relatively well-tolerated and biologically active. Here we describe novel IL-7R agonists that are unrelated in structure to IL-7, bind to the receptor subunits differently from IL-7, but closely emulate IL-7 biology. The small size, low structural complexity, and the natural amino acid composition of the pharmacologically active peptide MDK1472 allows facile incorporation into protein structures, such as the IgG2-Fc fusion MDK-703. This molecule possesses properties potentially better suited to therapeutic applications than native IL-7 or its derivatives. We compared these compounds with IL-7 for immune cell selectivity, induction of IL-7R signaling, receptor-mediated internalization, proliferation, and generation of immune cell phenotypes in human and non-human primate (NHP) peripheral blood cells in vitro; and found them to be similar in biological activity to IL-7. In cynomolgus macaques, MDK-703 exhibits a circulating half-life of 46 hr, and produces sustained T-cell expansion characteristic of IL-7 treatment. In the huCD34+-engrafted NSG mouse model of the human immune system, MDK-703 induces an immune cell profile very similar to that generated by IL-7-derived compounds; including the pronounced expansion of memory T-cells, particularly the population of stem-like memory T-cells (Tscm), which may be important for anti-tumor activities reported with IL-7 treatment. Clinical administration of IL-7 and modified variants has been reported to induce anti-drug antibodies (ADAs), including IL-7 neutralizing antibodies. The novel peptide agonist reported here scores very low in predicted immunogenicity, and because the peptide lacks sequence similarity with IL-7, the problematic immunogenic neutralization of endogenous cytokine should not occur. ### Competing Interest Statement I have read the journal's policy, and the authors of this manuscript have the following competing interests: All authors were employees of Medikine, Inc and received salary, stock options, and/or stock as part of standard employee compensation during the period the research was conducted and the manuscript was prepared. Relevant US patents and published applications naming Medikine inventors and assigned to Medikine are as follows, 1. US-11548914-B2. IL-2Rgamma binding compounds: Dower, William J. et al. 2023-01-10 2. US-11254729-B2. IL-7R-? binding compounds Dower, William J. et al. 2022-02-22 3. US-10689417-B2. IL-2R? binding compounds Dower, William J. et al. 2020-06-23 4. US-20200291067-A1. IL-2RGAMMA BINDING COMPOUNDS DOWER, WILLIAM J. et al. 2020-09-17 5. US-20200040036-A1. IL-2RGAMMA BINDING COMPOUNDS Dower, William J. et al. 2020-02-06