Abstract
Cytokines are potent immune modulating agents but are not ideal medicines in their natural form due to their short half-life and pleiotropic systemic effects. NKTR-214 is a clinical-stage biologic that comprises interleukin-2 (IL2) protein bound by multiple releasable polyethylene glycol (PEG) chains. In this highly PEG-bound form, the IL2 is inactive; therefore, NKTR-214 is a biologic prodrug. When administered in vivo, the PEG chains slowly release, creating a cascade of increasingly active IL2 protein conjugates bound by fewer PEG chains. The 1-PEG-IL2 and 2-PEG-IL2 species derived from NKTR-214 are the most active conjugated-IL2 species. Free-IL2 protein is undetectable in vivo as it is eliminated faster than formed. The PEG chains on NKTR-214 are located at the region of IL2 that contacts the alpha (α) subunit of the heterotrimeric IL2 receptor complex, IL2Rαβγ, reducing its ability to bind and activate the heterotrimer. The IL2Rαβγ complex is constitutively expressed on regulatory T cells (Tregs). Therefore, without the use of mutations, PEGylation reduces the affinity for IL2Rαβγ to a greater extent than for IL2Rβγ, the receptor complex predominant on CD8 T cells. NKTR-214 treatment in vivo favors activation of CD8 T cells over Tregs in the tumor microenvironment to provide anti-tumor efficacy in multiple syngeneic models. Mechanistic modeling based on in vitro and in vivo kinetic data provides insight into the mechanism of NKTR-214 pharmacology. The model reveals that conjugated-IL2 protein derived from NKTR-214 occupy IL-2Rβγ to a greater extent compared to free-IL2 protein. The model accurately describes the sustained in vivo signaling observed after a single dose of NKTR-214 and explains how the properties of NKTR-214 impart a unique kinetically-controlled immunological mechanism of action.
Highlights
Activation of the immune system is a key component of mounting an effective durable anti-tumor response
NKTR-214 was designed to be stable at pH < 6 and to slowly release polyethylene glycol (PEG) chains at physiological pH, providing a gradual increase of bioactivity [16]
NKTR-214 has 3 prominent mechanistic features: 1) biased receptor binding such that PEGylation impacts binding at IL-2Rαβγ to a greater extent than IL-2Rβγ relative to IL2; 2) sustained release of an array of conjugated-IL2 species; and 3) sustained activation of the IL2 pathway
Summary
Activation of the immune system is a key component of mounting an effective durable anti-tumor response. Most patients do not benefit from antagonist checkpoint blockade, suggesting that certain tumor microenvironments may require the addition of complementary immune agonist mechanisms to overcome tolerance and suppression [6]. High doses of IL2 are needed to activate CD8 T cells and NK cells, which tend to express the low-affinity IL2 receptor beta gamma subunits (IL2Rβγ). More recent studies indicate that in addition to these toxicities, IL2 stimulates proliferation and activation of regulatory T cells (Tregs). These cells constitutively express the highaffinity heterotrimeric IL2 receptor alpha beta gamma subunits (IL2Rαβγ). Treg activation may exacerbate immune suppression, potentially compromising the intended anti-tumor response [12,13,14,15]
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