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WO2020063433A1 - Utilisation anti-tumorale d'un anticorps anti-ligand de mort programmée 1 (pd-l1) - Google Patents

Utilisation anti-tumorale d'un anticorps anti-ligand de mort programmée 1 (pd-l1) Download PDF

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Publication number
WO2020063433A1
WO2020063433A1 PCT/CN2019/106599 CN2019106599W WO2020063433A1 WO 2020063433 A1 WO2020063433 A1 WO 2020063433A1 CN 2019106599 W CN2019106599 W CN 2019106599W WO 2020063433 A1 WO2020063433 A1 WO 2020063433A1
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Prior art keywords
antibody
antigen
binding portion
seq
days
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PCT/CN2019/106599
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English (en)
Chinese (zh)
Inventor
刘平
王军
肖亮
薛彤彤
罗毅
王利春
王晶翼
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四川科伦博泰生物医药股份有限公司
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Application filed by 四川科伦博泰生物医药股份有限公司 filed Critical 四川科伦博泰生物医药股份有限公司
Priority to CN201980059111.0A priority Critical patent/CN112672759B/zh
Publication of WO2020063433A1 publication Critical patent/WO2020063433A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the use of an anti-programmed death ligand-1 (PD-L1) antibody or an antigen-binding portion thereof, or a composition comprising the antibody or an antigen-binding portion thereof in the treatment of a tumor (such as a lymphoma or a solid tumor), and method.
  • a tumor such as a lymphoma or a solid tumor
  • Cancer has been a major global health burden. Despite advances in the treatment of cancer, there has been an unmet medical need for more effective and less toxic therapies, especially for those patients with advanced disease or cancer that are resistant to existing therapeutic agents.
  • the immune system is able to recognize tumor-associated antigens and eliminate cancer cells that express them.
  • This tumor immune surveillance or tumor immune editing process plays an important role in preventing and resisting tumor growth, and the level of tumor infiltrating lymphocytes (and more specifically cytotoxic T cells) is related to the prognosis of many cancers. Therefore, enhancing the immune response can provide a means to control the tumor.
  • a T cell inhibitory checkpoint pathway triggers signals through programmed death-1 (PD-1, CD279) and its ligand, programmed death ligand-1 (PD-L1, CD274, B7-H1).
  • PD-1 / PD-L1 pathway the primary function of the PD-1 / PD-L1 pathway is to limit autoimmunity by inhibiting the activity of peripheral T cells during chronic inflammation, infection, and cancer. This pathway is thought to transmit inhibitory signals that primarily regulate the T cell effector phase against tumor cells, and has been implicated in tumor growth and progression.
  • PD-1 is expressed in activated T cells and regulatory T cells, NK-T cells, B cells, and activated monocytes.
  • PD-L1 is expressed on T cells, B cells, dendritic cells, macrophages, mesenchymal stem cells, bone marrow-derived mast cells, and different non-hematopoietic cells.
  • PD-L1 also helps tumors avoid surveillance and clearance by the host's immune system by expressing on tumors and acting on multiple sites.
  • PD-L1 is highly frequently expressed in a wide range of cancers. In some cancers, PD-L1 expression is associated with reduced survival and adverse prognosis.
  • Antibodies that block the interaction between PD-1 and PD-L1 can alleviate PD-L1-dependent immunosuppressive effects and enhance the cytotoxic activity of anti-tumor T cells in vitro, and some of these antibodies have been used as cancer treatments . However, some of these marketed antibodies still have safety issues such as adverse reactions to medication. Therefore, there remains a highly unmet clinical need for effective therapies for treating cancers such as solid tumors or lymphomas.
  • the invention provides an antibody (anti-PD-L1 antibody) or an antigen-binding portion thereof that specifically binds PD-L1, or a composition comprising the antibody or the antigen-binding portion, in the preparation of a medicament for treating tumors in an individual.
  • an antibody anti-PD-L1 antibody
  • an antigen-binding portion thereof that specifically binds PD-L1
  • a composition comprising the antibody or the antigen-binding portion
  • the antibody or antigen-binding portion thereof comprises: a heavy chain variable region (VH) comprising HCDR1 having a sequence of SEQ ID NO: 15, HCDR2 having a sequence of SEQ ID NO: 16, and HCDR3 having a sequence of SEQ ID NO: 17; And, a light chain variable region (VL) containing LCDR1 with the sequence of SEQ ID NO: 18, LCDR2 with the sequence of SEQ ID NO: 19, and LCDR3 with the sequence of SEQ ID NO: 20;
  • VH heavy chain variable region
  • VL light chain variable region
  • the tumor is selected from solid tumors or lymphomas, wherein the solid tumor is selected from one or more of lung squamous cell carcinoma, Merkel cell carcinoma, nasopharyngeal carcinoma, and bile duct cancer.
  • the invention also provides a method for treating a tumor in an individual, said method comprising administering to said individual an anti-PD-L1 antibody or an antigen-binding portion thereof as described above, or comprising said antibody or an antigen-binding portion thereof
  • the tumor is selected from solid tumors or lymphomas, wherein the solid tumor is selected from one or more of lung squamous cell carcinoma, Merkel cell carcinoma, nasopharyngeal carcinoma, and bile duct cancer.
  • the lymphoma is Hodgkin's lymphoma or non-Hodgkin's lymphoma.
  • the non-Hodgkin's lymphoma is preferably one of peripheral T-cell lymphoma, angioimmunoblast T-cell lymphoma, NK / T-cell lymphoma, and B-cell non-Hodgkin's lymphoma. Or more.
  • the VH of the antibody or antigen-binding portion thereof comprises a sequence selected from:
  • sequence shown with any of SEQ ID NOs: 2, 6, 10 has at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least Sequences with 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity;
  • the VL of the antibody or antigen-binding portion thereof comprises a sequence selected from:
  • (v) has one or more substitutions, deletions or additions compared to the sequence shown in any one of SEQ ID NOs: 4, 8, 12 (e.g. 1, 2, 3, 4 or 5 substitutions, Missing or added); or
  • sequence shown in any one of SEQ ID NOs: 4, 8, 12 has at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least A sequence with 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity.
  • substitutions described in (ii) or (v) are conservative substitutions.
  • the antibody or antigen-binding portion thereof comprises:
  • VH as shown in SEQ ID NO: 10
  • VL 5C10H2L2 or 5C10H2L2-IgG1mt
  • VH as shown in SEQ ID NO: 6 and VL (5C10H1L2) as shown in SEQ ID NO: 12; or
  • VH shown in SEQ ID NO: 10 VL (5C10H2L1) shown in SEQ ID NO: 8.
  • amino acid sequences of the heavy chain CDRs of the 5 monoclonal antibodies are:
  • HCDR1 GFSLSNYD (SEQ ID NO: 15)
  • HCDR2 IWTGGAT (SEQ ID NO: 16)
  • HCDR3 VRDSNYRYDEPFTY (SEQ ID NO: 17)
  • amino acid sequences of the light chain CDRs of the 5 monoclonal antibodies are:
  • LCDR1 QSIGTN (SEQ ID NO: 18)
  • LCDR3 QQSNSWPYT (SEQ ID NO: 20).
  • the antibody or antigen-binding portion thereof is selected from the group consisting of Fab, Fab ', F (ab') 2 , Fd, Fv, dAb, complementarity determining region fragments, single chain antibodies (e.g., scFv), human Sourced, chimeric or diabody.
  • the antibody or antigen-binding portion thereof is less than about 100 nM, such as less than about 10 nM, 1 nM, 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM EC 50 of 0.1 nM or less binds to PD-L1 protein; preferably, the EC 50 is measured by an indirect ELISA method.
  • the antibody includes a non-CDR region, and the non-CDR region is from a species that is not a murine, such as from a human antibody.
  • the antibody or antigen-binding portion thereof may further comprise a constant region sequence or a variant thereof derived from a mammalian (eg, murine or human) immunoglobulin, said variant and Sequences have one or more substitutions, deletions or additions compared.
  • a mammalian (eg, murine or human) immunoglobulin said variant and Sequences have one or more substitutions, deletions or additions compared.
  • the antibody or antigen-binding portion thereof comprises a heavy chain constant region (CH) selected from, for example, a heavy chain constant region of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE ;
  • a heavy chain constant region selected from, for example, a heavy chain constant region of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE ;
  • the antibody or antigen-binding portion thereof comprises a light chain constant region (CL) selected from, for example, a light chain constant region of kappa or lambda, preferably a kappa light chain constant region (eg, a human kappa light chain) .
  • CL light chain constant region
  • the antibody or antigen-binding portion thereof has ADCC and / or CDC activity.
  • the constant region can be mutated to alter effector functions (eg, ADCC and / or CDC activity) mediated by the Fc region.
  • effector functions eg, ADCC and / or CDC activity
  • these effector functions are required for therapeutic antibodies; but in other cases, these effector functions may be unnecessary or even harmful, depending on the intended purpose.
  • the antibodies or antigen-binding portions thereof of the invention have reduced or even eliminated effector functions (e.g., ADCC and / or CDC activity).
  • the antibody or antigen-binding portion thereof comprises a mutated human IgG heavy chain constant region, such as a mutated human IgG1 or IgG4 heavy chain constant region; compared to a wild-type constant region sequence, the mutation
  • the antibody or antigen-binding fragment thereof is given a reduced affinity for FcyRIIIa and / or C1q, and / or the mutation confers reduced ADCC and / or CDC activity of the antibody or its antigen-binding fragment.
  • the antibody or antigen-binding fragment thereof comprises: a variant of the human IgG1 heavy chain constant region, said variant having the following substitutions compared to the wild-type sequence from which it is derived: L234A, L235A, and G237A (According to the location of the EU numbering system).
  • the antibody or antigen-binding portion thereof of the present invention is an antibody or antigen-binding portion selected from the group consisting of 5C10, 5C10H1L1, 5C10H1L2, 5C10H2L1, 5C10H2L2, or 5C10H2L2 described in International Patent Application WO2017148424 -IgG1mt.
  • the antibody or antigen-binding portion thereof of the present invention is 5C10H2L2-IgG1mt or an antigen-binding portion thereof.
  • the composition comprises the antibody or antigen-binding portion thereof and a pharmaceutically acceptable carrier and / or excipient.
  • the composition comprises the antibody or antigen-binding portion thereof at a concentration of 1-200 mg / ml, a buffer solution of about 10 mM to about 20 mM, sodium chloride of about 80 mM to about 160 mM, having about A pH of 5.0 to about 7.0.
  • the composition comprises an antibody or an antigen-binding portion thereof at a concentration of 10-100 mg / ml, sodium chloride at a concentration of 120 mM to about 160 mM, and histidine-histidine hydrochloride at a concentration of 15 mM to about 20 mM.
  • Polysorbate 80 at 0.01% w / v to about 0.02% w / v.
  • the tumor has a PD-L1 expression level of not less than 1%, such as at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6 %, At least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 20 %, At least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70 %, At least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100%.
  • 1% such as at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6 %, At least about 7%, at least about 8%, at least about 9%
  • the tumor has a PD-L1 expression level of about 1% -50%, such as about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19% About 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%.
  • the expression “the expression level of PD-L1 in tumors” refers to the proportion of cells that express PD-L1 (eg, on the cell surface) in tumor tissue samples.
  • the expression level of PD-L1 is detected by immunohistochemistry (IHC) (e.g., autoimmunohistochemistry) or in situ hybridization (e.g., fluorescent in situ hybridization).
  • IHC immunohistochemistry
  • in situ hybridization e.g., fluorescent in situ hybridization
  • the expression level of PD-L1 is detected by in vivo imaging or flow cytometry.
  • an antibody or an antigen-binding portion thereof or a composition comprising the antibody or an antigen-binding portion thereof according to the invention is administered, or a method according to the invention is used Prior to the method, PD-L1 expression levels in the tumors of the individuals were determined.
  • the determining comprises: (1) providing a tissue sample to be tested obtained from an individual having a tumor, the tissue sample to be tested comprising tumor cells and / or tumor-infiltrating inflammatory cells; (2) ) Determine the proportion of cells expressing PD-L1 on the cell surface in the tissue sample to be tested.
  • the PD-L1 expression level of a tumor of the individual may be provided as an intermediate result to a doctor or other health care provider for use in selecting an antibody or antigen-binding agent suitable for administration of the invention Partially treated patients.
  • the step of providing an intermediate result is performed by a medical practitioner or a person acting under the direction of a medical practitioner. In other embodiments, these steps are performed by an independent laboratory or by an independent person, such as a laboratory technician.
  • the proportion of PD-L1 expressing cells can be assessed by performing an assay for the presence of a PD-L1 polypeptide.
  • the presence of the PD-L1 polypeptide is determined by immunohistochemistry (IHC), enzyme-linked immunosorbent assay (ELISA), in vivo imaging, or flow cytometry.
  • the proportion of cells expressing PD-L1 is determined by IHC (eg, autoimmunohistochemistry).
  • the proportion of cells expressing PD-L1 can be assessed by performing an assay for the presence of a PD-L1 nucleic acid (eg, RNA).
  • a PD-L1 nucleic acid eg, RNA
  • the presence of PD-L1 nucleic acid is determined by RT-PCR, in situ hybridization, or RNase protection.
  • the proportion of cells expressing PD-L1 is determined by in situ hybridization (eg, fluorescent in situ hybridization).
  • the individual is a mammal.
  • the individual is a human.
  • the individual has not received additional cancer therapy (eg, chemotherapy). In other embodiments, the individual has received additional cancer therapy (eg, chemotherapy), but is resistant, relapsed, or refractory to the additional cancer therapy. In some embodiments, the individual receives at least one, at least two, at least three, at least four, or at least five frontline therapies to treat a tumor. "Previous line of therapy" refers to any therapy given to an individual for the treatment of a tumor that occurs before or concurrently with tumor recurrence. In certain embodiments, the front-line therapy comprises chemotherapy and / or radiation therapy.
  • the anti-PD-L1 antibody or antigen-binding portion thereof, or the composition of the invention can be administered by any suitable method known in the art, including, but not limited to, Oral, oral, sublingual, eyeball, topical, parenteral, rectal, intrathecal, intracytoplasmic reticulum, groin, intravesical, topical (eg, powder, ointment or drops), or nasal route.
  • the preferred route / mode of administration is parenteral (e.g., intravenous or bolus, subcutaneous, intraperitoneal, intramuscular).
  • the skilled person will understand that the route and / or mode of administration will vary depending on the intended purpose.
  • the anti-PD-L1 antibody or antigen-binding portion thereof, or the composition is administered by a parenteral route; preferably by intravenous infusion or subcutaneous injection; further preferably by intravenous infusion .
  • the anti-PD-L1 antibody or antigen-binding portion thereof, or the composition is administered every 7 to 28 days when used to treat a solid tumor, It is preferably administered every 14 to 21 days, and further preferably every 14 or 21 days.
  • the anti-PD-L1 antibody or antigen-binding portion thereof, or the composition is administered every 7 to 28 days when used to treat lymphoma, It is preferably administered every 14 to 21 days, and more preferably once every 14 days.
  • the anti-PD-L1 antibody or antigen-binding portion thereof, or the composition when used as maintenance therapy for a solid tumor, is every 7 days (1 week) to 90 days, or every 7 days (1 week) to 3 months; preferably every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 1 month, every 2 months, or every 3 months Apply once.
  • the anti-PD-L1 antibody or antigen-binding portion thereof, or the composition when used as maintenance therapy for lymphoma, is every 7 days (1 week) to 90 days, or every 7 days (1 week) to 3 months; preferably every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 1 month, every 2 months, or every 3 months Apply once.
  • each dose of the anti-PD-L1 antibody or antigen-binding portion thereof or the composition may be 100 mg to 5000 mg per body; preferably 300 mg to 2400 mg , More preferably 600 mg to 2400 mg, and still more preferably 600 mg, 900 mg, 1200 mg, 1500 mg, 1800 mg, 2000 mg, 2200 mg, or 2400 mg.
  • each dose of the anti-PD-L1 antibody, antigen-binding moiety, or the composition is 1 mg based on the weight of the patient when used to treat solid tumors / kg to 50mg / kg; preferably 2mg / kg to 40mg / kg body weight, more preferably 2mg / kg, 3mg / kg, 4mg / kg, 5mg / kg, 6mg / kg, 7mg / kg, 8mg / kg, 10mg / kg , 12 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 33 mg / kg, 36 mg / kg or 40 mg / kg.
  • the anti-PD-L1 antibody or antigen-binding portion thereof or the composition when used in the treatment of solid tumors, is administered in a first dosing regimen, the The first dosing regimen includes:
  • the anti-PD-L1 antibody or antigen-binding portion thereof ranges from 1 mg / kg to 50 mg / kg, preferably 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, based on the weight of the patient , 7 mg / kg, 8 mg / kg, 10 mg / kg, 12 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 33 mg / kg, 36 mg / kg, or 40 mg / kg, administered every 14 Or once every 21 days; 2) maintenance phase, wherein the anti-PD-L1 antibody or antigen-binding portion thereof is administered at a dose of 1 mg / kg to 50 mg / kg based on the patient's body weight every 1, 2, 3, or 4 weeks or every Administered once every 1, 2 or 3 months; or,
  • the anti-PD-L1 antibody or antigen-binding portion thereof or the composition is administered in a second dosing regimen, the second dosing regimen comprising:
  • an induction phase wherein the anti-PD-L1 antibody or antigen-binding portion thereof or the composition is administered at a dose of 600 mg to 2400 mg, preferably 600 mg, 900 mg, 1200 mg, 1500 mg, 1800 mg, 2000 mg, 2200 mg, or 2400 mg per body, Administered every 14 or 21 days; 2) a maintenance phase in which the anti-PD-L1 antibody or antigen-binding portion thereof or the composition is administered at a dose of 600 mg to 2400 mg per body, every 1, 2, 3 or 4 weeks Or at least once every 1, 2 or 3 months.
  • the anti-PD-L1 antibody or antigen-binding portion thereof or the composition is administered at a dose of 900 mg per body, once every 14 days Or at a dose of 1200mg, 1500mg or 1800mg, once every 21 days.
  • the drug treats a solid tumor
  • the administration of the anti-PD-L1 antibody, antigen-binding portion, or composition thereof is repeated every 7 to 28 days, preferably every 14 to 21 days
  • the administration is performed once, and it is more preferable to repeat the administration every 14 days or 21 days.
  • the drug treats lymphoma, and the administration of the anti-PD-L1 antibody, antigen-binding portion, or composition thereof is repeated every 7 to 28 days, preferably every 14 to 21 days
  • the administration is performed once, and it is more preferable to repeat the administration every 14 days.
  • the anti-PD-L1 antibody, antigen-binding portion, or composition thereof is administered every 7 days (1 week) to 90 days (3 months); It is preferably administered every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 1 month, 2 months, or 3 months.
  • the anti-PD-L1 antibody, antigen-binding portion, or composition thereof is administered every 7 days (1 week) to 90 days (3 months); It is preferably administered every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 1 month, 2 months, or 3 months.
  • the drug treats solid tumors or lymphomas
  • the anti-PD-L1 antibody and antigen-binding portion have a dose of 100 mg to 5000 mg each; preferably 300 mg to 2400 mg, more preferably 600 mg to 2400 mg, Further preferred are 600 mg, 900 mg, 1200 mg, 1500 mg, 1800 mg, 2000 mg, 2200 mg, and 2400 mg.
  • the medicament is used to treat solid tumors, and the anti-PD-L1 antibody and the antigen-binding portion are administered at a dose of 1 mg / kg to 50 mg / kg based on the weight of the patient; preferably 2 mg / kg to 40 mg / kg, more preferably 2mg / kg, 3mg / kg, 4mg / kg, 5mg / kg, 6mg / kg, 7mg / kg, 8mg / kg, 10mg / kg, 12mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 33mg / kg, 36mg / kg, 40mg / kg.
  • the medicament is used to treat solid tumors, and the dosing regimen is divided into: 1) an induction phase, wherein the anti-PD-L1 antibody or antigen-binding portion thereof is 1 mg / kg per dose based on the weight of the patient To 50 mg / kg, preferably 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 10 mg / kg, 12 mg / kg, 15 mg / kg per administration 20 mg / kg, 25 mg / kg, 30 mg / kg, 33 mg / kg, 36 mg / kg, 40 mg / kg, every 14 or 21 days; 2) maintenance phase, the anti-PD-L1 antibody or antigen-binding portion thereof Each administration dose is 1mg / kg-50mgkg, once every 1, 2, 3, 4 weeks or every 1, 2, 3 months;
  • the drug is used to treat solid tumors or lymphomas, wherein the anti-PD-L1 antibody or antigen-binding portion thereof is 600 mg to 2400 mg per administration, preferably 600 mg, 900 mg, 1200 mg per administration , 1500mg, 1800mg, 2000mg, 2200mg, 2400mg, administered every 14 or 21 days; 2) during the maintenance phase, the anti-PD-L1 antibody or its antigen-binding portion is repeatedly administered, the anti-PD-L1 antibody or its antigen The combined portion is administered at a dose of 600 mg to 2400 mg at least once every 1, 2, 3, 4 weeks or every 1, 2, 3 months;
  • the antibody or antigen-binding portion thereof received in the injection at the induction stage is administered at a dose of 900 mg per body, once every 14 days, or at a dose of 1200 mg or 1500 mg or 1800 mg per body, per 21 days. Apply once a day.
  • the administration of the anti-PD-L1 antibody or antigen-binding portion thereof enables an individual, such as a human patient, to achieve disease control (DC); the disease control includes complete Response (CR), Partial Response (PR), or Stable Disease (SD).
  • DC disease control
  • the disease control includes complete Response (CR), Partial Response (PR), or Stable Disease (SD).
  • the antibody or antigen-binding portion thereof can be used together with other ingredients having antitumor activity to prepare the medicament for treating the tumor.
  • the antibody or antigen-binding fragment thereof is provided as an isolated component or as a mixed component with the other component having antitumor activity.
  • the antibody or antigen-binding portion thereof may be administered in combination with other components having antitumor activity.
  • the antibody or the antigen-binding portion thereof of the present invention and the other components having antitumor activity can be administered simultaneously, separately, or sequentially.
  • the other component having antitumor activity may be selected from alkylating agents, mitotic inhibitors, antitumor antibiotics, antimetabolites, topoisomerase inhibitors, tyrosine kinase inhibitors, radioactive Nuclides, radiosensitizers, anti-angiogenic agents, cytokines, antibodies specifically targeting tumor cells, immune checkpoint inhibitors, etc.
  • Embodiment 1 A method for treating a tumor in an individual, said method comprising administering to said individual an anti-PD-L1 antibody or an antigen-binding portion thereof, or a composition, wherein,
  • the antibody or antigen-binding portion thereof comprises: a heavy chain variable region (VH) comprising HCDR1 having a sequence of SEQ ID NO: 15, HCDR2 having a sequence of SEQ ID NO: 16, and HCDR3 having a sequence of SEQ ID NO: 17; And, a light chain variable region (VL) containing LCDR1 with the sequence of SEQ ID NO: 18, LCDR2 with the sequence of SEQ ID NO: 19, and LCDR3 with the sequence of SEQ ID NO: 20;
  • VH heavy chain variable region
  • VL light chain variable region
  • the tumor is selected from solid tumors or lymphomas, wherein the solid tumor is selected from one or more of lung squamous cell carcinoma, Merkel cell carcinoma, nasopharyngeal carcinoma, and bile duct cancer;
  • the lymphoma is Hodgkin's lymphoma or non-Hodgkin's lymphoma; preferably, the non-Hodgkin's lymphoma is peripheral T-cell lymphoma, angioimmunoblast T-cell lymphoma, NK / One or more of T-cell lymphoma and B-cell non-Hodgkin's lymphoma;
  • the anti-PD-L1 antibody is a humanized antibody or a chimeric antibody.
  • Embodiment 2 The method of Embodiment 1, wherein the VH of the antibody or antigen-binding portion thereof comprises a sequence selected from the group consisting of SEQ ID NOs: 2, 6, and 10, or With the sequence shown in SEQ ID NOs: 2, 6, 10 at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, A sequence with at least 96%, at least 97%, at least 98%, or at least 99% sequence identity; and / or,
  • the VL of the antibody or antigen-binding portion thereof comprises a sequence selected from the group consisting of SEQ ID NOs: 4, 8, and 12 or a sequence selected from SEQ ID NOs: 4, 8, and 12
  • the sequence shown has at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least Sequences with 99% sequence identity.
  • Embodiment 3 The method according to embodiment 1 or 2, wherein the antibody or antigen-binding portion thereof comprises:
  • VH as shown in SEQ ID NO: 2 and VL as shown in SEQ ID NO: 4;
  • VH as shown in SEQ ID NO: 6, and VL as shown in SEQ ID NO: 8;
  • VH as shown in SEQ ID NO: 10
  • VL as shown in SEQ ID NO: 8.
  • Embodiment 4 The method according to any one of embodiments 1-3, wherein the antigen-binding portion is selected from the group consisting of Fab, Fab ', F (ab') 2 , Fd, Fv, dAb, a complementarity determining region fragment, a single Chain antibodies (e.g., scFv) or diabody.
  • the antigen-binding portion is selected from the group consisting of Fab, Fab ', F (ab') 2 , Fd, Fv, dAb, a complementarity determining region fragment, a single Chain antibodies (e.g., scFv) or diabody.
  • Embodiment 5 The method of any one of embodiments 1-4, wherein the antibody or antigen-binding portion thereof is less than about 100 nM, such as less than about 10 nM, 1 nM, 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM , 0.5nM, 0.4nM, 0.3nM, 0.2nM , 0.1nM EC 50 or less PD-L1 binding proteins (e.g. human PD-L1 protein); preferably, the EC 50 measured by indirect ELISA.
  • PD-L1 binding proteins e.g. human PD-L1 protein
  • Embodiment 6 The method of any one of embodiments 1-5, wherein the antibody or antigen-binding portion thereof comprises a non-CDR region, and the non-CDR region is from a species other than a mouse, such as from a human antibody;
  • the antibody or antigen-binding portion thereof comprises a human IgG heavy chain constant region, such as the heavy chain constant region of human IgG1, IgG2, IgG3, or IgG4; preferably, the antibody or antigen-binding portion thereof has ADCC and / or CDC activity;
  • the antibody or antigen-binding portion thereof comprises a mutated human IgG heavy chain constant region, such as a mutated human IgG1 or IgG4 heavy chain constant region; preferably, the mutation causes the antibody or antigen-binding fragment to have a reduced ADCC and / or CDC activity;
  • the antibody or antigen-binding fragment thereof comprises: a variant of the human IgG1 heavy chain constant region, which variant has the following substitutions compared to the wild-type sequence from which it is derived: L234A, L235A, and G237A (according to EU number The location of the system);
  • the antibody or antigen-binding portion thereof comprises a light chain constant region of human kappa or lambda.
  • Embodiment 7 The method of any one of embodiments 1-6, wherein the antibody or antigen-binding portion thereof is an antibody or antigen-binding portion selected from the group consisting of 5C10, 5C10H1L1, 5C10H1L2, 5C10H2L1, 5C10H2L2, or 5C10H2L2-IgG1mt.
  • Embodiment 8 The method according to any one of embodiments 1-7, wherein the antibody or an antigen-binding portion thereof is 5C10H2L2-IgG1mt or an antigen-binding portion thereof.
  • Embodiment 9 The method of any one of embodiments 1-8, wherein the composition comprises the antibody or an antigen-binding portion thereof and a pharmaceutically acceptable carrier and / or excipient.
  • Embodiment 10 The method according to any one of embodiments 1-9, wherein the tumor is relapsed or refractory;
  • the tumor is a relapsed or refractory Hodgkin's lymphoma.
  • Embodiment 11 The method according to any one of embodiments 1-10, wherein the Hodgkin lymphoma is classic Hodgkin lymphoma (cHL) or nodular lymphocyte predominant Hodgkin lymphoma ;
  • the Hodgkin's lymphoma is a classical Hodgkin's lymphoma type (cHL).
  • cHL Hodgkin's lymphoma type
  • Embodiment 12 The method according to any one of embodiments 1-11, wherein the PD-L1 expression level of the tumor is not less than 1%;
  • the tumor has a PD-L1 expression level of about 1% -50%;
  • the PD-L1 expression is detected by immunohistochemistry (e.g. autoimmunohistochemistry) or in situ hybridization (e.g. fluorescent in situ hybridization).
  • immunohistochemistry e.g. autoimmunohistochemistry
  • in situ hybridization e.g. fluorescent in situ hybridization
  • Embodiment 13 The method of any one of Embodiments 1-12, wherein the individual is a mammal;
  • the individual is a human.
  • Embodiment 14 The method according to any one of embodiments 1-13, wherein the anti-PD-L1 antibody or antigen-binding portion thereof, or the composition is administered parenterally; preferably by intravenous infusion or Administration is by subcutaneous injection; further preferably by intravenous infusion.
  • Embodiment 15 The method according to any one of embodiments 1-14, wherein the method is used to treat a solid tumor, and the anti-PD-L1 antibody or antigen-binding portion thereof, or the composition is every 7 days Administration once to 90 days; preferably once every 14 to 21 days; further preferably once every 14 or 21 days;
  • the method is used to treat lymphoma, and the anti-PD-L1 antibody or antigen-binding portion thereof, or the composition is administered every 7 to 90 days; preferably every 14 to 21 days, It is further preferred to repeat the administration every 14 days.
  • Embodiment 16 The method according to any one of embodiments 1 to 14, wherein the maintenance therapy for solid tumors comprises the anti-PD-L1 antibody or antigen-binding portion thereof, or the composition every 7 days (1 Week) to 90 days, or every 7 days (1 week) to 3 months; preferably every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 1 month, every 2 months or every Once every 3 months;
  • the anti-PD-L1 antibody or antigen-binding portion thereof, or the composition is every 7 days (1 week) to 90 days, or every 7 days It is administered once a day (1 week) to 3 months; preferably once every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 1 month, every 2 months, or every 3 months.
  • Embodiment 17 The method according to any one of embodiments 1-16, wherein each dose of the anti-PD-L1 antibody or antigen-binding portion thereof or the composition is 100 mg to 5000 mg per body; preferably 300 mg to 2400 mg, more preferably 600 mg to 2400 mg, and still more preferably 600 mg, 900 mg, 1200 mg, 1500 mg, 1800 mg, 2000 mg, 2200 mg, or 2400 mg.
  • Embodiment 18 The method according to any one of embodiments 1-16, wherein the method is used to treat a solid tumor, the anti-PD-L1 antibody or antigen-binding portion thereof or each administration of the composition
  • the dose is based on the patient's body weight from 1 mg / kg to 50 mg / kg; preferably 2 mg / kg to 40 mg / kg, further preferably 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 10 mg / kg, 12 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 33 mg / kg, 36 mg / kg or 40 mg / kg.
  • Embodiment 19 The method according to any one of embodiments 1-14, wherein the method is used to treat a solid tumor, and the anti-PD-L1 antibody or antigen-binding portion thereof or the composition is administered in a first administration Regimen administration, the first administration regimen includes:
  • the anti-PD-L1 antibody or antigen-binding portion thereof or the composition ranges from 1 mg / kg to 50 mg / kg (preferably 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / (kg, 6mg / kg, 7mg / kg, 8mg / kg, 10mg / kg, 12mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 33mg / kg, 36mg / kg or 40mg / kg) Administration at a dose of once every 14 or 21 days; 2) a maintenance phase, wherein the anti-PD-L1 antibody or antigen-binding portion thereof or the composition is administered at a dose of 1 mg / kg to 50 mg / kg based on the patient's body weight, It is administered every 1, 2, 3 or 4 weeks or every 1, 2 or 3 months.
  • Embodiment 20 The method according to any one of embodiments 1-14, wherein the method is used to treat a solid tumor or lymphoma, and the anti-PD-L1 antibody or antigen-binding portion thereof or the composition is Administration in two dosing regimens, the second dosing regimen comprising:
  • an induction phase wherein the anti-PD-L1 antibody or antigen-binding portion thereof or the composition is administered at a dose of 600 mg to 2400 mg, preferably 600 mg, 900 mg, 1200 mg, 1500 mg, 1800 mg, 2000 mg, 2200 mg, or 2400 mg per body, Administered every 14 or 21 days; 2) a maintenance phase in which the anti-PD-L1 antibody or antigen-binding portion thereof or the composition is administered at a dose of 600 mg to 2400 mg per body, every 1, 2, 3 or 4 weeks Or at least once every 1, 2 or 3 months;
  • the anti-PD-L1 antibody or antigen-binding portion thereof or the composition is administered at a dose of 900 mg per body, once every 14 days, or at a dose of 1200 mg, 1500 mg, or 1800 mg, Apply every 21 days.
  • Embodiment 21 The method of any one of Embodiments 1-20, wherein the method enables the individual to achieve disease control (DC); the disease control includes a complete response (CR), a partial response (PR) Or stable disease (SD).
  • DC disease control
  • the disease control includes a complete response (CR), a partial response (PR) Or stable disease (SD).
  • Embodiment 22 The method according to any one of embodiments 1-21, wherein the antibody or antigen-binding portion thereof can be administered in combination with other components having antitumor activity.
  • antibody refers to an immunoglobulin molecule that generally consists of two pairs of polypeptide chains, each pair having one "light” (L) chain and one "heavy” (H) chain. .
  • Antibody light chains can be classified into kappa and lambda light chains.
  • Heavy chains can be classified as ⁇ , ⁇ , ⁇ , ⁇ , or ⁇ , and the isotypes of antibodies are defined as IgM, IgD, IgG, IgA, and IgE, respectively.
  • the variable and constant regions are linked by a "J" region of about 12 or more amino acids, and the heavy chain also contains a "D" region of about 3 or more amino acids.
  • Each heavy chain is composed of a heavy chain variable region (V H ) and a heavy chain constant region (C H ).
  • the heavy chain constant region is comprised of three domains (C H 1, C H 2 and C H 3) components.
  • Each light chain is comprised of a light chain variable region (V L) and a light chain constant region (C L) components.
  • the light chain constant region is comprised of one domain, C L composition.
  • the constant region of an antibody can mediate the binding of immunoglobulins to host tissues or factors, including various cells of the immune system (eg, effector cells) and the first component (C1q) of the classical complement system.
  • V H and V L regions can also be subdivided into regions with high denaturation (referred to as complementarity determining regions (CDRs)) with a more conservative region called a framework region (FR) interspersed between them.
  • CDRs complementarity determining regions
  • FR framework region
  • Each V H and V L is composed of 3 CDRs and 4 FRs arranged in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4 from the amino terminal to the carboxy terminal.
  • the assignment of amino acids to regions or domains follows Kabat Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md.
  • antibody is not limited by any particular method of producing antibodies. For example, it includes, in particular, recombinant antibodies, monoclonal antibodies, and polyclonal antibodies.
  • the antibodies may be antibodies of different isotypes, for example, IgG (eg, IgG1, IgG2, IgG3 or IgG4 subtypes), IgA1, IgA2, IgD, IgE or IgM antibodies.
  • CDR complementarity determining region
  • the precise boundaries of these amino acid residues can be defined according to various numbering systems known in the art, for example, according to the Kabat numbering system (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health) Health, Bethesda, Md., 1991), Chothia numbering system (Chothia & Lesk (1987) J. Mol. Biol. 196: 901-917; Chothia et al.
  • an antibody refers to a polypeptide comprising a fragment of a full-length antibody that retains specific binding to the same antigen to which the full-length antibody binds.
  • Ability, and / or compete with full-length antibodies for specific binding to an antigen See generally, Fundamental Immunology, Ch. 7 (Paul, W., ed., 2nd edition, Raven Press, NY (1989), which is incorporated herein by reference in its entirety for all purposes.
  • Recombinant DNA technology can be used The antigen-binding fragment of the antibody is produced either by enzymatic or chemical cleavage of the intact antibody.
  • the antigen-binding fragment includes Fab, Fab ', F (ab') 2 , Fd, Fv, dAb, and complementarity determining region (CDR) Fragments, single-chain antibodies (e.g., scFv), chimeric antibodies, diabody, and polypeptides comprising at least a portion of an antibody sufficient to confer a polypeptide-specific antigen-binding ability.
  • CDR complementarity determining region
  • the term “Fd fragment” means an antibody fragment consisting of the VH and CH1 domains
  • the term “dAb fragment” means an antibody fragment consisting of the VH domain (Ward et al., Nature 341: 544 546 (1989))
  • the term “Fab fragment” means an antibody fragment consisting of the VL, VH, CL, and CH1 domains
  • the term “F (ab ') 2 fragment” means an antibody that is linked by a disulfide bridge on the hinge region An antibody fragment of two Fab fragments
  • the term “Fab 'fragment” means a fragment obtained by reducing the disulfide bonds linking two heavy chain fragments in the F (ab') 2 fragment, consisting of a complete light and heavy chain Fd fragment (consisting of VH and CH1 domains).
  • Fv fragment means an antibody fragment consisting of the VL and VH domains of one arm of an antibody. Fv fragments are generally considered to be the smallest antibody fragments that can form a complete antigen-binding site. It is generally believed that six CDRs confer antigen-binding specificity to an antibody. However, even a variable region (such as an Fd fragment containing only three antigen-specific CDRs) can recognize and bind the antigen, although its affinity may be lower than the complete binding site.
  • Fc fragment means formed by the binding of the second and third constant regions of the first heavy chain of an antibody and the second and third constant regions of the second heavy chain via a disulfide bond.
  • Antibody fragment The Fc fragment of an antibody has many different functions, but does not participate in antigen binding.
  • scFv refers to a single polypeptide chain comprising VL and VH domains, wherein the VL and VH are linked by a linker (see, for example, Bird et al., Science 242: 423 -426 (1988); Huston et al., Proc. Natl. Acad. Sci. USA 85: 5879-5883 (1988); and Pluckthun, The Pharmacology of Monoclonal Antibodies, Vol. 113, eds. Roseburg and Moore, Springer-Verlag, New York, pp. 269-315 (1994)).
  • Such scFv molecules may have a general structure: NH2-VL-linker-VH-COOH or NH2-VH-linker-VL-COOH.
  • a suitable prior art linker consists of a repeating GGGGS amino acid sequence or a variant thereof.
  • a linker having the amino acid sequence (GGGGS) 4 may be used, but a variant thereof may also be used (Holliger et al. (1993), Proc. Natl. Acad. Sci. USA 90: 6444-6448).
  • Other linkers useful in the present invention are Alfthan et al. (1995), Protein Eng. 8: 725-731, Choi et al. (2001), Eur. J. Immunol.
  • the term "diabody” means that its VH and VL domains are expressed on a single polypeptide chain, but use a linker that is too short to allow two domains of the same chain to be allowed Pairing, forcing the domain to pair with the complementary domain of another chain and creating two antigen-binding sites (see, for example, Holliger P. et al., Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993 ), And Poljak RJ et al., Structure 2: 1121-1123 (1994)).
  • Antigens of an antibody can be obtained from a given antibody (e.g., 5C10, 5C10H1L1, 5C10H1L2, 5C10H2L1, and 5C10H2L2) using conventional techniques known to those skilled in the art (e.g., recombinant DNA technology or enzymatic or chemical cleavage methods). Binding fragments (e.g., the antibody fragments described above), and the antigen-binding fragments of the antibodies are specifically screened for in the same manner as for intact antibodies.
  • a given antibody e.g., 5C10, 5C10H1L1, 5C10H1L2, 5C10H2L1, and 5C10H2L2L2
  • Binding fragments e.g., the antibody fragments described above
  • the antigen-binding fragments of the antibodies are specifically screened for in the same manner as for intact antibodies.
  • antibody As used herein, unless the context clearly indicates otherwise, when referring to the term “antibody”, it includes not only whole antibodies but also antigen-binding fragments of antibodies.
  • chimeric antibody refers to an antibody whose light or / and heavy chain part is derived from an antibody (which may be derived from a particular species or belong to a particular antibody class or Subclass), and another part of the light or / and heavy chain is derived from another antibody (which may be of the same or different species or belong to the same or different antibody class or subclass), but in any case, it remains Binding activity to target antigens (USP 4,816,567 to Cabilly et al .; Morrison et al., Proc. Natl. Acad. Sci. USA, 81: 6851 6685 (1984)).
  • chimeric antibody can include antibodies (e.g., human and mouse chimeric antibodies) in which the heavy and light chain variable regions of the antibody are derived from a first antibody (e.g., a mouse-derived antibody), and the heavy and The light chain constant region is derived from a second antibody (e.g., a human antibody).
  • a first antibody e.g., a mouse-derived antibody
  • a second antibody e.g., a human antibody
  • humanized antibody means that all or part of a CDR region of a human immunoglobulin (receptor antibody) is replaced by a CDR region of a non-human antibody (donor antibody).
  • the antibody or antibody fragment thereof, wherein the donor antibody may be a non-human (eg, mouse, rat, or rabbit) antibody having a desired specificity, affinity, or reactivity.
  • some amino acid residues of the framework region (FR) of the receptor antibody can also be replaced by the amino acid residues of the corresponding non-human antibody, or by the amino acid residues of other antibodies to further improve or optimize the performance of the antibody.
  • the term "identity" is used to refer to a sequence match between two polypeptides or between two nucleic acids.
  • a position in two compared sequences is occupied by the same base or amino acid monomer subunit (e.g., a position in each of the two DNA molecules is occupied by adenine, or two A certain position in each of the polypeptides is occupied by lysine)
  • the molecules are identical at that position.
  • the "percent identity” between two sequences is a function of the number of matching positions shared by the two sequences divided by the number of positions compared x 100. For example, if 6 of the 10 positions of two sequences match, the two sequences are 60% identical.
  • the DNA sequences CTGACT and CAGGTT share 50% identity (3 of the 6 positions match).
  • comparisons are made when two sequences are aligned to produce maximum identity.
  • alignment can be achieved by using, for example, the method of Needleman et al. (1970) J. Mol. Biol. 48: 443-453, which can be conveniently performed by a computer program such as the Align program (DNAstar, Inc.).
  • Align program DNAstar, Inc.
  • the algorithm of E.Meyers and W.Miller Comput.Appl.
  • the Needleman and Wunsch (J MoI Biol. 48: 444-453 (1970)) algorithm integrated into the GAP program of the GCG software package can be used, using the Blossom 62 matrix or PAM250 matrix with gap weights of 16, 14, 12, 10, 8, 6, or 4 and length weights of 1, 2, 3, 4, 5, or 6 to determine the percent identity between two amino acid sequences .
  • conservative substitution means an amino acid substitution that does not adversely affect or alter the intended properties of the protein / polypeptide comprising the amino acid sequence.
  • conservative substitutions can be introduced by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis.
  • Conservative amino acid substitutions include substitutions of amino acid residues with amino acid residues having similar side chains, such as those that are physically or functionally similar to the corresponding amino acid residue (e.g., have similar size, shape, charge, chemical properties, including The ability to form covalent or hydrogen bonds, etc.).
  • a family of amino acid residues with similar side chains has been defined in the art.
  • These families include those with basic side chains (e.g., lysine, arginine, and histidine), acidic side chains (e.g., aspartic acid, glutamic acid), and uncharged polar side chains (e.g., glycine) , Asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), non-polar side chains (e.g.
  • alanine, valine, leucine, isoleucine Proline, proline, phenylalanine, methionine
  • beta branched side chains e.g., threonine, valine, isoleucine
  • aromatic side chains e.g., tyrosine, Phenylalanine, tryptophan, histidine. Therefore, it is preferred to replace the corresponding amino acid residue with another amino acid residue from the same side chain family.
  • Methods for identifying conservative substitutions of amino acids are well known in the art (see, for example, Brummell et al., Biochem. 32: 1180-1187 (1993); Kobayashi et al. Protein Eng. 12 (10): 879-884 (1999) ; And Burks et al. Proc. Natl Acad. Set USA 94: 412-417 (1997), which is incorporated herein by reference).
  • the term "pharmaceutically acceptable carrier and / or excipient” refers to a carrier and / or excipient that is pharmacologically and / or physiologically compatible with the subject and the active ingredient. They are non-toxic to the cells or mammals to which they are exposed at the dosages and concentrations used. Including but not limited to: pH adjusters, surfactants, adjuvants, ionic strength enhancers, diluents, agents to maintain osmotic pressure, agents to delay absorption, preservatives.
  • pH adjusting agents include, but are not limited to, phosphate buffered saline.
  • Surfactants include, but are not limited to, cationic, anionic or non-ionic surfactants, such as Tween-80.
  • Ionic strength enhancers include, but are not limited to, sodium chloride.
  • Preservatives include, but are not limited to, various antibacterial and antifungal agents, such as parabens, trichlorot-butanol, phenol, sorbic acid, and the like.
  • Agents that maintain osmotic pressure include, but are not limited to, sugar, NaCl, and the like.
  • Agents that delay absorption include, but are not limited to, monostearate and gelatin.
  • Diluents include, but are not limited to, water, aqueous buffers (such as buffered saline), alcohols and polyols (such as glycerol), and the like.
  • Preservatives include, but are not limited to, various antibacterial and antifungal agents, such as thimerosal, 2-phenoxyethanol, parabens, trichlorot-butanol, phenol, sorbic acid, and the like.
  • Stabilizers have the meaning commonly understood by those skilled in the art, which are capable of stabilizing the desired activity of the active ingredients in the drug, including but not limited to sodium glutamate, gelatin, SPGA, sugars (such as sorbitol, mannitol, starch, sucrose , Lactose, dextran, or glucose), amino acids (such as glutamic acid, glycine), proteins (such as dried whey, albumin, or casein) or their degradation products (such as lactalbumin hydrolysate) and the like.
  • sugars such as sorbitol, mannitol, starch, sucrose , Lactose, dextran, or glucose
  • amino acids such as glutamic acid, glycine
  • proteins such as dried whey, albumin, or casein
  • degradation products such as lactalbumin hydrolysate
  • effector function refers to those biological activities that are attributable to the Fc region of an antibody (a natural sequence Fc region or an amino acid sequence variant Fc region), and it varies with the antibody Isotype varies.
  • antibody effector functions include, but are not limited to: Fc receptor binding affinity, antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), antibody-dependent cell phagocytosis (ADCP) Down-regulation of cell surface receptors (such as B-cell receptors), B-cell activation, cytokine secretion, half-life / clearance of antibodies and antigen-antibody complexes, etc.
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • CDC complement-dependent cytotoxicity
  • ADCP antibody-dependent cell phagocytosis
  • Down-regulation of cell surface receptors such as B-cell receptors
  • B-cell activation such as B-cell activation
  • cytokine secretion half-life / clearance of antibodies and antigen-antibody complexes
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • cytotoxic cells such as natural killer (NK) cells, neutral Granulocytes or macrophages
  • FcR Fc receptors
  • Methods for detecting the ADCC activity of an antibody are known in the art, and can be evaluated, for example, by measuring the binding activity between a test antibody and an Fc receptor (eg, CD16a).
  • complement dependent cytotoxicity refers to a cytotoxic form of the complement cascade that is activated by binding complement component C1q to antibody Fc.
  • Methods for detecting the CDC activity of an antibody are known in the art, and can be evaluated, for example, by measuring the binding activity between a test antibody and an Fc receptor (eg, Clq).
  • the term "about” refers to a value within an acceptable error range for a particular value, as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or Determination, that is, the limitation of the measurement system. For example, “about” may mean a range of up to 10% (ie, ⁇ 10%). For example, about 1 mg may include any amount between 0.7 mg and 1.3 mg. In certain embodiments, the term “about” refers to plus or minus 10% or plus or minus 5% of a value described herein.
  • the term "adverse event” refers to any adverse medical event that occurs in a patient or clinical trial subject after the application of a drug.
  • the term “serious adverse event” refers to a serious adverse medical event that occurs in a patient or clinical trial subject after the application of a drug.
  • CCAE grade refers to the severity classification of adverse events, and the specific classification standards are based on the specific regulations recorded in National Institute of Criteria and Criteria for Adverse Events (NCI-CTCAE), version 4.03.
  • CR complete response
  • PR partial response
  • SD stable disease
  • PD progression of disease
  • Table 1 Evaluation criteria for the efficacy of lymphoma (2014 Lugano efficacy evaluation criteria)
  • CR complete response
  • PR partial response
  • SD stable disease
  • PD disease progression
  • SPD product of maximum vertical diameter
  • PPD product of longest diameter and its vertical meridian
  • LDi longest transverse diameter
  • SDi shortest axial diameter perpendicular to LDi.
  • CR Complete remission
  • Partial remission The sum of the diameters of the target lesions (minor diameter of the lymph nodes) is reduced by at least 30% from the baseline level. Non-target lesions did not progress significantly, and there were no new lesions.
  • PD Disease progression
  • Stable disease The target lesions did not decrease to PR, and the increase did not reach PD. Between the two, the minimum value of the sum of diameters can be used as a reference during the study.
  • the PD-L1 antibodies used in the present invention are 5C10, 5C10H1L1, 5C10H1L2, 5C10H2L1, 5C10H2L2, or 5C10H2L2-IgG1mt, and are prepared according to the methods of Examples 1-4 and 15 of WO2017 / 148424.
  • 5C10, 5C10H1L1, 5C10H1L2, 5C10H2L1, 5C10H2L2 heavy chain constant region is Ig gamma-1 chain C region
  • ACCESSION: P01857 light chain constant region is Ig kappa chain C region
  • ACCESSION: P01834 5C10H2L2-IgG1mt
  • heavy chain constant region is Igamma-1 chain region
  • ACCESSION: P01857 amino acid residues at positions 234, 235, and 237 are mutated as follows: L234A, L235A, G237A.
  • composition containing: anti-PD-L1 antibody (5C10H2L2-IgG1mt) 20 mg / ml, 140 mM sodium chloride, 20 mM histidine-histidine hydrochloride, and a polymer with a mass-volume ratio of 0.02%. Sorbate 80, pH 5.8.
  • the preparation method is as follows:
  • Configure buffer solution add 140 mM sodium chloride and 20 mM histidine to the water for injection, and adjust the pH to 5.8 with hydrochloric acid.
  • the antibody stock solution (batch number 1) was changed through ultrafiltration, dialyzed to the above buffer solution, adjusted the antibody concentration to 20 mg / ml, and added an appropriate amount of polysorbate 80 stock solution.
  • the configured sample is sterilized and filtered through a 0.22 ⁇ m pore size filter under laminar flow conditions, filled into a vial, and capped and capped to obtain a clinical research sample.
  • 5C10H2L2-IgG1mt Patients with Merkel cell carcinoma received 5C10H2L2-IgG1mt intravenously.
  • the dose of 5C10H2L2-IgG1mt was calculated as 5mg / kg based on the patient's body weight.
  • 1.0h ( ⁇ 5min) or 1.0h ( ⁇ 10min) was administered by intravenous drip on the first day of each cycle Or intravenous infusion on the first day of each cycle, 0 to 30 minutes of infusion per cycle, infusion of no more than 30ml infusion solution, the total infusion duration is not less than 120 minutes, every 21 days is a cycle, administration until Disease progression or intolerable toxicity or withdrawal of informed consent.
  • Example 3 Clinical study of 5C10H2L2-IgG1mt in the treatment of lung squamous cell carcinoma
  • Patients with lung squamous cell carcinoma received intravenous injection of 5C10H2L2-IgG1mt, of which 5C10H2L2-IgG1mt was administered at a dose of 600 mg / time, and 1.0h ( ⁇ 5min) or 1.0h ( ⁇ 10min) was administered intravenously on the first day of each cycle, or every Intravenous infusion on the first day of the cycle, 0 to 30 minutes of infusion per cycle, infusion of no more than 30ml infusion, the total infusion duration is not less than 120 minutes, every 21 days is a cycle, administration until the disease progresses or appears Intolerable toxicity or withdrawal of informed consent.
  • Patients with peripheral T-cell lymphoma receive 5C10H2L2-IgG1mt intravenously, of which 5C10H2L2-IgG1mt is administered at a dose of 1200 mg / time, 1.0 h ( ⁇ 5 min) or 1.0 h ( ⁇ 10 min) by intravenous infusion on the first day of each cycle, or It is an intravenous infusion on the first day of each cycle.
  • the infusion of each cycle is 0 to 30 minutes.
  • the infusion does not exceed 30ml.
  • the total infusion duration is not less than 120 minutes. Every 21 days is a cycle.
  • the drug is administered until the disease progresses. Patients may have intolerable toxicity or withdraw their informed consent. Patients can be accepted for study medication for up to 12 months before leaving the group.
  • Example 5 Clinical study of 5C10H2L2-IgG1mt in treatment of vascular immunoblast T-cell lymphoma
  • 5C10H2L2-IgG1mt is administered intravenously in patients with vascular immunoblast T-cell lymphoma, of which 5C10H2L2-IgG1mt is administered at a dose of 1200 mg / time, and 1.0h ( ⁇ 5min) or 1.0h ( ⁇ 10min) is administered intravenously on the first day of each cycle. ), Or intravenous infusion on the first day of each cycle, 0 to 30 minutes of infusion per cycle, infusion of no more than 30ml infusion solution, the total infusion time is not less than 120 minutes, every 21 days is a cycle, administration Until the disease progresses or intolerable toxicity or the informed consent is withdrawn, patients can be accepted for study medication for up to 12 months before leaving the group.
  • 5C10H2L2-IgG1mt Patients with Hodgkin's lymphoma received 5C10H2L2-IgG1mt intravenously.
  • the dosage of 5C10H2L2-IgG1mt was 600mg / time, 900mg / time, 1200mg / time, 1500mg / time, and intravenous drip was administered on the first day of each cycle.
  • the administration period is 600 mg / time, 1200 mg / time, 1500 mg / time, the administration cycle is 21 days, and the administration dose is 900 mg / time, the administration cycle is 14 days, and the medicine is administered until the disease progresses or appears.
  • the administration period is 600 mg / time, 1200 mg / time, 1500 mg / time
  • the administration cycle is 21 days
  • the administration dose is 900 mg / time
  • the administration cycle is 14 days
  • the medicine is administered until the disease progresses or appears.
  • patients can be withdrawn for a maximum of 12 months after the study drug is accepted.
  • Example 7 Clinical study of 5C10H2L2-IgG1mt in the treatment of nasopharyngeal carcinoma
  • Patients with nasopharyngeal carcinoma received intravenous injection of 5C10H2L2-IgG1mt, of which 5C10H2L2-IgG1mt was administered at a dose of 5mg / kg based on the patient's body weight.
  • 1.0h ( ⁇ 5min) or 1.0h ( ⁇ 10min) was administered intravenously on the first day of each cycle
  • intravenous infusion on the first day of each cycle 0 to 30 minutes of infusion per cycle, infusion of no more than 30ml infusion solution, the total infusion duration is not less than 120 minutes, every 21 days is a cycle, administration until Confirmed disease progression or intolerable toxicity or withdrawal of informed consent.
  • Example 8 Clinical study of 5C10H2L2-IgG1mt in the treatment of NK / T cell lymphoma
  • Patients with NK / T cell lymphoma received 5C10H2L2-IgG1mt intravenous injection treatment, of which 5C10H2L2-IgG1mt was administered at a dose of 1200mg / time, and 1.0h ( ⁇ 5min) or 1.0h ( ⁇ 10min) was administered intravenously on the first day of each cycle.
  • intravenous infusion on the first day of each cycle 0 to 30 minutes of infusion per cycle, no more than 30ml of infusion, the total infusion duration is not less than 120 minutes, every 21 days is a cycle, administration until disease Progress or intolerable toxicity or withdrawal of informed consent, if the above 3 conditions do not occur, the patient can be administered for up to 48 weeks.
  • Example 9 Clinical study of 5C10H2L2-IgG1mt in the treatment of cholangiocarcinoma
  • 5C10H2L2-IgG1mt is administered at a dose of 600 to 1500 mg / time, or 5 mg / kg based on the patient's body weight.
  • Intravenous infusion of 1.0 h ( ⁇ 5 min) or 1.0 h ( ⁇ 10 min) on the first day of each cycle, or every cycle Intravenous infusion on the first day, 0 to 30 minutes of infusion per cycle, infusion of no more than 30 ml of infusion, the total infusion duration is not less than 120 minutes, every 14 to 21 days is a cycle, and the drug is administered until the disease progresses or Intolerable toxicity or withdrawal of informed consent.

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Abstract

La présente invention concerne une utilisation d'un anticorps anti-ligand de mort programmée 1 (PD-L1) dans la préparation de médicaments pour le traitement de tumeurs, telles que des lymphomes ou des tumeurs solides.
PCT/CN2019/106599 2018-09-29 2019-09-19 Utilisation anti-tumorale d'un anticorps anti-ligand de mort programmée 1 (pd-l1) WO2020063433A1 (fr)

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WO2017148424A1 (fr) * 2016-03-04 2017-09-08 四川科伦博泰生物医药股份有限公司 Anticorps anti-pdl-1, composition pharmaceutique et utilisations de celui-ci

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SI1907000T2 (sl) * 2005-06-08 2020-07-31 Dana-Farber Cancer Institute Postopki in sestavki za zdravljenje persistentne HIV infekcije z inhibicijo programiranih celični smrtnih 1 (PD-1) poti
US10585100B2 (en) * 2015-04-30 2020-03-10 Kyoto University Method of predicting effect of treatment by PD-1/PD-L1 blockade using abnormality of PD-L1 (CD274) as index
CN107496933B (zh) * 2017-08-21 2019-12-24 山东新华制药股份有限公司 一种用于治疗胰腺癌的抗体药物偶联物及其制备方法

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Publication number Priority date Publication date Assignee Title
WO2017148424A1 (fr) * 2016-03-04 2017-09-08 四川科伦博泰生物医药股份有限公司 Anticorps anti-pdl-1, composition pharmaceutique et utilisations de celui-ci
CN107151269A (zh) * 2016-03-04 2017-09-12 四川科伦博泰生物医药股份有限公司 一种pdl‑1抗体、其药物组合物及其用途

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