Novel antibody cocktail targeting Bet v 1 rapidly and sustainably treats birch allergy symptoms in a phase 1 study

Abstract

Background: The efficacy of an allergen-specific IgG cocktail to treat cat allergy suggests that allergen-specific IgG may be a major protective mechanism elicited by allergen immunotherapy. Objectives: Extending these findings, we tested a Bet v 1-specific antibody cocktail in birch-allergic subjects. Methods: This was a phase 1, randomized, double-blind, study with 2 parts. Part A administered ascending doses of the Bet v 1-specific antibody cocktail REGN5713/14/15 (150-900 mg) in 32 healthy adults. Part B administered a single subcutaneous 900-mg dose or placebo in 64 birch-allergic subjects. Total nasal symptom score response to titrated birch extract nasal allergen challenge and skin prick test (SPT) with birch and alder allergen were assessed at screening and days 8, 29, 57, and 113 (SPT only); basophil activation tests (n 5 26) were conducted. Results: Single-dose REGN5713/14/15 significantly reduced total nasal symptom score following birch nasal allergen challenge relative to baseline. Differences in total nasal symptom score areas under the curve (0-1 hour) for subjects treated with REGN5713/14/15 versus those given placebo (day

Targeting immunodominant Bet v 1 epitopes with monoclonal antibodies prevents the birch allergic response

“…The utility of this approach to achieve symptomatic relief in individuals with birch allergy has been realized in a proof-of-principle clinical study evaluating the ability of REGN5713/14/15 to block acute allergic symptoms triggered by nasal provocation with birch pollen extract. 64 Together with the positive results achieved in a similar clinical study using 2 distinct IgG mAbs REGN1908/09 that target the major cat allergen, Fel d 1, in patients with cat allergy, 21 our findings support the notion that passive administration of allergenspecific mAbs may possibly offer a new and more convenient treatment approach for allergy and presents the potential of establishing a repertoire of antiallergen therapeutics for personalized allergy management.…”

Isolation of nanobodies with potential to reduce patients' IgE binding to Bet v 1

“…20 This study provides evidence for the applicability of nanobodies for passive immunotherapy of allergy, similar to monoclonal antibodies as has been shown only recently. [18][19][20][21] Since nanobodies per se have a very short in vivo half-life, several strategies to extend the in vivo half-life of nanobody-based constructs have been developed. 46 As most appropriate formats, we consider to engineer bi-specific nanobodies with specificities against Bet v 1 and albumin due to its high abundance and long circulation in the blood.…”

“…In this context, it was recently demonstrated that large quantities of Bet v 1-specific monoclonal antibodies (i.e., 900 mg/patient) were needed to sufficiently inhibit allergen-induced mast cell degranulation during the entire birch pollen season. 20,21 Once reformatted, Bet v 1-specific nanobodies may represent an attractive cost-effective alternative to monoclonal antibodies worth to be tested for their clinical efficacy. Furthermore, passive administration of pre-selected formatted Bet v 1-specific blocking nanobodies may also be considered as more convenient treatment approach compared to anti-histamines which have to be applied every day and still bear some side effects.…”

“…Very recently, studies have demonstrated that passively administered allergen-specific monoclonal antibodies comparably reduce allergic responses as those induced in the course of AIT if they are directed to or overlap with IgE epitopes. [18][19][20][21] These trials showed for the first time that passive immunization with allergenspecific IgG antibodies able to inhibit patients' IgE binding to major allergens is a rapid, effective, and well-tolerated treatment to reduce allergic inflammation. [18][19][20][21] Since the generation and identification of blocking monoclonal human or humanized antibodies are laborious and expensive, recombinant antibody fragments including nanobodies turned out to be attractive molecules extensively studied for diverse applications in the recent past.…”

The Role of IgA in Chronic Upper Airway Disease: Friend or Foe?

“…One of the possibilities is the administration of a so-called passive AIT under the form of antigen-specific immunosuppressive antibodies that have the ability of competing with IgE for allergen binding and functionally preventing the immediate hypersensitivity response. This hypothesis has been tested in both cat- and birch-allergic patients, receiving subcutaneous injections with a pre-selected allergen-blocking IgG against the respective major allergens showing beneficial results for over 2 months after only one injection ( 157 , 158 ). Because of the mucosal advantage of IgA over IgG, a similar therapeutic potential may lie in the local administration of isolated allergen-specific IgA, which has been shown to be effective in an in vivo mouse model of airway allergy ( 104 ).…”