Safety, pharmacokinetics, and pharmacodynamics of MK-6194, an IL-2 mutein designed to selectively activate regulatory T cells: single ascending dose and multiple ascending dose trial data

• Published in: ImmunoHorizons Vol. 9; no. 5
• Main Authors: Scheid, Johannes F, Cunningham-Bussel, Kiki, Kim, Nancy, Agarwal, Shiuli, Nieddu, Garrett, Cote, Josee, Lemoine, Lieselotte, Decaesteker, Tatjana, Mendez, Luis, Paul, Erina, Love-Gregory, Latisha, Contreras, Alejandra Virginia, Zhao, Xuemei, Franco-Dilone, Lucia, Pang, Ling, Baltus, Gretchen A, Beaumont, Maribel, Shah, Ketal, Higginson-Scott, Nathan, Kis-Toth, Katalin, Otipoby, Kevin L, Viney, Joanne L, Sicard, Eric, Rottey, Sylvie, Sundy, John S, Van Dyck, Kristien, Laethem, Tine, Larson, Patrick, Sutradhar, Santosh, Wnek, Richard, Bueters, Tjerk, Lai, Eseng, Stoch, S Aubrey, Iwamoto, Marian, Robbins, Jonathan A
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 26.03.2025
• Subjects: Adolescent; Adult; Dose-Response Relationship, Drug; Double-Blind Method; Female; Healthy Volunteers; Humans; Interleukin-2 - administration & dosage; Interleukin-2 - adverse effects; Interleukin-2 - analogs & derivatives; Interleukin-2 - pharmacokinetics; Male; Middle Aged; Recombinant Proteins; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; Young Adult; regulatory T cells; interleukin-2; IL-2; FOXP3; Tregs
• ISSN: 2573-7732; 2573-7732
• DOI: 10.1093/immhor/vlaf005

MK-6194, an interleukin-2 mutein designed to selectively activate regulatory T cells (Tregs), was evaluated for safety, pharmacokinetics (PK), immunogenicity, and pharmacodynamics in healthy participants. In a single ascending dose trial (N = 56), participants received subcutaneous MK-6194 or placebo (3:1 ratio) across dose levels ranging from 1 to 10 mg. In a multiple ascending dose trial (N = 54), participants received subcutaneous MK-6194 or placebo (3:1 ratio) at dose levels ranging from 0.5 to 5 mg every 2 wk (total 3 doses) as well as 5 mg every 4 wk (total 2 doses). Baseline characteristics were comparable between trials, with participants mostly male with a mean age of 36 yr. There were no serious adverse events or dose-limiting toxicities. The most common adverse events were injection site erythema and eosinophil count elevations (with no indication of severe eosinophilia or eosinophilia-related organ damage). PK showed dose-proportionality and repeated doses of MK-6194 did not result in accumulation or time-dependent PK. Immunogenicity was low with no impact on PK or safety. Treg expansion as assessed by flow cytometry and Treg-specific demethylation region analysis was observed in a dose-dependent manner during both trials and expanded within about 8 d postdose up to about 5-fold and returned to baseline by 14 to 29 d postdose. Minimal impact was observed on other lymphocytes including total T lymphocyte and natural killer cell counts. These findings support the further development of MK-6194 as a potential treatment for autoimmune disorders.