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WO2024255880A1 - Procédé de traitement de tumeurs solides avec un conjugué anticorps-médicament ciblant la claudine 18,2 - Google Patents

Procédé de traitement de tumeurs solides avec un conjugué anticorps-médicament ciblant la claudine 18,2 Download PDF

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WO2024255880A1
WO2024255880A1 PCT/CN2024/099382 CN2024099382W WO2024255880A1 WO 2024255880 A1 WO2024255880 A1 WO 2024255880A1 CN 2024099382 W CN2024099382 W CN 2024099382W WO 2024255880 A1 WO2024255880 A1 WO 2024255880A1
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antibody
amino acid
drug conjugate
targeting
pharmaceutically acceptable
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Hui Zhou
Yang Luo
Ye Chen
Xin Zhao
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Fortvita Biologics Singapore Pte Ltd
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Fortvita Biologics Singapore Pte Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68037—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a camptothecin [CPT] or derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6863—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from stomach or intestines cancer cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

  • the present invention relates to the field of disease treatment. Specifically, the present invention relates to a method for treating a solid tumor using an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof.
  • Gastric cancer is one of the most common malignant tumors in the world, and it is one of the main causes of death due to cancer worldwide. According to GLOBOCAN data, in 2020, the incidence rate and mortality of gastric cancer ranked the fifth and the fourth respectively, and the 5-year survival rate of patients with metastatic gastric cancer was less than 5%.
  • surgical resection remains the only curative treatment for gastric cancer, and the chemotherapy with a combination of fluoropyrimidine and a platinum chemotherapeutic agent is the standard treatment for patients with advanced metastatic gastric cancer.
  • immunotherapy and targeted therapy such as trastuzumab and ramucirumab, the options for treating gastric cancer have increased.
  • nivolumab has been approved in Japan for use in the patients with advanced gastric and gastro-esophageal junction cancer after receiving at least two systemic therapies but the treatments were failed.
  • Pancreatic cancer is one of the most common malignant digestive system tumors. In 2020, there were 496 thousand new cases of pancreatic cancer, and 466 thousand deaths worldwide, ranking the seventh among all malignant tumors. The prognosis of pancreatic cancer is poor because the diagnosis is often in advanced stage. According to the statistics of the SEER (Surveillance, Epidemiology and End Results) database at the US National Cancer Institute, the 5-year survival rate of pancreatic cancer is only 8%, and only 28.6%of patients survive for more than one year after initial diagnosis. In addition, due to the high degree of malignancy, despite surgical intervention, the patients with pancreatic cancer still often relapse, and the 5-year survival rate of pancreatic cancer patients after radical resection is only 18-27%.
  • SEER Sudveillance, Epidemiology and End Results
  • Pancreatic ductal adenocarcinoma is the most common pancreatic cancer, and accounts for more than 90%of pancreatic cancer cases. Although traditional therapies such as chemotherapy, surgery, and radiation therapy have been applied, no significant improvement in survival rates has been found. Surgical resection and chemotherapy (gemcitabine combined with albumin-bound paclitaxel and FOLFIRINOX) have been shown to improve the survival of patients with early pancreatic cancer, but these are not enough to treat patients with advanced pancreatic cancer.
  • Biliary tract cancer is divided into cholangiocarcinoma and gallbladder cancer, and the cholangiocarcinoma can also be divided into extrahepatic cholangiocarcinoma and intrahepatic cholangiocarcinoma based on anatomy.
  • the incidence rate of cholangiocarcinoma is extremely low.
  • the incidence rate and mortality of intrahepatic cholangiocarcinoma are increasing.
  • Cholangiocarcinoma is invasive and is usually diagnosed in the advanced stage.
  • Pembrolizumab has been approved for the treatment of MSI-H/dMMR solid tumors that have progressed after previous treatment, but due to the rarity of MSI-H/dMMR in advanced cholangiocarcinoma, most patients are not suitable for this treatment.
  • a phase IIa trial (NCT01197885, MONO) was used to evaluate the efficacy and safety of zolbetuximab monotherapy in 54 patients with recurrent or refractory advanced gastric or lower esophageal adenocarcinoma, who exhibited moderate or high CLDN18.2 expression in ⁇ 50%of tumor cells. It had been shown that 10 out of 43 evaluable subjects had clinical benefits, in which 4 subjects achieved partial response (PR) (objective response rate (ORR) of 9%) , while 6 subjects achieved stable disease (SD) (14%) .
  • PR partial response
  • ORR objective response rate
  • SD stable disease
  • DoR stable disease
  • the most commonly reported TEAEs in the Zolbetuximab + EOX group were nausea (81.8%) and vomiting (67.5%) .
  • the incidence of vomiting was lower in patients undergoing previous gastrectomy, and there was a dose-dependent relationship between the incidence and severity of vomiting and zolbetuximab.
  • the most commonly reported serious adverse events (SAEs) in the Zolbetuximab + EOX group were malignant tumors (3.9%) , pneumonia (2.6%) , and febrile neutropenia (2.6%) .
  • the most commonly reported SAEs in the EOX group were malignant tumors (8.3%) , gastric bleeding (3.6%) , nausea, renal failure, pulmonary embolism, and febrile neutropenia (2.4%for each) .
  • NCT03504397/NCT03653507 Two phase III clinical trials (NCT03504397/NCT03653507) are currently underway to evaluate the efficacy of zolbetuximab combined with different chemotherapy regimens (mFOLFOX6 or CAPOX) in the first-line treatment of CLDN18.2-positive and HER2-negative locally advanced and unresectable or metastatic G/GEJ AC, and the obtained results provide safety and efficacy data for drug targeting CLDN18.2.
  • Gastric cancer, pancreatic cancer and biliary tract cancer are characterized by high malignancy and poor prognosis.
  • the efficacy and benefits of systemic chemotherapy and immune checkpoint inhibitors are very limited for advanced gastric cancer, pancreatic cancer and biliary tract cancer, and thus it is urgent to explore and develop new therapeutic targets and combination therapies.
  • CLDN18.2 is highly expressed in gastric cancer tissues and pancreatic cancer tissues, with the expression rate of 80%in gastric cancer patients; the positive expression in pancreatic cancer accounts for about 60%, in which the medium and high expression is responsible for 54.6%.
  • zolbetuximab is only effective in first-line treatment of gastric/gastro-esophageal junction adenocarcinoma patients with high expression of CLDN18.2, but there is no effective treatment regimen for gastric/gastro-esophageal junction adenocarcinoma with medium/low expression of CLDN18.2 and/or standard treatment failure, as well as other tumors expressing CLDN18.2.
  • the present invention meets the above-described needs by providing a method for treating solid tumors using an antibody-drug conjugate targeting Claudin18.2.
  • the present invention firstly provides a method for preventing or treating a solid tumor in a subject, which comprises administering to a subject in need thereof an effective amount of the antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a single dosage unit comprising an effective amount of the antibody-drug conjugate targeting Claudin18.2 or the pharmaceutically acceptable salt thereof according to the present invention.
  • the present invention also provides a kit of parts comprising an effective amount of the antibody-drug conjugate targeting Claudin18.2 or the pharmaceutically acceptable salt thereof according to the present invention.
  • the present invention also provides use of the single dosage unit or kit of parts according to the invention in the manufacture of a medicament for the prevention or treatment of a solid tumor.
  • the present invention evaluates the safety and efficacy of the antibody-drug conjugate targeting Claudin18.2 or the pharmaceutically acceptable salt thereof for treating solid tumors expressing CLDN18.2 and the correlation of the expression level of CLDN18.2 in tumor tissues and the efficacy of the antibody-drug conjugate targeting Claudin18.2 or the pharmaceutically acceptable salt thereof of the present invention.
  • the antibody-drug conjugate targeting Claudin18.2 or the pharmaceutically acceptable salt thereof according to the present invention as an ADC with bystander effect has a remarkable tumor inhibition effect in a mouse tumor-bearing model with high expression and low expression of CLDN18.2.
  • subjects with various tumor types and different expression levels of CLDN18.2 were subjected to a dosing regimen exploration test.
  • Claudin proteins are widely present in mammalian epithelial and endothelial cells, primarily on the lateral surface of epithelial cells and on the plasma membrane of basal cells. Different Claudin proteins have their respective specific expression in different tissues, wherein the Claudin18 (CLDN18) gene is located at 3q22.3, has a molecular weight of 24 kDa, comprises 261 amino acid residues, and is a member of the Claudins superfamily.
  • Its protein structure comprises 2 extracellular loops and 4 transmembrane region.
  • Two subtypes of human CLDN18 or Claudin18 protein are Claudin18.1 or CLDN18.1 (UniProt ID: P56856-1) and Claudin18.2 or CLDN18.2 (UniProt ID: P56856-2) , respectively.
  • CLDN18.1 and CLDN18.2 differ by only 8 amino acids.
  • the intergeneric and inerspecies sequence homology of the two subtypes of CLDN18 protein is also very high.
  • CLDN18.2 The sequences of the extracellular loop 1 of CLDN18.2 are completely identical in different species such as human, mouse and rhesus monkey, while the homology of human and mouse CLDN18.2 proteins reaches 84%, indicating that the sequence of CLDN18.2 protein is extremely conserved (O. Tureci. et al., Gene, 481: 83-92, 2011) .
  • CLDN18.2 or any variants and isoforms thereof may be isolated from cells or tissues in which they are naturally expressed, or recombinantly produced using techniques well known in the art and/or those described herein.
  • the CLDN18.2 as described herein is a human CLDN18.2.
  • antibody targeting CLDN18.2 refers to an antibody capable of binding to (human) CLDN18.2 with sufficient affinity such that the antibody can be used as a therapeutic agent targeting (human) CLDN18.2.
  • the (human) CLDN18.2 antibody binds to (human) CLDN18.2 with high affinity in vitro or in vivo.
  • the (human) CLDN18.2 antibody does not bind to CLDN18.1. In an embodiment, the (human) CLDN18.2 antibody binds to cells expressing CLDN18.2 but does not bind to cells expressing CLDN18.1. In some embodiments, the binding is determined, e.g., by radioimmunoassay (RIA) , bio-layer interferometry (BLI) , MSD assay, surface plasmon resonance (SPR) or flow cytometry.
  • RIA radioimmunoassay
  • BBI bio-layer interferometry
  • MSD assay assay
  • SPR surface plasmon resonance
  • the expression of CLDN18.2 in cell may be determined by multiple method, for example anti-CLDN18.2 antibody.
  • the binding strength of cell with “high expression of CLDN18.2” and anti-CLDN18.2 antibody e.g., determined by FACS
  • the binding strength of cell with “moderate expression of CLDN18.2” and anti-CLDN18.2 antibody may be 5-500 times than that of anti-CLDN18.2 antibody and cell without CLDN18.2 expression, such as 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100 times or higher, but no more than 500 times.
  • the full-length antibody heavy chain generally consists of heavy chain variable regions (abbreviated herein as VH) and heavy chain constant regions, wherein the heavy chain constant region comprises at least 3 domains CH1, CH2, and CH3.
  • the full-length antibody light chain consists of light chain variable regions (abbreviated herein as VL) and light chains constant region, wherein the light chain constant region consists of one domain CL.
  • Each heavy chain variable region VH or each light chain variable region consists of three CDRs and 4 FRs, arranged from amino-terminus to carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • antibody fragment includes a portion of a whole antibody.
  • the antibody fragment is antigen-binding fragment.
  • Antigen-binding fragment refers to a molecule different from a whole antibody, which comprises a portion of the whole antibody and binds to an antigen to which the whole antibody binds.
  • the antibody fragment include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F (ab') 2 ; a dAb (domain antibody) ; a linear antibody; a single-chain antibody (e.g., scFv) ; a single-domain antibody, for example VHH; a bivalent or bispecific antibody or a fragment thereof; a Camelidae antibody.
  • antigen refers to the molecule that elicits an immune response. This immune response may involve the production of antibody or the activation of specific immune cells, or both. Technicans will understand that any large molecule, including almost all proteins or peptides, can be used as antigens. In addition, antigens can be derived from recombinant or genomic DNA. As used herein, the term “epitope” refers to a moiety of an antigen (e.g., CLDN18.2) that specifically interacts with an antibody molecule.
  • an antigen e.g., CLDN18.2
  • CDR region is a region in an antibody variable domain that is highly variable in sequence and forms a structurally defined loop ( “hypervariable loop” ) and/or comprises antigen-contacting residues ( “antigen contact site” ) .
  • CDRs are primarily responsible for binding to antigen epitopes.
  • the CDRs of heavy and light chains are generally referred to as CDR1, CDR2, and CDR3, which are numbered sequentially from N-terminus.
  • the CDRs located in heavy chains variable domain of an antibody are referred to as HCDR1, HCDR2, and HCDR3, whereas the CDRs located in light chains variable domain of an antibody are referred to as LCDR1, LCDR2, and LCDR3.
  • each CDR can be determined using any one or a combination of many well-known antibody CDR numbering systems including, e.g., Chothia based on the three-dimensional structure of antibodies and the topology of the CDR loops (Chothia et al. (1989) Nature 342: 877-883; Al-Lazikani et al., Standard conformations for the canonical structures of immunoglobulins, Journal of Molecular Biology, 273: 927-948 (1997) ) , Kabat based on antibody sequence variability (Kabat et al., Sequences of Proteins of Immunological Interest, 4th edition, U.S.
  • CDRs may also be determined based on having the same Kabat numbering positions as the reference CDR sequences (e.g., any of the exemplary CDRs of the present invention) .
  • CDR CDR sequence
  • residue positions of an antibody variable region are positions numbered according to the Kabat numbering system (Kabat et al, Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991) )
  • the heavy chain variable region CDR of the antibody of the present invention is determined according to the following schemes:
  • VH CDR1 is determined according to AbM scheme; and VH CDR2 and 3 are determined according to Kabat scheme.
  • the light chain variable region CDR of the antibody of the present invention is determined according to the Kabat scheme.
  • the heavy chain variable region CDR of the antibody of the present invention is determined according to the following schemes: VH CDR1 is determined according to the AbM schem; and VH CDR2 and 3 are determined according to Kabat scheme; and CDRs of light chain variable area are determined according to Kabat scheme.
  • Antibodies with different specificities have different CDRs (under the same assignment system) .
  • CDRs differ from antibody to antibody, only a limited number of amino acid positions within the CDRs are directly involved in antigen binding. The smallest overlapping region can be determined using at least two of the Kabat, Chothia, AbM, Contact, and North methods, thereby providing a "minimal binding unit" for antigen binding.
  • the minimal binding unit may be a sub-portion of the CDR.
  • residues of the rest CDR sequences can be determined via antibody structure and protein folding. Therefore, any variants of the CDRs given herein are also contemplated in the present invention.
  • the amino acid residues in the minimal binding unit may remain unchanged, while the other CDR residues defined by Kabat or Chothia may be substituted by conservative amino acid residues.
  • Fc region is used herein to define a C-terminus region of an immunoglobulin heavy chain, which comprises at least one portion of a constant region.
  • the term includes Fc regions of native sequences and variant Fc regions.
  • Fc domain of a native immunoglobulin comprises two or three constant domains, namely a CH2 region and a CH3 region, and optionally comprises a CH4 region.
  • an immunoglobulin Fc domain in native antibody comprises the second and the third constant domains (aCH2 region and a CH3 region) derived from two heavy chains of IgG, IgA and IgD, or comprises the second and the third and the fourth constant domains (aCH2 region, a CH3 region and a CH4 region) derived from two heavy chains of IgM and IgE.
  • the numbering of amino acid residues in the Fc region or constant region is based on an EU numbering system, which is also called 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.
  • Fc region does not comprise the heavy chain variable region VH and the light chain variable region VL and the heavy chain constant region CH1 and the light chain constant region CL of an immunoglobulin, but may comprise the hinge region in the N-terminus of the heavy chain chain constant region in some cases.
  • Antibody in IgG form refers to the IgG form that the heavy chain constant region of the antibody belonging to. All antibodies of the same type have the same heavy chain constant region. Heavy chain constant regions of antibodies of different types are different. For example, an antibody in the form of IgG4 refers to its heavy chain constant region is derived from IgG4, or an antibody in the form of IgG1 refers to its heavy chain constant region is derived from IgG1.
  • binding means that binding interactions to antigen are selective and can be distinguished from unwanted or non-specific interactions.
  • the ability of antigen binding sites to bind to specific antigens can be determined by enzyme-linked immunosorbent assay (ELISA) or conventional binding assay known in the art, such as radioimmunoassay (RIA) , thin-layer biomembrane interference assay, MSD assay or surface plasmon resonance (SPR) .
  • ELISA enzyme-linked immunosorbent assay
  • RIA radioimmunoassay
  • MSD assay thin-layer biomembrane interference assay
  • SPR surface plasmon resonance
  • antibody-drug conjugate refers to a compound obtained by linking an antibody and a drug via a linker.
  • site-specific conjugation refers to conjugations by which a drug/an active substance is specifically linked to a specific position of an antibody through a linker.
  • pharmaceutically acceptable salt represents a salt that retains the biological effects and properties of the antibody-drug conjugate (ADC) of the present invention, and is not biologically or otherwise undesired.
  • ADC of the present invention may exist in the form of their pharmaceutically acceptable salts, including acid addition salts or base addition salts.
  • a pharmaceutically acceptable non-toxic acid addition salt represents a salt formed by the ADC conjugate of the present invention and an organic or inorganic acid, including but not limited to hydrochloric acid, sulfuric acid, hydrobromic acid, hydriodic acid, phosphoric acid, nitric acid, perchloric acid, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, p-toluenesulfonic acid, malic acid, etc.
  • an organic or inorganic acid including but not limited to hydrochloric acid, sulfuric acid, hydrobromic acid, hydriodic acid, phosphoric acid, nitric acid, perchloric acid, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzen
  • the pharmaceutically acceptable non-toxic base addition salt represents a salt formed by the ADC conjugate of the present invention and an organic or inorganic base, including but not limited to an alkali metal salt, such as a lithium, a sodium or a potassium salt; an alkaline earth metal salt, such as a calcium or a magnesium salt; a salt of an organic base, such as an ammonium salt formed with a N group-containing organic base.
  • an alkali metal salt such as a lithium, a sodium or a potassium salt
  • an alkaline earth metal salt such as a calcium or a magnesium salt
  • a salt of an organic base such as an ammonium salt formed with a N group-containing organic base.
  • DAR drug-to-antibody ratio
  • DAR refers to the ratio of small molecule drug moiety (D) conjugated to the Ab moiety as described herein to the Ab moiety.
  • DAR may be 1 to 20, such as 2-18, 4-16, 5-12, 6-10, 2-8, 3-8, 2-6, 4-6, 6-10, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.
  • DAR can also be calculated as the average DAR of the molecule population in the product, i.e., the overall ratio of the small molecule drug moiety (D) conjugated to the Ab moiety as described herein to the Ab moiety in the product, as measured by detection methods (e.g., by conventional methods such as mass spectrometry, ELISA assay, electrophoresis and/or HPLC) , such DAR is referred to as the average DAR in the context. It should be understood that the overall ratio described above is molar ratio.
  • the conjugates of the invention have an average DAR value of 1 to 20, such as for example 2-18, 4-16, 5-12, 6-10, 2-8, 3-8, 2-6, 4-6, 6-10, for example 1.0-8.0, 2.0-6.0, for example 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1,
  • an effective amount refers to an amount or dose of the antibody-drug conjugate or a pharmaceutically acceptable salt thereof, antibody or fragment or composition or combination of the present invention, which will produce expected effects in patients or subjects in need of treatment or prevention after being administered to patients or subjects in a single dose or multiple doses.
  • Therapeutically effective amount refers to an amount that can effectively achieve desired therapeutic results at a required dose for a required period of time.
  • the therapeutically effective amount is also such an amount, at which any toxic or harmful effect of the antibody-drug conjugate or a pharmaceutically acceptable salt thereof, antibody or antibody fragment or composition or combination is inferior to the therapeutic beneficial effect.
  • "Therapeutically effective amount” preferably inhibits a measurable parameter (e.g., tumor volume) by at least about 30%, or even more preferably by at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or even 100%compared with untreated subjects.
  • prophylactically effective amount refers to an amount that can effectively achieve desired prevention results at a required dose for a required period of time. Generally, since the prophylactic dose is administered before or at an earlier stage of the disease in a subject, the prophylactically effective amount will be less than the therapeutically effective amount.
  • host cell refers to cells into which exogenous nucleic acids are introduced, including the descendants of such cells.
  • Host cells include “transformants” and “transformed cells” , which include primary transformed cells and descendants derived from them, regardless of the number of passages.
  • the descendants may not be exactly the same as parent cells in term of nucleic acid content, and may contain mutations.
  • the mutant descendants with the same function or biological activity screened or selected from the initially transformed cells are included herein.
  • label refers to a compound or composition that is directly or indirectly conjugated or fused to an agent (such as a polynucleotide probe or antibody) and facilitates the detection of the agent to which it is conjugated or fused.
  • the label itself can be detectable (for example, radioisotope label or fluorescent label) or can catalyze a chemical change of a detectable substrate compound or composition in the case of enzymatic labeling.
  • the term is intended to cover direct labeling of a probe or an antibody by coupling (i.e., physically connecting) a detectable substance to the probe or antibody and indirect labeling of a probe or an antibody by reacting with another directly labeled reagent.
  • “Individual” or “subject” include mammals. Mammal include, but is not limited to, domestic animal (such as cattle, sheep, cat, dog and horse) , primate (such as human and non-human primate, e.g. monkey) , rabbit, and rodent (such as mouse and rat) . In some embodiments, the individual or subject is a human.
  • an “Isolated” antibody or other molecule is such an antibody or molecule that has been separated from components in their natural environment or the environment in which it is expressed.
  • the antibody or ADC molecule is purified to more than 95%or 99%purity, as measured by, such as by electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF) , capillary electrophoresis) or chromatography (e.g., ion exchange or reverse phase HPLC) .
  • anti-tumor effect refers to biological effects that can be demonstrated by various means, including but not limited to, for example, reduction of tumor volume, reduction of tumor cell number, reduction of tumor cell proliferation or reduction of tumor cell survival.
  • tumor and cancer are sometimes used interchangeably herein, covering solid tumors and blood tumors.
  • cancer and “cancerous” refer to or describe physiological diseases in mammals characterized by unregulated cell growth.
  • cancer suitable for treatment by the antibody-drug conjugate of the present invention includes gastric cancer, pancreatic cancer, or gastroesophageal junction cancer, including metastatic forms of those cancers.
  • tumor refers to growth and proliferation of all neoplastic cells, whether malignant or benign, as well as all pre-cancerous and cancerous cells and tissues.
  • cancer cancer, cancer, cancerous and tumor cells and tissues.
  • solid tumor includes an advanced malignant solid tumor, a tumor associated with Claudin18.2, such as a Claudin18.2 positive tumor, for example selected from one or more of the following: gastric cancer, breast cancer, liver cancer, colon cancer, lung cancer, gallbladder cancer, esophageal cancer, gastric/gastro-esophageal junction adenocarcinoma, pancreatic ductal adenocarcinoma and biliary tract cancer (biliary tract cancer is classified as cholangiocarcinoma and gallbladder cancer) .
  • a tumor associated with Claudin18.2 positive tumor for example selected from one or more of the following: gastric cancer, breast cancer, liver cancer, colon cancer, lung cancer, gallbladder cancer, esophageal cancer, gastric/gastro-esophageal junction adenocarcinoma, pancreatic ductal adenocarcinoma and biliary tract cancer (biliary tract cancer is classified as chol
  • the solid tumor may be a first-line (1L) gastric/gastro-esophageal junction adenocarcinoma, a posterior-line gastric/gastro-esophageal junction adenocarcinoma; preferably, the posterior-line gastric/gastro-esophageal junction adenocarcinoma is 2L and thereafter gastric/gastro-esophageal junction adenocarcinoma; more preferably, the posterior-line gastric/gastro-esophageal junction adenocarcinoma is 3L gastric/gastro-esophageal junction adenocarcinoma.
  • the solid tumor is a first-line (1L) gastric cancer, a posterior-line gastric cancer; preferably, the posterior-line gastric cancer is 2L and thereafter gastric cancer; more preferably, the gastric cancer is 3L gastric cancer.
  • the solid tumor is a first-line (1L) pancreatic ductal adenocarcinoma, a posterior-line pancreatic ductal adenocarcinoma; preferably, the posterior-line pancreatic ductal adenocarcinoma is 2L pancreatic ductal adenocarcinoma.
  • gastric/gastro-esophageal junction adenocarcinoma may refer to gastric cancer or gastro-esophageal junction adenocarcinoma.
  • first-line tumor refers to tumors that have not been treated with a systemic anti-tumor treatment.
  • first-line (1L) gastric/gastroesophageal junction adenocarcinoma refers to gastric/gastroesophageal junction adenocarcinoma that has not been treated with a systemic anti-tumor treatment.
  • first-line (1L) gastric cancer and “first-line (1L) " pancreatic ductal adenocarcinoma” refer to gastric cancer and pancreatic ductal adenocarcinoma, respectively, that have not been treated with a systemic anti-tumor treatment.
  • second-line tumor or “2L tumor” refer to tumors that have failed first-line treatment (e.g., are refractory or intolerant to first-line treatment) .
  • second-line pancreatic ductal adenocarcinoma or 2L pancreatic ductal adenocarcinoma refers to pancreatic ductal adenocarcinoma that has failed first-line treatment, for example, is refractory or intolerant to first-line treatment.
  • third-line tumor refers to tumors that have failed second-line treatment (e.g., are refractory or intolerant to second-line treatment) .
  • third-line (3L) gastric/gastroesophageal junction adenocarcinoma refers to a gastric/gastroesophageal junction adenocarcinoma that has failed second-line treatment, for example, is refractory or intolerant to second-line treatment.
  • posterior-line tumor refers to a tumor for which first-line treatment and subsequent treatments (such as second-line treatment or third-line treatment) have failed (such as being refractory or intolerant to the treatment) .
  • First-line treatment refers to the first round of treatment after tumor diagnosis
  • second-line treatment refers to the patient's tumor progression after first-line treatment, and resistance to the first-line treatment regimen, and need to be treated with a different treatment regimen
  • the treatment regimens are approved or recommended by authoritative agencies such as NMPA or FDA.
  • first-line treatment includes but is not limited to fluorouracils (fluorouracil or capecitabine) combined with platinum drugs (oxaliplatin or cisplatin) .
  • Second-line treatment includes but is not limited to paclitaxel combined with ramucirumab.
  • Third-line treatment includes but is not limited to nivolumab, irinotecan, or trifluridine/tipiracil.
  • treatment refers to slowing, interrupting, arresting, alleviating, stopping, reducing, or reversing the progression or severity of an existing symptom, condition, state, or disease.
  • prevention includes the inhibition of the onset or development of a disease or disorder or a symptom of a particular disease or disorder.
  • subjects with family history of cancer are candidates for prophylactic regimens.
  • prevention refers to an administration of a drug prior to the onset of signs or symptoms of a cancer, particularly in subjects at risk of cancer.
  • vector refers to a nucleic acid molecule capable of proliferating another nucleic acid to which it is linked.
  • the term includes vectors that serve as self-replicating nucleic acid structures as well as vectors binding to the genome of a host cell into which they have been introduced. Some vectors are capable of directing the expression of a nucleic acid to which they are operably linked. Such vectors are called "expression vectors" herein.
  • Subject/patient/individual sample refers to a collection of cells or fluids obtained from a patient or subject.
  • the source of the tissue or cell samples may be solid tissues, e.g., from fresh, frozen and/or preserved organ or tissue samples or biopsy samples or puncture samples; blood or any blood component; body fluids such as cerebrospinal fluids, amniotic fluids, peritoneal fluids, or interstitial fluids; cells from a subject at any time during pregnancy or development.
  • Tissue samples may comprise compounds which are naturally not mixed with tissues, such as preservatives, anticoagulants, buffers, fixatives, nutrients, antibiotics, and the like.
  • lyophilized formulation refers to a composition obtained by a lyophilization process of a liquid formulation. Preferably, it is a solid composition having a water content of less than 5%, preferably less than 3%.
  • buffer refers to a pH buffer that can keep the pH of a solution stable.
  • the buffer can keep pH of the liquid formulation of the present invention or the liquid formulation obtained by reconstituting the lyophilized formulation of the present invention at about 5.5 to 7.5, for example about 6.0-6.5, about 5.5-7.2, about 6.0-7.0, or about 6.3-6.8.
  • the buffer is selected from one or more of histidine, citric acid, succinic acid, glutamic acid, phosphoric acid, acetic acid or a salt thereof.
  • the salt includes, but is not limited to a salt formed with acid, such as hydrochloride or sulfuric acid, a salt formed with alkali metal, such as lithium, sodium or potassium salt, for example histidine hydrochloride.
  • the term “stabilizer” refers to a chemical substance that can keep stability of a formulation in terms of chemical, physical and/or biological aspects.
  • the stabilizer is selected from one or more of carbohydrates, polyols.
  • the carbohydrates can select from, but are not limited to: sucrose, trehalose, glucose, lactose, maltose, cyclodextrin, maltodextrin and dextran.
  • the polyols can select from, but are not limited to: mannitol, sorbitol and xylitol.
  • the carbohydrate or polyol may be in the form of hydrate.
  • surfactant refers to a substance that can significantly reduce the surface tension of a solution system.
  • concentration of the surfactant in the liquid formulation is, for example, about 0.05-1, about 0.05-2, about 0.1-0.5, about 0.1-0.4, about 0.1-0.3, about 0.2-0.4 mg/ml.
  • the surfactant is a nonionic surfactant, includes but is not limited to alkyl poly (ethylene oxide) ; polysorbates, such as polysorbate-20, polysorbate-80, polysorbate-60, or polysorbate-40; pluronics; or a combination thereof, and the like.
  • reconstituted formulation means the liquid formulation obtained by dissolving and/or suspending a solid formulation (e.g., a lyophilized formulation) in a physiologically acceptable solution.
  • a solid formulation e.g., a lyophilized formulation
  • reconstituted and redissolved are used interchangeably in term of the formulation.
  • the present invention provides a method for preventing or treating a solid tumor in a subject, which comprises administering to a subject in need thereof an effective amount of an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof.
  • the antibody-drug conjugate targeting Claudin18.2 is selected from
  • Ab is an antibody or antigen-binding fragment thereof targeting Claudin18.2;
  • q represents an average DAR, and is 2 to 11; for example, q is from 2 to 5, e.g., q is a number from 3 to 5, 3.5 to 4.5, 3.2 to 4.2, or 3 to 4, more specifically q is 2, 2.5, 3, 3.5, 4, 4.8, or 5.
  • variable after the square brackets in the ADC structural formula is designated as an average DAR, e.g., q in formula IA, it represents the ratio of drug moiety (i.e., Exatecan) to Ab as determined by a conventional determination method, as described in the Definitions section herein.
  • the average DAR may be a decimal.
  • q is 3-5
  • q is a number from 3 to 5
  • the antibody-drug conjugate targeting Claudin18.2 is selected from
  • Ab is an antibody or antigen-binding fragment thereof targeting Claudin18.2;
  • y is an integer of 1 or 2.
  • variable after the square brackets of the ADC structural formula is not specified as an average DAR, such as y in Formula IB, it does not represent an average DAR, but refers to the number of Linker-payloads (i.e., the structures in the square brackets of Formula IB) linked to each Ab in said ADC molecule, unless otherwise specified or contradictory according to the context.
  • y 2
  • the antibody or antigen-binding fragment thereof targeting Claudin18.2 comprise a HCDR1, a HCDR2, a HCDR3 respectively consisting of amino acid sequences set forth in SEQ ID NO: 1 (GFTFSSYVMS) , SEQ ID NO: 2 (TISHSGGSTYYADSVKG) and SEQ ID NO:3 (DAPYYDILTGYRY) , as well as an LCDR1, an LCDR2 and an LCDR3 respectively consisting of amino acid sequences set forth in SEQ ID NO: 6 (RASQSISSWLA) , SEQ ID NO: 7 (KASSLES) and SEQ ID NO:8 (QQYNSYSYT) .
  • the antibody or antigen-binding fragment thereof targeting Claudin18.2 comprises a heavy chain variable region and/or a light chain variable region, wherein the heavy chain variable region
  • (ii) comprises or consists an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identity to the amino acid set forth in SEQ ID NO: 4; or
  • (iii) comprises or consists of an amino acid sequence having one or more (preferably no more than 10, and more preferably no more than 5, 4, 3, 2, or 1) amino acid alterations (preferably amino acid replacements, and more preferably conservative amino acid replacements) compared with an amino acid sequence set forth in SEQ ID NO: 4, preferably, the amino acid alterations do not occur in the CDRs; and/or
  • (ii) comprises or consists an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identity to the amino acid set forth in SEQ ID NO: 9; or
  • (iii) comprises or consists of an amino acid sequence having one or more (preferably no more than 10, and more preferably no more than 5, 4, 3, 2, or 1) amino acid alterations (preferably amino acid replacements, and more preferably conservative amino acid replacements) compared with an amino acid sequence set forth in SEQ ID NO: 9, preferably, the amino acid alterations do not occur in the CDRs.
  • the antibody or antigen-binding fragment thereof targeting Claudin18.2 comprises a heavy chain and a light chain
  • (ii) comprises or consists an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identity to the amino acid set forth in SEQ ID NO: 11; or
  • amino acid sequence comprising or consists of an amino acid sequence having one or more (preferably no more than 20 or 10, and more preferably no more than 5, 4, 3, 2, or 1) amino acid alterations (preferably amino acid replacements, and more preferably conservative amino acid replacements) compared with an amino acid sequence set forth in SEQ ID NO: 11; and/or
  • (ii) comprises or consists an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identity to the amino acid set forth in SEQ ID NO: 12; or
  • (iii) comprises or consists of an amino acid sequence having one or more (preferably no more than 20 or 10, and more preferably no more than 5, 4, 3, 2, or 1) amino acid alterations (preferably amino acid replacements, and more preferably conservative amino acid replacements) compared with an amino acid sequence set forth in SEQ ID NO: 12.
  • N-acetylglucosamine (GlcNAc) connected to Ab is present at Asn 297-glycosylation sites of both heavy chains of the antibody.
  • the antibody-drug conjugate targeting Claudin18.2, or the pharmaceutically acceptable salt thereof is formulated as a formulation for administration.
  • the formulation of the antibody-drug conjugate targeting Claudin18.2, or the pharmaceutically acceptable salt thereof is a liquid formulation comprising:
  • the pH of the formulation is about 5.5-7.5, preferably about 6.0-6.5, more preferably about 6.5.
  • the buffer is a combination of histidine and histidine hydrochloride or is histidine;
  • the stabilizer is sucrose
  • the surfactant is polysorbate 80.
  • the formulation of the antibody-drug conjugate targeting Claudin18.2, or the pharmaceutically acceptable salt thereof has the following composition or formula: 20 mg/mL of the antibody-drug conjugate targeting Claudin18.2, or the pharmaceutically acceptable salt thereof, 20mM histidine buffer, 8%sucrose (w/v) , 0.02%polysorbate 80 (w/v) , pH 6.5.
  • the formulation of the present invention when it is a liquid formulation, it further comprises a vehicle, including, but not limited to, for example, purified water such as ultrapure water, water for injection, sterile water, double distilled water, and the like.
  • Vehicles that can be used to reconstitute the lyophilized formulation of the present invention include, but are not limited to, for example, purified water such as ultrapure water, water for injection, sterile water, double distilled water, physiological saline, ringer's solution, glucose injection solution, and the like.
  • the formulation of the antibody-drug conjugate targeting Claudin18.2, or the pharmaceutically acceptable salt thereof is a lyophilized formulation.
  • the lyophilized formulation is prepared by lyophilizing the pharmaceutical formulation of the present invention.
  • the lyophilized formulation is prepared by lyophilizing the liquid pharmaceutical formulation described in the above embodiments.
  • the lyophilized formulation is reconstituted prior to administration to a subject.
  • the solid tumor in the method for preventing or treating a solid tumor in a subject according to the present invention, is an advanced malignant solid tumor, and/or
  • the solid tumor may be a tumor associated with Claudin18.2, such as a Claudin18.2 positive tumor, for example selected from one or more of the following: gastric cancer, breast cancer, liver cancer, colon cancer, lung cancer, gallbladder cancer, esophageal cancer, gastric/gastro-esophageal junction adenocarcinoma, pancreatic ductal adenocarcinoma and biliary tract cancer (biliary tract cancer is classified as cholangiocarcinoma and gallbladder cancer) .
  • Claudin18.2 positive tumor for example selected from one or more of the following: gastric cancer, breast cancer, liver cancer, colon cancer, lung cancer, gallbladder cancer, esophageal cancer, gastric/gastro-esophageal junction adenocarcinoma, pancreatic ductal adenocarcinoma and biliary tract cancer (biliary tract cancer is classified as cholangiocarcinoma and gallblad
  • the advanced solid tumor is a tumor that has not been treated with a systemic anti-tumor treatment, a tumor that has failed at least one systemic anti-tumor treatment, a tumor that has failed first-line treatment (such as being refractory or intolerant to first-line treatment) , a tumor that has failed second-line treatment (such as being refractory or intolerant to second-line treatment) .
  • the advanced malignant solid tumor is a locally advanced unresectable or metastatic solid tumor.
  • the advanced solid tumor is gastric cancer or gastro-esophageal junction adenocarcinoma.
  • the solid tumor is a first-line (1L) gastric/gastro-esophageal junction adenocarcinoma, a posterior-line gastric/gastro-esophageal junction adenocarcinoma; preferably, the posterior-line gastric/gastro-esophageal junction adenocarcinoma is 2L and thereafter gastric/gastro-esophageal junction adenocarcinoma; more preferably, the posterior-line gastric/gastro-esophageal junction adenocarcinoma is 3L gastric/gastro-esophageal junction adenocarcinoma.
  • the solid tumor is a first-line (1L) gastric cancer, a posterior-line gastric cancer; preferably, the posterior-line gastric cancer is 2L and thereafter gastric cancer; more preferably, the gastric cancer is 3L gastric cancer.
  • the solid tumor is a first-line (1L) pancreatic ductal adenocarcinoma, a posterior-line pancreatic ductal adenocarcinoma; preferably, the posterior-line pancreatic ductal adenocarcinoma is 2L pancreatic ductal adenocarcinoma.
  • the advanced malignant solid tumor is a locally advanced unresectable or metastatic gastric/gastro-esophageal junction adenocarcinoma.
  • the advanced malignant solid tumor is Her-2 negative.
  • the subject has previously received treatment for said solid tumor.
  • the method for preventing or treating advanced malignant solid tumors in a subject of the invention comprises administering to the subject 0.1mg/kg-100mg/kg of the antibody-drug conjugate targeting Claudin18.2 or the pharmaceutically acceptable salt thereof; further, the method comprises administering to the subject 0.2mg/kg-50mg/kg of the antibody-drug conjugate targeting Claudin18.2 or the pharmaceutically acceptable salt thereof; still further, the method comprises administering to the subject 0.3mg/kg-30mg/kg of the antibody-drug conjugate targeting Claudin18.2 or the pharmaceutically acceptable salt thereof.
  • the method comprises administering to the subject 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 4.5 mg/kg, 6 mg/kg, 7.5 mg/kg, 8 mg/kg, 10 mg/kg, 11 mg/kg, 12 mg/kg, 13.5 mg/kg, or 15 mg/kg of the antibody-drug conjugate targeting Claudin18.2 or the pharmaceutically acceptable salt thereof.
  • the method comprises administering to the subject 0.3mg/kg-10mg/kg such as 2 mg/kg-9 mg/kg, 4 mg/kg-8 mg/kg, or 5 mg/kg-7 mg/kg of the antibody-drug conjugate targeting Claudin18.2 or the pharmaceutically acceptable salt thereof.
  • the method comprises administering to the subject 6 mg/kg of the antibody-drug conjugate targeting Claudin18.2 or the pharmaceutically acceptable salt thereof.
  • the method for preventing or treating advanced malignant solid tumors in a subject according to the present invention comprises administering to the subject 10 mg to 1500 mg, such as 50 mg to 1000 mg, 100 mg to 800 mg, 200 mg to 600 mg, or 300 mg to 500 mg of the antibody-drug conjugate targeting Claudin18.2, or the pharmaceutically acceptable salt thereof.
  • the antibody-drug conjugate targeting Claudin18.2, or a pharmaceutically acceptable salt thereof is administered according to an administration cycle.
  • the administration cycle of the method is 2 weeks/14 days (Q2W) to 5 weeks/35 days (Q5W) , such as 18-24 days, 16-28 days or 15-30 days; e.g., 19, 20, 21, 22 or 23 days, administering once per administration cycle; further, the administration cycle of the method is 2 weeks/14 days (Q2W) , 3 weeks/21 days (Q3W) , 4 weeks/28 days (Q4W) , or 5 weeks/35 days (Q5W) , administering once per administration cycle, i.e., once every two weeks, once every three weeks, once every four weeks, or once every five weeks; preferably administering once on day 1 per administration cycle.
  • the method comprises administering to the subject 6 mg/kg of the antibody-drug conjugate targeting Claudin18.2, or the pharmaceutically acceptable salt thereof, at a frequency of once every 3 weeks/21 days (administering once on day 1 per administration cycle) .
  • the mode of administration of the method of the invention includes intravenous infusion, such as intravenous drip or intravenous bolus; wherein the intravenous drip may be performed through a peripheral vein, central venous catheter, or infusion port.
  • intravenous infusion such as intravenous drip or intravenous bolus
  • Antibody-drug conjugates or pharmaceutically acceptable salts thereof for use in therapy are provided.
  • the invention provides an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of a solid tumor in a subject;
  • antibody-drug conjugate targeting Claudin18.2 is selected from the antibody-drug conjugate of formula IA or formula IB as defined herein, for example, in the “Method of treatment” section.
  • the antibody or antigen-binding fragment thereof targeting Claudin18.2 is as defined herein, e.g., in the “Method of treatment” section.
  • the solid tumor is as defined herein, e.g., in the “Method of treatment” section.
  • the antibody-drug conjugate targeting Claudin18.2, or the pharmaceutically acceptable salt thereof is administered to the subject at a dose as described herein, e.g., in the “Method of treatment” section.
  • the antibody-drug conjugate targeting Claudin18.2, or the pharmaceutically acceptable salt thereof is administered in a dosing regimen as described herein, e.g., in the “Method of treatment” section.
  • the invention provides a use of an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for preventing or treating a solid tumor in a subject,
  • antibody-drug conjugate targeting Claudin18.2 is selected from the antibody-drug conjugate of formula IA or formula IB as defined herein, for example, in the “Method of treatment” section.
  • the antibody or antigen-binding fragment thereof targeting Claudin18.2 is as defined herein, e.g., in the “Method of treatment” section.
  • the solid tumor is as defined herein, e.g., in the “Method of treatment” section.
  • the antibody-drug conjugate targeting Claudin18.2, or the pharmaceutically acceptable salt thereof is administered to the subject at a dose as described herein, e.g., in the “Method of treatment” section.
  • the antibody-drug conjugate targeting Claudin18.2, or the pharmaceutically acceptable salt thereof is administered in a dosing regimen as described herein, e.g., in the “Method of treatment” section.
  • a single dosage unit comprising an effective amount of the antibody-drug conjugate targeting Claudin18.2 or the pharmaceutically acceptable salt thereof according to the present invention.
  • a fixed dose of 1-500mg such as 100-500mg of the antibody-drug conjugate targeting Claudin18.2 or the pharmaceutically acceptable salt thereof is comprised.
  • a fixed dose of 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200 or 500 mg of the antibody-drug conjugate targeting Claudin18.2 or the pharmaceutically acceptable salt thereof is comprised.
  • the single dosage unit is a unit dosage form.
  • kits of parts comprising an effective amount of the antibody-drug conjugate targeting Claudin18.2, or the pharmaceutically acceptable salt thereof according to the invention;
  • a fixed dose of 1-500mg, e.g., 100-500mg, of the antibody-drug conjugate targeting Claudin18.2, or the pharmaceutically acceptable salt thereof is comprised.
  • a fixed dose of 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, or 500mg of the antibody-drug conjugate targeting Claudin18.2, or the pharmaceutically acceptable salt thereof is comprised.
  • the kit of parts further comprises a package insert on which instructions for using the antibody-drug conjugate targeting Claudin18.2 or the pharmaceutically acceptable salt thereof to prevent or treat an advanced malignant solid tumor in a subject are printed.
  • a medicament for the prevention or treatment of an advanced malignant solid tumor including but not limited to gastric cancer, breast cancer, liver cancer, colon cancer, lung cancer, gallbladder cancer, esophageal cancer, gastric/gastro-esophageal junction adenocarcinoma, pancreatic ductal adenocarcinoma, biliary tract cancer (biliary tract cancer is classified as cholangiocarcinoma and gallbladder cancer) .
  • Anti-CLDN18.2 monoclonal antibody HB37A6 (see CN202010570517. X (corresponding to PCT application PCT/CN2021/100870) ) and control antibody zolbetuximab (Zmab for short, sequence derived from INN117) were expressed in HEK293 cells (Invitrogen, A14527) in the form of full-length monoclonal antibodies.
  • a ADC (IEX019-02) was further designed and synthesized as described below.
  • the specific synthesis steps may also refer to the preparation steps of IEX019-02 in PCT/CN2022/139637 (which is incorporated herein as a reference in its entirety) .
  • chlorosulfonyl isocyanate (0.87 mL, 1.4 g, 10 mmol) , Et 3 N (2.8 mL, 2.0 g, 20 mmol) and 2- (2-aminoethoxy) ethanol (1.2 mL, 1.26 g, 12 mmol) were added to a solution of BCN-OH (5, 1.5 g, 10 mmol) in DCM (150 mL) .
  • the mixture was stirred for 10 minutes and quenched by adding NH 4 Cl aqueous solution (saturated, 150mL) .
  • the aqueous layer was extracted with DCM (150mL) after separation.
  • the combined organic layer was dried (Na 2 SO 4 ) and concentrated.
  • HB37A6 was expressed in HEK293 cells and purified. The obtained HB37A6 (16.4 mg/mL) was incubated with EndoSH (1%w/w) as described in PCT/EP2017/052792 to obtain trimmed HB37A6 with -GlcNAc or with GlcNAc (Fuc) at the Asn297 position.
  • the bioconjugate IEX019-02 of the present invention was prepared by conjugating compound 1 (linker-payload) as the linker-conjugate to azide-modified HB37A6- (GlcNAc (Fuc) 1 -6-N 3 -GalNAc) 2 asthe biomolecule.
  • HB37A6- (GlcNAc (Fuc) 1 -6-N 3 -GalNAc) 2 (10.8 mL, 350 mg, 32.6 mg/ml, PBS pH 7.4) were added PBS pH 7.4 (808 ⁇ L) , and 1, 2-propylene glycol (11.3 mL) and compound 1 (350 ⁇ L, 40 mM DMF solution) .
  • Mass spectrometry analysis of the IdeS-digested samples revealed that the two main products corresponded to the obtained ADC, namely HB37A6-SYNtecan E conjugate.
  • 1 st peak the observed mass is 26469 Da (calculated mass is 26465 Da) , corresponding to the conjugated Fc/2 fragment (2x blocked lactone form of the payload) .
  • 2 ed peak the observed mass of 26499 Da (calculated mass 26501 Da) , corresponding to the bound Fc/2 fragment (2x open carboxylate form of the payload) .
  • the resulting structure is as follows.
  • concentration, DAR value and SEC purity of ADC products were determined by UV, SEC, RP-HPLC and LC-MS.
  • the purity of the monomer detected by SE-HPLC was >99%, and the concentration was 6.12 mg/ml.
  • q represents an average DAR, for example 3-5, 3.2-4.8, or 3.5-4.5, such as 3.52.
  • the average DAR is the DAR measured for the prepared ADC product, and the average DAR of different batches of products may vary.
  • freeze-drying process 20 mg/mL IEX019-02 ADC, 20 mM histidine solution, 8% (w/v) sucrose, 0.02% (w/v) polysorbate 80, pH 6.5 were freeze-dried (the freeze-drying process can be prepared according to the conventional process in the art) , and the freeze-drying process parameters are shown in Table 1.
  • Dose escalation stage in Phase Ia According to the response evaluation criteria in solid tumor RECIST v1.1, there should be at least one evaluable lesion; Dose expansion stage in Phase Ia, and Phase Ib: According to the response evaluation criteria in solid tumor RECIST v1.1, there should be at least one measurable lesion.
  • the age was ⁇ 18 years old, regardless of gender.
  • the expected survival was ⁇ 12 weeks.
  • ANC ⁇ 1.5 ⁇ 10 9 /L; Platelet count ⁇ 100 ⁇ 10 9 /L; Hemoglobin content ⁇ 9.0 g/dL, the subject cannot receive treatment with blood transfusion products (including red blood cell suspension, apheresis platelets, cryoprecipitation, etc. ) , erythropoietin (EPO) , G-colony-stimulating factor (G-CSF) , or granulocyte macrophage colony-stimulating factor (GM-CSF) within 7 days before blood collection;
  • blood transfusion products including red blood cell suspension, apheresis platelets, cryoprecipitation, etc.
  • EPO erythropoietin
  • G-CSF G-colony-stimulating factor
  • GM-CSF granulocyte macrophage colony-stimulating factor
  • Liver function TBIL ⁇ 1.5 ⁇ ULN (allowing TBIL ⁇ 3 ⁇ ULN in subjects with Gilbert syndrome) ; ALT and AST ⁇ 2.5 ⁇ ULN in subjects without liver metastasis, as well as ALT and AST ⁇ 5 ⁇ ULN in subjects with liver metastasis; Albumin ⁇ 28 g/L;
  • Renal function serum creatinine ⁇ 1.5 ⁇ ULN or creatinine clearance ⁇ 60 mL/min (using Cockcroft-Gault formula) ; Urinary protein ⁇ 2+ or 24 h total urine protein ⁇ 1 g;
  • Coagulation function International normalized ratio (INR) ⁇ 1.5 and activated partial thromboplastin time (APTT) ⁇ 1.5 ⁇ ULN (subjects who have received anticoagulant treatment and have coagulation function within the above range were allowable) .
  • *CLDN18.2-positive confirmed by histopathological testing (high **CLDN18.2 expression subjects were preferably enrolled for G/GEJ AC, while medium and high **CLDN18.2 expression subjects were preferably enrolled for PDAC) .
  • **High CLDN18.2 expression The intensity of Claudin18.2 immunohistochemical membrane staining was ⁇ 2+ in ⁇ 75%of tumor cells.
  • Symptomatic pleural effusion, ascites, or pericardial effusion that required intervention (such as drainage) .
  • Esophageal or gastric varices that required immediate intervention such as bandaging or sclerotherapy
  • a medical history of deep vein thrombosis, pulmonary embolism, or any other severe venous thromboembolism within 3 months prior to the first administration of the investigational drug (implantable venous access port or catheter-related thrombosis, or superficial venous thrombosis was not considered as "severe" venous thromboembolism) .
  • Having a risk of intestinal obstruction or perforation including but not limited to a history of acute diverticulitis and abdominal abscess) or a history of the following diseases: inflammatory bowel disease or extensive bowel resection (partial colectomy or extensive small bowel resection complicated with chronic diarrhea) , Crohn's disease, ulcerative colitis, or chronic diarrhea.
  • Dosage 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 4.5 mg/kg, 6 mg/kg, 8 mg/kg, 10 mg/kg.
  • the actual dosage (mg) would be calculated based on the subject's weight (kg) .
  • the initial dose was calculated based on the baseline weight of the subjects. If the weight of the subject changed by less than ⁇ 10%from the baseline (the weight for the first administration during the study) , the baseline weight would be used to calculate the dosage. Otherwise, the actual dosage would be calculated based on the weight on the pre-determined dosing day or the day before dosing.
  • Intravenous drip peripheral vein, central venous catheter or infusion port
  • an infusion pump could be used.
  • Dosing frequency The administration cycle was 3 weeks/21 days (Q3W) , with one administration on the first day of each cycle.
  • ADA assay would be conducted on all subjects, and neutralizing antibody (NAb) assay would be performed on ADA positive serum samples (if necessary) .
  • NAb neutralizing antibody
  • PK characteristics of drugs in the human body after single and multiple administration determining key PK parameters, including but not limited to: AUC, Tmax, Ctrough, Cmax, CL, V, and t 1/2 .
  • Dose expansion stage (Phase Ia) : For each tumor type: 2-4 doses were intended to be selected for expansion, with approximately 6-60 subjects enrolled for each expansion dose, totaling approximately 40-140 cases.
  • the 6 mg/kg Q3W dosing regimen was the best dosing regimen that balances clinical benefits and safety.
  • the expected survival was ⁇ 12 weeks.
  • ANC ⁇ 1.5 ⁇ 10 9 /L; Platelet count ⁇ 100 ⁇ 10 9 /L; Hemoglobin content ⁇ 9.0 g/dL, the subject should not receive treatment with blood transfusion products (including red blood cell suspension, apheresis platelets, cryoprecipitation, etc. ) , erythropoietin (EPO) , Granulocyte-colony-stimulating factor (G-CSF) , or granulocyte macrophage colony-stimulating factor (GM-CSF) within 7 days before blood collection;
  • blood transfusion products including red blood cell suspension, apheresis platelets, cryoprecipitation, etc.
  • EPO erythropoietin
  • G-CSF Granulocyte-colony-stimulating factor
  • GM-CSF granulocyte macrophage colony-stimulating factor
  • Liver function TBIL ⁇ 1.5 ⁇ ULN (allowing TBIL ⁇ 3 ⁇ ULN in subjects with Gilbert syndrome) ; ALT and AST ⁇ 2.5 ⁇ ULN in subjects without liver metastasis, as well as ALT and AST ⁇ 5 ⁇ ULN in subjects with liver metastasis; Albumin ⁇ 28 g/L (Subjects were not allowed to receive treatment with human serum albumin infusion within 7 days prior to blood collection) ;
  • Renal function creatinine clearance ⁇ 60 mL/min (using Cockcroft-Gault formula) ; Urinary protein ⁇ 2+or 24 h total urine protein ⁇ 1 g;
  • Coagulation function International normalized ratio (INR) ⁇ 1.5 and activated partial thromboplastin time (APTT) ⁇ 1.5 ⁇ ULN (subjects were allowed to receive anticoagulant treatment and had coagulation function within the above range) .
  • G/GEJA Gastric/gastro-Esophageal Junction Adenocarcinoma
  • CLDN18.2* was confirmed by pathological tissue testing in the central laboratory. For subjects who had previously received any anti-CLDN18.2 treatment, tumor samples should be collected again after the relevant anti-CLDN18.2 treatment was completed.
  • HER2 positivity immunohistochemistry [IHC] 3+, or IHC 2+ and in situ hybridization positivity. HER2 positive subjects who had received anti-HER2 treatment in the past did not meet the exclusion criteria if HER-2 detection was negative in tissue samples taken after anti-HER2 treatment. (For primary study stages)
  • CYP3A4 cytochrome P450 3A4
  • Symptomatic metastasis to central nervous system and/or spinal compression symptoms For subjects with asymptomatic brain metastases (i.e. no neurological symptoms, no glucocorticoid treatment required, all brain metastases being ⁇ 1.5 cm) or subjects with stable symptoms after treatment of brain metastases, all of the following criteria must be met to be enrolled in this study: no metastasis to midbrain, pons, cerebellum, meninges, medulla oblongata, or spinal cord; maintaining a stable clinical state for at least 4 weeks, with clinical evidence confirming the absence of new or enlarged brain metastases, and discontinuing corticosteroid and anticonvulsant therapy for at least 2 weeks before the first administration of the investigational drug. Note: The central nervous system was not a target lesion.
  • HIV Human immunodeficiency virus
  • ⁇ Acute or chronic active hepatitis B [Subjects who are positive for hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibody (HBcAb) need to undergo further hepatitis B virus (HBV) DNA testing. If the copy number of HBV DNA is 104 ⁇ copies/mL or ⁇ 2000 IU/mL or lower than the detection limit, the subject can be included in the study. ] or acute or chronic active hepatitis C [with positive hepatitis C virus antibody (HCVAb) , HCV RNA >103 copies/mL] . Subjects who had undergone nucleotides antiviral therapy and were below the above standards, as well as those who were HCV antibody positive but RNA test negative, were allowed to be enrolled.
  • HBV hepatitis B virus
  • the overall significance level of OS would be adjusted as follows: the first OS futility interim analysis would conduct by two sets of unbound futility tests based on the Gamma Family cost function with parameter -2. The ⁇ margin of the second validity interim analysis and final analysis of OS were approximated by the Lan-Demets method to the O'brien-Fleming boundary allocation and PFS final analysis results (determining whether to recover ⁇ of PFS) .
  • the descriptive summary of continuous variables would include number of cases, mean, standard deviation, median, minimum and maximum values.
  • the descriptive summary of categorical variables would include the number of cases and percentages.
  • the primary analysis for comparing PFS and OS groups was conducted using a stratified log-rank test.
  • the Kaplan-Meier method was used to estimate the median PFS and OS, as well as their 95%confidence interval (CI) , and survival curves were plotted.
  • CI 95%confidence interval
  • a stratified Cox proportional hazard model was used to estimate inter group HR and its 95%CI, and the stratification factor was a random stratification factor.
  • the data currently obtained show that, as confirmed by Phase Ia and Ib trials, the antibody-drug conjugate targeting CLAUDIN18.2 of the present invention has a good safety and excellent therapeutic efficacy as shown by, for example, PFS, OS, ORR and/or DCR.

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Abstract

L'invention concerne un procédé de traitement de tumeurs solides par l'administration d'un conjugué anticorps-médicament ciblant la claudine 18,2, ou d'un sel pharmaceutiquement acceptable de celui-ci, à un sujet en ayant besoin, ainsi que des unités de dose unique, des kits de pièces et leurs utilisations.
PCT/CN2024/099382 2023-06-16 2024-06-14 Procédé de traitement de tumeurs solides avec un conjugué anticorps-médicament ciblant la claudine 18,2 Pending WO2024255880A1 (fr)

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WO2025077815A1 (fr) * 2023-10-11 2025-04-17 福佑泰生物制药（新加坡）公司 Procédé d'utilisation d'un conjugué anticorps-médicament ciblant la claudine 18.2 en polythérapie pour le cancer

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016165762A1 (fr) * 2015-04-15 2016-10-20 Ganymed Pharmaceuticals Ag Conjugués de médicaments comprenant des anticorps contre la claudine 18.2
WO2021228141A1 (fr) * 2020-05-15 2021-11-18 四川科伦博泰生物医药股份有限公司 Conjugué anticorps-médicament, son procédé de préparation et son utilisation
WO2022058395A1 (fr) * 2020-09-15 2022-03-24 Synaffix B.V. Conjugués anticorps-exatecan
WO2022136642A1 (fr) * 2020-12-23 2022-06-30 Sotio Biotech A.S. Conjugués anticorps-médicament anti-claudine 18.2 spécifiques d'une tumeur
WO2022237666A1 (fr) * 2021-05-08 2022-11-17 荣昌生物制药(烟台)股份有限公司 Anticorps anti-claudine 18.2 et conjugué anticorps-médicament de celui-ci
CN115969997A (zh) * 2022-12-19 2023-04-18 华润生物医药有限公司 一种靶向cldn18.2的抗体药物偶联物及其应用

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016165762A1 (fr) * 2015-04-15 2016-10-20 Ganymed Pharmaceuticals Ag Conjugués de médicaments comprenant des anticorps contre la claudine 18.2
WO2021228141A1 (fr) * 2020-05-15 2021-11-18 四川科伦博泰生物医药股份有限公司 Conjugué anticorps-médicament, son procédé de préparation et son utilisation
WO2022058395A1 (fr) * 2020-09-15 2022-03-24 Synaffix B.V. Conjugués anticorps-exatecan
WO2022136642A1 (fr) * 2020-12-23 2022-06-30 Sotio Biotech A.S. Conjugués anticorps-médicament anti-claudine 18.2 spécifiques d'une tumeur
WO2022237666A1 (fr) * 2021-05-08 2022-11-17 荣昌生物制药(烟台)股份有限公司 Anticorps anti-claudine 18.2 et conjugué anticorps-médicament de celui-ci
CN115969997A (zh) * 2022-12-19 2023-04-18 华润生物医药有限公司 一种靶向cldn18.2的抗体药物偶联物及其应用

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