Immunotherapy-induced neutralizing antibodies disrupt allergen binding and sustain allergen tolerance in peanut allergy

LaHood, Nicole; Min, Ji-Young; Keswani, Tarun; Richardson, Crystal; Amoako, Kwasi; Zhou, Jingjia; Marini-Rapoport, Orlee; Bernard, Hervé; Hazebrouck, Stéphane; Shreffler, Wayne G.; Love, J. Christopher; Pomés, Anna; Pedersen, Lars C.; Mueller, Geoffrey A.; Patil, Sarita U.

doi:10.1172/jci164501

Cited by 28 publications

(42 citation statements)

References 62 publications

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“…Studies have shown that OIT induces strong IgG responses, which encompasses all IgG subclasses, but only modest reductions in specific IgE antibodies 46,47,[57][58][59] . Moreover, these allergen-specific IgGs effectively neutralize allergens and also compete for IgE binding via interactions with FcγRIIB, thus suppressing IgE-mediated effector cell activation 60,61 . The BLG-p(Man) treatment substantially increased the BLG-specific IgG levels, which outcompeted the increase in IgE, resulting in a reduced IgE/IgG ratio (Figure 5E-G).…”

Section: Resultsmentioning

confidence: 99%

“…Studies have shown that OIT induces strong IgG responses, which encompasses all IgG subclasses, but only modest reductions in specific IgE antibodies 43, 44, 47–49 . Moreover, these allergen-specific IgGs effectively neutralize allergen to suppress IgE-mediated effector cell activation 50 . In our research, we observed that anti-CD20 mAb treatment significantly reduced the BLG-specific IgE/IgG ratio, and subsequent SCIT treatment with BLG-p(Man) further lowered it by 34% ( Figure 5G ), which is consistent with the profile of clinically approved OIT treatments and provides a mechanistic basis for the ameliorated anaphylactic responses after oral BLG challenge.…”

Section: Discussionmentioning

confidence: 99%

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Glycosylation-modified antigens as a tolerance-inducing vaccine platform prevent anaphylaxis in a pre-clinical model of food allergy

Cao

Maulloo

Raczy

et al. 2023

Preprint

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The only FDA-approved oral immunotherapy for a food allergy provides protection against accidental exposure to peanuts. However, this therapy often causes discomfort or side effects and requires long-term commitment. Better preventive and therapeutic solutions are urgently needed. We have developed an inverse vaccine technology that utilizes glycopolymer-conjugated antigens to induce antigen-specific non-responsiveness. The glycopolymer conjugates were administered intravenously (i.v.) or subcutaneously (s.c.) and were found to traffic to the liver or lymph nodes, respectively, leading to preferential internalization by antigen-presenting cells, educating the immune system to respond in an innocuous way. In a mouse model of cow's milk allergy, treatment with glycopolymer-conjugated β-lactoglobulin (BLG) was effective in preventing the onset of allergy. In addition, s.c. administration of glycopolymer-conjugated BLG showed superior safety and potential in treating existing allergies in combination with an anti-CD20 co-therapy. This platform may provide an antigen-specific immunomodulatory strategy to prevent and treat food allergies.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Glycosylation-modified antigens as a tolerance-inducing vaccine platform prevent anaphylaxis in a pre-clinical model of food allergy

Cao

Maulloo

Raczy

et al. 2023

Preprint

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“…Hence, reducing IgE binding by modifying the allergen Ara h 2 has been suggested as a way to make peanut OIT safer 10,11 . Recent studies of anti‐Ara h 2‐specific B cells cloned from patients undergoing oral immunotherapy found a surprising convergence of immunoglobulin sequences suggesting that Ara h 2 antibody paratopes recognize common epitopes on Ara h 2 12–14 . These studies primarily identified IgG sequences but other studies have identified shared Ara h 2‐specific IgE and IgG antibody clones, 12,15,16 which supported a paradigm of sequential switching from IgG to IgE.…”

Section: Introductionmentioning

confidence: 98%

“…Ideally, the proposed modifications to the allergen would remove the antigenic determinants that drive pathogenicity while preserving its therapeutic benefit of retraining the immune system. In this work, we utilized our previous studies on the epitopes of Ara h 2, 14 along with the crystal structures of an additional conformational epitope, to test whether we can engineer a hypoallergen with mutations that would abrogate IgE binding. Further, we tested if this hypoallergen would reduce IgE binding in vitro and reduce the risk of anaphylaxis in a mouse model of passive cutaneous anaphylaxis.…”

Section: Introductionmentioning

confidence: 99%

Design of an Ara h 2 hypoallergen from conformational epitopes

Min,

Keswani,

LaHood

et al. 2024

Clin Experimental Allergy

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IntroductionAdverse reactions are relatively common during peanut oral immunotherapy. To reduce the risk to the patient, some researchers have proposed modifying the allergen to reduce IgE reactivity, creating a putative hypoallergen. Analysis of recently cloned human IgG from patients treated with peanut immunotherapy suggested that there are three common conformational epitopes for the major peanut allergen Ara h 2. We sought to test if structural information on these epitopes could indicate mutagenesis targets for designing a hypoallergen and evaluated the reduction in IgE binding via immunochemistry and a mouse model of passive cutaneous anaphylaxis (PCA).MethodsX‐ray crystallography characterized the conformational epitopes in detail, followed by mutational analysis of key residues to modify monoclonal antibody (mAb) and serum IgE binding, assessed by ELISA and biolayer interferometry. A designed Ara h 2 hypoallergen was tested for reduced vascularization in mouse PCA experiments using pooled peanut allergic patient serum.ResultsA ternary crystal structure of Ara h 2 in complex with patient antibodies 13T1 and 13T5 was determined. Site‐specific mutants were designed that reduced 13T1, 13T5, and 22S1 mAbs binding by orders of magnitude. By combining designed mutations from the three major conformational bins, a hexamutant (Ara h 2 E46R, E89R, E97R, E114R, Q146A, R147E) was created that reduced IgE binding in serum from allergic patients. Further, in the PCA model where mice were primed with peanut allergic patient serum, reactivity upon allergen challenge was significantly decreased using the hexamutant.ConclusionThese studies demonstrate that prior knowledge of common conformational epitopes can be used to engineer reduced IgE reactivity, an important first step in hypoallergen design.

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“…In clinical practice, there are several possibilities to avoid the activity of IgE and many pharmaceutical interventions aim to prevent IgE production and/or make the immune system more tolerant to allergens by inducing a shift in Th cell responses from Th2 to Th1 or regulatory T cells 6,7 ; more recently, the concept of mAbs targeting and blocking IgE directly has been introduced 8 . Alternatively, it may be possible to block the action of IgE indirecty by induction of allergen-specific IgG through passive 9 or active vaccination 10,11 . This approach is supported by the clinical observation that successful specific immunotherapy may correlate with an increase of the IgG/IgE ratio, and more recently, that polyclonal and monoclonal allergen specific IgG antibodies were able to curb allergic immune responses both in mice and humans as a form of passive vaccination [12][13][14] .…”

Section: Allergy Affinity Antibody Ige Igg1 Introductionmentioning

confidence: 99%

On the role of antibody affinity in the IgE mediated allergic response

Vogel

Bachmann

Mohsen

et al. 2023

Preprint

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Type I hypersensitivity, also known as classical allergy, is mediated via allergen-specific IgE antibodies bound to type I FcR (FcεRI) on the surface of mast cells and basophils upon cross-linking by allergens. This IgE-mediated cellular activation may be blocked by allergen-specific IgG through multiple mechanisms, including direct neutralization of the allergen or engagement of the inhibitory receptor FcγRIIb which blocks IgE signal transduction. In addition, co-engagement of FceRI and FcγRIIb by IgE-IgG-allergen immune-complexes causes down-regulation of receptor bound IgE, resulting in desensitization of the cells. Both, activation of FceRI by allergen-specific IgE and engagement of FcγRIIb by allergen-specific IgG are driven by allergen-binding. Here we delineate the distinct roles of antibody affinity versus avidity in driving these processes and discuss the role of IgG subclasses in inhibiting basophil and mast cell activation.

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Immunotherapy-induced neutralizing antibodies disrupt allergen binding and sustain allergen tolerance in peanut allergy

Cited by 28 publications

References 62 publications

Glycosylation-modified antigens as a tolerance-inducing vaccine platform prevent anaphylaxis in a pre-clinical model of food allergy

Glycosylation-modified antigens as a tolerance-inducing vaccine platform prevent anaphylaxis in a pre-clinical model of food allergy

Design of an Ara h 2 hypoallergen from conformational epitopes

On the role of antibody affinity in the IgE mediated allergic response

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