RT Journal Article
SR Electronic
T1 NKTR-255, a novel polymer-conjugated rhIL-15 with potent antitumor efficacy
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e002024
DO 10.1136/jitc-2020-002024
VO 9
IS 5
A1 Miyazaki, Takahiro
A1 Maiti, Mekhala
A1 Hennessy, Marlene
A1 Chang, Thomas
A1 Kuo, Peiwen
A1 Addepalli, Murali
A1 Obalapur, Palakshi
A1 Sheibani, Sara
A1 Wilczek, Joanna
A1 Pena, Rhoneil
A1 Quach, Phi
A1 Cetz, Janet
A1 Moffett, Andrew
A1 Tang, Yinyan
A1 Kirk, Peter
A1 Huang, Jicai
A1 Sheng, Dawei
A1 Zhang, Ping
A1 Rubas, Werner
A1 Madakamutil, Loui
A1 Kivimäe, Saul
A1 Zalevsky, Jonathan
YR 2021
UL http://jitc.bmj.com/content/9/5/e002024.abstract
AB Background NKTR-255 is a novel polyethylene glycol-conjugate of recombinant human interleukin-15 (rhIL-15), which was designed to retain all known receptor binding interactions of the IL-15 molecule. We explored the biologic and pharmacologic differences between endogenous IL-15 receptor α (IL-15Rα)-dependent (NKTR-255 and rhIL-15) and IL-15Rα-independent (precomplexed rhIL-15/IL-15Rα) cytokines.Methods In vitro pharmacological properties of rhIL-15, NKTR-255 and precomplex cytokines (rhIL-15/IL-15Rα and rhIL-15 N72D/IL-15Rα Fc) were investigated in receptor binding, signaling and cell function. In vivo pharmacokinetic (PK) and pharmacodynamic profile of the cytokines were evaluated in normal mice. Finally, immunomodulatory effect and antitumor activity were assessed in a Daudi lymphoma model.Results NKTR-255 and rhIL-15 exhibited similar in vitro properties in receptor affinity, signaling and leukocyte degranulation, which collectively differed from precomplexed cytokines. Notably, NKTR-255 and rhIL-15 stimulated greater granzyme B secretion in human peripheral blood mononuclear cells versus precomplexed cytokines. In vivo, NKTR-255 exhibited a PK profile with reduced clearance and a longer half-life relative to rhIL-15 and demonstrated prolonged IL-15R engagement in lymphocytes compared with only transient engagement observed for rhIL-15 and precomplexed rhIL-15 N72D/IL-15Rα Fc. As a consequent, NKTR-255 provided a durable and sustained proliferation and activation of natural killer (NK) and CD8+ T cells. Importantly, NKTR-255 is more effective than the precomplexed cytokine at inducing functionally competent, cytotoxic NK cells in the tumor microenvironment and the properties of NKTR-255 translated into superior antitumor activity in a B-cell lymphoma model versus the precomplexed cytokine.Conclusions Our results show that the novel immunotherapeutic, NKTR-255, retains the full spectrum of IL-15 biology, but with improved PK properties, over rhIL-15. These findings support the ongoing phase 1 first-in-human trial (NCT04136756) of NKTR-255 in participants with relapsed or refractory hematologic malignancies, potentially advancing rhIL-15-based immunotherapies for the treatment of cancer.All data relevant to the study are included in the article or uploaded as supplementary information.