WO2023198138A1 - Anticorps ou fragment de liaison à l'antigène de celui-ci et son utilisation médicale - Google Patents

Anticorps ou fragment de liaison à l'antigène de celui-ci et son utilisation médicale Download PDF

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WO2023198138A1
WO2023198138A1 PCT/CN2023/087967 CN2023087967W WO2023198138A1 WO 2023198138 A1 WO2023198138 A1 WO 2023198138A1 CN 2023087967 W CN2023087967 W CN 2023087967W WO 2023198138 A1 WO2023198138 A1 WO 2023198138A1
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seq
variable region
chain variable
antigen
heavy chain
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PCT/CN2023/087967
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Chinese (zh)
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毛东杰
谢岳峻
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上海翰森生物医药科技有限公司
常州恒邦药业有限公司
江苏豪森药业集团有限公司
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Publication of WO2023198138A1 publication Critical patent/WO2023198138A1/fr

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    • 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • 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
    • 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

Definitions

  • the present invention relates to ERBB3 antibodies or antigen-binding fragments thereof. Further, the present invention relates to ERBB3 fully human antibodies or antigen-binding fragments thereof comprising CDR regions; the present invention also relates to ERBB3 fully human antibodies or antigen-binding fragments thereof comprising said ERBB3 fully human antibodies or antigen-binding fragments thereof. Pharmaceutical compositions, and their use as diagnostic and therapeutic agents for ERBB3-related diseases.
  • ERBB receptor is widely expressed in neuronal cells, epithelial cells, and mesenchymal cells. It is related to the development of cardiovascular, neural, musculoskeletal and other organs, and is involved in the pathogenesis of cancer.
  • ERBB receptor has four family proteins: EGFR, ERBB2, ERBB3 and ERBB4. They are all membrane proteins with similar molecular structures, including extracellular domain (ECD), transmembrane domain, and intracellular domain with tyrosine kinase activity. and the C terminus.
  • ECD can be subdivided into 4 subdomains: subdomain I, II, III, IV (BMC Bioinformatics 2001,2:4.; Mol Cell 2003,11:507-17.), among which I and III are rich in leucine, It is the ligand binding functional domain; II and IV are rich in cysteine and are the functional domains that form dimers.
  • subdomain I, II, III, IV BMC Bioinformatics 2001,2:4.; Mol Cell 2003,11:507-17.
  • I and III are rich in leucine
  • II and IV are rich in cysteine and are the functional domains that form dimers.
  • the other three ERBB receptors bind II and IV in the inactive state, and are opened when bound and activated by ligands, exposing II to form dimers.
  • ERBB3 has received increasing attention.
  • ERBB3 bypass plays a key role in EGFR and ERBB2-related drug resistance
  • ERBB3 plays a key role in breast cancer, lung cancer, prostate cancer, colorectal cancer, ovarian cancer, gastric cancer, and bladder cancer.
  • melanoma and other tumors so ERBB3 is another potential target for tumor treatment.
  • ERBB3 has two ligands, NRG1 and NRG2.
  • the ligands can activate the kinase activity of ERBB3.
  • the activated ERBB3 can form a heterodimer with EGFR or ERBB2 and phosphorylate the latter, thereby transmitting signals to downstream pathways and promoting Growth and proliferation of tumor cells.
  • ERBB3 can also transmit signals through "cross talk" with other RTKs, such as forming complexes with IGF1R, FGFR2 and HGFR (c-Met) (BioDrugs 2017, 31:63-73). It can be seen that ERBB3 plays an important role in tumors. plays an important role in growth.
  • ERBB3-targeted treatments can include: monoclonal antibodies, bispecific antibodies, anti-ERBB3 vaccines, ligand traps, RNA inhibitors that lock ERBB3, small molecules that inhibit ERBB3 kinase activity, etc.
  • monoclonal antibodies bispecific antibodies
  • anti-ERBB3 vaccines ligand traps
  • RNA inhibitors that lock ERBB3, small molecules that inhibit ERBB3 kinase activity, etc.
  • the research and development of antibodies targeting ERBB3 is relatively hot.
  • an ERBB3 antibody derived from mice can significantly inhibit the growth of patients' cell tumors (citing Celldex data).
  • the ERBB3 antibodies currently under development include humanized antibodies that are mouse-derived antibodies that have been humanized.
  • the immunogenicity of humanized antibodies during immunization is higher than that of fully human antibodies that do not contain mouse-derived antibody components. This is a disadvantage when applied to humans; there are also some ERBB3 antibody drugs under development that are fully developed through phage library display technology. Humanized antibodies can solve the problem of immunogenicity.
  • Phage display technology is the fusion expression of foreign proteins or polypeptides with the phage coat protein, thereby expressing the foreign protein on the surface of the phage.
  • the phage antibody library is an antibody library established using comprehensive technical means that combines phage display technology, PCR amplification technology, and protein expression technology.
  • Phage libraries generally include synthetic libraries, immune libraries and natural libraries.
  • the most commonly used phage library is the natural library.
  • the natural library is usually a fully human antibody library constructed from immune cells from human peripheral blood. Its biggest advantage is that it does not require additional In vivo immunity can obtain highly diverse fully human antibodies produced by the human body.
  • the phage antibody library also has the following advantages: 1 It achieves the unification of genotype and phenotype. In addition, the experimental method is simple and fast. The traditional antibody production method through hybridoma technology takes several months, while the antibody library technology only takes a few weeks. 2 What is expressed is a fully human antibody with a small molecular weight. It is mainly expressed in the form of active fragment Fab and scFV.
  • ERBB3 antibodies have been reported in WO2007077028 and other patents. Most of them are mouse antibodies or humanized antibodies, and some are fully human antibodies obtained from phage libraries. Most of them are in clinical use at home and abroad. In the early and discovery stages, there are no antibody drugs targeting ERBB3 on the market. Therefore, it is necessary to further develop fully human ERBB3 antibodies with higher activity, high affinity and high stability for treatment research and application of related diseases.
  • the invention provides an anti-ERBB3 antibody or an antigen-binding fragment thereof, which includes: a heavy chain variable region and a light chain variable region; wherein, the heavy chain variable region includes SEQ ID NO: 1, 60 respectively. and HCDR1, HCDR2 and HCDR3 shown in 61 and 61, the light chain variable region includes LCDR1, LCDR2 and LCDR3 shown in SEQ ID NO: 62, 6 and 63 respectively, wherein said SEQ ID NO: 60, SEQ ID NO: 61.
  • SEQ ID NO: 62 and SEQ ID NO: 63 respectively have the amino acid sequences represented by the following general formulas:
  • the present invention also relates to a preferred embodiment, an anti-ERBB3 antibody or an antigen-binding fragment thereof as described above, which contains a heavy chain variable region and an antibody light chain variable region, wherein,
  • the heavy chain variable region includes HCDR1 as shown in SEQ ID NO: 1, as shown in SEQ ID NO: 3 or 30
  • the HCDR2 shown is the HCDR3 shown in any amino acid sequence of SEQ ID NO: 4, 28, 31, 32, 33 or 34;
  • the light chain variable region includes LCDR1 as shown in any amino acid sequence of SEQ ID NO: 5, 19, 21, 23, 25, 27, 29 or 35, LCDR2 as shown in SEQ ID NO: 6, as SEQ ID NO: LCDR3 shown in any amino acid sequence of 7, 20, 22, 24 or 26.
  • the present invention also relates to a preferred embodiment, an anti-ERBB3 antibody or an antigen-binding fragment thereof as described above, which contains a heavy chain variable region and a light chain variable region, wherein:
  • the heavy chain variable region includes HCDR1 shown in SEQ ID NO:1, HCDR2 shown in SEQ ID NO:3, and HCDR3 shown in SEQ ID NO:4; the light chain variable region includes SEQ ID NO:1 LCDR1 shown in ID NO:5, LCDR2 shown in SEQ ID NO:6, and LCDR3 shown in SEQ ID NO:7; or,
  • the heavy chain variable region includes: HCDR1 shown in SEQ ID NO:1, HCDR2 shown in SEQ ID NO:3, and HCDR3 shown in SEQ ID NO:4; the light chain variable region includes : LCDR1 shown in SEQ ID NO:19, LCDR2 shown in SEQ ID NO:6, and LCDR3 shown in SEQ ID NO:20; or,
  • the heavy chain variable region includes: HCDR1 shown in SEQ ID NO:1, HCDR2 shown in SEQ ID NO:3, and HCDR3 shown in SEQ ID NO:4; the light chain variable region includes : LCDR1 shown in SEQ ID NO:21, LCDR2 shown in SEQ ID NO:6, and LCDR3 shown in SEQ ID NO:22; or,
  • the heavy chain variable region includes: HCDR1 shown in SEQ ID NO:1, HCDR2 shown in SEQ ID NO:3, and HCDR3 shown in SEQ ID NO:4; the light chain variable region includes : LCDR1 shown in SEQ ID NO:23, LCDR2 shown in SEQ ID NO:6, and LCDR3 shown in SEQ ID NO:24; or,
  • the heavy chain variable region includes: HCDR1 shown in SEQ ID NO:1, HCDR2 shown in SEQ ID NO:3, and HCDR3 shown in SEQ ID NO:4; the light chain variable region includes : LCDR1 shown in SEQ ID NO:25, LCDR2 shown in SEQ ID NO:6, and LCDR3 shown in SEQ ID NO:26; or,
  • the heavy chain variable region includes: HCDR1 shown in SEQ ID NO:1, HCDR2 shown in SEQ ID NO:3, and HCDR3 shown in SEQ ID NO:4; the light chain variable region includes : LCDR1 shown in SEQ ID NO:27, LCDR2 shown in SEQ ID NO:6, and LCDR3 shown in SEQ ID NO:22; or,
  • the heavy chain variable region includes: HCDR1 shown in SEQ ID NO:1, HCDR2 shown in SEQ ID NO:3, and HCDR3 shown in SEQ ID NO:28; the light chain variable region includes : LCDR1 shown in SEQ ID NO:29, LCDR2 shown in SEQ ID NO:6, and LCDR3 shown in SEQ ID NO:7; or,
  • the heavy chain variable region includes: HCDR1 shown in SEQ ID NO:1, HCDR2 shown in SEQ ID NO:30, and HCDR3 shown in SEQ ID NO:31; the light chain variable region includes : LCDR1 shown in SEQ ID NO:5, LCDR2 shown in SEQ ID NO:6, and LCDR3 shown in SEQ ID NO:7; or,
  • the heavy chain variable region includes: HCDR1 shown in SEQ ID NO:1, HCDR2 shown in SEQ ID NO:3, and HCDR3 shown in SEQ ID NO:32; the light chain variable region includes : LCDR1 shown in SEQ ID NO:5, LCDR2 shown in SEQ ID NO:6, and LCDR3 shown in SEQ ID NO:7; or,
  • the heavy chain variable region includes: HCDR1 shown in SEQ ID NO:1, HCDR2 shown in SEQ ID NO:3, and HCDR3 shown in SEQ ID NO:33; the light chain variable region includes : LCDR1 shown in SEQ ID NO:29, LCDR2 shown in SEQ ID NO:6, and LCDR3 shown in SEQ ID NO:7; or,
  • the heavy chain variable region includes: HCDR1 shown in SEQ ID NO:1, HCDR2 shown in SEQ ID NO:3, and HCDR3 shown in SEQ ID NO:34; the light chain variable region includes : LCDR1 shown in SEQ ID NO:35, LCDR2 shown in SEQ ID NO:6, and LCDR3 shown in SEQ ID NO:7.
  • the present invention also relates to a preferred embodiment, an anti-ERBB3 antibody or an antigen-binding fragment thereof as described above, wherein the heavy chain variable region is at least one selected from the heavy chain variable region shown in the following sequence: SEQ ID NO:9, SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45 and SEQ ID NO:46, or at least 70%, 75%, 80%, 85% thereof , a heavy chain variable region with 90%, 95% or 99% homology.
  • the present invention also relates to a preferred embodiment, an anti-ERBB3 antibody or an antigen-binding fragment thereof as described above, wherein the light chain variable region is at least one light chain variable region selected from the following sequence: SEQ ID NO:10, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:42, SEQ ID NO:47, or related to A light chain variable region of at least 70%, 75%, 80%, 85%, 90%, 95% or 99% homology.
  • the present invention also relates to a preferred embodiment, an anti-ERBB3 antibody or an antigen-binding fragment thereof as described above, wherein the anti-ERBB3 antibody or an antigen-binding fragment thereof comprises the heavy chain variable region shown in SEQ ID NO: 9, and the light chain variable region shown in SEQ ID NO:10; or,
  • the anti-ERBB3 antibody or antigen-binding fragment thereof includes the heavy chain variable region shown in SEQ ID NO: 9, and the light chain variable region shown in SEQ ID NO: 36; or,
  • the anti-ERBB3 antibody or antigen-binding fragment thereof includes the heavy chain variable region shown in SEQ ID NO: 9, and the light chain variable region shown in SEQ ID NO: 37; or,
  • the anti-ERBB3 antibody or antigen-binding fragment thereof includes the heavy chain variable region shown in SEQ ID NO: 9, and the light chain variable region shown in SEQ ID NO: 38; or,
  • the anti-ERBB3 antibody or antigen-binding fragment thereof includes the heavy chain variable region shown in SEQ ID NO: 9, and the light chain variable region shown in SEQ ID NO: 39; or,
  • the anti-ERBB3 antibody or antigen-binding fragment thereof includes the heavy chain variable region shown in SEQ ID NO: 9, and the light chain variable region shown in SEQ ID NO: 40; or,
  • the anti-ERBB3 antibody or antigen-binding fragment thereof includes the heavy chain variable region shown in SEQ ID NO: 41, and the light chain variable region shown in SEQ ID NO: 42; or,
  • the anti-ERBB3 antibody or antigen-binding fragment thereof includes the heavy chain variable region shown in SEQ ID NO: 43, and the light chain variable region shown in SEQ ID NO: 10; or,
  • the anti-ERBB3 antibody or antigen-binding fragment thereof comprises the heavy chain variable region shown in SEQ ID NO:44, and the light chain variable region shown in SEQ ID NO:10; or,
  • the anti-ERBB3 antibody or antigen-binding fragment thereof comprises the heavy chain variable region shown in SEQ ID NO:45, and the light chain variable region shown in SEQ ID NO:42, or,
  • the anti-ERBB3 antibody or antigen-binding fragment thereof includes the heavy chain variable region shown in SEQ ID NO: 46, and the light chain variable region shown in SEQ ID NO: 47.
  • the anti-ERBB3 antibody or antigen-binding fragment thereof further comprises Heavy chain constant regions derived from human IgG1, IgG2, IgG3 or IgG4 or mutants thereof;
  • the anti-ERBB3 antibody or antigen-binding fragment thereof further comprises the heavy chain constant region of human IgG1 or a variant thereof;
  • the anti-ERBB3 antibody or antigen-binding fragment thereof further comprises a human IgG1 heavy chain constant region
  • the anti-ERBB3 antibody or antigen-binding fragment thereof further comprises a heavy chain constant region as shown in SEQ ID NO: 17;
  • the anti-ERBB3 antibody or antigen-binding fragment thereof further comprises a light chain constant region derived from human kappa chain, lambda chain or mutants thereof;
  • the anti-ERBB3 antibody or antigen-binding fragment thereof further comprises a light chain constant region derived from a human lambda chain.
  • the anti-ERBB3 antibody or antigen-binding fragment thereof further comprises a light chain constant region as shown in SEQ ID NO: 18.
  • the anti-ERBB3 antibody or antigen-binding fragment thereof comprises a heavy chain selected from the following: SEQ ID NO: 12, SEQ ID NO: 53, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57 or SEQ ID NO:58, or a heavy chain having at least 80%, 85%, 90%, 95% or 99% homology thereto.
  • the anti-ERBB3 antibody or antigen-binding fragment thereof wherein the anti-ERBB3 antibody or antigen-binding fragment thereof includes light chain: SEQ ID NO: 13, SEQ ID NO: 48, SEQ ID NO: 49 , SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:59, or is at least 80%, 85%, 90%, 95% or 99% identical to source of light chains.
  • the present invention also relates to a preferred embodiment, an anti-ERBB3 antibody or an antigen-binding fragment thereof as described above, wherein the anti-ERBB3 antibody or an antigen-binding fragment thereof comprises the heavy chain shown in SEQ ID NO: 12, and SEQ ID NO.
  • the anti-ERBB3 antibody or antigen-binding fragment thereof includes the heavy chain shown in SEQ ID NO: 12, and the light chain shown in SEQ ID NO: 48; or,
  • the anti-ERBB3 antibody or antigen-binding fragment thereof includes the heavy chain shown in SEQ ID NO: 12, and the light chain shown in SEQ ID NO: 49; or,
  • the anti-ERBB3 antibody or antigen-binding fragment thereof includes the heavy chain shown in SEQ ID NO: 12, and the light chain shown in SEQ ID NO: 50; or,
  • the anti-ERBB3 antibody or antigen-binding fragment thereof includes the heavy chain shown in SEQ ID NO: 12, and the light chain shown in SEQ ID NO: 51; or,
  • the anti-ERBB3 antibody or antigen-binding fragment thereof includes the heavy chain shown in SEQ ID NO: 12, and the light chain shown in SEQ ID NO: 52; or,
  • the anti-ERBB3 antibody or antigen-binding fragment thereof comprises the heavy chain shown in SEQ ID NO: 53, and the light chain shown in SEQ ID NO: 54; or,
  • the anti-ERBB3 antibody or antigen-binding fragment thereof includes the heavy chain shown in SEQ ID NO: 55, and the light chain shown in SEQ ID NO: 13; or,
  • the anti-ERBB3 antibody or antigen-binding fragment thereof includes the heavy chain shown in SEQ ID NO: 56, and the light chain shown in SEQ ID NO: 13; or,
  • the anti-ERBB3 antibody or antigen-binding fragment thereof includes the heavy chain shown in SEQ ID NO: 57, and the light chain shown in SEQ ID NO: 54; or,
  • the anti-ERBB3 antibody or antigen-binding fragment thereof includes the heavy chain shown in SEQ ID NO: 58, and the light chain shown in SEQ ID NO: 59.
  • the present invention further provides a polynucleotide encoding the above-mentioned anti-ERBB3 antibody or antigen-binding fragment thereof.
  • the present invention further provides an expression vector containing the above-mentioned polynucleotide.
  • the present invention further provides a host cell, which is introduced or contains the above-mentioned expression vector.
  • the above-mentioned host cell is a bacterium, preferably Escherichia coli.
  • the above-mentioned host cell is yeast, preferably Pichia pastoris.
  • the above-mentioned host cells are mammalian cells, preferably CHO cells or HEK293 cells.
  • the invention further provides a method for producing anti-ERBB3 antibodies or antigen-binding fragments thereof, comprising the steps:
  • the present invention further provides a pharmaceutical composition, which contains the above-mentioned anti-ERBB3 antibody or antigen-binding fragment thereof, and a pharmaceutically acceptable excipient, diluent or carrier.
  • the present invention further provides a detection or diagnostic reagent, which contains the above-mentioned anti-ERBB3 antibody or antigen-binding fragment thereof and an excipient, diluent or carrier that can be used for detection or diagnosis.
  • the present invention further provides the use of the above-mentioned anti-ERBB3 antibody or antigen-binding fragment thereof or the above-mentioned composition in the preparation of a medicament for treating or preventing ERBB3-mediated diseases or disorders.
  • the present invention further provides the use of the above-mentioned anti-ERBB3 antibody or antigen-binding fragment thereof or the above-mentioned detection or diagnostic reagent in preparing a kit for detecting, diagnosing, and prognosticating ERBB3-mediated diseases or disorders.
  • the disease or condition mentioned above is cancer
  • the present invention further provides a method for treating or preventing ERBB3-mediated diseases, including the steps:
  • the diseases are selected from: breast cancer, ovarian cancer, prostate cancer, endometrial cancer, thyroid cancer, kidney cancer, lung cancer, stomach cancer, colon cancer, bladder cancer, cervical cancer, gallbladder cancer, pancreatic cancer, testicular cancer, soft tissue sarcoma, Head and neck cancer, glioma, or melanoma.
  • antibody used in this application refers to an immunoglobulin, which is a tetrapeptide chain structure composed of two identical heavy chains and two identical light chains connected by inter-chain disulfide bonds.
  • the amino acid composition and sequence of the immunoglobulin heavy chain constant region are different, so their antigenicity is also different. Accordingly, immunoglobulins can be divided into five categories, or isotypes of immunoglobulins, namely IgM, IgD, IgG, IgA and IgE, and their corresponding heavy chains are ⁇ chain, ⁇ chain and ⁇ chain respectively. , ⁇ chain and ⁇ chain.
  • IgG can be divided into different subclasses based on differences in the amino acid composition of its hinge region and the number and position of heavy chain disulfide bonds.
  • IgG can be divided into IgG1, IgG2, IgG3, and IgG4.
  • Light chains are divided into kappa or lambda chains through differences in constant regions.
  • Each of the five types of Ig can have a kappa chain or a lambda chain.
  • the antibody light chain variable region described in this application may further comprise a light chain constant region, and the light chain constant region includes human or murine kappa, lambda chains or variants thereof.
  • the antibody heavy chain variable region described in this application may further comprise a heavy chain constant region, which includes human or murine IgG1, IgG2, IgG3, IgG4 or variants thereof. body.
  • variable region The sequence of about 110 amino acids near the N-terminus of antibody heavy and light chains varies greatly and is the variable region (V region); the remaining amino acid sequences near the C-terminus are relatively stable and is the constant region (C region).
  • the variable region includes 3 hypervariable regions (HVR) and 4 framework regions (FR) with relatively conserved sequences. Three hypervariable regions determine the specificity of the antibody, also known as complementarity determining regions (CDRs).
  • CDRs complementarity determining regions
  • Each light chain variable region (VL) and heavy chain variable region (VH) consists of 3 CDR regions and 4 FR regions. The order from the amino terminus to the carboxyl terminus is: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the three CDR regions of the light chain refer to LCDR1, LCDR2, and LCDR3; the three CDR regions of the heavy chain refer to HCDR1, HCDR2, and HCDR3.
  • the number and position of the CDR amino acid residues in the VL and VH regions of the antibody or antigen-binding fragment described in this application comply with the known Kabat or Chothia or ABM definition rules (http://bioinf.org.uk/abs/) .
  • APC antigen presenting cell
  • DCs dendritic cells
  • PBMCs peripheral blood mononuclear cells
  • monocytes B lymphoblasts
  • monocyte-derived dendritic cells monocyte-derived dendritic cells
  • antigen presentation refers to the process by which APCs capture antigens and enable their recognition by T cells, for example as components of MHC-I/MHC-II conjugates.
  • recombinant human antibody includes human antibodies prepared, expressed, created or isolated by recombinant methods using techniques and methods well known in the art, such as:
  • Antibodies isolated from transgenic or transchromosomal animals (such as mice) of human immunoglobulin genes or hybridomas prepared therefrom;
  • Antibodies isolated from host cells transformed to express antibodies such as transfectomas;
  • Antibodies prepared, expressed, created or isolated by splicing human immunoglobulin gene sequences into other DNA sequences.
  • Such recombinant human antibodies contain variable and constant regions that utilize specific human germline immunoglobulin sequences encoded by germline genes, but also include subsequent rearrangements and mutations such as those that occur during antibody maturation.
  • human antibody includes antibodies having variable and constant regions of human germline immunoglobulin sequences.
  • the human antibodies of the present application may include amino acid residues that are not encoded by human germline immunoglobulin sequences (eg, mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo).
  • the term “human antibody” does not include antibodies in which CDR sequences derived from the germline of another mammalian species (such as mouse) have been grafted onto human backbone sequences (i.e., "humanized antibodies”) .
  • antigen-binding fragment refers to antigen-binding fragments of antibodies and antibody analogs, which generally include at least part of the antigen-binding region or variable region (such as one or more CDRs) of the parent antibody.
  • Antibody fragments retain at least some of the binding specificity of the parent antibody. Typically, an antibody fragment retains at least 10% of the parent binding activity when activity is expressed on a molar basis. Preferably, the antibody fragment retains at least 20%, 50%, 70%, 80%, 90%, 95% or 100% or more of the binding affinity of the parent antibody for the target.
  • antigen-binding fragments include, but are not limited to: Fab, Fab', F(ab')2, Fv fragments, linear antibodies, single chain antibodies, Nanobodies, domain antibodies and multispecific antibodies. Engineered antibody variants are reviewed in Holliger and Hudson, 2005, Nat. Biotechnol. 23: 1126-1136.
  • a "Fab fragment” consists of the CH1 and variable regions of a light chain and a heavy chain.
  • the heavy chain of a Fab molecule cannot form disulfide bonds with another heavy chain molecule.
  • the "Fc” region contains two heavy chain fragments comprising the CH1 and CH2 domains of the antibody.
  • the two heavy chain segments are held together by two or more disulfide bonds and by hydrophobic interactions of the CH3 domains.
  • a “Fab' fragment” contains a light chain and a portion of a heavy chain including the VH domain and the CH1 domain and the region between the CH1 and CH2 domains, whereby between the two heavy chains of two Fab' fragments Interchain disulfide bonds are formed to form F(ab')2 molecules.
  • F(ab')2 fragment contains two light chains and two heavy chains comprising part of the constant region between the CH1 and CH2 domains, thereby forming an interchain disulfide bond between the two heavy chains. Therefore, the F(ab')2 fragment consists of two Fab' fragments held together by a disulfide bond between the two heavy chains.
  • An "Fv region” contains variable regions from both heavy and light chains, but lacks constant regions.
  • multispecific antibody is used in its broadest sense to encompass antibodies with multiple epitope specificities.
  • These multispecific antibodies include, but are not limited to: antibodies comprising a heavy chain variable region VH and a light chain variable region VL, wherein the VH-VL unit Antibodies with multi-epitope specificity; antibodies with two or more VL and VH regions, each VH-VL unit binds to different targets or different epitopes of the same target; antibodies with two or more single Antibodies with variable regions, each single variable region binds to different targets or different epitopes of the same target; full-length antibodies, antibody fragments, diabodies, bispecific diabodies and tribodies (triabodies), antibody fragments that have been covalently or non-covalently linked together, etc.
  • single-chain antibody is a single-chain recombinant protein composed of an antibody's heavy chain variable region VH and light chain variable region VL connected through a connecting peptide. It is the smallest antibody fragment with a complete antigen-binding site.
  • domain antibody fragment is an immunologically functional immunoglobulin fragment containing only a heavy chain variable region or a light chain variable region chain.
  • two or more VH regions are covalently linked to a peptide linker to form a bivalent domain antibody fragment.
  • the two VH regions of a bivalent domain antibody fragment can target the same or different antigens.
  • binding to ERBB3 refers to the ability to interact with human ERBB3.
  • antigen binding site in this application refers to the three-dimensional space recognized by the antibody or antigen-binding fragment of this application.
  • epitope refers to a site on an antigen to which an immunoglobulin or antibody specifically binds.
  • Epitopes can be formed from adjacent amino acids, or non-adjacent amino acids that are juxtaposed by the tertiary folding of the protein. Epitopes formed by adjacent amino acids are usually maintained after exposure to denaturing solvents, whereas epitopes formed by tertiary folding are usually lost after treatment with denaturing solvents.
  • Epitopes usually include at least 3-15 amino acids in a unique spatial conformation. Methods for determining what epitope is bound by a given antibody are well known in the art and include immunoblotting and immunoprecipitation assays, among others. Methods for determining the spatial conformation of an epitope include techniques in the art and techniques described herein, such as X-ray crystallography and two-dimensional nuclear magnetic resonance.
  • telomere binding refers to the binding of an antibody to an epitope on a predetermined antigen.
  • ERBB3 is used as the analyte and an antibody is used as the ligand
  • SPR surface plasmon resonance
  • the antibody dissociates with an equilibrium dissociation constant of approximately less than 10 -7 M or even less ( KD ) binds to the predetermined antigen, and its affinity for binding to the predetermined antigen is at least twice the affinity for binding to the predetermined antigen or a non-specific antigen (such as BSA, etc.) other than the predetermined antigen or a closely related antigen.
  • antibody that recognizes an antigen is used interchangeably herein with the term “antibody that specifically binds.”
  • cross-reactivity refers to the ability of an antibody of the present application to bind to ERBB3 from a different species.
  • an antibody of the present application that binds human ERBB3 may also bind ERBB3 of another species.
  • Cross-reactivity is measured by detecting specific reactivity with purified antigen in binding assays such as SPR and ELISA, or binding or functional interaction with cells physiologically expressing ERBB3.
  • binding assays such as SPR and ELISA
  • Methods of determining cross-reactivity include standard binding assays as described herein, such as surface plasmon resonance (SPR) analysis, or flow cytometry.
  • SPR surface plasmon resonance
  • Inhibition or “blocking” are used interchangeably and encompass both partial and complete inhibition/blocking. Inhibition/blocking of a ligand preferably reduces or alters the normal level or type of activity that would occur if ligand binding occurred without inhibition or blocking. Inhibition and blocking are also intended to include any measurable reduction in binding affinity of the ligand when contacted with the anti-ERBB3 antibody compared to the ligand not contacted with the anti-ERBB3 antibody.
  • inhibition of growth is intended to include any measurable reduction in cell growth.
  • inducing an immune response and “enhancing an immune response” are used interchangeably and refer to stimulation of an immune response to a specific antigen (ie, passive or adaptive).
  • induction with respect to inducing CDC or ADCC refers to stimulating specific direct Cell killing mechanism.
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • cells expressing Fc receptors that are directly killed by recognizing the Fc segment of the antibody and are coated with the antibody. target cells.
  • the ADCC effector function of the antibody can be enhanced or reduced, reduced or eliminated by modifying the Fc segment of IgG.
  • the modification refers to mutation in the heavy chain constant region of the antibody.
  • the engineered antibodies or antigen-binding fragments of the present application can be prepared and purified by conventional methods.
  • the cDNA sequence of the corresponding antibody can be cloned and recombined into the GS expression vector.
  • the recombinant immunoglobulin expression vector can stably transfect CHO cells.
  • mammalian expression systems result in glycosylation of the antibody, particularly at the highly conserved N-terminus of the FC region.
  • Stable clones are obtained by expressing antibodies that specifically bind to human antigens. Positive clones were expanded in serum-free medium in bioreactors to produce antibodies.
  • the culture medium secreting antibodies can be purified and collected using conventional techniques.
  • Antibodies can be filtered and concentrated using conventional methods. Soluble mixtures and polymers can also be removed by conventional methods, such as molecular sieves and ion exchange.
  • the obtained product needs to be frozen immediately, such as -70°C, or freeze-dried.
  • administering when applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, mean the administration of an exogenous drug, therapeutic, diagnostic, or composition to the animal , contact with persons, subjects, cells, tissues, organs or biological fluids.
  • administering may refer to, for example, therapeutic, pharmacokinetic, diagnostic, research and experimental methods.
  • Treatment of cells includes contact of reagents with the cells, and contact of the reagents with a fluid, wherein the fluid is in contact with the cells.
  • administer also mean in vitro and ex vivo treatment of, for example, a cell by a reagent, a diagnostic, a binding composition or by another cell.
  • Treatment when applied to human, veterinary medicine or research subjects means therapeutic treatment, prophylactic or prophylactic measures, research and diagnostic applications.
  • Treat means administering an internal or external therapeutic agent, such as one comprising any of the antibodies of the present application, to a patient who has one or more disease symptoms for which the therapeutic agent is known to have a therapeutic effect.
  • a therapeutic agent is administered in an amount effective to alleviate one or more disease symptoms in the subject or population, either by inducing regression of such symptoms or inhibiting the progression of such symptoms to any clinically measurable extent.
  • the amount of therapeutic agent effective to alleviate the symptoms of any particular disease can vary depending on a variety of factors, such as the patient's disease state, age and weight, and the ability of the drug to produce the desired therapeutic effect in the patient.
  • Whether disease symptoms have been alleviated may be assessed by any of the clinical tests commonly used by physicians or other health care professionals to assess the severity or progression of symptoms.
  • embodiments of the present application e.g., treatments or articles of manufacture
  • naturally occurring refers to the fact that the object is found in nature.
  • organisms including viruses
  • a naturally occurring polypeptide sequence or polynucleotide sequence is one that is intentionally modified in the laboratory.
  • an "effective amount” includes an amount sufficient to ameliorate or prevent symptoms or symptoms of a medical disorder.
  • An effective amount also means an amount sufficient to allow or facilitate diagnosis.
  • the effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition being treated, the general health of the patient, the method, route and dosage of administration, and the severity of the side effects.
  • An effective amount may be the maximum dosage or dosage regimen that avoids significant side effects or toxic effects.
  • Exogenous refers to substances that are background produced outside an organism, cell or human body.
  • Endogenous refers to a substance that is produced in a cell, organism, or human body based on its background.
  • “Homology” refers to the sequence similarity between two polynucleotide sequences or between two polypeptides. When a position in two compared sequences is occupied by the same base or amino acid monomer subunit, for example if each position in two DNA molecules is occupied by adenine, then the molecules are homologous at that position .
  • the percent homology between two sequences is a function of the number of matching or homologous positions shared by the two sequences divided by the number of positions compared ⁇ 100%. For example, if 6 out of 10 positions in two sequences match or are homologous when the sequences are optimally aligned, then the two sequences are 60% homologous. In general, comparisons are made when aligning two sequences yields the greatest percent homology.
  • the expressions "cell,” “cell line,” and “cell culture” are used interchangeably, and all such designations include their progeny.
  • the words “transformant” and “transformed cell” include primary subject cells and cultures derived therefrom, regardless of the number of transfers. It should also be understood that all offspring are unlikely to be exactly the same in terms of DNA content due to intentional or unintentional mutations. Mutant progeny that have the same function or biological activity as screened in the originally transformed cells are included. Where different names are intended, this is clear from the context.
  • “Pharmaceutical composition” means containing one or more antibodies or antigen-binding fragments thereof as described herein, together with other ingredients such as physiologically/pharmaceutically acceptable carriers and excipients.
  • the purpose of pharmaceutical compositions is to facilitate administration to living organisms and facilitate the absorption of active ingredients to exert biological activity.
  • the amino acid sequence of the human ERBB3 protein shown in SEQ ID NO: 14 is used as a template for the antigen design of the present invention.
  • the following ERBB3 antigens unless otherwise specified refer to human ERBB3.
  • ERBB3 full-length protein: ERBB3 (SEQ ID NO: 14) sequence is as follows:
  • the ERBB3 antigen used for screening is the commercial product Biotinylated human ERBB3-His tag (Sino biological, cat#10201-H08H-B); the ERBB3 antigen used for detection is the commercial product human ERBB3-His tag (Sino biological, cat#10201-H08H) .
  • the ERBB3 antigen for detection is the ECD region sequence of human ERBB3, with a His tag at the C terminus.
  • the ERBB3 antigen for screening is biotinylated on this basis.
  • the ECD sequence of human ERBB3 is as follows:
  • the monkey ERBB3 antigen (SEQ ID NO: 16) used for detection is the commercial product Rhesus ERBB3 Protein-His Tag (Sino biological, cat#90043-K08H). It is the ECD region sequence of the monkey ERBB3 antigen with a His tag added to the C terminus. The sequence as follows:
  • PBMC from multiple individuals were collected, B cells were isolated, RNA was extracted, reverse transcribed into cDNA, and then the cDNA was used as a template to construct a natural phage surface Fab display library (library capacity: 1.6 ⁇ 10 11 ).
  • the liquid phase method is used for panning.
  • the phages are combined with biotinylated ERBB3 liquid phase and then separated using streptavidin magnetic beads.
  • biotinylated human ERBB3 was used for 2 to 3 rounds of screening, and 384 single clone colonies were selected and packaged into phage display Fab fragments for ELISA testing.
  • the sequences of the IgG1 heavy chain constant region and light chain constant region are as follows:
  • ERBB3 antigen protein and HEK293T cells overexpressing human ERBB3 (293T-human ERBB3) were used for 5 rounds of alternating enrichment, and 1056 clones were obtained through preliminary screening by ELISA. Then FACS re-screening was performed and samples were sent for sequencing. Finally, 103 unique candidate sequences were obtained, and 10 antibodies with top 10 binding capabilities were selected for production and purification.
  • the clones selected based on the mutation library of the Ab2 antibody sequence are different from the Ab2 antibody in HCDR2, HCDR3, LCDR1, and LCDR3 on the light and heavy chains.
  • the relevant CDR (the amino acid residues of the CDR are determined and annotated by the Kabat numbering system) sequence or general formula, the corresponding light/heavy chain variable region and its light and heavy chains are as follows:
  • cDNA fragments were synthesized based on the amino acid sequences of the light and heavy chains of Ab1 and Ab2 antibodies and inserted into the pcDNA3.1 expression vector (Life Technologies Cat. No. V790-20).
  • the expression vector and transfection reagent PEI (Polysciences, Inc. Cat. No. 23966) were transfected into HEK293 cells (Life Technologies Cat. No. 11625019) at a ratio of 1:2 and placed in a CO 2 incubator for 4- 5 days.
  • the 10 antibodies Ab2_M1-M10 with TOP10 binding capacity were produced and purified using the same method as above to obtain fully human antibody mutant proteins.
  • HEK293T cells overexpressing human ERBB3 (293T-human ERBB3) were digested with trypsin, collected by centrifugation, and the cell density was adjusted with FACS buffer (1 ⁇ PBS containing 2% FBS) before being spread on a 96-well U-bottom plate. Wells contain 1 ⁇ 10 5 to 2 ⁇ 10 5 cells. Centrifuge: 1200g, 5 minutes, discard the supernatant, add 100 ⁇ L of antibody solution that has been gradient diluted with FACS buffer, and incubate at 4°C for 1 hour.
  • PE anti-human IgG Fc Antibody Biolegend, Cat#409304
  • Example 4.1 Through the detection method of Example 4.1, the binding ability of 10 purified fully human antibody mutants to human breast cancer cells MX-1 expressing ERBB3 antigen was detected. MFI was used as the abscissa, and the concentration logarithm value was used as the abscissa. Log(agonist)vs.response--Variable slope(four parameters) formula is used for curve fitting and EC 50 is calculated. The results are shown in the table below.
  • human breast adenocarcinoma cell MX-1 expressing ERBB3 was used for evaluation.
  • the cells were digested with trypsin, collected and resuspended in pre-chilled FACS buffer, and the cell concentration was adjusted to 2 ⁇ 10 6 /mL.
  • Take the EP tube add 1 mL of cell suspension, centrifuge at 1500 rpm for 5 minutes, discard the supernatant, add 1 mL of the prepared antibody to be tested, resuspend the cells, the final concentration of the antibody is 20 ⁇ g/ml, and incubate on a shaker at 4°C for 1 hour.
  • Antibody endocytosis percentage (fluorescence intensity value at each time point - average fluorescence intensity value of Blank group) / (average fluorescence intensity value of 0 minute group - average fluorescence intensity value of Blank group) * 100, the specific results are as follows Table 12 shows:
  • the purpose of this experiment is to evaluate how candidate antibodies block the binding of ligand HRG to ERBB3 by binding to the ERBB3 receptor on the surface of tumor cell membranes, thereby blocking the formation of heterodimers between ERBB3 and other EGFR family members, and blocking phosphorylation-transduced cells. signal transduction, thereby inhibiting the proliferation of tumor cells.
  • ERBB3-positive tumor cells MCF-7 ATCC, Cat#CRL-3435
  • Inhibition rate % (positive control group signal value - experimental group signal value) / positive control group signal value * 100
  • the cRBA (cell-base receptor blocking assay) experiment was used to test the blocking effect of the antibody mutants on the binding between the ligand and human ERBB3 expressed on tumor cells.
  • Human breast cancer cells SK-BR-3 (Nanjing Kebai, Cat#CBP60413) expressing ERBB3 were trypsinized and counted, resuspended in FACS buffer to 1 ⁇ 10 6 /mL, and spread into 96 wells at 100 ⁇ L per well. plate, centrifuge: 1500 rpm, 4°C, 5 minutes, discard the supernatant.
  • Blocking rate (%) (control well MFI - sample well MFI)/control well MFI ⁇ 100.
  • the control well is a well without fully human antibody
  • the sample well is a well with fully human antibody in different concentration gradients.
  • the ligand HRG binds to the ERBB3 protein expressed in tumor cells to phosphorylate and activate it, and then forms a heterodimer with EGFR or ERBB2, thereby activating the downstream AKT and ERK pathways.
  • This experiment uses the phosphorylation detection kits of pHer3 (Cisbio, Cat#64HR3PEG), pAKT (Cisbio, Cat#64AKSPEG) and pERK (Cisbio, Cat#64ERKPPEH) to test the ligand expression of ERBB3-positive human breast cancer cells MCF-7. Blocking effect of fully human antibodies on the phosphorylation of Her3, AKT and ERK under activation conditions.
  • Cells MCF-7 (ATCC, Cat#CRL-3435) were digested with trypsin, centrifuged and the supernatant was discarded. Cell pellet was precipitated using Reaction medium (RPMI 1640 medium + 10% heat-inactivated FBS + 1% penicillin/streptomycin). Resuspend to 1 ⁇ 10 6 /mL, add 100uL cell suspension to each well of a flat-bottom 96-well plate (low adsorption plate), seal the empty wells on all sides with 200ul PBS, and incubate in a 37-degree incubator for 6 hours.
  • Reaction medium RPMI 1640 medium + 10% heat-inactivated FBS + 1% penicillin/streptomycin
  • Blocking rate (%) (sample well-negative control well)/(positive control well-background control well).

Abstract

L'invention concerne un anticorps anti-ERBB3 ou un fragment de liaison à l'antigène de celui-ci, et son utilisation médicale. L'invention concerne un anticorps entièrement humain anti-récepteur ERBB3 ou un fragment de liaison à l'antigène de celui-ci, et son utilisation médicale. L'invention concerne une composition pharmaceutique comprenant l'anticorps entièrement humain anti-ERBB3 ou le fragment de liaison à l'antigène de celui-ci, et l'utilisation de la composition pharmaceutique en tant que médicament anticancéreux.
PCT/CN2023/087967 2022-04-13 2023-04-13 Anticorps ou fragment de liaison à l'antigène de celui-ci et son utilisation médicale WO2023198138A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090291085A1 (en) * 2007-02-16 2009-11-26 Merrimack Pharmaceuticals, Inc. Antibodies against erbb3 and uses thereof
CN103002912A (zh) * 2009-08-21 2013-03-27 梅里麦克制药股份有限公司 针对ErbB3的胞外结构域的抗体及其用途
US20130224220A1 (en) * 2010-10-18 2013-08-29 Mediapharma S.R.L. ErbB3 BINDING ANTIBODY
CN105120890A (zh) * 2012-10-25 2015-12-02 索伦托治疗有限公司 与ErbB3结合的抗原结合蛋白
US20200339702A1 (en) * 2018-03-14 2020-10-29 UltraHuman Thirteen Limited De-immunised anti-erbb3 antibodies
WO2022078490A1 (fr) * 2020-10-15 2022-04-21 上海翰森生物医药科技有限公司 Anticorps anti-erbb3 ou fragment de liaison à l'antigène de celui-ci et utilisation médicale associée

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090291085A1 (en) * 2007-02-16 2009-11-26 Merrimack Pharmaceuticals, Inc. Antibodies against erbb3 and uses thereof
CN103002912A (zh) * 2009-08-21 2013-03-27 梅里麦克制药股份有限公司 针对ErbB3的胞外结构域的抗体及其用途
US20130224220A1 (en) * 2010-10-18 2013-08-29 Mediapharma S.R.L. ErbB3 BINDING ANTIBODY
CN105120890A (zh) * 2012-10-25 2015-12-02 索伦托治疗有限公司 与ErbB3结合的抗原结合蛋白
US20200339702A1 (en) * 2018-03-14 2020-10-29 UltraHuman Thirteen Limited De-immunised anti-erbb3 antibodies
WO2022078490A1 (fr) * 2020-10-15 2022-04-21 上海翰森生物医药科技有限公司 Anticorps anti-erbb3 ou fragment de liaison à l'antigène de celui-ci et utilisation médicale associée
CN115843256A (zh) * 2020-10-15 2023-03-24 上海翰森生物医药科技有限公司 抗erbb3抗体或其抗原结合片段及其医药用途

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