A novel bispecific DARPin targeting FcγRIIB and FcεRI‐bound IgE inhibits allergic responses

Abstract

The described bispecific DARPin protein has the ability to co-ligate FcγRIIB with FcεRI-bound IgE on allergic effector cells and represents an efficient dual-modality to interfere with allergic hypersensitivity reactions.

An unexpected protective role of low-affinity allergen-specific IgG through the inhibitory receptor FcγRIIb

“…SIT has been shown to induce high-affinity blocking antibodies with somatic mutations in their complementarity-determining region as an indication for affinity maturation. [10][11][12][13][14][15][16][17][18] These findings are recapitulated here because high-affinity Fel d 1-specific antibodies induced by immunizing mice with Fel d 1 coupled to Qb-derived virus-like particles showed a high degree of hypermutation, and affinity was dramatically lower on back-mutation of the variable regions to germline sequences. Despite vastly different affinities, the germline antibodies exhibited the same epitope specificity as the parental antibodies; indeed, somatic hypermutation usually does not change the epitopes recognized.…”

“…To confirm that the inhibitory effect of germline A044 antibody is mediated through the inhibitory receptor FcgRIIb rather than through competition with IgE for binding to Fel d 1, a biological inhibitor (based on DARPin technology) of mouse FcgRIIb receptor was used for blocking the receptor. 15 As shown in Fig 3, 50 mg/mL DARPin was sufficient to abrogate the inhibitory effect of both mature and germline IgG 2a A044 antibodies on IgE F127 antibody-loaded mast cells. In contrast, blocking FcgRIIb receptor had no effect on the neutralizing activity of mature IgG 2a F127 antibody.…”

A Single Monoclonal Antibody against the Peanut Allergen Ara h 2 Protects against Systemic and Local Peanut Allergy

“…Pricks on the ear skin were performed with 23-G (0.6 mm Å∼25 mm) needles (Microlance, BD, USA). To assess FcγRIIb receptor function, designed ankyrin repeat proteins (DARPins, described in Zellweger et al [13]) against mouse FcγRIIb receptor were used for blocking the receptor by means of local subcutaneous injection on the ears 10 min before the ear prick. Dye extravasations started immediately after antigen challenge.…”

“…To assess FcγRIIb receptor function, designed ankyrin repeat proteins (DARPins) [13] against mouse FcγRIIb receptor were used for blocking the receptor by means of local subcutaneous injection on the ears 10 min before the ear prick. To assess the role of the inhibitory FcγRIIb receptor on basophils and mast cells on a systemic level, mice were injected i.v.…”

Future research trends in understanding the mechanisms underlying allergic diseases for improved patient care

“…[3][4][5][6][7][8] In addition, a number of promising small molecule drugs and vaccines are in the development pipeline. [9][10][11] This new era is now calling for the development of biomarkers and phenoand endotyping of diseases for customized patient care, which is termed stratified medicine, precision medicine, or personalized medicine. 4 Distinguishing phenotypes of a complex disease covers the observable clinically relevant properties of the disease but does not show a direct relationship to disease etiology and pathophysiology.…”