EP4189396A1 - Épitope amélioré pour la détection et/ou la quantification d'auto-anticorps contre l'alpha-f?toprotéine - Google Patents

Épitope amélioré pour la détection et/ou la quantification d'auto-anticorps contre l'alpha-f?toprotéine

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Publication number
EP4189396A1
EP4189396A1 EP21755397.3A EP21755397A EP4189396A1 EP 4189396 A1 EP4189396 A1 EP 4189396A1 EP 21755397 A EP21755397 A EP 21755397A EP 4189396 A1 EP4189396 A1 EP 4189396A1
Authority
EP
European Patent Office
Prior art keywords
seq
epitope consisting
vitro method
antigen
epitope
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP21755397.3A
Other languages
German (de)
English (en)
Inventor
Juan Francisco Delgado De La Poza
Francesc Xavier Gallego Moreno
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Corporacio Sanitaria Parc Tauli
Original Assignee
Corporacio Sanitaria Parc Tauli
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 Corporacio Sanitaria Parc Tauli filed Critical Corporacio Sanitaria Parc Tauli
Publication of EP4189396A1 publication Critical patent/EP4189396A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57438—Specifically defined cancers of liver, pancreas or kidney
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4715—Pregnancy proteins, e.g. placenta proteins, alpha-feto-protein, pregnancy specific beta glycoprotein
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57476—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving oncofetal proteins
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
    • G01N33/57488—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites involving compounds identifable in body fluids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K17/00—Carrier-bound or immobilised peptides; Preparation thereof

Definitions

  • the present invention refers to the medical field. Particularly, a specific epitope has been identified in the present invention, which is herein used for detecting and/or quantifying autoantibodies against alpha-fetoprotein (AFP) in a biological sample, and consequently for the in vitro diagnosis of hepatocellular carcinoma (HCC) or liver cirrhosis.
  • AFP alpha-fetoprotein
  • the HCC is the second cause of mortality related to cancer, and the sixth most common cause of cancer worldwide.
  • Most patients diagnosed of HCC have liver cirrhosis as a baseline disease, thus mandatory HCC screening is performed with ultrasound every six months in all these patients.
  • most patients, even those included in a screening program are diagnosed at late stages, when survival prognosis is worst. Accordingly, the survival rate at 5 years in patients with HCC is less than 16%.
  • Discovery of new biomarkers or the improvement of those already described to detect HCC at early stages will be essential to develop better screening tests.
  • the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver call for the need to establish screening tests for at-risk patients, mainly those suffering from cirrhosis.
  • the screening protocol approved by both associations consists of abdominal ultrasound every 6 months. Other associations like British and Asian add AFP determination to ultrasound.
  • a recent meta-analysis sets the ultrasound sensitivity to detect HCC in 84%, the sensitivity drops to 47% when used for early detection.
  • This meta-analysis also studies the comparison of sensitivity between ultrasound with or without serum AFP detection as screening test. Results show that ultrasound without serum AFP detection has a sensitivity of 78% to detect HCC, while the sensitivity increases to 97% when both ultrasound and serum AFP detection are concurrently used.
  • early stage HCC detection shows a sensitivity of 45% when using ultrasound without serum AFP detection, and a sensitivity of 63%; when adding serum AFP detection to the ultrasound.
  • serum AFP detection alone shows a sensitivity of 46-59% and a specificity of 87-93% to early detect HCC.
  • Appropriate screening leads to early diagnosis, which leads to better management options, a higher proportion of treatable lesions, and better outcomes, including survival. Screening at-risk population to develop HCC also has been demonstrated to be cost-effective if the expected HCC risk exceeds 1.5% per year in patients with hepatitis C and 0.2% per year in patients with hepatitis B.
  • TAAs tumor-associated antigens
  • AFP could be a good TAA to detect serum autoantibodies due to; 1) its high specificity in the diagnosis of HCC, 2) its use in immunoassays, and 3) its similar sensitivity compared to other TAAs previously reported to detect serum autoantibodies. Consequently, the present invention aims to identify, and immunogenicity-optimize the AFP immunodominant epitope as a TAA to detect serum AFP autoantibodies in patients with HCC and liver cirrhosis.
  • AFP alpha-fetoprotein
  • SEQ ID NO: 1 of peptide 9.7.1 is present in several amino acid sequences which show good results.
  • the SEQ ID NO: 1 of peptide 9.7.1 is included in SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 12 and SEQ ID NO: 26 to 38. So, this sequence is herein presented as a key sequence for conferring immunogenicity to the epitope.
  • a validation process was carried out as shown in the Examples and peptides 9.7.8 of SEQ ID NO: 2 and, particularly, peptide 9.7 of SEQ ID NO: 3, were confirmed as good epitopes for AFP determination and/or quantification.
  • SEQ ID NO: 1 is included in SEQ ID NO: 2 which is in turn included in SEQ ID NO: 3.
  • the first embodiment of the present invention refers to an epitope, or to an antigen comprising the epitope, wherein the epitope consisting of SEQ ID NO: 1 or a sequence having an identity of at least 95% with the SEQ ID NO: 1.
  • the epitope consists of SEQ ID NO: 2 or a sequence having an identity of at least 95% with the SEQ ID NO: 2.
  • the epitope consists of SEQ ID NO: 3 or a sequence having an identity of at least 95% with the SEQ ID NO: 3.
  • the second embodiment of the present invention refers to an in vitro method for detecting and/or quantifying autoantibodies against alpha-fetoprotein (AFP) in a biological sample, wherein the autoantibodies bind to an epitope which comprises or consists of SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO: 3 and it is immobilized on a solid support.
  • the autoantibodies bind to an antigen comprising an epitope which in turn comprises or consists of SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO: 3 and it is immobilized on a solid support.
  • the detection and/or quantification of the autoantibodies is carried out by an immunochemical technique, preferably by ELISA, and most preferably by indirect ELISA, in which the antigen is bound by the primary antibody to be detected, that binds directly to the antigen, which then is detected by a labeled secondary antibody.
  • the indirect ELISA is a two-step ELISA which involves two binding process of primary antibody and labeled secondary antibody.
  • the primary antibody to be detected is incubated with the antigen followed by the incubation with the secondary antibody. Initially, micro-well plates are incubated with antigens characterized by comprising the epitope of the invention, washed up and blocked with BSA. After that, biological samples which may comprise the antibodies to be detected are added and washed. Moreover, enzyme linked secondary antibody are added and washed. A substrate is then added, and enzymes on the antibody elicit a chromogenic or fluorescent signal.
  • the present invention refers to an in vitro method which comprises: a) Immobilizing an epitope comprising or consisting of the SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO: 3, or an antigen comprising an epitope which in turn comprises or consists of SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO: 3 on a solid support, b) Adding the biological sample to be analysed on the solid support, c) Adding an antibody, conjugated with a detectable labelling agent, which reacts against the autoantibody which may be present in the biological sample, d) Detecting and/or quantifying the complex obtained, for example with a composition containing a chromogenic, fluorogenic and/or chemiluminescent indicator substrate.
  • the in vitro method described above further comprises treating the epitope or the antigen comprising the epitope, before it is immobilized on a solid support, by: a. Adding at least one charged molecule to a solution comprising the epitope consisting of SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO: 3, or the antigen comprising the epitope consisting of SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO: 3; and b. Adding at least one amino acid to the biomolecule solution.
  • the charged molecule is SDS.
  • the SDS is at a concentration of between 0.1% and 10% (w/v).
  • the amino acid is lysine, arginine, histidine or combinations thereof.
  • the amino acid is added to obtain a concentration between 12.5% (w/v) to 20% (w/v).
  • the sample is obtained from a subject who may be suffering from hepatocellular carcinoma or liver cirrhosis.
  • the sample is blood, serum or plasma.
  • the third embodiment of the present invention refers to an in vitro method for the diagnosis of hepatocellular carcinoma or liver cirrhosis which comprises detecting and/or quantifying autoantibodies against AFP by following the above described method.
  • the fourth embodiment of the present invention refers to the in vitro use of an epitope comprising or consisting of the SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO: 3, or an antigen comprising an epitope which in turn comprises or consists of SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO: 3 for detecting and/or quantifying autoantibodies AFP.
  • said epitope or antigen is used for the diagnosis of hepatocellular carcinoma or liver cirrhosis.
  • the fifth embodiment of the present invention refers to a kit for detecting and/or quantifying autoantibodies against AFP in a biological sample which comprises: a) An epitope comprising or consisting of the SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO: 3 or an antigen comprising an epitope which in turn comprises or consists of SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO: 3. b) At least a secondary antibody which reacts against the autoantibody which may be present in the biological sample.
  • this kit is intended for the diagnosis of hepatocellular carcinoma or liver cirrhosis.
  • the seventh embodiment of the present invention refers to a monoclonal antibody, or fragment thereof, specifically binding the epitope consisting of SEQ ID NO: 3 or an antigen comprising an epitope consisting of SEQ ID NO: 3.
  • the monoclonal antibody is characterized in that it comprises a light chain variable region (VL) and a heavy chain variable region (VH), wherein said VFl comprises HCDR1, HCDR2 and HCDR3 polypeptides and VL comprises LCDR1, LCDR2 and LCDR3 polypeptides and wherein HCDR1 consists of the sequence SEQ ID NO: 39, HCDR2 consists of the sequence SEQ ID NO: 40, HCDR3 consists of the sequence SPY, LCDR1 consists of the sequence SEQ ID NO: 41, LCDR2 consists of the sequence SEQ ID NO: 42 and LCDR3 consists of the sequence SEQ ID NO: 43.
  • VL light chain variable region
  • VH heavy chain variable region
  • the CDR sequences are as follows:
  • the CDR sequences are as follows:
  • LCDR1 SEQ ID NO: 41
  • RSSQRLVHSNGATYLH RSSQRLVHSNGATYLH.
  • LCDR3 SEQ ID NO: 43: SQSTHVPWT.
  • the present invention refers to an in vitro method which comprises: a) Immobilizing an epitope comprising or consisting of the SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO: 3, or an antigen comprising an epitope which in turn comprises or consists of SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO: 3 on a solid support, b) Adding the biological sample to be analyzed on the solid support, c) Assessing the presence in the biological sample of autoantibodies against the epitope or antigen described above, by determining whether antigen-antibody complexes have been formed, wherein, preferably, the antibody characterized by the sequences SEQ ID NO: 39, 40, SPY, 41, 42 and 43 is used as a calibrator or positive control.
  • the present invention is a computer-implemented invention, wherein a processing unit (hardware) and a software are configured to: a) Receive data/information about the signal emitted when a complex is formed between autoantibodies (which may be present in the biological sample) and the epitopes or antigens characterized by the SEQ ID NO: 1, 2 or 3, b) Process the data/information generated in step a) for finding substantial variations or deviations with respect to the signal emitted when a complex is formed between the antibody characterized by the sequences SEQ ID NO: 39, 40, SPY, 41, 42 and 43 (which is used as a calibrator or positive control) and the epitopes or antigens characterized by the SEQ ID NO: 1, 2 or 3, c) Provide an output through a terminal of any statistically significant variation or deviation identified according to step b) wherein, if the signal identified when the biological sample is added to the support is at least the same than the signal emitted by the complex formed when the antibody characterized by the
  • the present invention also refers to the in vitro use of any of the antibodies described above for the diagnosis of hepatocellular carcinoma or liver cirrhosis.
  • the present invention also refers to any of the antibodies described above for use in a method for the diagnosis of hepatocellular carcinoma or liver cirrhosis.
  • AFP is a 609 amino acid protein. It binds copper, nickel, and fatty acids as well as, and bilirubin less well than, serum albumin. Amino acids 1-18 correspond to the signal peptide and positions 19-609 correspond to the AFP chain.
  • Anti-human IgG antibody conjugated with HRP were diluted at 1/5000 in diluent buffer (Grifols).
  • results are expressed in optic density obtained from the ELISA described above and are summarized in Table 2 below, wherein the 15 peptides disclosed above were analyzed.
  • the mean of optical densities obtained by the different peptides in the group of patients was analyzed. This mean was higher for peptide 9 (0,320), which indicates that a greater number of antibodies bind to this sequence compared to the rest of the analyzed sequences. Therefore peptide 9 (SEQ ID NO: 12) showed the best results.
  • HCC Hepatocellular carcinoma patients
  • Cirr Cirr
  • NHS Normal human serum from blood donors
  • the optic density obtained in the ELISA are summarized in Table 4 below.
  • the mean of optical densities obtained by the different peptides in the group of patients was analyzed. This mean was higher for peptide 9.7 (0,381), which indicates that a greater number of antibodies bind to this sequence compared to the rest of the analyzed sequences. Therefore, the peptide that shows the best results is peptide 9.7 of SEQ ID NO: 3.
  • HCC Hepatocellular carcinoma patients
  • Cirr Cirr
  • NHS Normal human serum from blood donors
  • the optic density obtained in the ELISA are summarized in Table 6 below.
  • the mean of optical densities obtained by the different peptides in the group of patients was analyzed. This mean was higher for peptide 9.7.8 (0,217), which indicates that a greater number of antibodies bind to this sequence compared to the rest of the analyzed sequences. Therefore, peptide that shows the best results is peptide 9.7.8 (SEQ ID NO: 2).
  • HCC Hepatocellular carcinoma patients
  • Cirr Cirr
  • NHS Normal human serum from blood donors
  • HCC Hepatocellular carcinoma patients
  • CH Choronic hepatitis patients without cirrhosis
  • Example 9 Validation assay of the epitope of SEQ ID NO: 3 and antibody with CDRs consisting of SEQ ID NO: 39, SEQ ID NO: 40, SPY, SEQ ID NO: 41, SEQ ID NO: 42 and SEQ ID NO: 43
  • mice were immunized with SEQ ID NO: 3 to obtain monoclonal antibodies against said sequence from the hybridomas generated.
  • SEQ ID NO: 3 To choose the hybridoma with the highest antibody response against SEQ ID NO: 3, an ELISA test was performed with a standard protocol and with a modified protocol.
  • Anti-human IgG antibody conjugated with HRP were diluted at 1/2000 in diluent buffer (Grifols).
  • Anti-human IgG antibody conjugated with HRP were diluted at 1/2000 in diluent buffer (Grifols).

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  • General Physics & Mathematics (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Microbiology (AREA)
  • Biotechnology (AREA)
  • Hospice & Palliative Care (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Organic Chemistry (AREA)
  • Gynecology & Obstetrics (AREA)
  • Pregnancy & Childbirth (AREA)
  • Reproductive Health (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention concerne un épitope spécifique qui est utilisé pour détecter et/ou quantifier des auto-anticorps contre l'alpha-fœtoprotéine (AFP) dans un échantillon biologique, et par conséquent pour le diagnostic in vitro du carcinome hépatocellulaire (HCC) ou de la cirrhose du foie.
EP21755397.3A 2020-07-29 2021-07-29 Épitope amélioré pour la détection et/ou la quantification d'auto-anticorps contre l'alpha-f?toprotéine Withdrawn EP4189396A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP20382685.4A EP3945320A1 (fr) 2020-07-29 2020-07-29 Épitope amélioré pour la détection et/ou la quantification des auto-anticorps contre l'alpha-fétoprotéine
PCT/EP2021/071238 WO2022023461A1 (fr) 2020-07-29 2021-07-29 Épitope amélioré pour la détection et/ou la quantification d'auto-anticorps contre l'alpha-fœtoprotéine

Publications (1)

Publication Number Publication Date
EP4189396A1 true EP4189396A1 (fr) 2023-06-07

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EP20382685.4A Withdrawn EP3945320A1 (fr) 2020-07-29 2020-07-29 Épitope amélioré pour la détection et/ou la quantification des auto-anticorps contre l'alpha-fétoprotéine
EP21755397.3A Withdrawn EP4189396A1 (fr) 2020-07-29 2021-07-29 Épitope amélioré pour la détection et/ou la quantification d'auto-anticorps contre l'alpha-f?toprotéine

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EP20382685.4A Withdrawn EP3945320A1 (fr) 2020-07-29 2020-07-29 Épitope amélioré pour la détection et/ou la quantification des auto-anticorps contre l'alpha-fétoprotéine

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WO (1) WO2022023461A1 (fr)

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CN115894683B (zh) * 2022-12-22 2023-08-04 山东纳睿博恩生物医药科技有限公司 检测甲胎蛋白的单克隆抗体及其应用

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GB201814362D0 (en) * 2018-09-04 2018-10-17 Treos Bio Zrt Composition and process for preparing vaccine

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EP3945320A1 (fr) 2022-02-02

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