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WO1998053843A1 - INHIBITION DE LA PRODUCTION d'IgE SPECIFIQUE D'UN ANTIGENE PAR UN ANTIGENE COUPLE A UN PEPTIDE D'IgE MEMBRANAIRE - Google Patents

INHIBITION DE LA PRODUCTION d'IgE SPECIFIQUE D'UN ANTIGENE PAR UN ANTIGENE COUPLE A UN PEPTIDE D'IgE MEMBRANAIRE Download PDF

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Publication number
WO1998053843A1
WO1998053843A1 PCT/US1997/011707 US9711707W WO9853843A1 WO 1998053843 A1 WO1998053843 A1 WO 1998053843A1 US 9711707 W US9711707 W US 9711707W WO 9853843 A1 WO9853843 A1 WO 9853843A1
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WO
WIPO (PCT)
Prior art keywords
ige
antigen
migis
peptide
seq
Prior art date
Application number
PCT/US1997/011707
Other languages
English (en)
Inventor
Alex Chen
Tse Wen Chang
Original Assignee
Tanox Biosystems, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tanox Biosystems, Inc. filed Critical Tanox Biosystems, Inc.
Priority to AU35155/97A priority Critical patent/AU3515597A/en
Priority to PCT/US1997/011707 priority patent/WO1998053843A1/fr
Publication of WO1998053843A1 publication Critical patent/WO1998053843A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/35—Allergens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype

Definitions

  • the invention relates to use of peptide-antigen conjugates to suppress IgE production in an antigen-specific manner, to desensitize a subject to the antigen of the conjugate.
  • Immunoglobulins consist of two peptide chains, a heavy chain and a light chain. There are five classes of immunoglobulins: IgG, IgM, IgA, IgD, and IgE. In IgE, the heavy chain is designated as the e chain.
  • the membrane-bound form differs from the secreted form in that the former has a membrane-anchoring peptide extending from the C terminus of the e chain. This membrane-anchoring peptide affixes the membrane-bound immunoglobulin to the cell membrane surface.
  • Membrane-anchoring peptides can be divided into three segments in terms of locations in relation to the plasma membrane.
  • the middle segments have hydrophobic and uncharged amino acid residues, suggesting that they are in the membrane lipid bilayer.
  • the C-terminal hydrophilic segments and have fewer amino acid residues, suggesting that they are intracellular.
  • the segments toward the N-termini are highly acidic and hydrophilic, suggesting that they are on the extracellular surface of the plasma membrane.
  • the extracellular segments of these peptides are unique for different isotypes. Therefore, the extracellular segment of the e chain membrane anchoring peptide forms, in whole or in part, an epitope unique to the B cells which produce IgE.
  • the immediate-type hypersensitivities such as extrinsic asthma, hay fever, and allergic responses to certain foods or drugs, are mediated primarily by IgE.
  • IgE In an IgE-mediated allergic response, the allergen binds to the IgE which is bound to receptors on the surface of mast cells and basophilic leukocytes (basophils).
  • the binding of the allergen causes crosslinking of the surface IgE molecules and hence the underlying receptors for the Fc portion of IgE (FceR), thereby triggering the release of pharmacologic mediators such as histamine, the slow- reacting substance of anaphylaxis (SRA), and serotonin.
  • FceR Fc portion of IgE
  • SRA slow- reacting substance of anaphylaxis
  • serotonin serotonin
  • IgE is secreted by a particular class of B cells, which also express IgE on their surface. In individuals sensitized to specific allergens, the allergen-specific IgE is continuously produced by these B cells. Nevertheless, individuals who have no secreted IgE in their systems (and no IgE-producing B cells) appear to live normally, indicating that IgE is not essential in the immune response. IgE may, however, be useful in fighting infection by parasites.
  • the invention includes migis-e peptides, or fragments or derivatives thereof, conjugated with antigens, or fragments or derivatives thereof.
  • these conjugates are administered to suppress IgE specific for the antigen of the conjugate, and therefore, suppress the allergic response to that antigen.
  • Treatment with these conjugates will not result in IgE-anti-IgE complexes because the migis-e sequence is absent in the secretory IgE, and antibodies generated against the migis-e sequence, therefore, will not bind to the secretory IgE.
  • the invention also includes a number of variations and derivatives. There are two different isoforms of IgE present in humans, and either, or fragments or derivatives of either, can be conjugated to antigens and administered to reduce the
  • the first is represented by amino acid numbers 4 to 18 of SEQ ID NO.:l (Glu Leu Asp Val Cys Val Glu Glu Ala Glu Gly Glu Ala Pro Trp), and the second has this amino acid sequence 4 to 18 of SEQ ID NO.:l spliced to the C terminal end of amino acid numbers 4 to 55 of SEQ ID NO.:2 (Gly Leu Ala Gly Gly Ser Ala Gin Ser Gin Arg Ala Pro Asp Arg Val Leu Cys His Ser Gly Gin Gin Gin Gin Gly Leu Pro Arg Ala Ala Gly Gly Ser Val Pro His Pro His Cys His Cys Gly Ala Gly Arg Ala Asp T ⁇ Pro Gly Pro Pro). Fragments, variant sequences, or derivatives, of either of these segments could also be used in the conjugates of the invention. These segments could also be extended with additional amino acids or other moieties and used in the conjugates of the invention.
  • conjugates including either isoform (or fragments or derivatives thereof) as fusion proteins, including the allergen(s) of interest. This would be a desirable production method for most peptide allergens.
  • the invention also includes the nucleotide sequences for such fusion proteins, i.e. , an isoform with an allergen, as well as vectors and host cells including such nucleotide sequences.
  • the conjugates of the invention are preferably administered intravenously, subcutaneously, or intramuscularly, with an appropriate adjuvant.
  • the dosages and administration regimen can be readily extrapolated from the animal data presented below.
  • nucleotide sequences which encode for peptides in the membrane anchoring region of human e chain.
  • the deduced amino acid sequences encoded by these two nucleotide sequences are also different, indicating that there are two different isoforms of the human e chain membrane anchoring peptide.
  • the deduced amino acid sequence of isoform I shows that it has 67 amino acid residues, and a 15 amino acid peptide segment toward the N-terminus (SEQ ID NO: l). This 15 amino acid segment is proposed to be extracellular and to form, entirely or in-part, the migis-e peptide.
  • Isoform II has 119 amino acid residues, 67 of which are towards the N terminus and form the proposed extracellular migis-e segment (SEQ ID NO:2). Either isoform, or fragments or derivatives thereof, is appropriate for coupling to an antigen for use in the treatment method of the invention.
  • Example - Animal Model Studies in mice have shown that a conjugate with an antigen and a migis-e peptide can be a valuable therapeutic approach for desensitization to the antigen. These studies are described below.
  • Migis-e peptide was selected from the mouse IgE genomic sequence, and had the sequence: Glu Leu Asp He Gin Asp Leu Cys He Glu Glu Val Glu Gly Glu Glu Leu Glu Glu Leu (SEQ ID NO.: 3).
  • Secretory IgE peptides with some of the sequences from the CHel to CHe4 domains were also prepared. They had the sequences: Thr Thr Ser Gin Val Thr Ser T ⁇ Gly Lys Ser Ala Lys Asn Phe Thr Cys His Val Thr (SEQ ID NO. : 4) (residue numbers 190-210 of CHel); Gly Val Asp Tyr Leu Ala His Thr Arg (SEQ ID NO.
  • IgE peptides at 5 mg/ml were mixed with insulin B chain, BSA, KLH respectively, at 2 mg/ml in equal volumes to which glutaraldehyde was added at a final 0.05%, incubated at 25 °C for 4 hr, and dialyzed.
  • Monoclonal rat anti-mouse IgE antibodies EM 95 and BF815 were employed for the total IgE assay.
  • Biotinylated rat anti-mouse kappa was obtained from Zymed (San Francisco, CA). Eight week old female BALB/c mice were obtained from the Jackson
  • An a.n ⁇ -migis-e assay was performed as follows. 50 ⁇ l migis-e- SA at 10 ⁇ g/ml were coated onto 96- well plate at 37 °C for 1 hour. The plates were washed, blocked with Blotto, and added with 50 ⁇ l serum samples at appropriate dilutions. The plates were washed, incubated with biotinylated goat anti-mouse IgG or IgG subclasses, at 1 ⁇ g/ml for 1 hour at room temperature, washed, added with SA-AP, substrate, and read at 414 nM.
  • a total IgE sandwich assay was performed as follows. 96-well plates were coated with 50 ⁇ l MAb anti-e, EM95, at 10 ⁇ g/ml overnight at 4°C, washed, blocked, added with sera at appropriate dilutions, biotinylated MAb anti- e, BF815 was added, and plates developed as above.
  • Anti-NP IgE (lambda, e) was used to coat the 96-well plates at 10 ⁇ g/ml overnight at 4°C. The plates were washed and blocked. Sera were added at appropriate dilutions, washed, followed by biotinylated rat anti-mouse kappa light chain, and developed as above. migis-e protein administered in complete and incomplete Freund's adjuvant
  • CFA/ICFA inhibited IgE responses to the carrier protein.
  • Adult BALB/c mice were immunized five times i.p. with migis-e-KL (keyhole limpet hemocyanin) conjugates in CFA/ICFA, or in alum.
  • Anti-KLH IgE responses were assessed in individual mice. A normal magnitude of anti-KLH IgE responses was observed in mice immunized i.p. with 10 ⁇ g KLH in CFA/ICFA, or in alum.
  • mice treated with 1 ⁇ g or 10 ⁇ g migis-e-K H in CFA/ICFA exhibited profoundly suppressed KLH specific IgE responses.
  • Migis-e conjugated antigen did not affect antigen-specific IgG responses to the carrier. Comparable anti-KLH IgGl responses were observed in KLH or migis-e-KLH. immunized mice, while alum favored antigen- specific IgGl production over CFA/ICFA. Higher levels of anti-mi gis-e of IgGl subclass were observed in mice immunized with migis-e-KLH in alum. In contrast, anti-KLH and anti-migis-e of IgG2a and IgG2b subclasses were present in higher concentrations in mice immunized with migis-e-KLH in CFA/ICFA.
  • mice were pretreated with 1 to 50 ⁇ g migis-e-KLH in CFA/ICFA, or with 10 ⁇ g migis-e- KLH in CFA twice, followed by a challenge with migis-e-K H. along with OVA in ICFA, and further boosted with OVA/m/gw-e-KLH in ICFA twice.
  • mice were injected with 20 ⁇ g soluble migis-e-BGG or glutaraldehyde modified BGG (GA-BGG) subcutaneously, or intraperitoneally. Mice were then challenged with migis-e-BGG plus OVA, or BGG plus OVA in alum. Mice treated with soluble migis-e-BGG via either route, failed to elicit anti-BGG IgE when challenged with migis-e-BGG or BGG in alum, whereas anti-OVA IgE responses in these mice were normal.
  • GABA glutaraldehyde modified BGG
  • conjugates were designed for use in humans, with one of the isoforms or a fragment or derivative thereof, as shown in SEQ ID NOS.: 1 and 2, conjugated with an antigen, the same results would be expected. That is, one would expect to see: a) inhibition of antigen-specific IgE, but not IgG responses; b) no inhibition of IgE responses to unrelated, unconjugated antigens; c) no correlation between inhibition of antigen-specific IgE and levels of anti-migis-e or anti-IgE antibodies; d) total IgE levels would remain comparable among subjects treated with migis-e conjugated antigens and those exposed to the native antigen. This would be an effective method of desensitizing human subjects to allergens.
  • GTA AAT CCC GGG CTG GCT GGC GGC TCC GCG 30 Val Asn Pro Gly Leu Ala Gly Gly Ser Ala 1 5 10 CAG TCC CAG AGG GCC CCG GAT AGG GTG CTC 60 Gin Ser Gin Arg Ala Pro Asp Arg Val Leu

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
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  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne l'utilisation de la partie extracellulaire du domaine lié à la membrane de la chaîne ε (provenant d'IgE) et appelée peptides migis-ε, ou des fragments ou des dérivés de ceux-ci, conjugués avec un (des) antigène(s), ces peptides étant destinés à être utilisés dans la désensibilisation à ces antigènes conjugués. L'invention porte également sur deux isoformes différents du peptide migis-ε. Ces conjugués sont administrés pour supprimer IgE spécifique de l'antigène du conjugué, et par conséquent, supprimer la réponse allergique à cet antigène.
PCT/US1997/011707 1997-05-30 1997-05-30 INHIBITION DE LA PRODUCTION d'IgE SPECIFIQUE D'UN ANTIGENE PAR UN ANTIGENE COUPLE A UN PEPTIDE D'IgE MEMBRANAIRE WO1998053843A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU35155/97A AU3515597A (en) 1997-05-30 1997-05-30 Inhibition of antigen-specific ige production by antigen coupled to membrane igepetide
PCT/US1997/011707 WO1998053843A1 (fr) 1997-05-30 1997-05-30 INHIBITION DE LA PRODUCTION d'IgE SPECIFIQUE D'UN ANTIGENE PAR UN ANTIGENE COUPLE A UN PEPTIDE D'IgE MEMBRANAIRE

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1997/011707 WO1998053843A1 (fr) 1997-05-30 1997-05-30 INHIBITION DE LA PRODUCTION d'IgE SPECIFIQUE D'UN ANTIGENE PAR UN ANTIGENE COUPLE A UN PEPTIDE D'IgE MEMBRANAIRE

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WO1998053843A1 true WO1998053843A1 (fr) 1998-12-03

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1972640A1 (fr) * 2007-03-23 2008-09-24 Biomay AG Anticorps induisant l'apoptose
WO2007041171A3 (fr) * 2005-09-29 2009-04-09 Medimmune Inc Methode d'identification d'anticorps specifiques de membranes longueur d'onde et leurs utilisations pour cibler les cellules precurseurs productrices d'immunoglobuline
US8460664B2 (en) 2009-02-25 2013-06-11 Academia Sinica Anti-CεmX antibodies capable of binding to human mIgE on B lymphocytes
US9408897B2 (en) 2002-06-20 2016-08-09 The Trustees Of The University Of Pennsylvania Vaccines for suppressing IgE-mediated allergic disease and methods for using the same
WO2017005851A1 (fr) 2015-07-07 2017-01-12 Affiris Ag Vaccins pour le traitement et la prévention de maladies médiées par ige
US9587034B2 (en) 2012-04-20 2017-03-07 Academia Sinica Anti-mIgE antibodies that bind to the junction between CH4 and CεmX domains
US11439682B2 (en) 2017-10-31 2022-09-13 Oneness Biotech Co., Ltd. Treating IgE-mediated allergic diseases

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5254671A (en) * 1990-04-27 1993-10-19 Tanox Biosystems, Inc. Extracellular segments of human e immunoglobulin anchoring peptides and antibodies specific therefor
US5274075A (en) * 1987-12-31 1993-12-28 Tanox Biosystems, Inc. Newly identified human epsilon immunoglobulin peptides and related products
US5281699A (en) * 1990-06-01 1994-01-25 Tanox Biosystems, Inc. Treating B cell lymphoma or leukemia by targeting specific epitopes on B cell bound immunoglobulins

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5274075A (en) * 1987-12-31 1993-12-28 Tanox Biosystems, Inc. Newly identified human epsilon immunoglobulin peptides and related products
US5254671A (en) * 1990-04-27 1993-10-19 Tanox Biosystems, Inc. Extracellular segments of human e immunoglobulin anchoring peptides and antibodies specific therefor
US5281699A (en) * 1990-06-01 1994-01-25 Tanox Biosystems, Inc. Treating B cell lymphoma or leukemia by targeting specific epitopes on B cell bound immunoglobulins

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9408897B2 (en) 2002-06-20 2016-08-09 The Trustees Of The University Of Pennsylvania Vaccines for suppressing IgE-mediated allergic disease and methods for using the same
WO2007041171A3 (fr) * 2005-09-29 2009-04-09 Medimmune Inc Methode d'identification d'anticorps specifiques de membranes longueur d'onde et leurs utilisations pour cibler les cellules precurseurs productrices d'immunoglobuline
US8137670B2 (en) 2005-09-29 2012-03-20 Medimmune, Llc Method of identifying membrane IgE specific antibodies and use thereof for targeting IgE producing precursor cells
US8404236B2 (en) 2005-09-29 2013-03-26 Medimmune, Llc Method of identifying membrane Ig specific antibodies and use thereof for targeting immunoglobulin-producing precursor cells
EP1972640A1 (fr) * 2007-03-23 2008-09-24 Biomay AG Anticorps induisant l'apoptose
US8460664B2 (en) 2009-02-25 2013-06-11 Academia Sinica Anti-CεmX antibodies capable of binding to human mIgE on B lymphocytes
US8741294B2 (en) 2009-02-25 2014-06-03 Academia Sinica Anti-CεmX antibodies capable of binding to human mIgE on B lymphocytes
US8974794B2 (en) 2009-02-25 2015-03-10 Academia Sinica C(epsilon)mX peptides for inducing immune responses to human mIgE on B lymphocytes
US9587034B2 (en) 2012-04-20 2017-03-07 Academia Sinica Anti-mIgE antibodies that bind to the junction between CH4 and CεmX domains
WO2017005851A1 (fr) 2015-07-07 2017-01-12 Affiris Ag Vaccins pour le traitement et la prévention de maladies médiées par ige
US11439682B2 (en) 2017-10-31 2022-09-13 Oneness Biotech Co., Ltd. Treating IgE-mediated allergic diseases
US12083161B2 (en) 2017-10-31 2024-09-10 Oneness Biotech Co., Ltd. Treating IgE-mediated allergic diseases

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Publication number Publication date
AU3515597A (en) 1998-12-30

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