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WO2024212367A1 - Anticorps cd103 et son utilisation - Google Patents

Anticorps cd103 et son utilisation Download PDF

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Publication number
WO2024212367A1
WO2024212367A1 PCT/CN2023/104734 CN2023104734W WO2024212367A1 WO 2024212367 A1 WO2024212367 A1 WO 2024212367A1 CN 2023104734 W CN2023104734 W CN 2023104734W WO 2024212367 A1 WO2024212367 A1 WO 2024212367A1
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WO
WIPO (PCT)
Prior art keywords
antibody
seq
amino acid
acid sequence
cell
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Pending
Application number
PCT/CN2023/104734
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English (en)
Chinese (zh)
Inventor
黄启宽
朱国振
刘国卿
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Accurant Biotechnology Co Ltd
Accurant Biotechnology Co Ltd Shanghai
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Accurant Biotechnology Co Ltd
Accurant Biotechnology Co Ltd Shanghai
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Publication of WO2024212367A1 publication Critical patent/WO2024212367A1/fr
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Pending legal-status Critical Current

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Classifications

    • 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
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2839—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • G01N33/577—Immunoassay; Biospecific binding assay; Materials therefor involving monoclonal antibodies binding reaction mechanisms characterised by the use of monoclonal antibodies; monoclonal antibodies per se are classified with their corresponding antigens
    • 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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6872—Intracellular protein regulatory factors and their receptors, e.g. including ion channels
    • 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
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/70546—Integrin superfamily, e.g. VLAs, leuCAM, GPIIb/GPIIIa, LPAM
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to the technical field of antibodies, and in particular to an anti-CD103 antibody and its application in the diagnosis, prognosis, detection and treatment of diseases.
  • the integrin ⁇ E subunit is CD103, which forms ⁇ E ⁇ 7 with integrin ⁇ 7.
  • Integrin ⁇ E ⁇ 7 is highly expressed on leukocytes in the intestinal mucosa, including intraepithelial lymphocytes, dendritic cells, mast cells, and T regulatory cells. Integrin ⁇ E ⁇ 7 mediates the adhesion of lymphocytes to intestinal epithelial cells through interaction with cadherin, allowing lymphocytes to reside in the intestine, and this adhesion mainly depends on the metal ion-dependent adhesion site of the ⁇ -I domain within the integrin ⁇ E subunit.
  • CD103 is used as a molecular marker of tissue-resident memory (TRM) status, and the expression of CD103 on T cells indicates their ability to home and reside in tumor tissues.
  • CD8+ T cells, V ⁇ 1 T cells, and V ⁇ 2 T cells in tumors are mostly CD103+ TRM phenotypes. It is worth noting that many CD8+ T cells, some V ⁇ 1 T cells, and CD4+ T cells in normal lung tissue also show CD103+ TRM phenotypes.
  • an anti-CD103 antibody that can be used to detect CD103 and understand the expression characteristics of diseases, in particular, cancer-specific lymphocytes, and treat and prevent the corresponding cancer targets.
  • the present invention screened a hybridoma specific for anti-CD103 through hybridoma technology, prepared mouse ascites and purified antibodies to obtain a mouse monoclonal antibody (mAb) that can specifically bind to CD103.
  • the antibody has a high affinity for CD103 and has the ability to target CD103.
  • the present invention provides the following technical solutions:
  • the present invention provides an anti-CD103 antibody or an antigen-binding fragment thereof, wherein the complementarity determining region CDR1 of the heavy chain variable region has an amino acid sequence as shown in SEQ ID NO.1, CDR2 has an amino acid sequence as shown in SEQ ID NO.2, and CDR3 has an amino acid sequence as shown in SEQ ID NO.3.
  • the complementarity determining region CDR1 of the light chain variable region has an amino acid sequence as shown in SEQ ID NO.4, CDR2 has an amino acid sequence as shown in SEQ ID NO.5, and CDR3 has an amino acid sequence as shown in SEQ ID NO.6.
  • the heavy chain variable region of the anti-CD103 antibody or antigen-binding fragment thereof has an amino acid sequence as shown in SEQ ID NO. 7
  • the light chain variable region has an amino acid sequence as shown in SEQ ID NO. 8.
  • the anti-CD103 antibody is a murine monoclonal antibody.
  • the antigen-binding fragment may be selected from Fab, Fab', F(ab') 2 , Fd, Fv, dAb, complementary determining region fragment, single-chain antibody, humanized antibody, chimeric antibody, bispecific antibody or multispecific antibody.
  • the present invention provides a bispecific antibody or a multispecific antibody containing the anti-CD103 antibody or the antigen-binding fragment thereof.
  • the present invention provides a nucleic acid molecule encoding the anti-CD103 antibody or an antigen-binding fragment thereof.
  • nucleic acid molecule encoding the anti-CD103 antibody or its antigen-binding fragment can determine the nucleotide sequence of the nucleic acid molecule encoding the anti-CD103 antibody or its antigen-binding fragment, and select the nucleotide sequence of different nucleic acid molecules according to the codon preference of the host cell.
  • the present invention also provides a biological material, which contains a nucleic acid molecule encoding the anti-CD103 antibody or the antigen-binding fragment thereof, and the biological material is an expression cassette, a vector or a host cell.
  • the expression cassette mentioned above refers to a recombinant nucleic acid molecule obtained by connecting the upstream or downstream of the nucleic acid molecule to regulatory elements for transcription and translation.
  • the vector mentioned above refers to a nucleic acid delivery vehicle into which a nucleic acid molecule can be inserted, including but not limited to plasmids, artificial chromosomes, bacteriophages, animal viruses, etc., which can be expression vectors, cloning vectors or non-replicating vectors.
  • the host cells mentioned above can be microbial cells (such as Escherichia coli, yeast cells, etc.) or animal cells (such as insect cells, CHO cells, BHK cells, HEK293 cells, etc., which are cells used to express and prepare antibodies), wherein animal cells are cells that cannot reproduce into animal individuals.
  • microbial cells such as Escherichia coli, yeast cells, etc.
  • animal cells such as insect cells, CHO cells, BHK cells, HEK293 cells, etc., which are cells used to express and prepare antibodies
  • animal cells are cells that cannot reproduce into animal individuals.
  • the present invention provides any of the following applications of the anti-CD103 antibody or its antigen-binding fragment, the nucleic acid molecule or the biomaterial:
  • the detecting of CD103 described in (1) above includes detecting the presence or level of CD103.
  • the presence or level thereof can be imaged in vivo.
  • the cancers described in (2) above include hairy cell leukemia, HCLv, intestinal and extraintestinal lymphomas, enteropathy-associated T-cell lymphoma, T-lymphocytic leukemia/lymphoma, T-cell prolymphocytic leukemia, adult T-cell leukemia/lymphoma, mycosis fungoides, anaplastic large cell lymphoma ALCL, cutaneous T-cell lymphoma, and blastic plasmacytoid dendritic cell neoplasm.
  • the present invention provides an antibody conjugate, which is obtained by coupling the anti-CD103 antibody or antigen-binding fragment thereof with a carrier or a drug, or by coupling the anti-CD103 antibody or antigen-binding fragment thereof with a chemical or biological marker.
  • the carrier mentioned above can be any carrier or drug carrier that can be coupled to a protein.
  • the chemical labels mentioned above include isotopes, colloidal gold, fluorescein, biotin labels and the like.
  • biomarkers mentioned above include protein markers, enzyme markers and the like.
  • the present invention provides a detection reagent, which contains the anti-CD103 antibody or its antigen-binding fragment or contains the antibody conjugate.
  • the above-mentioned kit may also contain other reagents required for immunological detection, flow cytometric detection, etc.
  • the present invention provides a pharmaceutical composition, which contains the anti-CD103 antibody or its antigen-binding fragment or the antibody conjugate.
  • the pharmaceutical composition described above may further comprise a pharmaceutically acceptable carrier or excipient.
  • the type of carrier or excipient used may be selected according to the dosage form and administration method of the pharmaceutical composition.
  • the pharmaceutical composition may further comprise antibodies or active pharmaceutical ingredients having other effects.
  • the present invention provides a monoclonal antibody against CD103, which can specifically bind to CD103, has high specificity and high binding capacity, and can be used for detection such as immunofluorescence staining and flow cytometric staining of anti-CD103, and still has a good detection effect even at a higher dilution.
  • the antibody can also provide an effective potential selection tool for the treatment of CD103-positive tumors.
  • FIG1 is a graph showing data showing that the anti-CD103 antibodies of the present invention bind to CHO-hCD103;
  • FIG. 2 shows data showing that the anti-CD103 antibody of the present invention binds to CD103-positive T cells.
  • Example 1 Screening and preparation of hybridoma cells and monoclonal antibodies
  • the prepared plasmid encoding CD103 protein (integrin ⁇ E) was used to immunize mice, obtain hybridoma cells and screen them. After primary screening by ELISA, a monoclonal antibody with binding ability to CD103 was screened. The hybridoma was injected into the mouse peritoneum, and the mouse ascites was harvested about 10 days later. Protein G was used for purification to obtain purified monoclonal antibodies with a concentration of 2 mg/ml.
  • hybridoma cells were cultured, total cell RNA was extracted, antibody heavy chain and light chain genes were amplified by RT-PCR, and finally positive clones were selected for sequencing to obtain the full-length sequences of the antibody heavy chain and light chain.
  • amino acid sequences of the complementary determining regions CDR1, CDR2, and CDR3 of the heavy chain variable region of the anti-CD103 monoclonal antibody are shown in SEQ ID NOs. 1-3, respectively, and the amino acid sequences of the complementary determining regions CDR1, CDR2, and CDR3 of the light chain variable region are shown in SEQ ID NOs. 4-6, respectively.
  • the amino acid sequence of the heavy chain variable region is shown in SEQ ID NO. 7, and the amino acid sequence of the light chain variable region is shown in SEQ ID NO. 8, as shown in Table 1.
  • Example 2 Cell ELISA of the anti-CD103 antibody of the present invention
  • Chinese hamster ovary CHO cells were grown in DMEM/F12 (Gibco), 1% PenStrep (Gibco), 5% NCBS (Biowest) and cultured in a humidified atmosphere at 37°C and 5% CO 2.
  • MCF7 cells were grown in EMEM (ATCC), 1% PenStrep (Gibco), 10% FBS (Gibco) and cultured in a humidified atmosphere at 37°C and 5% CO 2.
  • the CHO-hCD103 cell line was derived by transfecting CHO cells with pCI-neo into the pcDNA3.1(+)-hygro vector encoding human integrin AlphaE (UniProt P38570).
  • CD103-positive T cells were generated as follows: Human peripheral blood mononuclear cells were isolated from healthy volunteers by Ficoll-Paque density gradient centrifugation. CD8-positive T cells were then negatively selected using the MagniSortTM Human CD8 T Cell Enrichment Kit. Subsequently, cells were stimulated with 10 pg/mL PHA, 6000 U/mL IL-2, and 10 ng/mL recombinant TGFP and cultured in RPMI (10% FCS and penicillin/streptomycin (100 U/mL)). Cells were cultured for at least 10 days to obtain > 80% CD103-positive CD8 cells.
  • CHO-hCD103 and CD103 positive T cells (30,000 cells/well) were seeded in 96-well plates. Subsequently, serially diluted anti-CD103 antibodies of the present invention and isotype controls were added to each well of the 96-well plate and incubated at 37°C for 1 hour. The wells were washed with PBS and incubated with rabbit anti-mouse/IgG-HRP (1:4000) at 37°C for 1 hour. Next, the wells were washed with PBS and TMB substrate (KPL) was added. The color reaction was stopped by adding 1M HCl solution and the absorbance was measured by a microplate reader (Thermo Scientific). The binding data of the antibodies of the present invention to these cell lines are shown in Figures 1 and 2. It can be seen from the data that the anti-CD103 antibodies of the present invention have a good binding effect on CD103 positive cells.
  • Characterization of anti-CD103 antibodies involved the ability to bind to CD103 expressed on CHO cell lines, CHO-hCD103, and CD103-positive T cells.
  • Cells were harvested, plated at 10 6 /ml in 96-well plates, and incubated in 100 ⁇ l PBS containing 2% FBS, 2mM EDTA, and 10 ⁇ g/ml antibody and Fc blocking reagent for 1 hour on ice. Cells were washed twice and incubated on ice for 30 minutes in 100 ⁇ l PBS containing 2% FBS, 2mM EDTA, and 5 ⁇ g/ml PE-conjugated secondary antibodies. Cells were washed twice in cold PBS and analyzed by flow cytometry on a BD FACS Canto.
  • MFI mean fluorescence intensity

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  • Health & Medical Sciences (AREA)
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  • General Physics & Mathematics (AREA)
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Abstract

La présente invention relève du domaine technique des anticorps, et concerne en particulier un anticorps anti-CD103 et son utilisation. L'invention concerne un anticorps anti-CD103, et une région déterminant la complémentarité CDR1 d'une région variable de chaîne lourde de celui-ci ayant une séquence d'acides aminés telle que représentée dans SEQ ID NO : 1, une région déterminant la complémentarité CDR2 a une séquence d'acides aminés telle que représentée dans SEQ ID NO : 2, et une région déterminant la complémentarité CDR3 a une séquence d'acides aminés telle que représentée dans SEQ ID NO : 3. Une région déterminant la complémentarité CDR1 d'une région variable de chaîne légère a une séquence d'acides aminés telle que représentée dans SEQ ID NO : 4, une région déterminant la complémentarité CDR2 a une séquence d'acides aminés telle que représentée dans SEQ ID NO : 5, et une région déterminant la complémentarité CDR3 a une séquence d'acides aminés telle que représentée dans SEQ ID NO : 6.
PCT/CN2023/104734 2023-04-14 2023-06-30 Anticorps cd103 et son utilisation Pending WO2024212367A1 (fr)

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CN202310397371.7 2023-04-14
CN202310397371.7A CN116333137B (zh) 2023-04-14 2023-04-14 一种cd103抗体及其应用

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116333137B (zh) * 2023-04-14 2023-09-26 上海精翰生物科技有限公司 一种cd103抗体及其应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110142860A1 (en) * 2006-08-30 2011-06-16 Gregg Allen Hadley Depletion of CD103 Expressing Cells for Treatment of Disorders
WO2018106972A1 (fr) * 2016-12-07 2018-06-14 La Jolla Institute For Allergy And Immunology Compositions pour le traitement du cancer ainsi que procédés et utilisations pour le traitement et le pronostic du cancer
WO2018226336A1 (fr) * 2017-06-09 2018-12-13 Providence Health & Services - Oregon Utilisation de cd39 et de cd103 pour l'identification de cellules tumorales humaines réactives pour le traitement du cancer
WO2021219871A2 (fr) * 2020-04-30 2021-11-04 Aduro Biotech Holdings, Europe B.V. Anticorps anti-cd103
CN116333137A (zh) * 2023-04-14 2023-06-27 上海精翰生物科技有限公司 一种cd103抗体及其应用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110142860A1 (en) * 2006-08-30 2011-06-16 Gregg Allen Hadley Depletion of CD103 Expressing Cells for Treatment of Disorders
WO2018106972A1 (fr) * 2016-12-07 2018-06-14 La Jolla Institute For Allergy And Immunology Compositions pour le traitement du cancer ainsi que procédés et utilisations pour le traitement et le pronostic du cancer
WO2018226336A1 (fr) * 2017-06-09 2018-12-13 Providence Health & Services - Oregon Utilisation de cd39 et de cd103 pour l'identification de cellules tumorales humaines réactives pour le traitement du cancer
WO2021219871A2 (fr) * 2020-04-30 2021-11-04 Aduro Biotech Holdings, Europe B.V. Anticorps anti-cd103
CN116333137A (zh) * 2023-04-14 2023-06-27 上海精翰生物科技有限公司 一种cd103抗体及其应用

Non-Patent Citations (2)

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Title
ÁLVARO DE MINGO PULIDO , ALYCIA GARDNER , SHANDI HIEBLER , HATEM SOLIMAN , HOPE S RUGO , MATTHEW F KRUMMEL , LISA M COUSSENS , BRI: "TIM-3 Regulates CD103+Dendritic Cell Function and Response to Chemotherapy in Breast Cancer", CANCER CELL, vol. 33, no. 1, 8 January 2018 (2018-01-08), US , pages 60 - 74 , e6, XP085334238, ISSN: 1535-6108, DOI: 10.1016/j.ccell.2017.11.019 *
JUNQI LI, LUO ZHENGXIU: "CD103+ Dendritic Cells in Chronic Immune-Inflammatory Diseases", JOURNAL OF PEDIATRIC PHARMACY, vol. 22, no. 2, 10 February 2016 (2016-02-10), pages 49 - 52, XP093221397, DOI: 10.13407/j.cnki.jpp.1672-108X.2016.02.018 *

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