Background/Purpose: Impaired IL-2 production and regulatory T cell (Treg) dysfunctions have been implicated as an immunological mechanism in multiple autoimmune diseases. While low-dose IL-2 can be used to stimulate Tregs for clinical benefit, poor pharmacokinetics necessitates daily delivery, adverse events are dose-limiting, and Treg increases are modest and short-lived. Nektar Therapeutics is developing NKTR-358, a novel product which utilizes the aldesleukin (Proleukin^®) amino acid sequence chemically conjugated with stable polyethylene glycol (PEG) moieties, intended for low dose subcutaneous administration to selectively restore Treg homeostasis with no impact on Tcon function.

Methods: The affinity to the IL-2 receptor was assessed by surface plasmon resonance. Activity in cynomolgus and human PBMC was measured by pSTAT5 induction in multiple lymphocyte populations utilizing flow cytometry. In vivo activity after subcutaneous administration in C57BL/6 mice or cynomolgus monkey was measured by changes in lymphocyte numbers and activation by flow cytometry. Ex vivo Treg function was determined by the inhibition of Tcon proliferation by isolated splenic Treg. Efficacy was examined in a model of cutaneous hypersensitivity in mice using keyhole limpet hemocyanin (KLH), and in cynomolgus monkey using tetnoid toxin. Efficacy in a model of systemic lupus erythematosus (SLE) was assessed using MRL/MpJ-Faslpr mice

Results: NKTR-358 has greatly attenuated affinity for human IL-2Rβ relative to IL-2Rα and IL-2Rαβ complexes, suggesting biological engagement favors activation of Treg which express the high affinity IL-2Rαβγ over Tcon, which express the low-affinity IL-2Rβγ. In vitro, Treg were far more sensitive to NKTR-358 stimulation relative to all other lymphocyte subsets in cynomolgus or human PBMC. In mice, a single administration led to sustained Treg mobilization for 7 to 10 days in blood and spleen without Tcon activation, an effect concomitant with increased Treg activation and suppressive capacity. In cynomolgus monkey, plasma exposure was even more prolonged leading to sustained Treg mobilization and activity for over 14 days after a single administration – a response superior in magnitude, duration and specificity compared to an equivalent total dose of rhIL-2 administered daily for five days. NKTR-358 administration suppressed the antigen-induced inflammatory response in the KLH hypersensitivity model, an effect which was antigen-specific and associated with establishment of Treg memory. Similar results were achieved in cynomolgus monkey using tetanus toxoid. Finally, NKTR-358 was efficacious a mouse model of SLE, with repeat administration over 12 weeks sustaining Treg elevation, significantly reducing blood urea nitrogen and returning urine protein levels and kidney histopathology to normal.

Conclusion: NKTR-358 delivers sustained, preferential activation of Tregs. Currently, NKTR-358 is being studied in a Phase 1 study in healthy subjects to measure Treg mobilization, functional activity, pharmacokinetics and safety, with the goal of establishing a range of dose levels to be advanced into a multiple-ascending dose trial in patients with SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/nktr-358-a-selective-first-in-class-il-2-pathway-agonist-which-increases-number-and-suppressive-function-of-regulatory-t-cells-for-the-treatment-of-immune-inflammatory-disorders/