WO2022100590A1 - Anticorps humanisé enrichi en adcc pour claudin 18a2 et application associée - Google Patents
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- WO2022100590A1 WO2022100590A1 PCT/CN2021/129660 CN2021129660W WO2022100590A1 WO 2022100590 A1 WO2022100590 A1 WO 2022100590A1 CN 2021129660 W CN2021129660 W CN 2021129660W WO 2022100590 A1 WO2022100590 A1 WO 2022100590A1
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
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- 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
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- 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
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
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- 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
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/10—Cells modified by introduction of foreign genetic material
- C12N5/12—Fused cells, e.g. hybridomas
- C12N5/16—Animal cells
- C12N5/163—Animal cells one of the fusion partners being a B or a T lymphocyte
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- 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
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- 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 belongs to the field of immunology, and more particularly, the present invention relates to an ADCC-enhanced humanized antibody against claudin 18.2 (Claudin 18.2, CLDN18A2, CLDN18.2). And, pharmaceutical compositions comprising the antibodies and related applications thereof in the treatment of cancer.
- Claudin 18 (Claudin 18, CLDN18) is an intrinsic membrane protein located in the tight junction of the epithelium and the endothelium with a molecular weight of about 27.9KD. to maintain the stability of the internal environment of the organization.
- human claudin 18 two isoforms are known to exist, splice variant 1 (CLDN18A1, CLDN18.1): GenBank accession numbers NP_057453, NM_016369, and splice variant 2 (CLDN18A2, CLDN18.2): GenBank The registration numbers are NP_001002026, NM_001002026.
- CLDN18A1 is selectively expressed in lung epithelium, while CLDN18A2 is specifically expressed in normal gastric epithelial differentiated cells, but not in gastric epithelial stem cells with cell division activity.
- CLDN18A2 is overexpressed in various cancer types, such as 75% of gastric cancer patients with high CLDN18A2 expression, 50% of pancreatic cancer patients with high CLDN18A2 expression, and 30% of esophageal cancer patients with high CLDN18A2 expression. It is also highly expressed in other cancer types. Therefore, finding an antibody that specifically binds CLDN18A2 but not CLDN18A1 is of great significance for the treatment and detection of cancer.
- the existing CLDN18.2 antibody IMAB362 has entered the clinical research stage.
- the clinical results show that in patients with gastric cancer with high expression of CLDN18.2, chemotherapy + IMAB362 compared with chemotherapy alone, the progression-free survival period was prolonged from 6.1 months to 9.1 months. Survival increased from 9.3 months to 16.6 months.
- at least three CLDN18.2 monoclonal antibodies are currently in phase I clinical research.
- CAR-T prepared for the CLDN18.2 target has also entered clinical research.
- these antibodies that have entered the clinical stage have weak affinity with CLDN18.2, and have weak preclinical in vivo anti-tumor effects with large side effects. Therefore, it is still necessary to continue to screen and prepare CLDN18.2 antibodies with higher activity, lower toxicity, and larger therapeutic safety window, in order to produce stronger efficacy at a smaller dose and improve the optimal drug use dose space.
- the present invention provides an anti-CLDN18.2 antibody or an antigen-binding fragment thereof, which specifically binds to CLDN18.2.
- the CLDN18.2 is a peptide with GenBank Accession No. NP_001002026 (mRNA: NM_001002026).
- the present invention provides an anti-CLDN18.2 antibody or an antigen-binding fragment thereof, the antibody or antigen-binding fragment thereof can specifically bind to CLDN18.2, comprising: a heavy chain variable region, the heavy chain variable region Comprising HCDR1, HCDR2 and HCDR3, whose sequences are shown in SEQ ID NOs: 1, 2, and 3, respectively; and, a light chain variable region, which comprises LCDR1, LCDR2 and LCDR3, whose sequences are respectively shown in SEQ ID NO: 1, 2, and 3; ID NO: 4, 5, 6; and, the antibody or antigen-binding fragment thereof further comprises an Fc region having amino acid substitutions at two positions S239D and S298A, the amino acid positions being numbered according to EU.
- the present invention also provides an anti-CLDN18.2 antibody or an antigen-binding fragment thereof, comprising a heavy chain variable region and a light chain variable region, the heavy chain variable region having at least 80% to SEQ ID NO:7 to 100% sequence identity; and, the light chain variable region has at least 80% to 100% sequence identity to SEQ ID NO: 8; and, the antibody or antigen-binding fragment thereof further comprises an Fc region, the The Fc region has amino acid substitutions at two positions S239D and S298A, which are numbered according to EU.
- the anti-CLDN18.2 antibody or antigen-binding fragment thereof of the present invention further comprises a heavy chain constant region and a light chain constant region, the heavy chain constant region having at least 80% to SEQ ID NO:9 100% sequence identity; and, the light chain constant region has at least 80% to 100% sequence identity to SEQ ID NO:10.
- the anti-CLDN18.2 antibody or antigen-binding fragment thereof of the invention comprises a full-length antibody, wherein the heavy chain has at least 80% to 100% sequence identity to SEQ ID NO: 11; and, The light chain has at least 80% to 100% sequence identity to SEQ ID NO:12.
- the anti-CLDN18.2 antibody is a monoclonal antibody.
- the anti-CLDN18.2 antibody is a murine antibody, a chimeric antibody or a humanized antibody.
- an anti-CLDN18.2 antibody or antigen-binding fragment thereof of the present invention is in the form of IgG1, IgG2, IgG3 or IgG4.
- the antigen-binding fragments of the present invention are Fab, Fv, scFv, F(ab') 2 , linear antibodies, single-domain antibodies or full-length antibodies.
- the present invention provides a conjugate formed by conjugating the aforementioned antibody or antigen-binding fragment thereof to a capture label or a detection label.
- detection labels include, but are not limited to, radionuclides, luminescent substances (eg, fluorescein), colored substances or enzymes.
- the present invention provides a bispecific or multispecific antibody in which an antigen binding domain comprises an anti-CLDN18.2 antibody of the invention or its antigen-binding fragment.
- the present invention provides an antibody drug conjugate comprising an antibody or antigen-binding fragment thereof as previously described.
- the structure of the antibody drug conjugate is well known in the art, which is formed by the interconnection of antibody-linker-drug (toxin).
- the present invention provides a chimeric antigen receptor whose extracellular recognition unit comprises an antibody or antigen-binding fragment thereof as previously described.
- the present invention provides nucleic acids encoding any of the foregoing antibodies or antigen-binding fragments thereof. According to another aspect of the present invention, the present invention provides a recombinant vector comprising the nucleic acid.
- the present invention provides a host cell comprising the expression vector of the present invention or a nucleic acid encoding the antibody or antigen-binding fragment thereof integrated into the genome.
- the host cell can be a prokaryotic cell, such as E. coli; it can also be a eukaryotic cell, such as yeast or mammalian cells, mammalian cells such as CHO cells, HEK293 cells, HEK293E cells or Expi293 cells.
- the present invention provides a method for preparing the antibody or antigen-binding fragment thereof, comprising: culturing the host cell of the present invention under suitable conditions, and purifying the expression product from the cell.
- the present invention provides use of the antibody or antigen-binding fragment thereof for the preparation of a drug specifically targeting tumor cells expressing CLDN18.2, such as monoclonal antibody drug, antibody drug conjugate , bispecific antibodies or multispecific antibodies; or for the preparation of chimeric antigen receptor-modified immune cells; or for the preparation of reagents for the diagnosis of CLDN18.2-expressing tumors; in some embodiments, the CLDN18.2-expressing The tumors include: gastric cancer, pancreatic cancer, esophageal cancer, lung cancer, ovarian cancer, colon cancer, rectal cancer, liver cancer, head and neck cancer and gallbladder cancer and their metastases, such as Keukenberg's tumor.
- the present invention provides a method for detecting CLDN18.2 expression in a sample, comprising: contacting the sample with the aforementioned anti-CLDN18.2 antibody or an antigen-binding fragment thereof; detecting the anti-CLDN18.2 antibody or its Formation of a complex of the antigen-binding fragment and CLDN18.2; optionally, the anti-CLDN18.2 antibody or antigen-binding fragment thereof is detectably labeled.
- the present invention provides a pharmaceutical composition comprising an effective amount of an antibody or antigen-binding fragment thereof of the present invention, or an effective amount of a nucleic acid encoding the antibody or antigen-binding fragment thereof, or comprising An effective amount of a recombinant vector containing an encoding nucleic acid, or an effective amount of a host cell containing an encoding nucleic acid, or an effective amount of an antibody drug conjugate of the present invention, or an effective amount of the chimeric antigen receptor of the present invention, or comprise an effective amount of a bispecific or multispecific antibody of the invention.
- the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
- the pharmaceutical composition further comprises one or more additional other therapeutic agents.
- additional therapeutic agents include: cytotoxic agents, cytostatic agents, anti-angiogenic agents, tumor reducing agents, chemotherapeutic agents, radiotherapeutic agents, targeted anti-cancer agents, biological response modifiers, cancer vaccines, cells Factors, hormones, anti-metastatic agents and immunotherapeutics.
- the present invention provides a kit or kit comprising a container, and a pharmaceutical composition of the present invention in the container.
- the present invention provides a method of inducing death of a cell expressing CLDN18.2, comprising contacting the cell with a pharmaceutical composition of the present invention.
- the cells are contacted with the pharmaceutical composition in vitro.
- the cells are contacted with the pharmaceutical composition in vivo.
- the cells are cancer cells.
- the cells are solid tumor cells.
- the cells are selected from the group consisting of gastric cancer cells, esophageal cancer cells, pancreatic cancer cells, Wilms tumor cells, lung cancer cells, ovarian cancer cells, colon cancer cells, rectal cancer cells, liver cancer cells, head and neck cancer cells , chronic myelogenous leukemia cells and gallbladder cancer cells.
- the present invention provides a method of treating a disease associated with the expression of CLDN18.2 in a subject, the method comprising administering to a subject in need thereof a pharmaceutical composition of the present invention.
- the disease is a tumor.
- the tumor is preferably gastric cancer, esophageal cancer, pancreatic cancer, Wilms tumor, lung cancer, ovarian cancer, colon cancer, rectal cancer, liver cancer, head and neck cancer, chronic myeloid leukemia, or gallbladder cancer.
- the method further comprises administering to the subject an additional therapeutic agent.
- Antibodies of the invention can be administered in combination with another additional therapeutic agent, including but not limited to chemotherapeutic agents, cytotoxic agents, radiotherapeutic agents, cancer vaccines, tumor reducing agents, targeted anticancer agents, antiangiogenic agents , biological response modifiers, cytokines, hormones, anti-metastatic agents and immunotherapeutics.
- additional therapeutic agent including but not limited to chemotherapeutic agents, cytotoxic agents, radiotherapeutic agents, cancer vaccines, tumor reducing agents, targeted anticancer agents, antiangiogenic agents , biological response modifiers, cytokines, hormones, anti-metastatic agents and immunotherapeutics.
- chemotherapeutic agents that can be used in combination with the antibodies or antigen-binding fragments thereof of the invention include, but are not limited to, mitotic inhibitors, including vincristine, vinblastine, vindesine, and novibine; Topoisomerase I inhibitors, such as camptothecin compounds, including irinotecan, topotecan, and other compounds derived from camptothecin and its analogs; podophyllotoxin derivatives, such as etoposide, tinib Posides and Midoxizoz; alkylating agents such as cisplatin, carboplatin, cyclophosphamide, nitrogen mustard, trimethylene phosphoramidite, carmustine, busulfan, chlorambucil , briquizine, uracil mustard, chloroprofen, and dacarbazine; antimetabolites, including cytarabine, 5-fluorouracil, methotrexate, mercaptopurine,
- the targeted anticancer agents include, but are not limited to, macromolecular targeted drugs, small molecule targeted drugs, and the like.
- macromolecular targeted drugs include but are not limited to drugs targeting epidermal growth factor, including cetuximab, panitumumab and nimotuzumab, etc.; HER-2 or HER-3 Signaling pathway inhibitors, including trastuzumab, pertuzumab, and T-DM1, etc.; anti-vascular endothelial growth factor drugs, including VEGF-TRAP, bevacizumab, and ramucirumab, etc.; and, Drugs targeting other targets, including but not limited to targets such as PI3K, PARP, PI3K ⁇ , PKB/AKT, and STAT3.
- drugs targeting epidermal growth factor including cetuximab, panitumumab and nimotuzumab, etc.
- HER-2 or HER-3 Signaling pathway inhibitors including trastuzumab, pertuzumab, and T-DM1, etc.
- anti-vascular endothelial growth factor drugs including VEGF-TRAP, bevaci
- small molecule targeted drugs include, but are not limited to, drugs targeting epidermal growth factor, including erlotinib or gefitinib, etc.; HER-2 or HER-3 signaling pathway inhibitors, including lapa Titinib or afatinib, etc.; tyrosine kinase inhibitors, including imatinib or sunitinib, etc.; anti-vascular endothelial growth factor drugs, including sorafenib, regoratinib, pazotinib , recombinant human endostatin and apatinib, etc.; drugs targeting c-Met/ROS1, including crizotinib, etc.; and other targeted drugs, including but not limited to vorinostat and marstat etc.; drugs targeting mTOR, including everolimus, etc.; and drugs targeting other targets, including but not limited to targets such as PI3K ⁇ , PKB/AKT, and STAT3.
- drugs targeting epidermal growth factor including er
- the immunotherapy drugs include but are not limited to immunosuppressants and agonists, and targets include PD-1/PD-L1, PD-L2, CTLA-4, LAG-3, IDO, TIM3, TIGIT , CD47, SIRP ⁇ , 4-1BB, CSF-1/CSF1R, GITR, OX40, CD40, CD27, CD28, B7H4, B7H3, TGF ⁇ , BTLA, VISTA, ICOS, CD39, CD73, A2AR, KIR and NKG2A; and Immunotherapy-related cell therapy.
- targets include PD-1/PD-L1, PD-L2, CTLA-4, LAG-3, IDO, TIM3, TIGIT , CD47, SIRP ⁇ , 4-1BB, CSF-1/CSF1R, GITR, OX40, CD40, CD27, CD28, B7H4, B7H3, TGF ⁇ , BTLA, VISTA, ICOS, CD39, CD73, A2AR, KIR and N
- immune checkpoint inhibitors targeting PD-1/PD-L1 include, but are not limited to, macromolecular drugs such as pembrolizumab, nivolumab, atezolizumab, avelumab and Sintilimab, Cemiplimab and Durvalumab, among others; and, small molecule drugs.
- immune checkpoint inhibitors targeting CTLA-4 include, but are not limited to, ipilimumab, etc.; cytokines include, but are not limited to, IL-10, IL-15, IL4, and IL13, etc.; BRAF-targeting Inhibitors include, but are not limited to, Binimetinib and the like.
- the other therapeutic agent is selected from the group consisting of oncolytic viruses, such as parvoviruses, adenoviruses, herpesviruses, poxviruses, polioviruses, reoviruses, alphaviruses, Maraba virus, retroviruses, and Coxsackie virus, etc.; or, another therapeutic agent is selected from cancer vaccines or protease inhibitors, such as bortezomib and the like.
- oncolytic viruses such as parvoviruses, adenoviruses, herpesviruses, poxviruses, polioviruses, reoviruses, alphaviruses, Maraba virus, retroviruses, and Coxsackie virus, etc.
- another therapeutic agent is selected from cancer vaccines or protease inhibitors, such as bortezomib and the like.
- Figures 1-3 show the ADCC results of the ADCC-enhanced humanized antibody of the present invention and the reference antibody on patient-derived GAXC031 tumor cells.
- Figure 4 shows the CDC results of the ADCC-enhanced humanized antibody of the present invention and the reference antibody on patient-derived GAXC031 tumor cells.
- Figure 5 shows the tumor inhibition results of the ADCC-enhanced humanized antibody of the present invention alone and in combination with EOF in the N87-Claudin18.2 human gastric cancer model.
- Figure 6 shows the tumor inhibition results of the ADCC-enhanced humanized antibody of the present invention in the MC38-Claudin18.2 mouse colon cancer model.
- the term “about” is meant to include ⁇ 20% of the specified value, or in some cases ⁇ 10%, or in some cases ⁇ 5%, or within ⁇ 1% in some cases, or ⁇ 0.1% in some cases.
- Claudin18.2 or "CLDN18.2” or “CLDN18A2” as used herein have the following meanings.
- Claudin 18 also known as claudin 18, abbreviated as CLDN18
- CLDN18 membrane-intrinsic proteins
- Splice variants CLDN18.1 and CLDN18.2 differ in the N-terminal portion comprising the first transmembrane (TM) region and loop 1, while the C-terminal primary protein sequence is identical.
- anti-Claudin18.2 antibody refers to antibodies capable of producing sufficient Avidity binds to the CLDN18.2 protein or fragment thereof, and does not bind significantly to CLDN18.1, such that the antibody can be used as a diagnostic and/or therapeutic agent targeting CLDN18.2.
- antibody typically refers to a composition comprising two heavy (H) polypeptide chains (HC) and two light (L) polypeptide chains (LC) held together by covalent disulfide bonds and non-covalent interactions ) of the Y-tetrameric protein.
- Natural IgG antibodies have such a structure. Each light chain consists of a variable domain (VL) and a constant domain (CL). Each heavy chain contains a variable domain (VH) and constant region (CH).
- IgA immunoglobulin A
- IgD immunoglobulin D
- IgE immunoglobulin G
- IgG immunoglobulin M
- the corresponding heavy chain constant domains are called ⁇ , ⁇ , ⁇ , ⁇ and ⁇ , respectively
- IgG and IgA can be further divided into different
- the subclasses, such as IgG can be divided into IgG1, IgG2, IgG3, IgG4, and IgA can be divided into IgA1 and IgA2.
- the light chains of antibodies from any vertebrate species can be assigned to one of two distinct types, called kappa and lambda, based on the amino acid sequence of their constant domains.
- the constant region comprises three domains called CH1, CH2 and CH3 (IgM and IgE have a fourth domain CH4).
- the CH1 and CH2 domains are separated by a flexible hinge region, which is a variable length proline and cysteine rich segment.
- Each class of antibodies further comprises interchain and intrachain disulfide bonds formed by paired cysteine residues.
- variable region exhibit significant changes in amino acid composition from one antibody to another, and are primarily responsible for antigen recognition and binding.
- the variable regions of each light/heavy chain pair form the antibody binding site such that an intact IgG antibody has two binding sites (ie it is bivalent).
- the variable region (VH) of the heavy chain and the variable region (VL) domain of the light chain each contain three regions of extreme variability known as hypervariable regions (HVRs), or more commonly, known as Complementarity determining regions (CDRs), VH and VL each have four framework regions FR (or called framework regions), which are represented by FR1, FR2, FR3, and FR4, respectively.
- CDR and FR sequences typically occur in the following sequences of the variable heavy domain (VH) (or variable light domain (VL)) of the heavy chain: FR1-HCDR1(LCDR1)-FR2-HCDR2(LCDR2)-FR3 -HCDR3(LCDR3)-FR4.
- VH variable heavy domain
- VL variable light domain
- Fc is used herein to define the C-terminal region of an immunoglobulin heavy chain, ie, two dimer-forming polypeptide chains comprising a C-terminal constant region of an immunoglobulin heavy chain capable of stabilizing self-association.
- the term includes native sequence Fc regions and variant Fc regions.
- a human IgG heavy chain Fc region is generally defined as extending from Cys226 or Pro230 to the carboxy-terminus of the heavy chain, e.g., an IgG Fc domain comprises IgG CH2 and IgG CH3 constant domains.
- the numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also known as the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.
- antibodies in a broad sense may include, for example, polyclonal antibodies, monoclonal antibodies, chimeric antibodies, humanized antibodies, and primatized antibodies, CDR-grafted antibodies (CDR- grafted antibodies), human antibodies (including recombinantly produced human antibodies), recombinantly produced antibodies, intrabodies, multispecific antibodies, bispecific antibodies, monovalent antibodies, multivalent antibodies, anti-idiotypic antibodies, synthetic antibodies (including mutant proteins and their variants) and so on.
- full-length antibody “intact antibody,” and “intact antibody” are used interchangeably herein to refer to an antibody that is substantially structurally similar to that of a native antibody or has an Fc region-containing region.
- monoclonal antibody refers to a substantially homogeneous antibody produced by a single cell clone directed against only a particular epitope.
- Monoclonal antibodies can be prepared using a variety of techniques known in the art, including hybridoma techniques, recombinant techniques, phage display techniques, transgenic animals, synthetic techniques, or a combination of the foregoing, and the like.
- chimeric antibody is a construct in which a portion of the heavy and/or light chain is identical or homologous to the corresponding sequence in an antibody from a particular species or belonging to a particular antibody class or subclass, and this or these The remainder of the chain is identical or homologous to corresponding sequences in antibodies from another species or belonging to another class or subclass of antibodies, and fragments of such antibodies.
- chimeric antibodies comprise all or most of the selected murine heavy and light chain variable regions operably linked to human light and heavy chain constant regions. Constant region sequences or variants or derivatives thereof can be operably associated with the disclosed heavy and light chain variable regions using standard molecular biology techniques to provide anti-CLDN18 that can be used as such or can be incorporated into the invention. 2 full-length antibodies.
- humanized antibody is a hybrid immunoglobulin, immunoglobulin chain or fragment thereof containing minimal sequence derived from a non-human immunoglobulin.
- humanized antibodies are human immunoglobulins (acceptor antibodies) in which residues from the acceptor CDRs are derived from non-human species with the desired specificity, affinity and properties (donor antibodies). ) residues in the CDRs of ), such as mouse, rat, rabbit or primate.
- donor antibodies residues in the CDRs of , such as mouse, rat, rabbit or primate.
- framework region residues of the human immunoglobulin are replaced by corresponding non-human residues.
- backmutations can be introduced into a humanized antibody in which residues in one or more FRs of the variable region of the recipient human antibody are replaced by corresponding residues from a non-human species donor antibody replace. Such backmutations can help maintain the proper three-dimensional configuration of one or more grafted CDRs and thus improve affinity and antibody stability.
- Antibodies from a variety of donor species can be used, including but not limited to mice, rats, rabbits, or non-human primates.
- the humanized antibody may contain novel residues not found in the recipient antibody or in the donor antibody in order to further improve antibody performance.
- sequence identity or “sequence similarity” or “sequence homology” mean that the sequences are aligned (and where necessary introduced gaps) for maximum percent sequence identity without any The percentage of amino acid residues in a candidate sequence that are identical to amino acid residues in a reference polypeptide sequence after conservative substitutions are considered part of sequence identity.
- Sequence alignments to determine percent amino acid sequence identity can be performed using various methods in the art, eg, using publicly available computer software such as BLAST, BLAST-2, ALIGN or MEGALIGN (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to obtain maximal alignment over the full length of the sequences being compared. Preferably at least 70%, 75%, 80%, 85% or 90% sequence identity, even more preferably at least 93%, 95%, 98% or 99% sequence identity.
- antibody fragment encompasses at least a portion of an intact antibody.
- a “fragment” of an antibody molecule includes an "antigen-binding fragment” of an antibody, and the term “antigen-binding fragment” refers to an immunoglobulin or antibody that specifically binds or reacts with a selected antigen or epitope thereof Polypeptide fragments, or fusion protein products further derived from such fragments, such as single-chain antibodies, extracellular binding domains in chimeric antigen receptors, etc.
- Exemplary antibody fragments or antigen-binding fragments thereof include, but are not limited to, variable light chain fragments (VL), variable heavy chain fragments (VH), Fab fragments, F(ab') 2 fragments, Fd fragments, Fv fragments, Single-domain antibodies, linear antibodies, single-chain antibodies (scFv), and bispecific or multispecific antibodies formed from antibody fragments, etc.
- VL variable light chain fragments
- VH variable heavy chain fragments
- Fab fragments F(ab') 2 fragments
- Fd fragments Fv fragments
- Single-domain antibodies linear antibodies
- single-chain antibodies scFv
- bispecific or multispecific antibodies formed from antibody fragments etc.
- an "antigen binding domain” or “binding domain” refers to a domain that specifically binds/interacts/recognizes a given target epitope on a target molecule (antigen).
- An "antigen-binding domain” can be a single “antigen-binding fragment” or a combination of "antigen-binding fragments”. Compared with an "antigen-binding fragment", an “antigen-binding domain” is a wider range of concept.
- Fab fragment includes the variable region of the heavy chain and the variable region of the light chain, and also includes the constant region of the light chain and the first constant region CH1 of the heavy chain, which are monovalent antibody fragments.
- F(ab') 2 fragment comprises two Fab fragments and a hinge region, which is a bivalent antibody fragment.
- Fd fragment generally contains a heavy chain variable region and a constant region CH1; the term “Fv fragment” contains an antibody heavy chain variable region and a light chain variable region, but no constant region, and has the smallest total antigen binding site. Antibody Fragments.
- single domain antibody also known as nanobody, exists in the peripheral blood of alpaca with a natural light chain-deficient antibody that contains only one heavy chain variable region (VHH) and two conventional CH2 and CH3 regions. .
- VHH heavy chain variable region
- CH2 and CH3 regions two conventional CH2 and CH3 regions.
- the independently cloned and expressed VHH structure has the same structural stability and antigen binding activity as the original heavy chain antibody, and is the smallest known unit that can bind to the target antigen, so it is also called Nanobody (Nb) .
- scFv refers to a fusion protein comprising at least one antibody fragment comprising a variable region of a light chain and at least one antibody fragment comprising a variable region of a heavy chain, wherein the light and heavy chain variable regions are contiguous (for example, via a synthetic linker such as a short flexible polypeptide linker), and can be expressed as a single-chain polypeptide, and wherein the scFv retains the specificity of the intact antibody from which it is derived.
- a synthetic linker such as a short flexible polypeptide linker
- the scFv may have the VL and VH variable regions described in any order (eg, relative to the N-terminal and C-terminal ends of the polypeptide), and the scFv may include a VL-linker-VH or may include a VH-linker-VL.
- Naturally occurring antibodies are usually monospecific, that is, they bind to a single antigen.
- the present invention provides molecules that bind simultaneously to cytotoxic cells (eg, CD3 on T cells) and target cells (eg, CLDN18.2 on cancer cells).
- the molecules bind to at least two different types of antigens, and are at least bispecific or multispecific.
- the binding molecules of the present invention may be at least trivalent.
- "valency" means the number of antigen binding sites in a molecule, eg, typical native IgG antibodies are bivalent.
- Antigen binding sites that bind to the same antigen may recognize the same epitope or different epitopes.
- Trivalent bispecific antibodies and tetravalent bispecific antibodies are known in the art.
- multispecific antibody refers to the functional linkage (eg, chemical conjugation, genetic fusion, non-covalent binding, or other methods) of an antibody or antibody fragment to one or more other binding molecules (including antibodies or antibody fragments or other molecules with binding ability), thereby forming new antibody constructs that bind to more than two different sites and/or targets.
- bispecific antibodies or “bispecific antigen binding molecules” or “diabodies”
- bispecific or multispecific antibodies comprise at least two distinct antigen (or epitope) binding domains.
- an antigen refers to a substance that is recognized and specifically bound by an antibody or antibody-binding fragment.
- an antigen can include any immunogenic fragment or determinant of a selected target, including mono-epitopes, poly-epitopes, mono-structures domain, multi-domain, or complete extracellular domain (ECD) or protein.
- ECD extracellular domain
- Peptides, proteins, glycoproteins, polysaccharides, and lipids, parts thereof, and combinations thereof can constitute antigens.
- Non-limiting exemplary antigens include tumor antigens or pathogen antigens, and the like.
- Antigen can also refer to a molecule that elicits an immune response.
- the antigen can be an isolated full-length protein, a cell surface protein (eg, immunized with a cell expressing at least a portion of the antigen on its surface), or a soluble protein (eg, immunized with only the ECD portion of the protein), or a protein Constructs (eg, Fc antigens).
- the antigen can be produced in genetically modified cells. Any of the foregoing antigens may be used alone or in combination with one or more immunogenicity enhancing adjuvants known in the art.
- the DNA encoding the antigen can be genomic or non-genomic (eg, cDNA) and can encode at least a portion of the ECD sufficient to elicit an immunogenic response.
- Cells in which the antigen is expressed can be transformed using any vector including, but not limited to, adenoviral vectors, lentiviral vectors, plasmids, and non-viral vectors such as cationic lipids.
- epitope refers to the site on an antigen to which an immunoglobulin or antibody specifically binds.
- Epitopes can be formed by adjacent amino acids, or non-adjacent amino acids juxtaposed by tertiary folding of the protein. Epitopes formed by adjacent amino acids are typically retained upon exposure to denaturing solvents, whereas epitopes formed by tertiary folding are typically lost upon treatment with denaturing solvents. Epitopes typically exist in unique spatial conformations and include at least 3-15 amino acids.
- Methods for determining the epitope to which a given antibody binds are well known in the art and include immunoblotting and immunoprecipitation assays, among others. Methods for determining the spatial conformation of epitopes include techniques in the art and those described herein, such as X-ray crystallography and two-dimensional nuclear magnetic resonance, among others.
- polypeptide polypeptide
- peptide protein
- polymer may be linear, cyclic or branched, it may contain modified amino acids, especially conservatively modified amino acids, and it may be interrupted by non-amino acids.
- amino acid polymers such as those that have been processed by sulfation, glycosylation, lipidation, acetylation, phosphorylation, iodination, methylation, oxidation, proteolytic processing, prenylation, elimination Amino acid polymers modified by spination, selenylation, transfer-RNA mediated amino addition such as arginylation, ubiquitination, or any other manipulation such as conjugation to labeling components.
- amino acid refers to natural and/or unnatural or synthetic amino acids, including glycine and D or L optical isomers, as well as amino acid analogs and peptidomimetics.
- a polypeptide or amino acid sequence "derived from" a specified protein refers to the source of the polypeptide.
- the term also includes polypeptides expressed from the specified nucleic acid sequence.
- amino acid modification includes amino acid substitutions, insertions and/or deletions in a polypeptide sequence.
- amino acid substitution or “substitution” or “substitution” herein means replacing an amino acid at a particular position in the parent polypeptide sequence with another amino acid.
- substitution S32A refers to the replacement of serine at position 32 with alanine.
- sequence identity or homology of the humanized antibody variable regions to the human receptor variable regions can be determined as discussed herein, and when so measured will preferably share at least 60% or 65% of the sequence identity, more preferably at least 70%, 75%, 80%, 85% or 90% sequence identity, even more preferably at least 93%, 95%, 98% or 99% sequence identity.
- residue positions that are not identical differ by conservative amino acid substitutions.
- a "conservative substitution” is an amino acid substitution in which one amino acid residue is replaced by another amino acid residue on a side chain (R group) of similar chemical properties (eg, charge or hydrophobicity). In general, conservative amino acid substitutions do not substantially alter the functional properties of the protein. Families of amino acid residues with similar side chains have been defined in the art.
- amino acids with basic side chains eg, lysine, arginine, histidine
- acidic side chains eg, aspartic acid, glutamic acid
- uncharged polar side chains eg, glycine, asparagine, serine, threonine, tyrosine, cysteine, tryptophan
- non-polar side chains eg, alanine, valine, leucine, isoleucine
- amino acid proline
- beta branched side chains eg, threonine, valine, isoleucine
- aromatic side chains eg, tyrosine, phenylalanine, tryptophan, histidine
- amino acid residues in the CDR regions or in the framework regions of the antibodies of the invention can be replaced with amino acid residues of other similar side chains.
- percent sequence identity or degree of similarity can be adjusted upwards to correct for the conservative nature of the substitution.
- PTM post-translational modification
- These PTMs may cause changes in the physicochemical properties of antibodies, alter the interaction with antibody Fc receptors, and affect the binding activity to target antigens; the occurrence of some PTMs may even reduce antibody stability and cause immunogenicity, etc.
- JARASCH et al., JOURNAL OF PHARMACEUTICAL SCIENCES, 2015 The negative effects of PTM sites can be eliminated by amino acid modifications such as conservative substitutions. Amino acid substitutions in the antibody CDRs for the purpose of engineering the PTM are also clearly within the scope of the present invention.
- ADCC antibody-dependent cell-mediated cytotoxicity
- complement-dependent cytotoxicity refers to the cytotoxic effect of complement, that is, the classical pathway of complement is activated by the binding of specific antibodies to the corresponding antigens on the surface of the cell membrane to form complexes, and the formed membrane attack complexes are harmful to target cells. exert a cracking effect.
- Antibodies of the invention may also include constant region (eg, Fc) substitutions or modifications, including but not limited to amino acid residue substitutions, mutations and/or modifications, which result in compounds having the following preferred characteristics, including but not limited to Limited to: altered pharmacokinetics, increased serum half-life, increased binding affinity, decreased immunogenicity, increased production, altered Fc ligand binding to Fc receptors (FcR), enhanced or reduced ADCC or CDC, altered glycosylation and/or disulfide bonds, and modified binding specificities.
- the antibody variant comprises an Fc region with one or more amino acid substitutions that enhance ADCC (eg, substitutions at positions 239 and 298 of the Fc region).
- the replacements are S239D and S298A.
- the term "specific" means that the antibody is selective for antigen binding and can be distinguished from unwanted or nonspecific interactions.
- affinity refers to the strength of the sum of all non-covalent interactions between a single binding site of a molecule (eg, an antibody) and its binding partner (eg, an antigen).
- KD refers to the dissociation constant for a particular antibody-antigen interaction. Binding affinity can be determined using various techniques known in the art, such as surface plasmon resonance, biolayer interferometry, dual polarization interferometry, static light scattering, dynamic light scattering, isothermal titration calorimetry, ELISA, analytical ultrafast Centrifugation and flow cytometry, etc.
- composition refers to a formulation that is in a form that permits the biological activity of the active ingredients contained therein to be effective and that does not contain additional ingredients that would be unacceptably toxic to the subject to whom the formulation is administered .
- pharmaceutically acceptable carrier refers to a diluent, adjuvant (eg, Freund's adjuvant (complete and incomplete)), excipient, or vehicle with which the therapeutic agent is administered.
- an effective amount refers to the dose of a pharmaceutical formulation comprising an active ingredient of the present invention which, after administration to the patient in single or multiple doses, produces the desired effect in the treated patient.
- An effective amount can be readily determined by the attending physician, who is skilled in the art, by taking into account a variety of factors such as ethnic differences; weight, age, and health; the specific disease involved; the severity of the disease; the individual patient's response; The particular antibody administered; the mode of administration; the bioavailability characteristics of the administered formulation; the chosen dosing regimen; and the use of any concomitant therapy.
- host cell refers to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells.
- Host cells include “transformants” and “transformed cells,” which include the primary transformed cell and progeny derived therefrom, regardless of the number of passages.
- the progeny may not be identical in nucleic acid content to the parental cell, but may contain mutations. Included herein are mutant progeny that have the same function or biological activity as screened or selected in the originally transformed cell.
- transfection refers to the introduction of exogenous nucleic acid into a eukaryotic cell. Transfection can be achieved by various means known in the art, including calcium phosphate-DNA co-precipitation, DEAE-dextran-mediated transfection, polybrene-mediated transfection, electroporation, microinjection, Liposome fusion, lipofection, protoplast fusion, retroviral infection and biolistics.
- stable transfection or “stable transfection” refers to the introduction and integration of exogenous nucleic acid, DNA or RNA into the genome of a transfected cell.
- stable transfectant refers to a cell that stably integrates foreign DNA into its genomic DNA.
- isolated polynucleotide or “isolated nucleic acid” refers to a nucleic acid molecule, DNA or RNA, that has been removed from its natural environment.
- isolated polynucleotide encoding a polypeptide contained in a vector is considered isolated for the purposes of the present invention.
- isolated polynucleotides include recombinant polynucleotides maintained in heterologous host cells or (partially or substantially) purified polynucleotides in solution.
- An isolated polynucleotide includes a polynucleotide molecule contained in a cell that normally contains the polynucleotide molecule, but the polynucleotide molecule is present extrachromosomally or at a chromosomal location different from its natural chromosomal location.
- Isolated RNA molecules include in vivo or in vitro RNA transcripts of the present invention, as well as positive and negative stranded and double stranded forms.
- the isolated polynucleotides or nucleic acids of the present invention also include synthetically produced such molecules.
- a polynucleotide or nucleic acid may or may not include regulatory elements, such as promoters, ribosome binding sites, or transcription terminators.
- nucleic acid molecule encoding refers to the sequence of deoxyribonucleotides along a deoxyribonucleic acid chain. The sequence of these deoxyribonucleotides determines the sequence of amino acids along the polypeptide (protein) chain. Thus, a nucleic acid sequence encodes an amino acid sequence.
- the antibody or its antigen-binding fragment of the invention is genetically engineered to add one or more human FR regions to the non-human CDR regions.
- Human FR germline sequences are available from the ImMunoGeneTics (IMGT) website at http://imgt.cines.fr, or from J. Immunoglobulins, (2001) ISBN: 012441351.
- the engineered antibodies or antigen-binding fragments thereof of the present invention can be prepared and purified using conventional methods.
- cDNA sequences encoding heavy and light chains can be cloned and recombined into expression vectors.
- the recombinant immunoglobulin expression vector can stably transfect CHO cells.
- mammalian-like expression systems lead to glycosylation of antibodies, especially 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 for antibody production.
- the antibody-secreted culture medium can be purified and collected by conventional techniques.
- Antibodies can be filtered and concentrated by conventional methods. Soluble mixtures and polymers can also be removed by conventional methods, such as molecular sieves, ion exchange.
- Subjects of the present invention refers to any animal, such as a mammal or a marsupial.
- Subjects of the present invention include, but are not limited to, humans, non-human primates (eg, cynomolgus or rhesus monkeys or other types of rhesus monkeys), mice, pigs, horses, donkeys, cattle, sheep, rats, and any species of poultry.
- ADC antibody drug conjugate
- ADC antibody drug conjugate
- ADC refers to an antibody to which a therapeutically active substance or active pharmaceutical ingredient (API) has been covalently coupled so that the therapeutically active substance or active pharmaceutical ingredient (API) can be targeted to the binding target of the antibody to demonstrate its pharmacological function.
- the therapeutically active substance or active pharmaceutical ingredient may be a cytotoxin capable of killing the cells targeted by the ADC, preferably malignant or cancer cells.
- Covalent attachment of therapeutically active substances, active pharmaceutical ingredients or cytotoxins can be performed in a non-site-specific manner using standard chemical linkers that couple the payload to lysine or cysteine residues, or preferably, conjugation This is done in a site-specific manner, which allows complete control of the conjugation site and the drug-to-antibody ratio of the resulting ADC.
- CAR chimeric antigen receptor
- CAR-engineered T cells are genetically engineered T cells loaded with chimeric receptors whose extracellular recognition unit contains an antibody-derived recognition domain and whose intracellular domain is derived from from the lymphocyte stimulation section.
- the structure of the prototype CAR is modular and designed to accommodate various functional domains, thereby enabling the selection of specificity and control of T cell activation.
- Preferred antibody-derived recognition units are single-chain variable fragments (scFvs) that combine the specificity and binding residues of the heavy and light chain variable regions of a monoclonal antibody.
- the most common lymphocyte activating moiety includes a T-cell costimulatory (eg CD28) domain in tandem with a T-cell triggering (eg CD3 ⁇ ) moiety.
- the CAR constructs are introduced ex vivo into T cells from peripheral lymphocytes of a given patient using retroviral or lentiviral vectors or transposons. After the resulting CAR-engineered T cells are infused back into the patient, they are transported, reach their target sites, and upon interaction with their target cells or tissues, they undergo activation and perform their pre-defined effector functions .
- Therapeutic targets for CAR approaches include cancer and HIV-infected cells, or autoimmune effector cells.
- tumor refers to a disease characterized by the pathological proliferation of cells or tissues, and its subsequent migration or invasion of other tissues or organs. Tumor growth is usually uncontrolled and progressive, and does not induce or inhibit normal cell proliferation. Tumors can affect a variety of cells, tissues or organs, including but not limited to those selected from the group consisting of bladder, bone, brain, breast, cartilage, glial cells, esophagus, fallopian tubes, gallbladder, heart, intestine, kidney, liver, lung, lymph nodes, Nervous tissue, ovary, pancreas, prostate, skeletal muscle, skin, spinal cord, spleen, stomach, testis, thymus, thyroid, trachea, urethra, ureter, urethra, uterus, vaginal organs, or tissue or corresponding cells.
- Tumors include cancers such as sarcomas, carcinomas, or plasmacytomas (malignant tumors of plasma cells).
- the tumors described in the present invention may include, but are not limited to, leukemia (such as acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute myeloid leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, Acute monocytic leukemia, chronic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, polycythemia vera), lymphoma (Hodgkin's disease, non-Hodgkin's disease), primary macroglobulinemia, severe Chain disease, solid tumors such as sarcomas and cancers (eg, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, endothelial sar
- the "tumor” includes but is not limited to: pancreatic cancer, liver cancer, lung cancer, gastric cancer, esophageal cancer, head and neck squamous cell carcinoma, prostate cancer, colon cancer, rectal cancer, breast cancer, lymphoma, Gallbladder cancer, kidney cancer, leukemia, multiple myeloma, ovarian cancer, cervical cancer and glioma.
- the terms “disease” or “condition” or “disorder” and the like refer to any alteration or disorder that impairs or interferes with the normal function of a cell, tissue or organ.
- the “disease” includes, but is not limited to, tumor, pathogen infection, autoimmune disease, T cell dysfunctional disease, or deficiency of immune tolerance (eg, transplant rejection).
- treatment refers to clinical intervention in an attempt to alter an individual or to manipulate a cell-induced disease process, either prophylactically or in a clinical pathological process.
- Therapeutic effects include, but are not limited to, preventing the occurrence or recurrence of the disease, alleviating symptoms, reducing the direct or indirect pathological consequences of any disease, preventing metastasis, slowing the rate of disease progression, improving or relieving the condition, relieving or improving the prognosis, etc.
- kits or “kit” includes an effective amount of one or more unit dosage forms of a pharmaceutical composition of the present invention.
- the kits may contain sterile containers; such containers may be in the form of boxes, ampoules, bottles, vials, tubes, bags, blister packs, or other suitable container forms known in the art. Such containers may be made of plastic, glass, laminated paper, metal foil, or other materials suitable for holding drugs.
- the kit also includes instructions for administering the pharmaceutical composition of the present invention to a subject. Methods of treating diseases using the pharmaceutical compositions of the present invention are generally included in the instructions.
- the mouse monoclonal antibody 299B2 against CLDN18.2 was obtained by hybridoma screening, and the variable region of 299B2 was spliced with the constant region of human IgG1 to form a chimeric antibody.
- Post-translational modification analysis of the variable region of the chimeric antibody was performed to engineer a deamidation site in the light chain CDRs.
- the mouse-derived framework regions are replaced with human-derived sequences to construct a humanized antibody.
- two mutations S239D and S298A were introduced into the Fc segment, and the mutated ADCC-enhanced humanized antibody was named hu299B2-2.
- the amino acid sequence of the antibody is shown in Table 1. shown. hu299B2-2 is expressed in a mammalian host cell line, and the recombinant plasmid containing the target gene is transfected into the host cell. After screening, a high-yield and stable monoclonal cell line for production is obtained, and the target protein is obtained by purification after feeding culture.
- PDX tumor cells
- PBMC peripheral blood mononuclear cells
- GAXC031 cells were collected by centrifugation, BATDA-labeled cells were added, and incubated at 37°C, 5% CO 2 for 20 minutes. Adjust the cell density, inoculate the cells into a 96-well cell plate, 100 ⁇ L per well, prepare a sample solution with a concentration of 4 times, and transfer the solution (complete medium for the control group) to the corresponding well of the 96-well cell plate, 50 ⁇ L per well, 37 °C, 5% CO2 for 10 min.
- the density of human peripheral blood mononuclear cells was adjusted, and effector cells were seeded into a 96-well plate, 50 ⁇ L per well, and placed in a cell culture incubator (37° C./5% CO 2 ) for further incubation for 2 hours.
- blank solvent control group target cell spontaneous release control group (TS), effector cell spontaneous release control group (ES), target cell and effector cell mixed spontaneous release group ((T+E).S) (that is, the antibody concentration is At 0 nM effector cell and target cell release group), target cell maximum release group (TM) and target cell and effector cell mixed maximum release group ((T+E).M).
- this experiment used human peripheral blood mononuclear cells from three donors (donorLP200429, donorLP200217 and donorLP191021) as effector cells to investigate the ADCC activity of the present and reference antibodies.
- Table 2 and Figures 1-3 show the ADCC results of the ADCC-enhanced humanized antibody hu299B2-2 of the present invention and the reference antibody ch-175D10 on patient-derived GAXC031 tumor cells.
- the experimental results showed that the maximum ADCC effect of hu299B2-2 of the present invention on GAXC031 cells was 77.32%, while the reference antibody ch-175D10 failed to achieve maximum lysis under the same reaction conditions.
- the concentrations (EC 50 ) of the antibody hu299B2-2 of the present invention to produce 50% ADCC effect are 0.006164nM, 0.005138nM, and 0.01572nM respectively. It can be seen from Figure 1-3 that among the three donors, the hu299B2-2 of the present invention All were stronger than the reference antibody ch-175D10 in ADCC activity.
- PNHS mixed healthy human serum
- cell viability was detected by CellTiter-Glo Luminescent Cell chemiluminescence cell viability assay kit (Promega).
- the negative control is irrelevant human IgG (HG1K)
- the positive control (reference antibody) is the chimeric antibody ch-175D10 disclosed in the patent CN103509110B.
- Collect GAXC031 tumor cells resuspend and adjust the cell density in medium, inoculate cells into 96-well cell plates, 50 ⁇ L per well, prepare 4-fold concentration of sample solution, transfer solution (control group is CDC diluent, and set serum at the same time) Control wells, with medium + complement as the maximum release well) to the corresponding wells of a 96-well cell plate, 25 ⁇ L per well, incubate for about 30 minutes at 37°C, 5% CO2 , and use the medium to dilute and mix healthy human serum to 4 times work concentration.
- the rate of cell lysis caused by the chimeric antibody in the CDC assay was calculated using the following formula:
- E, S and M are all chemiluminescence values, wherein, E: experimental group; S: cells + medium + complement; M: medium + complement.
- the experimental controls were: serum control wells: serum only (ie, 75 ⁇ L buffer+25 ⁇ L diluted serum).
- Cell control wells Serum was added to the wells of the GAXC031 tumor cell suspension (ie, 50 ⁇ L of cell suspension+25 ⁇ L of buffer+25 ⁇ L of diluted serum).
- Test wells Serum and antibody (ie, 50 ⁇ L of cell suspension+25 ⁇ L of antibody+25 ⁇ L of diluted serum) were added to the wells of the GAXC031 tumor cell suspension.
- Table 3 is the median killing concentration ( EC50 ) and the maximum lysis ratio calculated by GraphPad software.
- Table 3 and FIG. 4 show the CDC results of the ADCC-enhanced humanized antibody hu299B2-2 of the present invention and the reference antibody ch-175D10 on patient-derived GAXC031 tumor cells.
- the experimental results show that the antibody hu299B2-2 of the present invention has a maximum CDC effect of 60.63% on GAXC031 tumor cells, and the concentration (EC 50 ) that produces a 50% CDC effect is 5.161 nM, while the reference antibody ch-175D10 under the same reaction conditions The maximal lysis was not reached, and the EC 50 was 3561 nM.
- the results showed that the CDC activity of the ADCC-enhanced humanized antibody hu299B2-2 was significantly better than that of the reference antibody ch-175D10.
- mice Female BALB/c nude mice (Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.) were adaptively housed in the SPF animal room for 7 days for subsequent studies. N87-Claudin18.2 cells were inoculated subcutaneously in the right axilla of mice at 1 ⁇ 10 7 cells/0.1 mL.
- 1negative control group 2hu299B2-2 (10mg/kg) group, 3EOF (1mg/kg+3mg/kg+ 15mg/kg) group, 4EOF (0.5mg/kg+1.5mg/kg+7.5mg/kg) group, 5hu299B2-2 (10mg/kg)+EOF (1mg/kg+3mg/kg+15mg/kg) group, 6hu299B2-2(10mg/kg)+EOF(0.5mg/kg+1.5mg/kg+7.5mg/kg) group.
- the three doses involved in EOF represent the doses of epirubicin (E), oxaliplatin (O), and fluorouracil (F) in sequence.
- the administration method of the EOF group was as follows: firstly, oxaliplatin was administered by intraperitoneal injection, and after 4-6 hours interval, epirubicin and fluorouracil were administered by intraperitoneal injection; hu299B2-2 was given by injection, and the negative control group was given the same volume of 5% glucose injection and the preparation excipients of hu299B2-2 (without hu299B2-2), once a week for 6 weeks. Weigh the tumor once a week and measure the tumor diameter. At the end of the experiment, tumors were dissected and weighed.
- TGI% [1-(T i -T 0 )/(V i -V 0 )] ⁇ 100, where Ti and V i are the mean tumor volumes of the administration group and the negative control group on day i , respectively, T 0 and V 0 were the average tumor volume on the day of the administration group and the negative control group, respectively.
- Table 4 Taking the average tumor volume as the ordinate and the days of inoculation as the abscissa, the graph was drawn using GraphPad Prism software, and the results are shown in Figure 5.
- TGI Tumor inhibition evaluation
- Tumor weight inhibition rate % (1-T weight /C weight ) ⁇ 100
- C weight represents the average tumor weight of the negative control group
- T weight represents the average tumor weight of each drug treatment
- results of tumor weight inhibition rate are shown in Table 5.
- Tables 4, 5 and 5 show the tumor inhibition results of hu299B2-2 alone and in combination with EOF in the N87-Claudin18.2 human gastric cancer model.
- the experimental results showed that hu299B2-2 (10 mg/kg) had a certain inhibitory effect on tumors (TGI was 34.1%, tumor weight inhibition rate was 26.0%).
- the combination of hu299B2-2 (10 mg/kg) and EOF at high or low doses can significantly inhibit tumor growth (TGI were 79.2% and 75.5%, respectively; tumor weight inhibition rates were 53.2% and 52.1%, respectively), which was better than hu299B2-2, EOF alone.
- mice Female C57BL/6J mice (Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.) were adaptively housed in the SPF animal room for 7 days for subsequent studies.
- MC38-Claudin18.2 cells were inoculated subcutaneously in the right axilla of mice at 5 ⁇ 10 5 cells/0.1 mL.
- 32 patients with moderate tumor volume were randomly selected and divided into 4 groups: 1negative control group, 2hu299B2-2 (0.3mg/kg), 3hu299B2-2 (1mg/kg), 4hu299B2 -2 (3 mg/kg).
- Intravenous administration was started, once a week, 4 times a week, and a total of 7 tumor measurements were performed.
- TGI% [1-(T i -T 0 )/(V i -V 0 )] ⁇ 100, where Ti and V i are the mean tumor volumes of the administration group and the negative control group on day i , respectively, T 0 and V 0 are the average tumor volume on the day of the administration group and the negative control group, respectively.
- Table 6 Taking the average tumor volume as the ordinate and the days of inoculation as the abscissa, the graph was drawn using GraphPad Prism software, and the results are shown in Figure 6.
- TGI Tumor inhibition evaluation
- Table 6 and Figure 6 show the tumor inhibition results of hu299B2-2 in the MC38-Claudin18.2 mouse colon cancer model.
- the experimental results showed that hu299B2-2 (0.3mg/kg, 1mg/kg, 3mg/kg) could inhibit the growth of MC38-Claudin18.2 tumors (TGI% were 46.2%, 57.5%, 66.3%, respectively).
- the drug effect was significant (P ⁇ 0.01) at the dose of 0.3-3mg/kg, and had a certain dose-dependence.
Abstract
L'invention concerne un anticorps humanisé enrichi en ADCC anti-CLDN18.2, une composition pharmaceutique comprenant l'anticorps et une application associée correspondante dans le traitement de cancers.
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WO2023241629A1 (fr) * | 2022-06-15 | 2023-12-21 | 中山康方生物医药有限公司 | Anticorps anti-cldn18.2, composition pharmaceutique et utilisation associées |
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