| Autor: |
Christie Fanton, Richard Furie, Vishala Chindalore, Robert Levin, Isam Diab, Neha Dixit, Cat Haglund, Jacqueline Gibbons, Nathan Hanan, Daniel Dickerson, Jonathan Zalevsky, Brian L. Kotzin |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
|
| Zdroj: |
Journal of Translational Autoimmunity, Vol 5, Iss , Pp 100152- (2022) |
| Druh dokumentu: |
article |
| ISSN: |
2589-9090 |
| DOI: |
10.1016/j.jtauto.2022.100152 |
| Popis: |
Objective: To evaluate NKTR-358, a polyethylene glycol-interleukin-2 conjugate composition designed to selectively induce regulatory T cells (Tregs), in first-in-human studies. Methods: Healthy volunteers and patients with systemic lupus erythematosus (SLE) received single- or multiple-dose (biweekly) NKTR-358 or placebo in two sequential, randomized, phase 1 studies (single ascending dose [SAD; NCT04133116] and multiple ascending dose [MAD; NCT03556007]). Primary objectives were safety and tolerability; secondary objectives included pharmacokinetics (PK) and immune effects of NKTR-358; exploratory objectives included effects on SLE disease activity. Results: There were eight ascending dose cohorts in the SAD study (0.3–28.0 μg/kg: n = 76; placebo: n = 24) and four in the MAD study (3–24.0 μg/kg: n = 36; placebo: n = 12). Most adverse events (AEs) were grade 1–2 injection-site reactions, with no treatment‐related serious or severe AEs, or deaths. PK data showed dose proportionality and prolonged exposure (mean half-life: 7.4–12.9 days). Dose-dependent, selective, and sustained increases in percentages and absolute numbers of total CD4+ Tregs and CD25bright Tregs were observed, with no significant changes in conventional CD4+ and CD8+ T cells, and low-level increases in natural killer cells. At the highest doses tested, administration of NKTR-358 resulted in a 12–17-fold increase in CD25bright Tregs over baseline that was sustained for 20–30 days. Conclusion: NKTR-358 was well tolerated, had a suitable PK profile for biweekly dosing, and led to marked and selective dose-dependent increases in CD25bright Tregs, with no significant changes in conventional T cells. These results provide strong support for further testing in SLE and other inflammatory diseases. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
|
