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BACKGROUND: IL-33, found in high levels in participants with allergic disorders, is thought to mediate allergic reactions. Etokimab, an anti–IL-33 biologic, has previously demonstrated a good safety profile and favorable pharmacodynamic properties in many clinical studies. METHODS: In this 6-week placebo-controlled phase 2a study, we evaluated the safety and the ability of a single dose of etokimab to desensitize peanut-allergic adults. Participants received either etokimab ( n = 15) or blinded placebo ( n = 5). Clinical tests included oral food challenges and skin prick tests at days 15 and 45. Blood samples were collected for IgE levels and measurement of ex vivo peanut-stimulated T cell cytokine production. RESULTS: Efficacy measurements for active vs. placebo participants at the day 15 and 45 food challenge (tolerating a cumulative 275 mg of peanut protein, which was the food challenge outcome defined in this paper) demonstrated, respectively, 73% vs. 0% ( P = 0.008) to 57% vs. 0% (ns). The etokimab group had fewer adverse events compared with placebo. IL-4, IL-5, IL-9, IL-13, and ST2 levels in CD4 ⁺ T cells were reduced in the active vs. placebo arm upon peanut-induced T cell activation ( P = 0.036 for IL-13 and IL-9 at day 15), and peanut-specific IgE was reduced in active vs. placebo ( P = 0.014 at day 15). CONCLUSION: The phase 2a results suggest etokimab is safe and well tolerated and that a single dose of etokimab could have the potential to desensitize peanut-allergic participants and possibly reduce atopy-related adverse events. TRIAL REGISTRATION: ClinicalTrials.gov NCT02920021. FUNDING: This work was supported by NIH grant R01AI140134, AnaptysBio, the Hartman Vaccine Fund, and the Sean N. Parker Center for Allergy and Asthma Research at Stanford University.

Significance: The mechanisms through which successful immunotherapy induces possible deletion, replacement, or reprogramming of T cells are unknown. By evaluating the expression of T-cell–related genes, and using appropriate multivariate statistical approaches, our data show that successful immunotherapy can induce previously unidentified CD4+ T-cell subtypes during treatment that could help to predict an “immune-tolerant” clinical phenotype identified after cessation of treatment. The ability to use “anergic” transcriptional phenotypes in single T cells to predict successful “immune tolerance” induction in the clinic setting, as suggested by our findings, could lead to transformative impacts in the field of immunotherapy.