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

Dower, W. J.; Park, A. I.; Bakker, A. V.; Cwirla, S. E.; Pongtornpipat, P.; Williams, B. M.; Joshi, P.; Baxter, B. A.; Needels, M. C.; Barrett, R. W.

doi:10.1101/2023.05.24.542196

bioRxiv · 10.1101/2023.05.24.542196

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

Dower, W. J.·Park, A. I.·Bakker, A. V.·Cwirla, S. E.·Pongtornpipat, P.·Williams, B. M.·Joshi, P.·Baxter, B. A.·Needels, M. C.·Barrett, R. W.

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Abstract

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.

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Dower, W. J., Park, A. I., Bakker, A. V., Cwirla, S. E., Pongtornpipat, P., Williams, B. M., Joshi, P., Baxter, B. A., Needels, M. C., Barrett, R. W.. 2023-05-24. A mechanistically novel peptide agonist of the IL-7 receptor that addresses limitations of IL-7 cytokine therapy. https://doi.org/10.1101/2023.05.24.542196

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