Abstract
Acute allergic symptoms are caused by allergen-induced crosslinking of allergen-specific immunoglobulin E (IgE) bound to Fc-epsilon receptors on effector cells. Desensitization with allergen-specific immunotherapy (SIT) has been used for over a century, but the dominant protective mechanism remains unclear. One consistent observation is increased allergen-specific IgG, thought to competitively block allergen binding to IgE. Here we show that the blocking potency of the IgG response to Cat-SIT is heterogeneous. Next, using two potent, pre-selected allergen-blocking monoclonal IgG antibodies against the immunodominant cat allergen Fel d 1, we demonstrate that increasing the IgG/IgE ratio reduces the allergic response in mice and in cat-allergic patients: a single dose of blocking IgG reduces clinical symptoms in response to nasal provocation (ANCOVA, p = 0.0003), with a magnitude observed at day 8 similar to that reported with years of conventional SIT. This study suggests that simply augmenting the blocking IgG/IgE ratio may reverse allergy.
Highlights
Acute allergic symptoms are caused by allergen-induced crosslinking of allergen-specific immunoglobulin E (IgE) bound to Fc-epsilon receptors on effector cells
These data suggest that augmenting the allergenspecific blocking IgG/IgE ratio is critically important to reducing allergic symptoms
Polyclonal Fel d 1-specific IgG (Cat-specific immunotherapy (SIT)-IgG) from nine patient samples (Fig. 1b) bound recombinant Fel d 1 produced with a myc–myc–hexahistidine tag, with apparent KD values ranging from 0.36 to 9.8 nM (Fig. 1c, Supplementary Table 1)
Summary
Acute allergic symptoms are caused by allergen-induced crosslinking of allergen-specific immunoglobulin E (IgE) bound to Fc-epsilon receptors on effector cells. While titers of allergen-specific IgG generated through SIT have not consistently correlated with clinical improvement[13], greater correlation is observed when comparing symptom improvement with the ability of blocking IgG to compete with IgE for allergen binding[9] and functionally prevent the immediate hypersensitivity response[14,15]. These data suggest that augmenting the allergenspecific blocking IgG/IgE ratio is critically important to reducing allergic symptoms. To explore this fundamental question and test a therapeutic approach for allergy treatment, we generated two fully human IgG4 antibodies, REGN1908 and REGN1909, specific for Fel d 1, the major cat allergen[16]
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