PMID- 35517914 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220716 IS - 2589-9090 (Electronic) IS - 2589-9090 (Linking) VI - 5 DP - 2022 TI - Selective expansion of regulatory T cells by NKTR-358 in healthy volunteers and patients with systemic lupus erythematosus. PG - 100152 LID - 10.1016/j.jtauto.2022.100152 [doi] LID - 100152 AB - 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 mug/kg: n = 76; placebo: n = 24) and four in the MAD study (3-24.0 mug/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 CD25(bright) 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 CD25(bright) 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 CD25(bright) Tregs, with no significant changes in conventional T cells. These results provide strong support for further testing in SLE and other inflammatory diseases. CI - (c) 2022 The Authors. FAU - Fanton, Christie AU - Fanton C AD - Nektar Therapeutics, San Francisco, CA, USA. FAU - Furie, Richard AU - Furie R AD - Northwell Health, Great Neck, NY, USA. FAU - Chindalore, Vishala AU - Chindalore V AD - Pinnacle Research, Anniston, AL, USA. FAU - Levin, Robert AU - Levin R AD - Clinical Research of West Florida, Clearwater, FL, USA. FAU - Diab, Isam AU - Diab I AD - Paramount Medical Research, Middleburg Heights, OH, USA. FAU - Dixit, Neha AU - Dixit N AD - Nektar Therapeutics, San Francisco, CA, USA. FAU - Haglund, Cat AU - Haglund C AD - Nektar Therapeutics, San Francisco, CA, USA. FAU - Gibbons, Jacqueline AU - Gibbons J AD - Nektar Therapeutics, San Francisco, CA, USA. FAU - Hanan, Nathan AU - Hanan N AD - Nektar Therapeutics, San Francisco, CA, USA. FAU - Dickerson, Daniel AU - Dickerson D AD - ICON plc, Lenexa, KS, USA. FAU - Zalevsky, Jonathan AU - Zalevsky J AD - Nektar Therapeutics, San Francisco, CA, USA. FAU - Kotzin, Brian L AU - Kotzin BL AD - Nektar Therapeutics, San Francisco, CA, USA. LA - eng PT - Journal Article DEP - 20220328 PL - Netherlands TA - J Transl Autoimmun JT - Journal of translational autoimmunity JID - 101759413 PMC - PMC9062472 OTO - NOTNLM OT - Autoimmune disease OT - IL-2 receptor OT - Interleukin-2 OT - Regulatory T cells OT - Systemic lupus erythematosus COIS- The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CF, RF, VC, RL, ID, ND, CH, JG, NH, JZ and BK report financial support was provided by Nektar Therapeutics. CF reports a relationship with Nektar Therapeutics that includes: employment and equity or stocks. RF reports a relationship with Nektar Therapeutics that includes: consulting or advisory. RF reports a relationship with Genentech/Roche that incudes personal fees and grants. RF reports a relationship with AstraZeneca that includes: consulting or advisory. RF reports a relationship with Mallinckrodt Pharmaceuticals that includes: consulting or advisory. VC reports a relationship with AbbVie Inc that includes: funding grants. VC reports a relationship with Amgen Inc that includes: funding grants. VC reports a relationship with Boehringer Ingelheim Corp USA that includes: funding grants. VC reports a relationship with Boston Pharmaceuticals that includes: funding grants. VC reports a relationship with Eli Lilly and Company that includes: funding grants. VC reports a relationship with EMD Serono Inc that includes: funding grants. VC reports a relationship with Genentech that includes: funding grants. VC reports a relationship with GlaxoSmithKline USA that includes: funding grants. VC reports a relationship with Merck & Co Inc that includes: funding grants. VC reports a relationship with Nektar Therapeutics that includes: funding grants. VC reports a relationship with Novartis that includes: funding grants. VC reports a relationship with Pfizer that includes: funding grants. VC reports a relationship with Roche that includes: funding grants. VC reports that Pinnacle Research Group/Anniston Medical Clinic also received funding from Astellas Pharma Global Development Inc. RL reports a relationship with Gilead Sciences Inc that includes: consulting or advisory. RL reports a relationship with Exagen Inc that includes: consulting or advisory. RL reports a relationship with Myriad Genetics Inc that includes: consulting or advisory. RL reports a relationship with Sanofi that includes: paid expert testimony and speaking and lecture fees. RL reports a relationship with Regeneron Pharmaceuticals Inc that includes: paid expert testimony and speaking and lecture fees. RL reports a relationship with Bristol Myers Squibb Co that includes: paid expert testimony and speaking and lecture fees. RL reports a relationship with AbbVie that includes: paid expert testimony and speaking and lecture fees. ND reports a relationship with Nektar Therapeutics that includes: employment and equity or stocks. CH reports a relationship with Nektar Therapeutics that includes: employment and equity or stocks. JG reports a relationship with Nektar Therapeutics that includes: employment and equity or stocks. NH reports a relationship with GlaxoSmithKline that includes: employment. DD reports a relationship with PRA Health Sciences that includes: employment. DD reports a relationship with ICON plc that includes: employment. JZ reports a relationship with Nektar Therapeutics that includes: employment and equity or stocks. BK reports a relationship with Nektar Therapeutics that includes: employment and equity or stocks. ID has no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2022/05/07 06:00 MHDA- 2022/05/07 06:01 PMCR- 2022/03/28 CRDT- 2022/05/06 05:53 PHST- 2022/02/13 00:00 [received] PHST- 2022/03/15 00:00 [revised] PHST- 2022/03/21 00:00 [accepted] PHST- 2022/05/06 05:53 [entrez] PHST- 2022/05/07 06:00 [pubmed] PHST- 2022/05/07 06:01 [medline] PHST- 2022/03/28 00:00 [pmc-release] AID - S2589-9090(22)00013-2 [pii] AID - 100152 [pii] AID - 10.1016/j.jtauto.2022.100152 [doi] PST - epublish SO - J Transl Autoimmun. 2022 Mar 28;5:100152. doi: 10.1016/j.jtauto.2022.100152. eCollection 2022.