Modeling the receptor pharmacology, pharmacokinetics, and pharmacodynamics of NKTR-214, a kinetically-controlled interleukin-2 (IL2) receptor agonist for cancer immunotherapy

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.

NCI 8628: A randomized phase 2 study of ziv‐aflibercept and high‐dose interleukin 2 or high‐dose interleukin 2 alone for inoperable stage III or IV melanoma

“…It currently is in clinical development as both a monotherapy and in combination with anti-PD-1 antibodies. 30 The current study data may support a future combination strategy of NKTR-214 or ALKS-4230 and VEGF inhibition in the second-line or subsequent treatment setting in patients with advanced melanoma as an outpatient and potentially less toxic regimen.…”

“…NKTR-214 consists of the IL2 protein bound by multiple slowly releasable polyethylene glycol chains, acting as a kinetically-controlled IL2 receptor agonist with evidence that it favors activation of CD8+ T cells over regulatory T cells. It is currently in clinical development as both a monotherapy and in combination with anti-PD-1 antibodies 30 . Our data may support a future combination strategy of NKTR-214 or ALKS 4230 and VEGF inhibition in the second or subsequent line treatment setting in advanced melanoma as an outpatient and potentially less toxic regimen.…”

“…Efforts to overcome the limitations of the short half-life and pleiotropic systemic effects of systemic IL-2 led to the development of interesting molecules such as Cancer November 15, 2018 ALKS-4230 29 and NKTR-214. 30 ALKS 4230, currently in phase 1 development, consists of a circularly permuted IL-2 and IL-2 receptor (IL-2R) α designed to selectively target intermediate-affinity IL-2R (comprised of IL-2R-β and γc), which is expressed primarily on effector lymphocytes. 29 NKTR-214 consists of the IL-2 protein bound by multiple, slowly releasable polyethylene glycol chains, acting as a kinetically controlled IL-2R agonist with evidence that it favors activation of CD8-positive T cells over regulatory T cells.…”

Optical Control of Cytokine Signaling via Bioinspired, Polymer-Induced Latency

“…NKTR-214 36 ), these findings are encouraging and could lead to future integration with wearable or implanted lightdelivery devices [37][38][39][40][41] which modulate drug activation. Consistent with other PEGylated cytokines, 36 we found that bioinspired, polymer-induced latency was able to prolong scIL-12 plasma circulation approximately 16-fold, potentially precluding the need for frequent, high dosing and improving tissue drug exposure in treatment settings.…”

“…Polydimethylsiloxane (PDMS) tissue phantoms were prepared as described previously. [56][57][58] Briefly, Sylgard 184 elastomer and curing agent (Dow Corning) was doped with titanium dioxide (0.3-1.0 µm rutile, Atlantic Equipment Engineers) and india ink (Higgins 44201) to concentrations which approximate attenuated light transmission through human tissue (36,20, and 42% transmission of 365 nm light through epidermis, dermis, and 2 mm hypodermis tissue, respectively). 59 Solutions were degassed and sequentially cast into rectangular silicone molds prior to measurement of LED light transmission using a thermal power sensor (ThorLabs).…”