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WO2011157905A1 - Polyclonal antibody binding to acetylated hmgb1 - Google Patents

Polyclonal antibody binding to acetylated hmgb1 Download PDF

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Publication number
WO2011157905A1
WO2011157905A1 PCT/FI2011/050585 FI2011050585W WO2011157905A1 WO 2011157905 A1 WO2011157905 A1 WO 2011157905A1 FI 2011050585 W FI2011050585 W FI 2011050585W WO 2011157905 A1 WO2011157905 A1 WO 2011157905A1
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Prior art keywords
acetylated
peptide
antibody
hmgbl
hmgb1
Prior art date
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PCT/FI2011/050585
Other languages
French (fr)
Inventor
Heikki Rauvala
Ari Rouhiainen
Original Assignee
Helsingin Yliopisto
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
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Publication of WO2011157905A1 publication Critical patent/WO2011157905A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/44—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material not provided for elsewhere, e.g. haptens, metals, DNA, RNA, amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/10—Immunoglobulins specific features characterized by their source of isolation or production
    • C07K2317/11—Immunoglobulins specific features characterized by their source of isolation or production isolated from eggs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/23—Immunoglobulins specific features characterized by taxonomic origin from birds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues

Definitions

  • the present invention relates to the field of polyclonal antibodies binding to human HMGBl (high- mobility group box 1) protein and diagnostic and therapeutic use of same.
  • the present invention provides an isolated polyclonal antibody binding to hyperacetylated HMGBl but not binding to hypoacetylated HMGBl.
  • the present invention is directed to an isolated polyclonal IgY antibody generated in chicken binding to hyperacetylated HMGBl but not binding to hypoacetylated HMGBl.
  • the invention provides a method for detecting the presence or amount of an acetylated HMGBl in a biological sample.
  • HMGBl is a cytokine-like molecule that is secreted via a poorly characterized mechanisms as it lacks a classical signal peptide. Acetylation has been shown to be a mechanism that may regulate HMGBl secretion (Bonaldi et al., 2003, The EMBO Journal 22(20):5551-5560). The majority of HMGBl is in the hypoacetylated form and only a specific, minor pool of HMGBl that is directed to secretion is hyperacetylated. Acetylated HMGBl is actively secreted from the cells whereas hypoacetylated HMGBl can be released from the dying cells.
  • HMGBl-form having acetylated lysines in the positions 176-187 can be found in plasma during liver injury and in activated immune cells using mass spectrometry (Bonaldi et al., 2003, The EMBO Journal 22(20):5551-5560, Antoine DJ et al., 2009, Toxicol Sci. 112(2):521-531). Therefore, the ability to distinguish between the two forms of HMGBl (acetylated vs. non-acetylated) is critical.
  • An multiply acetylated protein HMGBl is disclosed in US 2006/0111287.
  • the non-histone nuclear protein HMGBl belonging to the B family of high mobility group proteins having acetylated lysines in one or more of the positions in the amino acid sequence of the protein is particularly described. No disclosure of a polyclonal antibody against the acetylated HMGBl is found in the publication.
  • FIG. 1 Anti-acetylated HMGBl IgY (1966) stains cytoplasmic vesicles in lipopolysaccharide (LPS) activated macrophages.
  • Figure 6. A higher magnification of anti-acetylated HMGBl-peptide antibody stained LPS activated macrophages. Arrows indicate some of the cytoplasmic vesicles that are stained with anti acetylated HMGBl peptide antibody.
  • the present invention provides an isolated polyclonal antibody binding to acetylated HMGBl but not binding to non-acetylated HMGBl.
  • said antibody is IgY antibody generated in chicken as shown in the Experimental Section below.
  • polyclonal antibody denotes herein a mixture of different antibody molecules which react with more than one immunogenic determinant of an antigen.
  • the invention also provides an isolated polyclonal antibody obtained by a method comprising the steps of: a) contacting a chicken with an acetylated peptide KAEKSKKKKEEC (SEQ ID NO:l) so that said chicken is immunized with said peptide; and b) collecting the polyclonal antibody from the egg yolk of an egg laid by said chicken.
  • all epsilon amino groups of lysine side chains of the antigen peptide are acetylated.
  • an alpha amino group of the amino terminal lysine is preferably acetylated.
  • Said peptide (without the cysteine residue) corresponds to positions 177-187 in the amino acid sequence of human HMGBl (Gene ID:3146; NP_002119.1).
  • the peptide can also be coupled to a carrier such as keyhole limpet hemocyanin (KLH) when used as an antigen.
  • KLH keyhole limpet hemocyanin
  • the peptide is linked to KLH via a cysteine added to the C-terminal of the peptide.
  • the polyclonal IgY obtained by this method can easily be recognized by a skilled person of the art by two simple test: i) to confirm the class and origin of the antibody, the skilled person may use anti-chicken IgY antibody, and ii) to confirm the specificity of the antibody, the skilled person may perform the Western blot described in the Experimental Section below (see, e.g., Figure 4). Further, the invention is directed to a method for detecting the presence or amount of an acetylated HMGB1 in a biological sample comprising contacting the sample with an isolated polyclonal antibody and determining the amount of the acetylated HMGB1 bound to the antibody. Said antibody is preferably labeled with a detectable label.
  • Such label can be a radioisotope, fluorescent compound, chemiluminescent compound, enzyme, or enzyme co-factor, or any other labels known in the art.
  • the antibody that binds to an entity one wishes to measure is not labeled, but is instead detected by binding of a labeled secondary antibody that specifically binds to the primary antibody.
  • Anti acetylated HMGB1 peptide antibody can be used for diagnosis or treatment in the pathological situations belonging to inflammatory, autoimmune, neurodegenerative or malignant
  • diseases/disorders include sepsis, rheumatoid arthritis, septicemia, shock, organ ischemia, reperfusion injury, atherosclerosis, stroke, multiple sclerosis, and cancer.
  • the antibodies of the present invention are useful as diagnostic antibodies to detect specifically the acetylated form of HMGB1 in tissue fluids like plasma, cerebrospinal fluid or synovial fluid. Further, the antibodies of the present invention are useful as diagnostic antibodies to detect specifically the acetylated form of HMGB1 in tissues.
  • the antibodies of the present invention are also useful to block specifically the acetylated form of HMGB1 in patients with inflammatory, autoimmune, neurodegenerative or malignant
  • the present invention is further directed to a peptide comprising or consisting of sequence
  • KAEKSKKKKEEC SEQ ID NO:l
  • lysines of the peptide are partly ot totally acetylated, and its use as an antigen (see Experimental Section below).
  • the peptide of the invention can be synthesized by well-known methods (see, e.g., Atherton, E.; Sheppard, R.C., 1989, Solid Phase peptide synthesis: a practical approach. Oxford, England: IRL Press. ISBN 0199630674).
  • Antibodies were generated in two chickens using keyhole limpet hemocyanin (KLH) coupled acetylated HMGBl-peptide as an antigen (see, e.g, R Schade et al., Chicken Yolk Antibodies, Production and Application, IgY-Technology, Springer-Verlag Berlin Heidelberg, New York (2001) pp. 201, 203, 204).
  • Antigen peptide was synthetized and acetylated using solid phase peptide synthesis.
  • Peptide sequence was (Ac-)(Ac-K)AE(Ac-K)S(Ac-K)(Ac-K)(Ac-K)(Ac-K)EEC(-COOH).
  • Peptide was linked to KLH via C-terminal cysteine. Chickens were immunized with KLH-coupled peptide and adjuvants as described in Figure 1.
  • Lipopolysaccharide (LPS) treated mouse macrophages (RAW 264.7 cells) were stained with anti- acetylated HMGB1 peptide antibody.
  • RAW 264.7 cells were cultured in medium containing 10% foetal calf serum and treated over night with or without 10 micrograms/milliliter of LPS. Cells were fixed with 4% paraformaldehyde and permeabilized with 0.25% Triton X-100. Cells were treated with 0.12% glycine followed by 50 mM NH 4 CI treatment, and blocked with 5% milk powder in phosphate buffered saline (PBS).
  • PBS phosphate buffered saline

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Peptides Or Proteins (AREA)

Abstract

The present invention provides an isolated polyclonal antibody binding to hyperacetylated HMGB but not binding to hypoacetylated HMGB1. In particular, the present invention is directed to an isolated polyclonal Ig Y antibody generated in chicken binding to hyperacetylated HMGB1 but not binding to hypoacetylated HMGB1. Further, the invention provides a method for detecting the presence or amount of an acetylated HMGB1 in a biological sample.

Description

Polyclonal antibody binding to acetylated HMGBl
FIELD OF THE INVENTION
The present invention relates to the field of polyclonal antibodies binding to human HMGBl (high- mobility group box 1) protein and diagnostic and therapeutic use of same. The present invention provides an isolated polyclonal antibody binding to hyperacetylated HMGBl but not binding to hypoacetylated HMGBl. In particular, the present invention is directed to an isolated polyclonal IgY antibody generated in chicken binding to hyperacetylated HMGBl but not binding to hypoacetylated HMGBl. Further, the invention provides a method for detecting the presence or amount of an acetylated HMGBl in a biological sample.
BACKGROUND OF THE INVENTION
HMGBl is a cytokine-like molecule that is secreted via a poorly characterized mechanisms as it lacks a classical signal peptide. Acetylation has been shown to be a mechanism that may regulate HMGBl secretion (Bonaldi et al., 2003, The EMBO Journal 22(20):5551-5560). The majority of HMGBl is in the hypoacetylated form and only a specific, minor pool of HMGBl that is directed to secretion is hyperacetylated. Acetylated HMGBl is actively secreted from the cells whereas hypoacetylated HMGBl can be released from the dying cells. HMGBl-form having acetylated lysines in the positions 176-187 can be found in plasma during liver injury and in activated immune cells using mass spectrometry (Bonaldi et al., 2003, The EMBO Journal 22(20):5551-5560, Antoine DJ et al., 2009, Toxicol Sci. 112(2):521-531). Therefore, the ability to distinguish between the two forms of HMGBl (acetylated vs. non-acetylated) is critical. An multiply acetylated protein HMGBl is disclosed in US 2006/0111287. The non-histone nuclear protein HMGBl belonging to the B family of high mobility group proteins having acetylated lysines in one or more of the positions in the amino acid sequence of the protein is particularly described. No disclosure of a polyclonal antibody against the acetylated HMGBl is found in the publication.
In US 2010/0061987, high affinity antibodies against HMGBl are disclosed. However, these antibodies are raised against non-acetylated HMGBl and thus are not able to distinguish acetylated and non-acetylated HMGBls.
Other publications disclosing antibodies for non-acetylated HMGBl are US 2009/0297546,
EP 2123299, EP 2123298 and EP 2123297.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1. Immunization scheme used.
Figure 2. The antibody titers against the antigen peptide tested with ELISA.
Figure 3. Western blot analyses of hypo- and hyperacetylated recHMGBl proteins.
Figure 4. IgY directed against acetylated lysine HMGBl peptide detects hyper- but not
hypoacetylated HMGBl.
Figure 5. Anti-acetylated HMGBl IgY (1966) stains cytoplasmic vesicles in lipopolysaccharide (LPS) activated macrophages. Figure 6. A higher magnification of anti-acetylated HMGBl-peptide antibody stained LPS activated macrophages. Arrows indicate some of the cytoplasmic vesicles that are stained with anti acetylated HMGBl peptide antibody.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an isolated polyclonal antibody binding to acetylated HMGBl but not binding to non-acetylated HMGBl. Preferably, said antibody is IgY antibody generated in chicken as shown in the Experimental Section below. The term "polyclonal antibody" denotes herein a mixture of different antibody molecules which react with more than one immunogenic determinant of an antigen.
The invention also provides an isolated polyclonal antibody obtained by a method comprising the steps of: a) contacting a chicken with an acetylated peptide KAEKSKKKKEEC (SEQ ID NO:l) so that said chicken is immunized with said peptide; and b) collecting the polyclonal antibody from the egg yolk of an egg laid by said chicken. Preferably, all epsilon amino groups of lysine side chains of the antigen peptide are acetylated. Further, an alpha amino group of the amino terminal lysine is preferably acetylated. Said peptide (without the cysteine residue) corresponds to positions 177-187 in the amino acid sequence of human HMGBl (Gene ID:3146; NP_002119.1). The peptide can also be coupled to a carrier such as keyhole limpet hemocyanin (KLH) when used as an antigen. Preferably, the peptide is linked to KLH via a cysteine added to the C-terminal of the peptide. The polyclonal IgY obtained by this method can easily be recognized by a skilled person of the art by two simple test: i) to confirm the class and origin of the antibody, the skilled person may use anti-chicken IgY antibody, and ii) to confirm the specificity of the antibody, the skilled person may perform the Western blot described in the Experimental Section below (see, e.g., Figure 4). Further, the invention is directed to a method for detecting the presence or amount of an acetylated HMGB1 in a biological sample comprising contacting the sample with an isolated polyclonal antibody and determining the amount of the acetylated HMGB1 bound to the antibody. Said antibody is preferably labeled with a detectable label. Such label can be a radioisotope, fluorescent compound, chemiluminescent compound, enzyme, or enzyme co-factor, or any other labels known in the art. In some aspects, the antibody that binds to an entity one wishes to measure (the primary antibody) is not labeled, but is instead detected by binding of a labeled secondary antibody that specifically binds to the primary antibody.
Anti acetylated HMGB1 peptide antibody can be used for diagnosis or treatment in the pathological situations belonging to inflammatory, autoimmune, neurodegenerative or malignant
diseases/disorders. The pathologies belonging to these diseases/disorders include sepsis, rheumatoid arthritis, septicemia, shock, organ ischemia, reperfusion injury, atherosclerosis, stroke, multiple sclerosis, and cancer.
The antibodies of the present invention are useful as diagnostic antibodies to detect specifically the acetylated form of HMGB1 in tissue fluids like plasma, cerebrospinal fluid or synovial fluid. Further, the antibodies of the present invention are useful as diagnostic antibodies to detect specifically the acetylated form of HMGB1 in tissues.
The antibodies of the present invention are also useful to block specifically the acetylated form of HMGB1 in patients with inflammatory, autoimmune, neurodegenerative or malignant
diseases/disorders.
The present invention is further directed to a peptide comprising or consisting of sequence
KAEKSKKKKEEC (SEQ ID NO:l), wherein the lysines of the peptide are partly ot totally acetylated, and its use as an antigen (see Experimental Section below). The peptide of the invention can be synthesized by well-known methods (see, e.g., Atherton, E.; Sheppard, R.C., 1989, Solid Phase peptide synthesis: a practical approach. Oxford, England: IRL Press. ISBN 0199630674).
The publications and other materials used herein to illuminate the background of the invention, and in particular, to provide additional details with respect to its practice, are incorporated herein by reference. The present invention is further described in the following examples, which are not intended to limit the scope of the invention.
EXPERIMENTAL SECTION
Antibodies were generated in two chickens using keyhole limpet hemocyanin (KLH) coupled acetylated HMGBl-peptide as an antigen (see, e.g, R Schade et al., Chicken Yolk Antibodies, Production and Application, IgY-Technology, Springer-Verlag Berlin Heidelberg, New York (2001) pp. 201, 203, 204). Antigen peptide was synthetized and acetylated using solid phase peptide synthesis. Peptide sequence was (Ac-)(Ac-K)AE(Ac-K)S(Ac-K)(Ac-K)(Ac-K)(Ac-K)EEC(-COOH). Peptide was linked to KLH via C-terminal cysteine. Chickens were immunized with KLH-coupled peptide and adjuvants as described in Figure 1.
Pre immune yolks were collected before immunization. Immune yolks were collected after third immunization. The antibody titers against antigen peptide were tested with ELISA as described in Figure 2.
Recombinant HMGBl was produced as described by Parkkinen et al. (J Biol Chem. 1993; 268: 19726- 19738). Lysines of recombinant HMGBl were acetylated using adenyl acetylate as described by Ramponi et al. (Biochemistry. 1975; 14: 2681-2685). Both hypo- and hyperacetylated HMGBl proteins (= total HMGB1) were analysed in Western blot with anti peptide V antibody (Parkkinen et al., J Biol Chem. 1993; 268: 19726-19738) that recognizes both HMGB1 forms, and with anti acetylated lysine antibody (Cell Signaling Technology, Inc.) that recognizes only acetylated HMGB1 (Figure 3). Hypo- and hyperacetylated HMGB1 proteins (= total HMGB1) were similarly analyzed Western blots with anti acetylated HMGBl-peptide antibodies 1965 and 1966, and with horse radish peroxidase conjugated anti-chicken IgY antibodies (Figure 4). Amount of loaded protein in blots was analyzed using Ponceau S staining.
Lipopolysaccharide (LPS) treated mouse macrophages (RAW 264.7 cells) were stained with anti- acetylated HMGB1 peptide antibody. RAW 264.7 cells were cultured in medium containing 10% foetal calf serum and treated over night with or without 10 micrograms/milliliter of LPS. Cells were fixed with 4% paraformaldehyde and permeabilized with 0.25% Triton X-100. Cells were treated with 0.12% glycine followed by 50 mM NH4CI treatment, and blocked with 5% milk powder in phosphate buffered saline (PBS). Cells were stained with pre immune or immune yolk 1966, and with Alexa fluor 546 goat anti-chicken IgG (Molecular Probes, Inc). Cells were analyzed in fluorescence microscopy (Figure 5). Anti acetylated HMGB1 peptide antibody stains cytoplasmic vesicles that are called secretory lysosomes (Figure 6). Acetylated HMGB1 is concentrated to secretory lysosomes before release from the cells.

Claims

1. An isolated polyclonal antibody binding to acetylated HMGB1 but not binding to non-acetylated HMGB1, wherein said antibody is an IgY antibody generated in chicken.
2. The isolated polyclonal antibody according to claim 1, wherein said IgY antibody is specifically binding to peptide KAEKSKKKKEEC (SEQ ID NO:l), wherein the lysines of the peptide are partly or totally acetylated.
3. An isolated polyclonal antibody obtained by a method comprising the steps of: a) contacting a chicken with a peptide comprising or consisting of sequence KAEKSKKKKEEC (SEQ ID NO:l), wherein the lysines of the peptide are partly or totally acetylated; and b) collecting the polyclonal antibody from the egg yolk of an egg laid by said chicken.
4. A method for detecting the presence or amount of an acetylated HMGB1 in a biological sample comprising contacting the sample with an isolated polyclonal antibody of claim 1, 2 or 3, and determining the amount of the acetylated HMGB1 bound to the antibody.
5. The method according to claim 4, wherein the antibody is labeled with a detectable label.
6. A peptide comprising or consisting of sequence KAEKSKKKKEEC (SEQ ID NO:l), wherein the lysines of the peptide are partly or totally acetylated.
7. The peptide according to claim 6, wherein the length of said peptide is 12-15 amino acids.
8. The peptide according to claim 6 or 7 for use as an antigen.
9. Method for producing a polyclonal IgY antibody binding to acetylated HMGBl but not binding to non-acetylated HMGBl, the method comprising the steps of a) contacting a chicken with a peptide comprising or consisting of sequence KAEKSKKKKEEC (SEQ ID NO:l) , wherein the lysines of the peptide are partly or totally acetylated; and b) collecting the polyclonal antibody from the egg yolk of an egg laid by said chicken.
PCT/FI2011/050585 2010-06-18 2011-06-17 Polyclonal antibody binding to acetylated hmgb1 WO2011157905A1 (en)

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WO2015175375A1 (en) 2014-05-13 2015-11-19 Short Jay M Conditionally active biological proteins
WO2016033331A1 (en) 2014-08-28 2016-03-03 Bioatla, Llc Conditionally active chimeric antigen receptors for modified t-cells
WO2016118531A1 (en) * 2015-01-21 2016-07-28 University Of Hawaii Methods and kits for analysis of hmgb1 isoforms
US10900064B2 (en) 2011-09-01 2021-01-26 Belgian Volition Sprl Method for detecting nucleosomes containing nucleotides
US11111288B2 (en) 2014-08-28 2021-09-07 Bioatla, Inc. Conditionally active chimeric antigen receptors for modified t-cells
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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10900064B2 (en) 2011-09-01 2021-01-26 Belgian Volition Sprl Method for detecting nucleosomes containing nucleotides
US9187780B2 (en) 2011-12-07 2015-11-17 Singapore Volition Pte. Limited Method for detecting nucleosome adducts
US11193939B2 (en) 2011-12-07 2021-12-07 Belgian Volition Sprl Method for detecting nucleosome adducts
US9709569B2 (en) 2011-12-07 2017-07-18 Singapore Volition Pte. Limited Method for detecting nucleosome adducts
WO2015175375A1 (en) 2014-05-13 2015-11-19 Short Jay M Conditionally active biological proteins
US10329556B2 (en) 2014-05-13 2019-06-25 Bioatla, Llc Conditionally active biological proteins
EP4074735A1 (en) 2014-08-28 2022-10-19 BioAtla, Inc. Conditionally active chimeric antigen receptors for modified t-cells
US11111288B2 (en) 2014-08-28 2021-09-07 Bioatla, Inc. Conditionally active chimeric antigen receptors for modified t-cells
WO2016033331A1 (en) 2014-08-28 2016-03-03 Bioatla, Llc Conditionally active chimeric antigen receptors for modified t-cells
US11584927B2 (en) 2014-08-28 2023-02-21 Bioatla, Inc. Conditionally active chimeric antigen receptors for modified T-cells
WO2016118531A1 (en) * 2015-01-21 2016-07-28 University Of Hawaii Methods and kits for analysis of hmgb1 isoforms
US11879011B2 (en) 2016-05-13 2024-01-23 Bioatla, Inc. Anti-ROR2 antibodies, antibody fragments, their immunoconjucates and uses thereof
WO2024016944A1 (en) * 2022-07-18 2024-01-25 华东师范大学 Marker for preventing and protecting against cerebral ischemic diseases and application of aspirin derivative in preventing and protecting against cerebral ischemic diseases

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