Allergy · 2025
Subcutaneous Allergen Immunotherapy With Hypoallergenic Bet v 1 Compared to Conventional Extract: Poorer Blocking Antibody Capacity Dominated by IgG1 Instead of IgG4.
СтатьяРандомизированное исследованиеНазвание и аннотация: Перевод в очереди
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Aglas Lorenz, Tannert Line Kring, Versteeg Serge A, Smith Scott A, Bartko Ewa A, Wenger Mario, Kraiem Amin, Widauer Hannah, Nunes Natália, Sinkunaite Sibile, Stolz Frank, Jongejan Laurian, Neubauer Angela, Blom Lars H, Ferreira Fatima, Poulsen Lars K, Bindslev-Jensen Carsten, van Ree Ronald
Аннотация
BACKGROUND: Hypoallergenic recombinant fold-variants of major allergens have been suggested as safer and more effective AIT candidates. The Bet v 1-fold variant BM41, with confirmed preclinical hypoallergenicity and increased immunogenicity, was proposed for the treatment of birch pollen allergy.
METHODS: We performed a 6-month randomized, double-blind, placebo-controlled first-in-human clinical trial with BM41, a licensed birch pollen extract-based treatment, as the active comparator (AC), and placebo (n = 16, n = 16, and n = 15, respectively). The primary endpoint was safety. Secondary outcomes were Bet v 1-specific (s)IgE, IgG, IgG1, and IgG4 responses measured by ImmunoCAP, and sIgE-blocking activity using mediator release and facilitated antigen binding assays.
RESULTS: Despite SPT-confirmed hypoallergenicity (~50% compared to natural Bet v 1), more adverse events occurred in response to BM41. Although similar sIgG and sIgG1 levels were induced, sIgG4 levels increased 3-fold more in AC compared to the BM41 group. In AC, the sIgG4/sIgG1 ratio tripled over time, whereas for BM41 it stagnated. BM41 induced efficient serum inhibitory activity for sIgE compared to placebo but was 12%-32% less efficient than AC. Both sIgG4 and sIgG1 contributed to the blocking effect in AC, while in BM41 both sIgG subclasses showed a lowered functional capacity.
CONCLUSION: Preclinically established hypoallergenicity of BM41 did not result in a lower number of adverse events. The reduced induction of sIgG4 by the fold variant in the course of the treatment was less efficient in blocking sIgE-mediated responses. This is the first study providing evidence that, instead of a Th1-favored IgG1-dominated response, "modified Th2"-skewed IgG4-dominated humoral responses are beneficial in AIT vaccine design.
METHODS: We performed a 6-month randomized, double-blind, placebo-controlled first-in-human clinical trial with BM41, a licensed birch pollen extract-based treatment, as the active comparator (AC), and placebo (n = 16, n = 16, and n = 15, respectively). The primary endpoint was safety. Secondary outcomes were Bet v 1-specific (s)IgE, IgG, IgG1, and IgG4 responses measured by ImmunoCAP, and sIgE-blocking activity using mediator release and facilitated antigen binding assays.
RESULTS: Despite SPT-confirmed hypoallergenicity (~50% compared to natural Bet v 1), more adverse events occurred in response to BM41. Although similar sIgG and sIgG1 levels were induced, sIgG4 levels increased 3-fold more in AC compared to the BM41 group. In AC, the sIgG4/sIgG1 ratio tripled over time, whereas for BM41 it stagnated. BM41 induced efficient serum inhibitory activity for sIgE compared to placebo but was 12%-32% less efficient than AC. Both sIgG4 and sIgG1 contributed to the blocking effect in AC, while in BM41 both sIgG subclasses showed a lowered functional capacity.
CONCLUSION: Preclinically established hypoallergenicity of BM41 did not result in a lower number of adverse events. The reduced induction of sIgG4 by the fold variant in the course of the treatment was less efficient in blocking sIgE-mediated responses. This is the first study providing evidence that, instead of a Th1-favored IgG1-dominated response, "modified Th2"-skewed IgG4-dominated humoral responses are beneficial in AIT vaccine design.