Preclinical efficacy of peanut-specific IgG4 antibody therapeutic IGNX001

Derek Croote; Joyce J.W. Wong; Paige Creeks; Venu Aruva; Jeffrey J. Landers; Matthew Kwok; Zainab Jama; Robert G. Hamilton; Alexandra F. Santos; Jessica J. O'Konek; Roger Ferrini; G. Roger Thomas; Henry B. Lowman

doi:10.1016/j.jaci.2024.07.014

Preclinical efficacy of peanut-specific IgG4 antibody therapeutic IGNX001

Derek Croote^*, Joyce J.W. Wong, Paige Creeks, Venu Aruva, Jeffrey J. Landers, Matthew Kwok, Zainab Jama, Robert G. Hamilton, Alexandra F. Santos, Jessica J. O'Konek, Roger Ferrini, G. Roger Thomas, Henry B. Lowman

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Background: Existing therapeutic strategies are challenged by long times to achieve effect and often require frequent administration. Peanut-allergic individuals would benefit from a therapeutic that provides rapid protection against accidental exposure within days of administration while carrying little risk of adverse reactions. Objective: Guided by the repertoire of human IgE mAbs from allergic individuals, we sought to develop a treatment approach leveraging the known protective effects of allergen-specific IgG4 antibodies. Methods: We applied our single-cell RNA-sequencing SEQ SIFTER platform (IgGenix, Inc, South San Francisco, Calif) to whole blood samples from peanut-allergic individuals to discover IgE mAbs. These were then class-switched by replacing the IgE constant region with IgG4 while retaining the allergen-specific variable regions. In vitro mast cell activation tests, basophil activation tests, ELISAs, and an in vivo peanut allergy mouse model were used to evaluate the specificity, affinity, and activity of these recombinant IgG4 mAbs. Results: We determined that human peanut-specific IgE mAbs predominantly target immunodominant epitopes on Ara h 2 and Ara h 6 and that recombinant IgG4 mAbs effectively block these epitopes. IGNX001, a mixture of 2 such high-affinity IgG4 mAbs, provided robust protection against peanut-mediated mast cell activation in vitro as well as against anaphylaxis upon intragastric peanut challenge in a peanut allergy mouse model. Conclusions: We developed a peanut-specific IgG4 antibody therapeutic with convincing preclinical efficacy starting from a large repertoire of human IgE mAbs from demographically and geographically diverse individuals. These results warrant further clinical investigation of IGNX001 and underscore the opportunity for the application of this therapeutic development strategy in other food and environmental allergies.

Original language	English
Pages (from-to)	1241-1248.e7
Journal	Journal of Allergy and Clinical Immunology
Volume	154
Issue number	5
DOIs	https://doi.org/10.1016/j.jaci.2024.07.014
Publication status	Published - Nov 2024

Keywords

allergy
allergy biologics
Ara h 2
Ara h 6
food allergy
Human monoclonal IgE antibodies
IgG4
mast cell activation tests
peanut allergy
scRNA-seq
single-cell RNA sequencing
therapeutics

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10.1016/j.jaci.2024.07.014

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Croote, D., Wong, J. J. W., Creeks, P., Aruva, V., Landers, J. J., Kwok, M., Jama, Z., Hamilton, R. G., Santos, A. F., O'Konek, J. J., Ferrini, R., Thomas, G. R., & Lowman, H. B. (2024). Preclinical efficacy of peanut-specific IgG4 antibody therapeutic IGNX001. Journal of Allergy and Clinical Immunology, 154(5), 1241-1248.e7. https://doi.org/10.1016/j.jaci.2024.07.014

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title = "Preclinical efficacy of peanut-specific IgG4 antibody therapeutic IGNX001",

abstract = "Background: Existing therapeutic strategies are challenged by long times to achieve effect and often require frequent administration. Peanut-allergic individuals would benefit from a therapeutic that provides rapid protection against accidental exposure within days of administration while carrying little risk of adverse reactions. Objective: Guided by the repertoire of human IgE mAbs from allergic individuals, we sought to develop a treatment approach leveraging the known protective effects of allergen-specific IgG4 antibodies. Methods: We applied our single-cell RNA-sequencing SEQ SIFTER platform (IgGenix, Inc, South San Francisco, Calif) to whole blood samples from peanut-allergic individuals to discover IgE mAbs. These were then class-switched by replacing the IgE constant region with IgG4 while retaining the allergen-specific variable regions. In vitro mast cell activation tests, basophil activation tests, ELISAs, and an in vivo peanut allergy mouse model were used to evaluate the specificity, affinity, and activity of these recombinant IgG4 mAbs. Results: We determined that human peanut-specific IgE mAbs predominantly target immunodominant epitopes on Ara h 2 and Ara h 6 and that recombinant IgG4 mAbs effectively block these epitopes. IGNX001, a mixture of 2 such high-affinity IgG4 mAbs, provided robust protection against peanut-mediated mast cell activation in vitro as well as against anaphylaxis upon intragastric peanut challenge in a peanut allergy mouse model. Conclusions: We developed a peanut-specific IgG4 antibody therapeutic with convincing preclinical efficacy starting from a large repertoire of human IgE mAbs from demographically and geographically diverse individuals. These results warrant further clinical investigation of IGNX001 and underscore the opportunity for the application of this therapeutic development strategy in other food and environmental allergies.",

keywords = "allergy, allergy biologics, Ara h 2, Ara h 6, food allergy, Human monoclonal IgE antibodies, IgG4, mast cell activation tests, peanut allergy, scRNA-seq, single-cell RNA sequencing, therapeutics",

author = "Derek Croote and Wong, {Joyce J.W.} and Paige Creeks and Venu Aruva and Landers, {Jeffrey J.} and Matthew Kwok and Zainab Jama and Hamilton, {Robert G.} and Santos, {Alexandra F.} and O'Konek, {Jessica J.} and Roger Ferrini and Thomas, {G. Roger} and Lowman, {Henry B.}",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors",

year = "2024",

month = nov,

doi = "10.1016/j.jaci.2024.07.014",

language = "English",

volume = "154",

pages = "1241--1248.e7",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "MOSBY, INC",

number = "5",

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TY - JOUR

T1 - Preclinical efficacy of peanut-specific IgG4 antibody therapeutic IGNX001

AU - Croote, Derek

AU - Wong, Joyce J.W.

AU - Creeks, Paige

AU - Aruva, Venu

AU - Landers, Jeffrey J.

AU - Kwok, Matthew

AU - Jama, Zainab

AU - Hamilton, Robert G.

AU - Santos, Alexandra F.

AU - O'Konek, Jessica J.

AU - Ferrini, Roger

AU - Thomas, G. Roger

AU - Lowman, Henry B.

PY - 2024/11

Y1 - 2024/11

N2 - Background: Existing therapeutic strategies are challenged by long times to achieve effect and often require frequent administration. Peanut-allergic individuals would benefit from a therapeutic that provides rapid protection against accidental exposure within days of administration while carrying little risk of adverse reactions. Objective: Guided by the repertoire of human IgE mAbs from allergic individuals, we sought to develop a treatment approach leveraging the known protective effects of allergen-specific IgG4 antibodies. Methods: We applied our single-cell RNA-sequencing SEQ SIFTER platform (IgGenix, Inc, South San Francisco, Calif) to whole blood samples from peanut-allergic individuals to discover IgE mAbs. These were then class-switched by replacing the IgE constant region with IgG4 while retaining the allergen-specific variable regions. In vitro mast cell activation tests, basophil activation tests, ELISAs, and an in vivo peanut allergy mouse model were used to evaluate the specificity, affinity, and activity of these recombinant IgG4 mAbs. Results: We determined that human peanut-specific IgE mAbs predominantly target immunodominant epitopes on Ara h 2 and Ara h 6 and that recombinant IgG4 mAbs effectively block these epitopes. IGNX001, a mixture of 2 such high-affinity IgG4 mAbs, provided robust protection against peanut-mediated mast cell activation in vitro as well as against anaphylaxis upon intragastric peanut challenge in a peanut allergy mouse model. Conclusions: We developed a peanut-specific IgG4 antibody therapeutic with convincing preclinical efficacy starting from a large repertoire of human IgE mAbs from demographically and geographically diverse individuals. These results warrant further clinical investigation of IGNX001 and underscore the opportunity for the application of this therapeutic development strategy in other food and environmental allergies.

AB - Background: Existing therapeutic strategies are challenged by long times to achieve effect and often require frequent administration. Peanut-allergic individuals would benefit from a therapeutic that provides rapid protection against accidental exposure within days of administration while carrying little risk of adverse reactions. Objective: Guided by the repertoire of human IgE mAbs from allergic individuals, we sought to develop a treatment approach leveraging the known protective effects of allergen-specific IgG4 antibodies. Methods: We applied our single-cell RNA-sequencing SEQ SIFTER platform (IgGenix, Inc, South San Francisco, Calif) to whole blood samples from peanut-allergic individuals to discover IgE mAbs. These were then class-switched by replacing the IgE constant region with IgG4 while retaining the allergen-specific variable regions. In vitro mast cell activation tests, basophil activation tests, ELISAs, and an in vivo peanut allergy mouse model were used to evaluate the specificity, affinity, and activity of these recombinant IgG4 mAbs. Results: We determined that human peanut-specific IgE mAbs predominantly target immunodominant epitopes on Ara h 2 and Ara h 6 and that recombinant IgG4 mAbs effectively block these epitopes. IGNX001, a mixture of 2 such high-affinity IgG4 mAbs, provided robust protection against peanut-mediated mast cell activation in vitro as well as against anaphylaxis upon intragastric peanut challenge in a peanut allergy mouse model. Conclusions: We developed a peanut-specific IgG4 antibody therapeutic with convincing preclinical efficacy starting from a large repertoire of human IgE mAbs from demographically and geographically diverse individuals. These results warrant further clinical investigation of IGNX001 and underscore the opportunity for the application of this therapeutic development strategy in other food and environmental allergies.

KW - allergy

KW - allergy biologics

KW - Ara h 2

KW - Ara h 6

KW - food allergy

KW - Human monoclonal IgE antibodies

KW - IgG4

KW - mast cell activation tests

KW - peanut allergy

KW - scRNA-seq

KW - single-cell RNA sequencing

KW - therapeutics

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U2 - 10.1016/j.jaci.2024.07.014

DO - 10.1016/j.jaci.2024.07.014

M3 - Article

C2 - 39069172

AN - SCOPUS:85202848051

SN - 0091-6749

VL - 154

SP - 1241-1248.e7

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 5

ER -

Preclinical efficacy of peanut-specific IgG4 antibody therapeutic IGNX001

Abstract

Keywords

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