NKTR-358: A novel regulatory T-cell stimulator that selectively stimulates expansion and suppressive function of regulatory T cells for the treatment of autoimmune and inflammatory diseases.

Impaired interleukin-2 (IL-2) production and regulatory T-cell dysfunction have been implicated as immunological mechanisms central to the pathogenesis of multiple autoimmune and inflammatory diseases. NKTR-358, a novel regulatory T-cell stimulator, is an investigational therapeutic that selectively restores regulatory T-cell homeostasis in these diseases. We investigated NKTR-358's selectivity for regulatory T-cells, receptor-binding properties, ex vivo and in vivo pharmacodynamics, ability to suppress conventional T-cell proliferation in mice and non-human primates, and functional activity in a murine model of systemic lupus erythematosus. In vitro, NKTR-358 demonstrated decreased affinity for IL-2Rα, IL-2Rß, and IL-2Rαß compared with recombinant human IL-2 (rhIL-2). A single dose of NKTR-358 in cynomolgus monkeys produced a greater than 15-fold increase in regulatory T-cells, and the increase lasted until day 14, while daily rhIL-2 administration for 5 days only elicited a 3-fold increase, which lasted until day 7. Repeated dosing of NKTR-358 over 6 months in cynomolgus monkeys elicited cyclical, robust increases in regulatory T-cells with no loss in drug activity over the course of treatment. Regulatory T-cells isolated from NKTR-358-treated mice displayed a sustained, higher suppression of conventional T-cell proliferation than regulatory T-cells isolated from vehicle-treated mice. NKTR-358 treatment in a mouse model (MRL/MpJ-Faslpr) of systemic lupus erythematosus for 12 weeks maintained elevated regulatory T-cells for the treatment duration and ameliorated disease progression. Together, these results suggest that NKTR-358 has the ability to elicit sustained and preferential proliferation and activation of regulatory T-cells without corresponding effects on conventional T-cells, with improved pharmacokinetics compared with rhIL-2.

NKTR-255, a novel polymer-conjugated rhIL-15 with potent antitumor efficacy.

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.

Influenza H1N1pdm-specific maternal antibodies offer limited protection against wild-type virus replication and influence influenza vaccination in ferrets.

OBJECTIVE: The objective was to study passively acquired influenza H1N1 pandemic (H1N1pdm) maternal antibody kinetics and its impact on subsequent influenza infection and vaccination in ferrets during an outbreak of the H1N1pdm. DESIGN AND MAIN OUTCOME MEASURES: Infectivity of the H1N1pdm in the respiratory tract of ferrets was compared with the previous seasonal A/South Dakota/6/2007 (SD07, H1N1). Influenza-specific antibodies were quantitated and antibody-mediated protection against the homologous and heterologous H1N1 virus challenge infection was determined. RESULTS: H1N1pdm virus was approximately 10 times more infectious than SD07 in ferrets, replicated to higher viral titers in the upper respiratory tract and shed for a longer duration. Influenza-specific antibodies after natural infection persisted much longer in the circulation than passively acquired maternal antibodies. The protection conferred by the maternal antibodies was limited to the homologous virus strain and was ineffective against SD07 and H3N2 virus. Serum antibodies from maternal transmission or passive transfer interfered with homologous vaccine strain-mediated antibody responses in the ferret. A booster immunization was required to elicit a high level of antibody. CONCLUSIONS: The findings support the rationale for a prime and boost immunization strategy in young children in whom maternal antibodies are present.