WO2020135415A1 - 抗pd-l1单克隆抗体治疗癌症的用途 - Google Patents

抗pd-l1单克隆抗体治疗癌症的用途 Download PDF

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WO2020135415A1
WO2020135415A1 PCT/CN2019/127891 CN2019127891W WO2020135415A1 WO 2020135415 A1 WO2020135415 A1 WO 2020135415A1 CN 2019127891 W CN2019127891 W CN 2019127891W WO 2020135415 A1 WO2020135415 A1 WO 2020135415A1
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seq
antibody
amino acid
subject
acid sequence
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PCT/CN2019/127891
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English (en)
French (fr)
Inventor
张喜全
王训强
赵伟
熊征江
苏楠
吴若男
邵小文
张驰
闫云霞
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正大天晴药业集团股份有限公司
正大天晴药业集团南京顺欣制药有限公司
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Priority to CN201980081462.1A priority Critical patent/CN113164599B/zh
Publication of WO2020135415A1 publication Critical patent/WO2020135415A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants

Definitions

  • the present invention provides a method of treating cancer in a subject, which comprises administering to the subject a therapeutically effective amount of an inhibitor of the interaction between the PD-1 receptor and its ligand PD-L1.
  • the natural immune system containing T lymphocytes has a strong anti-cancer ability, which has a wide range of capabilities and fine specificity, thus responding to various tumor antigens.
  • Emerging cancer immunotherapy enhances anti-tumor immune responses through adoptive transfer of activated effector cells, immunization against relevant antigens, or the provision of non-specific immunostimulants.
  • researchers have worked hard to develop specific immune checkpoint inhibitors and hope to provide new immunotherapeutic solutions for the treatment of cancer, including the development of antibodies that bind to and inhibit CTLA-4 (antibody) ipilimumab ( Ipilimumab)
  • CTLA-4 antibody
  • Ipilimumab ipilimumab
  • PD-1 programmed death receptor-1
  • PD-1 is a key immune checkpoint receptor expressed by activated T lymphocytes and B lymphocytes and mediates immunosuppression
  • its ligands include at least PD-L1 And PD-L2.
  • PD-L1 Programmed death-ligand 1
  • CD247 and B7-H1 are a 40kDa type 1 transmembrane protein encoded by the CD274 gene and is a ligand of PD-1.
  • Both PD-L1 and PD-1 belong to the immunoglobulin superfamily and are composed of two extracellular Ig domains, namely the N-terminal V domain and the C-terminal constant domain.
  • the binding interface between PD-L1 and programmed death receptor-1 (PD-1) and B7-1 (CD80) is on the IgV-like domain (Lin et al. (2008) PNAS 105:3011-3016).
  • PD-L1 contains a conserved short intracellular tail region (about 30 amino acids)
  • PD-1 contains two cytoplasmic tyrosine-based signaling motifs, namely the immunoreceptor tyrosine-based inhibitory motif (ITIM ) And the immunoreceptor tyrosine-based switching motif (ITSM).
  • ITIM immunoreceptor tyrosine-based inhibitory motif
  • ITSM immunoreceptor tyrosine-based switching motif
  • PD-L1 is not only widely distributed on white blood cells and non-hematopoietic cells in lymphatic and non-lymphoid tissues, but also widely distributed in various cancer cells, and is highly expressed on the surface of various tumor cells. Moreover, the malignant degree of tumors and poor prognosis and The expression level of PD-L1 is closely related. There are clinical data indicating that high tumor expression of PD-L1 is associated with increased tumor aggressiveness and poor prognosis.
  • the formation of the PD-1/PD-L1 complex transmits inhibitory signals and negatively regulates T cell immune responses; it inhibits TCR-mediated T cell activation, cytokine production, and T cell proliferation (Fife et al. (2011) Nature Immunology 10:1185 -1193); induce failure or anergy among T-cells specific for cognate antigens (Hofmeyer et al. (2011) Journal of Biomedicine and Biotechnology 2011: 1-9); promote Th1 cell differentiation into Foxp3+ regulatory T cells (Armanath (2011) Science TransMed 3:1-13; Francisco et al. (2009) J. Exp. Med. 206:3015-3029); and induce apoptosis of effector T cells.
  • Anti-PD-L1 antibodies can block the interaction of PD-L1 with PD-1 and CD80, so that the related negative regulatory signals cannot be initiated and transmitted, thereby avoiding the inhibition of the activity of effector T cells in the tumor microenvironment. , So that T cells can play the role of killing and inhibiting tumor cells. Since anti-PD-L1 antibody can directly act on tumor tissue, it has high specificity and safety. At present, the main anti-PD-L1 monoclonal antibody drug products include Roche's Atezolizumab, AstraZeneca's Durvalumab and Merck & Pfizer's Avelumab.
  • Patent WO2016022630 also discloses anti-PD-L1 antibodies, which have a high affinity for PD-L1, can significantly inhibit the interaction of PD-L1 and PD-1 on the cell surface, and significantly promote the secretion of IL-2 and IFN- by T cells ⁇ .
  • Hodgkin's lymphoma is a type of lymphoma, which is a Carcinogenesis of lymphocytes (Bower, Mark; Waxman, Jonathan. Lecture Notes: Oncology 2. John Wiley & Sons. 2011: 195.
  • Symptoms include fever, night sweats, and weight loss, common neck, upper arm , And painless enlargement of the groin lymph nodes, patients may also feel tired or itchy (Adult Hodgkin Lymphoma Treatment -Patient Version.NCI.August 3,2016). About half of Hodgkin's lymphoma is caused by Epstein-Barr virus, other risk factors include family history, or individuals have been infected with HIV (World Cancer Report 2014. World Health Organization.2014: Chapter 2.4.ISBN 928320429-8. ).
  • Hodgkin lymphoma is mainly divided into classical Hodgkin lymphoma and nodular lymphocyte-based Hodgkin lymphoma (SEER Stat Fact Sheets: Hodgkin Lymphoma.NCI.April 2016) Among them, cHL accounts for about 95%, which can be assisted by finding Hodgkin lymphocytes in lymph nodes, such as RS cells.
  • Hodgkin's lymphoma can be treated by chemotherapy, radiation therapy, and bone marrow transplantation. The choice of treatment is generally judged by the degree of disease progression and its characteristics.
  • HDT high-dose chemotherapy
  • ASCT autologous hematopoietic stem cell transplantation
  • the present invention provides a method of treating, relieving or ameliorating cancer in a subject, which comprises administering to the subject a therapeutically effective amount of an inhibitor of the interaction between the PD-1 receptor and its ligand PD-L1, wherein The inhibitor is PD-L1 antibody.
  • the present invention also provides the use of anti-PD-L1 antibody to treat, alleviate or ameliorate cancer, which includes administering to the subject a therapeutically effective amount of an inhibitor of the interaction between the PD-1 receptor and its ligand PD-L1, Among them, the inhibitor is an anti-PD-L1 antibody.
  • the present invention also provides the use of anti-PD-L1 antibodies in the preparation of a medicament for treating, alleviating, or ameliorating cancer.
  • the present invention also provides anti-PD-L1 antibodies for treating, relieving or ameliorating cancer in a subject.
  • the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain CDR1 region having at least 80% homology with the amino acid sequence shown in SEQ ID NO: 1 or SEQ ID NO: 4; and SEQ ID
  • the heavy chain CDR2 region of the amino acid sequence shown in NO: 2 or SEQ ID NO: 5 is at least 80% homologous; at least 80% homologous to the amino acid sequence shown in SEQ ID NO: 3 or SEQ ID NO: 6
  • the anti-PD-L1 antibody is at 1 mg/kg, 2 mg/kg, 3 mg/kg, 5 mg/kg, 6 mg/kg, 9 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 30 mg /kg body weight is administered continuously.
  • the anti-PD-L1 antibody is administered in one or more uniform doses that can effectively treat the cancer.
  • the unified dose is in the range of about 20 mg to about 2000 mg of anti-PD-L1 antibody.
  • the unified dose is selected from about 300 mg, about 600 mg, about 900 mg, about 1000 mg, about 1200 mg, about 1500 mg, about 1800 mg, about 2100 mg, or about 2400 mg of anti-PD-L1 antibody.
  • the uniform dose is selected from about 1200 mg anti-PD-L1 antibody.
  • the anti-PD-L1 antibody is administered about every week (q1w), about every 2 weeks (q1w), about every 3 weeks (q1w), or about every 4 weeks (q1w).
  • the patient is administered a uniform dose of anti-PD-L1 antibody approximately every 3 weeks.
  • the anti-PD-L1 antibody is administered at a dose of 1200 mg per patient, approximately every 3 weeks, and continuous administration.
  • the anti-PD-L1 antibody is administered as an intravenous infusion. In some embodiments, the anti-PD-L1 antibody is administered as an intravenous infusion for about 1-2 hours, preferably about 1 hour.
  • the anti-PD-L1 antibody is a naked antibody, an intact antibody, or an antibody fragment including an antigen binding region.
  • the method results in an objective response, preferably a complete response or a partial response.
  • the subject has previously received surgery, chemotherapy, and/or radiation therapy. In some embodiments, the subject relapses after the operation has been completely relieved. In some specific embodiments, the subject has not been completely relieved or partially relieved after surgery. In some specific embodiments, the subject relapses after the chemotherapy has been completely relieved. In some specific embodiments, the subject fails to completely or partially remit after chemotherapy. In some specific embodiments, the subject relapses after the radiation therapy to achieve complete remission. In some specific embodiments, the subject fails to completely or partially resolve after radiation therapy. In some protocols, the subject has previously undergone surgery and chemotherapy. In some specific embodiments, the subject relapses after the operation and chemotherapy, and the disease progresses again.
  • the subject fails to completely or partially resolve after surgery and chemotherapy. In some protocols, the subject has previously received surgery and radiation therapy. In some specific embodiments, the subject reappears with disease progression after complete remission after surgery and radiation therapy. In some specific embodiments, the subject fails to completely or partially resolve after surgery and radiation therapy. In some protocols, the subject has previously received chemotherapy and radiation therapy. In some specific embodiments, the subject reappears with disease progression after complete remission after chemotherapy and radiation therapy. In some specific embodiments, the subject fails to completely or partially resolve after chemotherapy and radiation therapy. In some protocols, the subject has previously received surgery, chemotherapy, and radiation therapy. In some specific embodiments, the subject reappears with disease progression after complete remission after surgery, chemotherapy, and radiation therapy. In some specific embodiments, the subject fails to completely or partially resolve after surgery, chemotherapy, and radiation therapy.
  • the subject has undergone autologous stem cell transplantation after surgery, chemotherapy, and/or radiation therapy. In some specific embodiments, the subject reappears with disease progression after complete remission after surgery, chemotherapy, and/or autologous stem cell transplantation. In some embodiments, the subject has not been completely or partially relieved after surgery, chemotherapy, and/or autologous stem cell transplantation. In some protocols, the subject has undergone autologous stem cell transplantation after surgery. In some specific embodiments, the subject reappears disease progression after complete remission after surgery and autologous stem cell transplantation. In some specific embodiments, the subject has not been completely or partially relieved after surgery and autologous stem cell transplantation. In some protocols, the subject has undergone autologous stem cell transplantation after receiving chemotherapy.
  • the subject reappears with disease progression after complete remission after chemotherapy and autologous stem cell transplantation. In some specific embodiments, the subject has not been completely or partially relieved after chemotherapy and autologous stem cell transplantation. In some protocols, the subject has undergone autologous stem cell transplantation after receiving radiation therapy. In some embodiments, the subject relapses after radiation therapy and autologous stem cell transplantation and complete remission. In some specific embodiments, the subject fails to completely or partially resolves after radiation therapy and autologous stem cell transplantation. In some protocols, the subject has undergone autologous stem cell transplantation after surgery and chemotherapy. In some embodiments, the subject relapses after surgery, chemotherapy, and autologous stem cell transplantation, and then the disease progresses again.
  • the subject has not been completely or partially relieved after surgery, chemotherapy, and autologous stem cell transplantation.
  • the subject has undergone autologous stem cell transplantation after surgery and radiation therapy.
  • the subject reappears disease progression after complete remission after surgery, radiation therapy, and autologous stem cell transplantation.
  • the subject fails to completely or partially resolve after surgery, radiation therapy, and autologous stem cell transplantation.
  • the subject has undergone autologous stem cell transplantation after receiving chemotherapy and radiation therapy.
  • the subject relapses after chemotherapy, radiation therapy, and autologous stem cell transplantation after complete remission.
  • the subject fails to completely or partially resolve after chemotherapy, radiation therapy, and autologous stem cell transplantation.
  • the subject has undergone autologous stem cell transplantation after surgery. In some specific embodiments, the subject relapses after the autologous stem cell transplantation is completely relieved. In some specific embodiments, the subject has not been completely relieved or partially relieved after autologous stem cell transplantation.
  • the cancer is Hodgkin's lymphoma.
  • the cancer is classical Hodgkin lymphoma (cHL).
  • the classical Hodgkin lymphoma has progressed after chemotherapy and/or radiation therapy.
  • the cancer is relapsed or refractory classic Hodgkin lymphoma.
  • the classical Hodgkin lymphoma is relapsed.
  • the classical Hodgkin lymphoma is refractory.
  • the classical Hodgkin lymphoma is metastatic.
  • the cancer treatment is a third-line treatment of relapsed or refractory classic Hodgkin lymphoma.
  • the cancer treatment is a third-line treatment of metastatic classic Hodgkin lymphoma.
  • the relapsed or refractory classic Hodgkin lymphoma does not progress during the completion of first-line chemotherapy and/or after radiation therapy.
  • the metastatic classic Hodgkin lymphoma does not progress during the completion of first-line chemotherapy and/or after radiation therapy.
  • the relapsed or refractory classic Hodgkin lymphoma has progressed after chemotherapy and/or radiation therapy.
  • the metastatic classic Hodgkin lymphoma has progressed after chemotherapy and/or radiation therapy.
  • the present invention provides an article comprising a container containing a fixed dose of anti-PD-L1 antibody.
  • the invention also provides the use of an anti-PD-L1 antibody in the preparation of a product for the treatment of cancer comprising a container of a fixed dose of anti-PD-L1 antibody.
  • the container is a vial.
  • the fixed dose is selected from about 300 mg, about 600 mg, about 900 mg, about 1000 mg, about 1200 mg, about 1500 mg, about 1800 mg, about 2100 mg, and about 2400 mg of anti-PD-L1 antibody.
  • the article of manufacture further includes a package insert or a package insert that instructs the user to administer the fixed dose to the cancer patient.
  • the article includes one or more vials containing approximately 300 mg or 600 mg of anti-PD-L1 antibody. In some embodiments, the preparation includes a vial containing approximately 300 mg of anti-PD-L1 antibody. In some embodiments, the preparation includes 1 vial containing approximately 600 mg of anti-PD-L1 antibody.
  • the present invention provides a method for treating a subject suffering from cancer or tumor, which comprises administering to the subject a therapeutically effective amount of an inhibitor of the interaction between the PD-1 receptor and its ligand PD-L1 .
  • the present invention also provides a method for treating a subject suffering from cancer or tumor, the method comprising administering to the subject a therapeutically effective amount of: combined with Programmed Death Ligand 1 (PD-L1) and/or inhibition PD-L1 active antibody or antigen-binding portion thereof.
  • PD-L1 Programmed Death Ligand 1
  • the present invention also provides a monotherapy for treating a subject suffering from cancer or tumor, the method comprising separately administering to the subject a therapeutically effective amount of: combined with Programmed Death Ligand 1 (PD-L1) and/or Or an antibody or antigen-binding portion that inhibits PD-L1 activity.
  • PD-L1 Programmed Death Ligand 1
  • the present invention also provides a method of treating a subject suffering from cancer or tumor, which is classical Hodgkin's lymphoma, the method comprising: (i) measuring PD- in a sample of the subject L1 level, where the subject is PD-L1 positive, and (ii) a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding portion thereof is administered to the subject.
  • the present invention provides a method for treating a subject suffering from cancer or tumor.
  • the subject is a patient diagnosed with Hodgkin's lymphoma by histopathology.
  • the subject is a patient diagnosed with histopathology as classical Hodgkin's lymphoma (cHL).
  • the subject is a patient with relapsed or refractory classic Hodgkin's lymphoma (cHL), for example, is a) Relapse after receiving autologous stem cell transplantation after salvage chemotherapy and/or radiotherapy Or patients with advanced disease, or b) patients whose first-line chemotherapy is systemic multi-drug combined chemotherapy, and at least one line of follow-up chemotherapy is systemic multi-drug combined chemotherapy, or c) refractory patients, such as ⁇ 2 cycles of treatment For patients with partial remission (PR) or treatment course ⁇ 4 cycles who have not achieved complete remission (CR), the number of courses is not required if the best response or the end of the previous treatment is disease progression (PD), or d) relapse patients, for example Patients who have received at least second-line chemotherapy in the near-term before relapse.
  • cHL Hodgkin's lymphoma
  • the subject is a patient with relapsed or refractory classic Hodgkin lymphoma (cHL).
  • the subject is a patient with relapsed classic Hodgkin's lymphoma (cHL), and the relapse refers to the recurrence of disease progression after complete remission by treatment.
  • the subject is a patient with refractory classic Hodgkin's lymphoma (cHL), which refers to failure to obtain complete or partial remission after treatment.
  • the subject is a patient with metastatic classic Hodgkin lymphoma (cHL).
  • the metastasis is lymph node metastasis.
  • the metastasis is pleural and/or local chest wall metastasis.
  • the subject is a patient with relapsed and refractory classic Hodgkin's lymphoma (cHL). In some protocols, the subject is a patient with metastatic, relapsed and refractory classic Hodgkin lymphoma (cHL). In some protocols, the subject is a patient with metastatic, relapsed or refractory classic Hodgkin lymphoma (cHL).
  • First-line chemotherapy for classic Hodgkin's lymphoma may include but is not limited to ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), increasing doses of BEACOPP (bleomycin, etoposide , Doxorubicin, cyclophosphamide, vincristine, benzylhydrazine, prednisone) or StanfordV (doxorubicin, vinblastine, nitrogen mustard, etoposide, vincristine, bleomycin, Prednisone) and so on.
  • ABVD doxorubicin, bleomycin, vinblastine, dacarbazine
  • BEACOPP bleomycin, etoposide , Doxorubicin, cyclophosphamide, vincristine, benzylhydrazine, prednisone
  • StanfordV doxorubicin, vinblastine, nitrogen mustard, etoposide, vincri
  • Classic second-line chemotherapy for Hodgkin's lymphoma may include but is not limited to Brentuximab (Brentuximab vedotin), DHAP (dexamethasone, cisplatin, cytarabine), ESHAP (etoposide, methylprednisolone) Pine, cytarabine, cisplatin), gemcitabine, bendamustine, vinorelbine, GVD (gemcitabine, vinorelbine, liposomal doxorubicin), ICE (ifosfamide, card Wave, etoposide), IGEV (ifosfamide, gemcitabine, and vinorelbine), or a combination thereof.
  • the present invention also provides a method for identifying a subject suffering from classical Hodgkin lymphoma, which is suitable for anti-PD-L1 antibody therapy, the method comprising measuring a sample of the subject The level of PD-L1 in, and wherein the subject is administered a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding portion thereof.
  • the present invention also provides a kit for treating a subject suffering from classic Hodgkin lymphoma, the kit comprising: (a) an anti-PD-L1 antibody or antigen-binding portion thereof; (b) regarding treatment Instructions for the tumor.
  • the present invention provides methods for treating cancer using one or more immune checkpoint inhibitors (eg, anti-PD-L1 antibody or antigen-binding portion thereof, or anti-PD-1 antibody or antigen-binding portion thereof).
  • the cancer is a primary cancer.
  • the cancer is metastatic or recurrent cancer.
  • the cancer is a relapsed or refractory cancer.
  • the cancer is Hodgkin's lymphoma.
  • the cancer is relapsed or refractory Hodgkin lymphoma.
  • the invention also provides the use of anti-PD-L1 antibody in the first-line treatment of classic Hodgkin lymphoma.
  • the invention also provides the use of anti-PD-L1 antibody in the second-line treatment of classic Hodgkin lymphoma.
  • the invention also provides the use of anti-PD-L1 antibody in the third-line treatment of classic Hodgkin lymphoma.
  • the anti-PD-L1 antibody is used for second-line treatment of relapsed or refractory classic Hodgkin lymphoma.
  • the anti-PD-L1 antibody is used for third-line treatment of relapsed or refractory classic Hodgkin lymphoma.
  • the anti-PD-L1 antibody is used alone as a third-line treatment for relapsed or refractory classic Hodgkin lymphoma. In some protocols, the anti-PD-L1 antibody is used for the subsequent treatment of relapsed or refractory classic Hodgkin lymphoma.
  • the anti-PD-L1 antibody is used alone as a third-line treatment for patients with relapsed or refractory classic Hodgkin lymphoma who has previously received, including but not limited to ABVD (Doxorubicin) Star, bleomycin, vinblastine, dacarbazine), ABVD combined with radiation therapy (eg ISRT), increasing doses of BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine , Benzhydrazide, prednisone), increasing doses of BEACOPP followed by ABVD and radiation therapy (eg ISRT), or Stanford V (doxorubicin, vinblastine, nitrogen mustard, etoposide, vincristine, First-line treatment of bleomycin, prednisone, etc.
  • ABVD Doxorubicin
  • bleomycin bleomycin
  • vinblastine dacarbazine
  • ABVD combined with radiation therapy
  • the anti-PD-L1 antibody is used alone as a third-line treatment for patients with relapsed or refractory classic Hodgkin lymphoma, who has previously received, including but not limited to, bentuximab (Brentuximabvedotin), DHAP (dexamethasone, cisplatin, cytarabine), ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin), gemcitabine, bendamustine, Vinorelbine, GVD (gemcitabine, vinorelbine, liposomal doxorubicin), ICE (ifosfamide, carbomer, etoposide), IGEV (ifosfamide, gemcitabine, and vinorelbine), Or a combination of second-line treatment.
  • the subject is a human patient.
  • the subject has received another cancer treatment (eg, chemotherapy), but is treatment resistant or refractory to such another cancer.
  • another cancer treatment eg, chemotherapy
  • the present invention provides a method for treating a subject suffering from a tumor, the method comprising administering to the subject a therapeutically effective amount of an immune checkpoint inhibitor, for example, an anti-PD-L1 antibody .
  • the present invention relates to a method of treating a subject with a tumor that is recurrent or refractory classic Hodgkin lymphoma, the method comprising: (i) measuring PD-L1 levels in a sample of the subject, wherein the subject expresses PD-L1, and (ii) administering to the subject a therapeutically effective amount of an immune checkpoint inhibitor, for example, an anti-PD-L1 antibody or antigen binding thereof section.
  • the anti-PD-L1 antibody is 13C5, 5G11, ch13C5-hIgG1, ch13C5-hIgG4, ch5G11-hIgG1, ch5G11-hIgG4, hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1, or hu5G11-hIgG4 MAb.
  • the anti-PD-L1 antibody competes with 5G11 monoclonal antibody for binding.
  • the cancer or tumor expresses PD-L1.
  • the PD-L1 expression level of the tumor in the subject can be measured.
  • the tumor's PD-L1 expression level is at least about 0.5%, at least about 0.6%, at least about 0.7%, at least about 0.8%, at least about 0.9%, 1%, 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%, or greater than at least about 20%.
  • the tumor has a PD-L1 expression level of at least about 1%. In other embodiments, the subject's PD-L1 expression level is at least about 5%. In a specific embodiment, the tumor's PD-L1 expression level is at least about 10%. Using methods such as antibodies, in situ mRNA hybridization, and automated IHC, PD-L1 expression levels can be measured.
  • the present invention provides a method of treating a subject of cancer or tumor, the method comprising administering to the subject a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding portion thereof, wherein a tumor sample obtained from the patient has been determined to constitute about 1% or more Many (eg, about 1%, about 2%, about 3%, or about 4% or more) cells have detectable levels of PD-L1 expression.
  • the tumor sample obtained from the patient has been determined to constitute about 1% to about 65% or more (eg, about 1% to about 5%, about 5% to about 10%, about 10% to about 20 %, about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, or about 50% to about 65%) cells have detectable expression levels of PD-L1.
  • the present invention also provides a method of determining whether a patient suffering from classic Hodgkin's lymphoma is likely to respond to treatment with a therapeutic agent containing an anti-PD-L1 antibody, the method comprising measuring PD in tumor cells in a tumor sample obtained from the patient -The expression level of L1, wherein the detectable expression level of PD-L1 in the cells constituting about 1% or more of the tumor sample indicates that the patient is likely to respond to treatment with a therapeutic agent containing an anti-PD-L1 antibody.
  • the present invention also provides a method for predicting the response of a patient suffering from classic Hodgkin lymphoma to treatment with a therapeutic agent containing an anti-PD-L1 antibody, the method comprising measuring cells in a tumor sample obtained from the patient The expression level of PD-L1, wherein the detectable expression level of PD-L1 in tumor cells constituting about 1% or more of the tumor sample indicates that the patient is likely to respond to treatment with a therapeutic agent containing an anti-PD-L1 antibody.
  • the present invention also provides a method for selecting therapy for a patient suffering from classic Hodgkin's lymphoma, the method comprising measuring the expression level of PD-L1 in tumor cells in a tumor sample obtained from the patient, and based on the composition of about 1 % Or more of the detectable expression levels of PD-L1 in the tumor cells of the tumor sample are for the patient to select therapies containing anti-PD-L1 antibody therapeutic agents.
  • the tumor sample obtained from the patient has been determined to have detectable expression levels of PD-L1 in tumor cells constituting about 5% or more of the tumor sample.
  • a tumor sample obtained from the patient has been determined to have detectable expression levels of PD-L1 in tumor cells constituting at least about 10% of the tumor sample.
  • the present invention also provides a method for determining whether a patient suffering from classic Hodgkin's lymphoma is likely to respond to treatment with a therapeutic agent containing an anti-PD-L1 antibody or antigen-binding portion thereof, the method comprising according to a tumor sample obtained from the patient Identify the subtype of the tumor, where recurrent and/or refractory classic Hodgkin lymphoma indicates that the patient is likely to respond to treatment with a therapeutic agent containing an anti-PD-L1 antibody.
  • the present invention provides a method for predicting the responsiveness of a patient suffering from classic Hodgkin lymphoma to treatment with a therapeutic agent containing an anti-PD-L1 antibody, the method comprising determining the subtype of the tumor based on a tumor sample obtained from the patient Type, in which recurrent and/or refractory classic Hodgkin's lymphoma indicates that the patient is likely to respond to treatment with an anti-PD-L1 antibody-containing therapeutic agent.
  • the present invention provides a method for selecting therapy for a patient suffering from classic Hodgkin's lymphoma, the method comprising determining a subtype of the tumor based on a tumor sample obtained from the patient, and determining that the tumor is recurrent based on the tumor and/or Or refractory classic Hodgkin's lymphoma is selected for this patient's therapy containing anti-PD-L1 antibody therapeutics.
  • the method further comprises administering to the patient a therapeutically effective amount of a therapeutic agent of anti-PD-L1 antibody based on the expression level of PD-L1 in tumor cells in the tumor sample.
  • the expression level of at least one of CD15, CD30, PAX5, CD20, EBV-EBER, CCL17, and/or CCL22 in a tumor sample or blood tissue sample obtained from the patient has been determined relative to the at least one
  • the reference level of the gene changes, for example, an increase occurs; and/or the expression level of at least one of CD15, CD45, CD20, CD99, and/or CD3 in the tumor sample obtained from the patient has been determined relative to the The reference level of at least one gene changes, for example, the reduction is reduced.
  • the expression level of miR135a in the tumor sample obtained from the patient has been determined to change relative to the reference level of the microRNA (microRNA), in some specific embodiments, the change is a decrease in the expression level .
  • the reference level is based on a non-tumor sample or blood tissue sample from a non-diseased subject. In some embodiments, the reference level is based on a patient's non-tumor sample.
  • the reference level is based on a non-tumor sample or blood tissue sample from a non-diseased subject. In some embodiments, the reference level is based on a patient's non-tumor sample.
  • the objective response rate of a subject to which a therapeutically effective amount of anti-PD-L1 antibody is administered is between about 10% to about 40% (eg, about 10% to about 20%, about 20% to about 30%, Between about 30% and about 40%).
  • the objective response rate of patients administered a therapeutically effective amount of anti-PD-L1 antibody or antigen-binding portion thereof is between about 15% to about 25%.
  • the objective response rate of a patient who is administered a therapeutically effective amount of an anti-PD-L1 antibody therapeutic agent is at least about 15%.
  • the objective response rate of a patient administered a therapeutically effective amount of an anti-PD-L1 antibody therapeutic agent is at least about 20%.
  • the therapies of the invention are effective to increase the duration of survival of the subject.
  • the anti-PD-L1 antibody therapy of the invention increases the duration of survival of the subject compared to standard of care therapy.
  • the therapy of the invention increases the overall survival of the subject.
  • the subject exhibits at least about 6 months, 7 months, 8 months, 9 months, 10 months, at least about 11 months, at least about 12 months, at least About 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 Total survival of at least about 22 months, at least about 23 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years.
  • the duration of survival or total survival of the subject increases by at least about 5%, at least about 10%, at least about 15% when compared to another subject treated with standard of care therapy only , At least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, or at least about 75%.
  • the duration of survival or total survival of the subject increases by at least about 1 month, at least about 2 months, at least about 3 when compared to another subject treated with standard-of-care treatment only Months, at least about 4 months, at least about 6 months, at least about 1 year, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years.
  • the therapy of the present invention effectively increases the duration of progression-free survival of the subject.
  • the subject's progression-free survival increased by at least about 2 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 Months, at least about 6 months, or at least about 1 year.
  • the subject after administration of anti-PD-L1 antibody therapy, the subject exhibits a response rate of at least about 30%, 35%, 36%, 37%, 39%, compared to the response rate after administration of standard-of-care therapy 40%, 45% or 50% overall response rate.
  • Immune checkpoint inhibitors suitable for use in the disclosed methods include anti-PD-L1 antibodies, which bind PD-L1 with high specificity and affinity, block the binding of PD-L1, and inhibit immunosuppression of the PD-1 signaling pathway effect.
  • the anti-PD-1 or anti-PD-L1 "antibody” includes an antigen binding moiety that binds to the PD-1 or PD-L1 receptor, respectively, and inhibits ligand binding and upregulates the immune system Shows the functional properties similar to those of intact antibodies.
  • the anti-PD-1 antibody, anti-PD-L1 antibody, or antigen-binding portion thereof is a chimeric, humanized, or human monoclonal antibody or portion thereof.
  • the antibody is a humanized antibody. In other embodiments related to the treatment of human subjects, the antibody is a human antibody. Antibodies of the IgG1, IgG2, IgG3 or IgG4 isotype can be used.
  • the anti-PD-1 antibody, anti-PD-L1 antibody, or antigen-binding portion thereof comprises a heavy chain constant region of human IgG1 or IgG4 isotype.
  • the sequence of the IgG4 heavy chain constant region of the anti-PD-1 antibody, anti-PD-L1 antibody, or antigen-binding portion thereof contains the S228P mutation, which is usually found at the corresponding position of the IgG1 isotype antibody Of proline residues replace serine residues in the hinge region.
  • the mutation present in the monoclonal antibody prevents Fab arm exchange with the endogenous IgG4 antibody, while retaining low affinity for activation of the Fc receptor associated with the wild-type IgG4 antibody (Wang et al., 2014 Cancer Immunol Res. 2(9 ):846-56).
  • the antibody comprises a light chain constant region, which is a human kappa or lambda constant region.
  • the anti-PD-1 antibody, anti-PD-L1 antibody, or antigen-binding portion thereof is a mAb or antigen-binding portion thereof.
  • Anti-PD-L1 antibody has been disclosed in WO2016022630, which has a high affinity for PD-L1, can significantly inhibit the interaction of PD-L1 and PD-1 on the cell surface, and significantly promote the secretion of IL-2 and IFN by T cells - ⁇ .
  • the anti-PD-L1 antibody or fragment thereof cross-competes with 5G11 or 13C5 monoclonal antibodies. In other embodiments, the anti-PD-L1 antibody or fragment thereof binds to the same or similar epitope as the 5G11 or 13C5 monoclonal antibody. In certain embodiments, the anti-PD-L1 antibody has the same CDR as the 5G11 or 13C5 monoclonal antibody.
  • the anti-PD-L1 antibody cross-competes with 5G11 or 13C5 monoclonal antibodies for binding to the same epitope region of human PD-L1.
  • these cross-competitive antibodies are chimeric antibodies or humanized antibodies or human antibodies.
  • Such chimeric, humanized or human mAbs can be prepared and isolated by methods well known in the art.
  • the anti-PD-L1 antibody useful in the disclosed inventive method also includes the antigen-binding portion of the aforementioned antibody. It has been fully confirmed that the antigen-binding function of antibodies can be performed by fragments of full-length antibodies.
  • binding fragments encompassed by the term "antigen binding portion" of an antibody include: (i) Fab fragments, that is, monovalent fragments composed of VL, VH, CL, and CH1 domains; (ii) F(ab') 2 fragments, That is, a bivalent fragment containing 2 Fab fragments connected by a disulfide bond in the hinge region; (iii) an Fd fragment composed of VH and CH1 domains; and (iv) a VL and Fv fragments composed of VH domains (including, for example, scFv).
  • Anti-PD-L1 antibodies suitable for use in the disclosed compositions are immunosuppressive with high specificity and affinity for binding to PD-L1, blocking the binding of PD-1 and inhibiting the PD-L1/PD-1 signaling pathway Of antibodies.
  • anti-PD-L1 "antibodies” include antigens that bind to PD-L1 ligands and exhibit functional properties similar to those of intact antibodies in inhibiting receptor binding and up-regulating the immune system Combine parts or fragments.
  • the anti-PD-L1 antibody or antigen-binding portion thereof cross-competes with 5G11 or 13C5 monoclonal antibodies for binding to human PD-L1.
  • the anti-PD-L1 antibody or antigen-binding portion thereof is a chimeric, humanized or human monoclonal antibody or portion thereof.
  • the antibody is a humanized antibody.
  • the antibody is a human antibody.
  • Antibodies of the IgG1, IgG2, IgG3 or IgG4 isotype can be used.
  • the anti-PD-L1 antibody used in the method may be replaced with another anti-PD-1 antagonist or anti-PD-L1 antagonist.
  • anti-PD-L1 antibodies prevent the interaction between PD-1 and PD-L1, and thus play a similar role in the PD-1 signaling pathway
  • anti-PD-1 antibodies can replace anti-PD-L1 antibodies in Application of the method disclosed herein. Therefore, in one embodiment, the present invention relates to a method for treating a subject suffering from a tumor that is classical Hodgkin's lymphoma, the method comprising administering to the subject a therapeutically effective amount of anti-PD -L1 antibody.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof is 13C5, 5G11, ch13C5-hIgG1, ch13C5-hIgG4, ch5G11-hIgG1, ch5G11-hIgG4, hu13C5-hIgG1, hu13C5-hIgG4, hu5G11- hIgG1 or hu5G11-hIgG4 monoclonal antibody or antigen-binding fragment thereof (see WO2016022630 or CN107001463A).
  • the present invention provides an antigen binding polypeptide or a pharmaceutical composition containing the antigen binding polypeptide for treating cancer or tumor.
  • the antigen-binding polypeptide is an antibody or antigen-binding portion thereof that binds to PD-L1 and/or inhibits PD-L1 activity.
  • the antigen binding polypeptide is an anti-PD-L1 antibody.
  • the present invention provides an isolated antibody or fragment thereof that binds to PD-L1, wherein the antibody can be produced by a hybridoma selected from the group consisting of hybridomas referred to herein as 13C5, 5G11. Therefore, the present invention also includes hybridomas 13C5, 5G11, and any hybridoma that produces the antibodies disclosed herein.
  • the invention also provides isolated polynucleotides encoding the antibodies and fragments thereof provided herein.
  • the present invention also includes an expression vector containing the isolated polynucleotide, and a host cell containing the expression vector.
  • the present invention provides an anti-PD-L1 antibody comprising a heavy chain complementarity determining region (CDR) selected from 13C5 or 5G11 antibodies, and a light chain complementarity determining region selected from 13C5 or 5G11 antibodies.
  • the present invention provides an anti-PD-L1 antibody comprising a variable heavy chain selected from ch5G11-hIgG1, ch5G11-hIgG4, ch13C5-hIgG1, ch13C5-hIgG4 chimeric antibody, and selected from ch5G11-hIgG1 , Ch5G11-hIgG4, ch13C5-hIgG1, ch13C5-hIgG4 chimeric antibody variable light chain.
  • the present invention provides an anti-PD-L1 antibody comprising a variable heavy chain selected from hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1, or hu5G11-hIgG4 humanized antibody, and selected from hu13C5- The variable light chain of hIgG1, hu13C5-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG4 humanized antibody.
  • HCDR1 sequence is SYGMS (SEQ ID NO: 4)
  • HCDR2 sequence is SISSGGSTYYPDSVKG (SEQ ID ID NO: 5 )
  • HCDR3 sequence is GYDSGFAY (SEQ ID NO: 6)
  • LCDR1 sequence is ASQSVSTSSSSFMH (SEQ ID NO: 10)
  • LCDR2 sequence is YASNLES (SEQ ID NO: 11)
  • LCDR3 sequence is QHSWEIPYT (SEQ ID NO: 12); 5G11, ch5G11-hIgG1, ch5G11-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG1 HCDR1 sequence is TYGVH (
  • the isolated anti-PD-L1 antibody described herein comprises: a heavy chain CDR1 region having the amino acid sequence shown in SEQ ID NO: 1 and an amino acid sequence shown in SEQ ID NO: 2 CDR2 region of the heavy chain, the CDR3 region of the heavy chain having the amino acid sequence shown in SEQ ID NO: 3; and the CDR1 region of the light chain having the amino acid sequence shown in SEQ ID NO: 7, having the CDR ID NO: 8
  • the light chain CDR2 region of the shown amino acid sequence has the light chain CDR3 region of the amino acid sequence shown in SEQ ID NO: 9.
  • the immune checkpoint inhibitor (eg, anti-PD-L1 antagonist) used in the present invention is a PD-L1 Fc fusion protein.
  • the present invention administers a therapeutically effective amount of anti-PD-L1 antibody to a subject, wherein the anti-PD-L1 antibody is administered alone.
  • the administration alone means that the anti-PD-L1 antibody may not be used in combination with other anti-cancer drugs, and/or not administered simultaneously with other anti-cancer drugs.
  • the administration alone means that the anti-PD-L1 antibody may not be used in combination with chemotherapy drugs, and/or not administered simultaneously with chemotherapy drugs.
  • the administration alone means that the anti-PD-L1 antibody may not be used in combination with other targeted drugs, and/or not administered simultaneously with other targeted drugs.
  • the administration alone means that the anti-PD-L1 antibody may not be used in combination with other anti-cancer antibodies, and/or not administered simultaneously with other anti-cancer antibodies. In some specific embodiments, the administration alone means that the anti-PD-L1 antibody may not be used in combination with radiation therapy, and/or not administered simultaneously with radiation therapy.
  • the present invention administers a therapeutically effective amount of anti-PD-L1 antibody to a subject, wherein the anti-PD-L1 antibody is administered in combination.
  • an immune checkpoint inhibitor eg, anti-PD-1 antibody or anti-PD-L1 antibody
  • an immune checkpoint inhibitor is administered in combination with one or more other anti-cancer drugs.
  • the one or more anti-cancer drugs have been administered prior to the administration of the anti-PD-1 antibody or anti-PD-L1 antibody or in combination with the anti-PD-1 antibody or anti-PD-L1 antibody
  • the medicine is administered to the subject.
  • the one or more anticancer drugs are not effective in treating the cancer.
  • the other anticancer drug is any anticancer drug described herein or known in the art.
  • the anti-PD-1 antibody or anti-PD-L1 antibody can be combined with another immunotherapy.
  • immunotherapy involving the blocking of immune checkpoints is administered as a monotherapy.
  • immunotherapy involving the blocking of immune checkpoints is administered in combination with other therapies.
  • the therapeutic agent of the present invention can be constituted in a composition, for example, a pharmaceutical composition containing an antibody and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. that are physiologically compatible.
  • the carrier for the antibody-containing composition is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (eg, by injection or infusion), and for containing TKI (tyramine Carriers of compositions of acid kinase inhibitors) are suitable for parenteral (eg, oral) administration.
  • the pharmaceutical composition of the present invention may include one or more pharmaceutically acceptable salts, antioxidants, aqueous and non-aqueous carriers, and/or adjuvants, such as preservatives, wetting agents, emulsifying agents, and dispersing agents.
  • the dosage regimen is adjusted to provide the optimal desired response, for example, maximum therapeutic response and/or minimum adverse effects.
  • the methods of the present invention can be used with uniform or weight-based doses.
  • the anti-PD-1 antibody, anti-PD-L1 antibody, or antigen-binding portion thereof is administered as a unified dose.
  • the anti-PD-1 antibody, anti-PD-L1 antibody, or antigen-binding portion thereof is administered as a weight-based dose.
  • the dosage may be in the range of about 0.01 to about 40 mg/kg, about 0.1 to about 30 mg/kg, about 0.1 to About 20 mg/kg, about 0.1 to about 15 mg/kg, about 0.1 to about 10 mg/kg, about 1 to about 15 mg/kg, about 1 to about 20 mg/kg, about 1 to about 3 mg/kg, about 3 to about 10 mg /kg, about 3 to about 15 mg/kg, about 3 to about 20 mg/kg, about 3 to about 30 mg/kg, about 10 to about 20 mg/kg, or about 15 to about 20 mg/kg body weight, or about 60 mg to At least about 2400 mg, about 90 mg to at least about 1800 mg, about 120 mg to at least about 1500 mg, about 300 mg to at least about 9000 mg, about 600 mg to at least about 900 mg, about 300 mg to at least about 1200 mg, about 600 mg to at least about 1200 mg, or about 900 mg to At least about 1
  • the dosage may be about 0.1, about 1, about 2, about 3, about 5, about 6, about 9, about 10, about 15, about 20 or about 30 mg/kg body weight; or about 30 mg, about 60 mg, about 120 mg , About 150 mg, about 180 mg, about 300 mg, about 600 mg, about 900 mg, about 1200 mg, about 1800 mg, about 2100 mg, or about 2400 mg.
  • the dosing schedule is usually designed to achieve exposure that leads to continuous receptor occupancy (RO) (based on the typical pharmacokinetic properties of antibodies).
  • RO receptor occupancy
  • An exemplary treatment regimen requires about once a week (q1w), about once every 2 weeks (q2w), about once every 3 weeks (q3w), about once every 4 weeks (q4w), about once a month (q1m) , About once every 3-6 months or longer.
  • anti-PD-L1 antibodies such as 13C5, ch13C5-hIgG1, ch13C5-hIgG4, hu13C5-hIgG1, hu13C5-hIgG4, 5G11, ch5G11-hIgG1, ch5G11-hIgG4, hu5G11-hIgG1 are administered about once every 2 weeks Or hu5G11-hIgG4 monoclonal antibody is administered to the subject. In other embodiments, the antibody is administered about every 3 weeks. The dosage and schedule may vary during the course of treatment.
  • the dosage regimen of the anti-PD-L1 antibody of the present invention comprises via intravenous administration of at least about 1 to at least about 30 mg/kg body weight, at least about 3 to at least about 20 mg/kg Body weight, at least about 10 to at least about 15 mg/kg body weight, or at least about 300 to at least about 1200 mg, the antibody is administered every about 14-21 days over a period of up to about 6 weeks or about 12 weeks until a complete response or confirmation is performed sexual diseases.
  • anti-PD-L1 monotherapy is administered at 3 mg/kg every 2 weeks until progressive disease or unacceptable toxicity.
  • anti-PD-L1 monotherapy is administered at 1200 mg every 3 weeks until progressive disease or unacceptable toxicity.
  • the antibody treatment or any combination treatment disclosed herein continues for at least about 1 month, at least about 3 months, at least about 6 months, at least about 9 months, at least about 1 year, at least about 18 months, at least about 24 months, at least about 3 years, at least about 5 years, or at least about 10 years.
  • the dose of anti-PD-L1 antibody can be reduced relative to the monotherapy dose.
  • the dose of hIgG4 monoclonal antibody is a sub-therapeutic dose.
  • the sub-therapeutic dose of anti-PD-L1 antibody used in the method herein is higher than 0.001 mg/kg and lower than 20 mg/kg.
  • the sub-therapeutic dose is about 0.001 mg/kg to about 3 mg/kg, about 0.01 mg/kg to about 3 mg/kg, about 0.001 mg/kg to about 10 mg/kg, or about 0.01 mg/kg To about 10 mg/kg body weight.
  • the sub-therapeutic dose is at least about 0.001 mg/kg, at least about 0.005 mg/kg, at least about 0.01 mg/kg, at least about 0.05 mg/kg, at least about 0.1 mg/kg, at least about 0.5 mg/kg, at least about 1.0 mg/kg body weight, or at least about 3.0 mg/kg body weight.
  • the sub-therapeutic unified dose is less than about 600 mg every 3 weeks, for example about 300 mg or about 120 mg every 3 weeks. In certain embodiments, 3 mg/kg administration may allow sufficient exposure to result in maximum biological activity.
  • the dose of anti-PD-L1 antibody or anti-PD-1 antibody is a fixed dose in the pharmaceutical composition.
  • the method of the present invention may be used at a uniform dose (the dose administered to a patient regardless of the patient's weight).
  • the unified dose of 13C5, ch13C5-hIgG1, ch13C5-hIgG4, hu13C5-hIgG1, hu13C5-hIgG4, 5G11, ch5G11-hIgG1, ch5G11-hIgG4, hu5G11-hIgG1, or hu5G11-hIgG4 monoclonal antibody may be about 1200 mg.
  • the anti-PD-L1 antibody or antigen-binding portion thereof is administered at a dose of about 1200 mg. In certain embodiments, the anti-PD-L1 antibody or antigen-binding portion thereof is administered at a dose of about 900 mg. In certain embodiments, the anti-PD-L1 antibody or antigen-binding portion thereof is administered at a dose of about 600 mg. In one embodiment, 900 mg of the anti-PD-L1 antibody or antigen-binding fragment is administered every 3 weeks. In another embodiment, 1200 mg of the anti-PD-L1 antibody or antigen-binding fragment is administered every 4 weeks.
  • the dosage may be in the following range: about 0.01 to about 20 mg/kg, about 0.1 to about 10 mg/kg, about 0.1 to About 5 mg/kg, about 3 to about 5 mg/kg, about 3 to about 10 mg/kg, about 3 to about 15 mg/kg, or about 0.1 to about 30 mg/kg body weight or about 80 mg to at least about 800 mg, about 80 mg to At least about 700 mg, about 80 mg to at least about 600 mg, about 80 mg to at least about 500 mg, about 80 mg to at least about 400 mg, about 80 mg to at least about 300 mg, about 100 mg to at least about 300 mg, or about 200 mg to about 300 mg.
  • the dosage may be about 0.1, about 0.3, about 1, about 2, about 3, about 5, or about 10 mg/kg body weight, or about 0.3, about 1, about 2, about 3, or about 5 mg/kg body weight; or about 80 mg, about 100 mg, about 160 mg, about 200 mg, about 240 mg, about 300 mg, about 320 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, or about 800 mg.
  • the dosing schedule is usually designed to achieve exposure that leads to continuous receptor occupancy (RO) (based on the typical pharmacokinetic properties of antibodies).
  • RO receptor occupancy
  • An exemplary treatment regimen requires about once a week, about once every 2 weeks, about once every 3 weeks, about once every 4 weeks, about once every month, about once every 3-6 months or longer Apply.
  • the body receives an intravenous infusion of about 3 mg/kg to about 30 mg/kg of body weight on the first day of each cycle (D1), about 21 days for 1 cycle, until the effect is evaluated as disease progression and intolerance Subject to toxic reactions.
  • an intravenous infusion of about 3 mg/kg to about 20 mg/kg body weight is received on the first day of each cycle (D1), about 21 days for 1 cycle, until the effect is evaluated as disease progression, intolerance occurs Toxicity.
  • a 3 mg/kg dose is administered intravenously on the first day of each cycle (D1) for about 21 days for 1 cycle until the therapeutic effect is evaluated as disease progression and an intolerable toxic reaction.
  • an intravenous infusion of about 10 mg/kg body weight is received on the first day of each cycle (D1) for about 21 days for 1 cycle until the therapeutic effect is evaluated as disease progression and an intolerable toxic reaction occurs.
  • each day on the first day of the cycle (D1) receives an intravenous infusion of about 15 mg/kg body weight, and about 21 days is a cycle until the therapeutic effect is evaluated as disease progression and an intolerable toxic reaction.
  • each cycle receives an intravenous infusion of about 20 mg/kg body weight on the first day (D1), and 21 days is a cycle until the therapeutic effect is evaluated as disease progression and an intolerable toxic reaction.
  • each cycle receives an intravenous infusion of about 30 mg/kg body weight on the first day (D1), and 21 days is a cycle until the therapeutic effect is evaluated as disease progression and an intolerable toxic reaction.
  • an intravenous infusion of about 3 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, or 30 mg/kg body weight is administered for about 2 weeks, about 3 weeks, or The cycle is about 4 weeks, until the evaluation of the effect is disease progression and the occurrence of intolerable toxic reactions.
  • a single-dose intravenous infusion of about 1200 mg is received on the first day of each cycle (D1) for about 2 weeks, about 3 weeks, or about 4 weeks as a cycle until the effect is evaluated as disease progression and intolerance Subject to toxic reactions.
  • a single dose of about 600 mg to about 1200 mg of intravenous drip is received on the first day of each cycle (D1), and about 21 days is a cycle until the therapeutic effect is evaluated as disease progression and an intolerable toxic reaction.
  • a single dose of about 600 mg to about 900 mg of intravenous drip is received on the first day (D1) of each cycle, and about 21 days is a cycle until the therapeutic effect is evaluated as disease progression and an intolerable toxic reaction.
  • a single dose of 1200 mg intravenous drip is received on the first day of each cycle (D1) for approximately 21 days as a cycle until the therapeutic effect is evaluated as disease progression and an intolerable toxic reaction.
  • a single dose of about 900 mg to about 1200 mg of intravenous drip is received on the first day (D1) of each cycle, and about 21 days is a cycle until the therapeutic effect is evaluated as disease progression and an intolerable toxic reaction.
  • a 600 mg uniform dose of intravenous drip is received on the first day (D1) of each cycle, and 21 days is a cycle until the therapeutic effect is evaluated as disease progression and an intolerable toxic reaction.
  • a single dose of 900 mg intravenous infusion is received on the first day (D1) of each cycle, and 21 days is a cycle until the therapeutic effect is evaluated as disease progression and an intolerable toxic reaction.
  • a single dose of 1200 mg intravenous drip is received on the first day (D1) of each cycle, and 21 days is a cycle until the therapeutic effect is evaluated as disease progression and an intolerable toxic reaction.
  • a single dose of approximately 900 mg of intravenous drip is received on the first day of each cycle (D1) for approximately 2 weeks, approximately 3 weeks, or approximately 4 weeks as a cycle until the effect is evaluated as disease progression and intolerance Subject to toxic reactions.
  • a single-dose intravenous infusion of about 1200 mg is received on the first day of each cycle (D1) for about 2 weeks, about 3 weeks, or about 4 weeks as a cycle until the effect is evaluated as disease progression and intolerance Subject to toxic reactions.
  • the dose of anti-PD-L1 antibody or anti-PD-1 antibody is a fixed dose in the pharmaceutical composition.
  • the dose of anti-PD-L1 antibody or anti-PD-1 antibody is a fixed dose in a pharmaceutical composition containing a second anticancer drug.
  • the actual dosage level of one or more active ingredients in the pharmaceutical composition of the invention can be varied to obtain an amount of active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition and mode of administration, while The patient has no inappropriate toxicity.
  • the dosage level chosen will depend on a variety of pharmacokinetic factors, including the activity of the particular composition of the invention employed, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of treatment, and the specific Other drugs, compounds and/or materials used in combination with the composition, the age, sex, weight, condition, general health and previous medical history of the patient being treated, and similar factors well known in the medical field.
  • the compositions of the present invention can be administered via one or more routes of administration. The skilled person will understand that the route and/or mode of administration will vary with the desired result.
  • the object of the present invention is at least to provide a pharmaceutical composition characterized in that the pharmaceutical composition comprises an antibody and at least one or more of a buffer, an isotonicity regulator, a stabilizer and/or a surfactant Species.
  • the pharmaceutical composition comprises 1-150 mg/mL anti-PD-L1 humanized monoclonal antibody (mAb), 3-50 mM buffer, 2-150 mg/mL isotonic regulator/stabilizer and 0.01- 0.8mg/mL surfactant, and the pH is about 4.5-6.8.
  • the anti-PD-L1 humanized monoclonal antibody concentration is about 5-150 mg/mL in w/v; preferably about 10-60 mg/mL; more preferably about 10-30 mg/mL.
  • the anti-PD-L1 humanized monoclonal antibody mass volume concentration is about 10 mg/mL, about 20 mg/mL, about 30 mg/mL, about 40 mg/mL, about 50 mg/mL, about 60 mg/mL, about 70mg/mL, about 80mg/mL, about 90mg/mL, about 100mg/mL, about 110mg/mL or about 120mg/mL, preferably about 10mg/mL, about 20mg/mL, about 30mg/mL, about 40mg/mL , About 50 mg/mL or about 60 mg/mL, more preferably about 10 mg/mL, about 20 mg/mL or about 30 mg/mL.
  • the anti-PD-L1 humanized monoclonal antibody mass volume concentration is about 10 mg/mL. In other embodiments, the anti-PD-L1 humanized monoclonal antibody has a mass volume concentration of about 30 mg/ml. In other embodiments, the anti-PD-L1 humanized monoclonal antibody has a mass volume concentration of about 60 mg/mL.
  • the buffer is a histidine buffer.
  • the concentration of the histidine buffer is about 5-30 mM, preferably about 10-25 mM, more preferably about 10-20 mM, and most preferably about 10-15 mM.
  • the histidine salt buffer is about 5 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, or about 30 mM.
  • the histidine salt buffer is about 10 mM.
  • the histidine buffer is about 15 mM.
  • the histidine salt buffer is about 20 mM.
  • the histidine buffer contains histidine and hydrochloric acid.
  • the isotonicity regulator/stabilizer is about 20-150 mg/mL sucrose, preferably about 40-100 mg/mL sucrose, more preferably about 60-80 mg/mL in terms of w/v Sucrose.
  • the concentration of the sucrose is about 40 mg/mL, 50 mg/mL, 60 mg/mL, 70 mg/mL, 80 mg/mL, 90 mg/mL, or 100 mg/mL.
  • the concentration of the sucrose is about 60 mg/mL.
  • the concentration of sucrose is about 70 mg/mL.
  • the concentration of the sucrose is about 80 mg/mL.
  • the sucrose concentration is about 90 mg/mL.
  • the surfactant is selected from polysorbate 80, polysorbate 20, and poloxamer 188; preferably polysorbate 80 or polysorbate 20; and more preferably polysorbate 80.
  • the concentration of the surfactant is about 0.05-0.6 mg/mL, preferably about 0.1-0.4 mg/mL, and more preferably about 0.2-0.3 mg/mL in terms of w/v.
  • the surfactant is about 0.01-0.8 mg/mL of polysorbate 80 or polysorbate 20 in terms of w/v. In some embodiments, the surfactant is about 0.05-0.6 mg/mL polysorbate 80, preferably about 0.1-0.4 mg/mL polysorbate 80, and more preferably about 0.2-0.3 mg/mL. Of polysorbate 80, most preferably about 0.2 mg/mL of polysorbate 80.
  • the content of polysorbate 80 in the pharmaceutical composition is about 0.1 mg/mL, 0.2 mg/mL, 0.3 mg/mL, 0.4 mg/mL, 0.5 mg/ml, or 0.6 mg/mL; preferably Preferably, the content of polysorbate 80 in the pharmaceutical composition is about 0.2 mg/mL, 0.3 mg/mL, 0.4 mg/mL, or 0.5 mg/mL; more preferably, the content of polysorbate 80 in the pharmaceutical composition About 0.2 mg/mL, 0.3 mg/mL or 0.4 mg/mL; optimally, the content of polysorbate 80 in the pharmaceutical composition is about 0.2 mg/mL.
  • the content of polysorbate 80 in the pharmaceutical composition is about 0.1 mg/mL. In other embodiments, the polysorbate 80 content of the pharmaceutical composition is about 0.2 mg/mL. In some embodiments, the content of polysorbate 80 in the pharmaceutical composition is about 0.3 mg/mL. In other embodiments, the polysorbate 80 content of the pharmaceutical composition is about 0.4 mg/mL. In some embodiments, the polysorbate 80 content of the pharmaceutical composition is about 0.5 mg/mL.
  • the pH of the aqueous solution of the pharmaceutical composition is selected from 4.0-6.8; preferably 4.5-6.5; more preferably 5.5-6.0; most preferably 5.5.
  • the pH of the aqueous pharmaceutical composition solution is about 4.5, about 4.8, about 5.0, about 5.2, about 5.4, about 5.5, about 5.6, about 5.8, or about 6.0, preferably about 5.0, about 5.2, about 5.4, about 5.5 or about 5.6, more preferably about 5.5.
  • the pH of the aqueous pharmaceutical composition solution is about 5.0.
  • the pH of the aqueous pharmaceutical composition solution is about 5.2.
  • the pH of the aqueous pharmaceutical composition solution is about 5.4.
  • the pH of the aqueous pharmaceutical composition solution is about 5.5. In some embodiments, the pH of the aqueous pharmaceutical composition solution is about 5.6. In some embodiments, the pH of the aqueous pharmaceutical composition solution is about 5.8. In some embodiments, the pH of the aqueous pharmaceutical composition solution is about 6.0.
  • the present invention provides isolated antibodies or fragments thereof that bind to PD-L1.
  • the anti-PD-L1 humanized monoclonal antibody provided by the present invention comprises the following amino acid sequence: at least 80% (for example, 81%, 82%, 83%, or 80% of the amino acid sequence shown in SEQ ID NO: 1 or SEQ ID NO: 4 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% ) Homology heavy chain CDR1 region; at least 80% (eg 81%, 82%, 83%, 84%, 85%, 86%) of the amino acid sequence shown in SEQ ID NO: 2 or SEQ ID NO: 5 , 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology of heavy chain CDR2 Region; at least 80% of the amino acid sequence shown
  • the anti-PD-L1 humanized monoclonal antibody provided by the present invention comprises the following amino acid sequence: selected from the heavy chain CDR1 region shown in SEQ ID NO: 1 or SEQ ID NO: 4; selected from CDR2 region shown in SEQ ID NO: 2 or SEQ ID NO: 5; selected from CDR3 region shown in SEQ ID NO: 3 or SEQ ID NO: 6; selected from SEQ ID NO: 7 or Light chain CDR1 region shown in SEQ ID NO: 10; selected from light chain CDR2 regions shown in SEQ ID NO: 8 or SEQ ID NO: 11; selected from SEQ ID NO: 9 or SEQ ID NO: 12 CDR3 region of the light chain.
  • the anti-PD-L1 humanized monoclonal antibody provided by the present invention comprises the following amino acid sequence: at least 80% (for example, 81%, 82%, 83) of the amino acid sequence shown in SEQ ID NO: 13 or SEQ ID NO: 14 %, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homologous heavy chain variable region; at least 80% (eg 81%, 82%, 83%, 84%, 85%) of the amino acid sequence shown in SEQ ID NO: 15 or SEQ ID NO: 16 , 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology Light chain variable region.
  • amino acid sequence at least 80% (for example, 81%, 82%, 83) of the amino acid sequence shown in SEQ ID NO: 13 or S
  • the anti-PD-L1 humanized monoclonal antibody provided by the present invention comprises the following amino acid sequence, such as the heavy chain variable region shown in SEQ ID NO: 13; the light chain shown in SEQ ID NO: 15 Chain variable region.
  • the anti-PD-L1 humanized monoclonal antibody provided by the present invention comprises the following amino acid sequence, such as the heavy chain variable region shown in SEQ ID NO: 14; as shown in SEQ ID NO: 16 Light chain variable region.
  • the CDR regions described herein and the various variants described above can specifically recognize and bind PD-L1, thereby effectively blocking the signaling between PD-L1 and PD-1.
  • the anti-PD-L1 humanized monoclonal antibody provided by the present invention comprises the heavy chain amino acid sequence shown in SEQ ID NO. 17, and the light chain amino acid sequence shown in SEQ ID NO. 18.
  • the anti-PD-L1 humanized monoclonal antibody provided by the present invention comprises the heavy chain amino acid sequence shown in SEQ ID NO. 19, and the light chain amino acid sequence shown in SEQ ID NO. 20.
  • the anti-PD-L1 humanized monoclonal antibody provided by the present invention comprises the heavy chain amino acid sequence shown in SEQ ID NO. 21, and the light chain amino acid sequence shown in SEQ ID NO. 18.
  • the anti-PD-L1 humanized monoclonal antibody provided by the present invention comprises SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO :5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, One of SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 19, SEQ ID NO. 20, SEQ ID NO. 21 Or multiple conservative substitution variants.
  • the anti-PD-L1 humanized monoclonal antibody comprising the conservative substitution variant retains the ability to specifically recognize and bind PD-L1.
  • the anti-PD-L1 humanized monoclonal antibody provided by the present invention may be an IgG1 or IgG4 antibody.
  • the anti-PD-L1 humanized monoclonal antibody is an IgG1 antibody, more preferably a glycosylated IgG1 antibody.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 humanized monoclonal antibody with a mass volume concentration of about 20 mg/mL, and (b) a mass volume concentration of about 70 mg/mL Sucrose, (c) polysorbate 80 with a mass volume concentration of about 0.1 mg/mL, (d) histidine with a molar concentration of about 20 mM, (e) an appropriate amount of hydrochloric acid, and adjusting the pH of the composition to about 5.0 .
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 humanized monoclonal antibody with a mass volume concentration of about 10 mg/mL, and (b) a mass volume concentration of about 80 mg/mL mL of sucrose, (c) polysorbate 80 with a mass volume concentration of about 0.2 mg/mL, (d) histidine with a molar concentration of about 10 mM, (e) an appropriate amount of hydrochloric acid, and adjusting the pH of the composition About 5.5.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 humanized monoclonal antibody with a mass volume concentration of about 50 mg/mL, and (b) a mass volume concentration of about 80 mg/mL mL of sucrose, (c) polysorbate 80 with a mass volume concentration of about 0.3 mg/mL, (d) histidine with a molar concentration of about 10 mM, (e) an appropriate amount of hydrochloric acid, and adjusting the pH of the composition About 5.5.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 humanized monoclonal antibody with a mass volume concentration of about 100 mg/mL, and (b) a mass volume concentration of about 80 mg /mL of sucrose, (c) polysorbate 80 with a mass volume concentration of about 0.5 mg/mL, (d) histidine with a molar concentration of about 10 mM, (e) an appropriate amount of hydrochloric acid, to adjust the pH of the composition Is about 5.5.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 humanized monoclonal antibody with a mass volume concentration of about 30 mg/mL, and (b) a mass volume concentration of about 80 mg/ mL of sucrose, (c) polysorbate 80 with a mass volume concentration of about 0.2 mg/mL, (d) histidine with a molar concentration of about 10 mM, (e) an appropriate amount of hydrochloric acid, and adjusting the pH of the composition About 5.5.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 humanized monoclonal antibody with a mass volume concentration of about 60 mg/mL, and (b) a mass volume concentration of about 80 mg/mL mL of sucrose, (c) polysorbate 80 with a mass volume concentration of about 0.2 mg/mL, (d) histidine with a molar concentration of about 10 mM, (e) an appropriate amount of hydrochloric acid, and adjusting the pH of the composition About 5.5.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 humanized monoclonal antibody with a mass volume concentration of about 10 mg/mL, and (b) a mass volume concentration of about 70 mg/ mL of sucrose, (c) polysorbate 80 with a mass volume concentration of about 0.4 mg/mL, (d) histidine with a molar concentration of about 20 mM, (e) an appropriate amount of acetic acid, and adjusting the pH of the composition About 6.5.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 humanized monoclonal antibody with a mass volume concentration of about 10 mg/mL, (b) a mass volume concentration of about 80 mg/ mL of sucrose, (c) polysorbate 80 with a mass volume concentration of about 0.2 mg/mL, (d) histidine with a molar concentration of about 20 mM, (e) an appropriate amount of hydrochloric acid, and adjusting the pH of the composition About 5.5.
  • the pharmaceutical composition is a water-soluble injection solution, which includes but is not limited to a non-lyophilized water-soluble preparation or a lyophilized powder reconstituted water-soluble preparation.
  • the pharmaceutical composition is a lyophilized preparation.
  • the lyophilized preparation refers to the preparation of an aqueous solution undergoing a lyophilization process.
  • the lyophilization is a stabilization process in which the substance is first frozen and then the amount of solvent is reduced by sublimation (primary drying process), and then the amount of solvent is reduced by desorption (Secondary drying process) until the amount of solvent is a value that no longer supports biological activity or chemical reaction.
  • the lyophilized formulation of the present invention can also be dried by other methods known in the art, such as spray drying and bubble drying.
  • the preparation provided by the present invention has a polymer not exceeding 1.1%, preferably not exceeding 0.9%, and more preferably not exceeding 0.5% when stored at 2-8°C or 25°C for at least 6 months.
  • the present invention also provides a method for preparing the aforementioned pharmaceutical composition, which includes mixing the anti-PD-L1 humanized monoclonal antibody with other reagents, such as a buffer, an isotonicity regulator/stabilizer, and/or a surfactant One or more types are mixed.
  • other reagents such as a buffer, an isotonicity regulator/stabilizer, and/or a surfactant One or more types are mixed.
  • the present invention also provides a method for treating a neoplastic condition in a subject, comprising administering the aforementioned pharmaceutical composition to the subject.
  • the present invention provides an article comprising a container containing a fixed dose of anti-PD-L1 antibody.
  • the invention also provides the use of an anti-PD-L1 antibody in the preparation of a product for the treatment of cancer comprising a container of a fixed dose of anti-PD-L1 antibody.
  • the container is a vial.
  • the fixed dose is selected from about 300 mg, about 600 mg, about 900 mg, about 1000 mg, about 1200 mg, about 1500 mg, about 1800 mg, about 2100 mg, and about 2400 mg of anti-PD-L1 antibody.
  • the article of manufacture further includes a package insert or a package insert that instructs the user to administer the fixed dose to the cancer patient.
  • the article includes one or more vials containing approximately 300 mg or 600 mg of anti-PD-L1 antibody. In some embodiments, the article includes 1 vial containing approximately 300 mg of anti-PD-L1 antibody. In some embodiments, the article includes one or more vials, each vial containing approximately 10 mL of a pharmaceutical composition containing an anti-PD-L1 antibody. In some embodiments, the article includes one or more vials, each vial containing approximately 20 mL of a pharmaceutical composition containing an anti-PD-L1 antibody.
  • the pharmaceutical composition comprises 1-150 mg/mL anti-PD-L1 humanized monoclonal antibody (mAb), 3-50 mM buffer, 2-150 mg/mL isotonic modulator/stable Agent and 0.01-0.8 mg/mL surfactant, and the pH is about 4.5-6.8.
  • the article includes one or more vials, each vial containing approximately 10 mL of a pharmaceutical composition containing an anti-PD-L1 antibody, wherein the pharmaceutical composition Contains 30mg/mL anti-PD-L1 humanized monoclonal antibody.
  • the article includes one or more vials, each vial containing approximately 20 mL of a pharmaceutical composition containing an anti-PD-L1 antibody, wherein the pharmaceutical composition Contains 30mg/mL anti-PD-L1 humanized monoclonal antibody.
  • the pharmaceutical composition is any one of the pharmaceutical compositions provided herein.
  • the term "antibody” refers to a binding protein having at least one antigen binding domain.
  • the antibodies of the invention and fragments thereof may be whole antibodies or any fragments thereof. Therefore, the antibodies and fragments of the present invention include monoclonal antibodies or fragments thereof and antibody variants or fragments thereof, and immunoconjugates. Examples of antibody fragments include Fab fragments, Fab' fragments, F(ab') 2 fragments, Fv fragments, isolated CDR regions, single chain Fv molecules (scFv), Fd fragments, and other antibody fragments known in the art. Antibodies and fragments thereof may also include recombinant polypeptides, fusion proteins, and bispecific antibodies.
  • the anti-PD-L1 antibodies and fragments thereof disclosed herein may be of the IgG1, IgG2, IgG3 or IgG4 isotype.
  • the term "isotype" refers to the type of antibody encoded by the heavy chain constant region gene.
  • the anti-PD-L1 antibodies and fragments thereof disclosed herein are of IgG1 or IgG4 isotype.
  • the PD-L1 antibodies and fragments thereof of the present invention can be derived from any species, including but not limited to mice, rats, rabbits, primates, llamas, and humans.
  • the PD-L1 antibody and fragments thereof may be chimeric antibodies, humanized antibodies, or intact human antibodies.
  • the anti-PD-L1 antibody is an antibody produced by a mouse-derived hybridoma cell line. Therefore, in one embodiment, the anti-PD-L1 antibody is a murine antibody. In another embodiment, the anti-PD-L1 antibody is a chimeric antibody. In another embodiment, the chimeric antibody is a mouse-human chimeric antibody. In another embodiment, the antibody is a humanized antibody. In another embodiment, the antibody is derived from a murine antibody and is humanized.
  • a “humanized antibody” is an antibody that contains a complementarity determining region (CDR) derived from a non-human antibody; and a framework region and a constant region derived from a human antibody.
  • the anti-PD-L1 antibodies provided herein may comprise CDRs derived from one or more murine antibodies, as well as human framework and constant regions. Therefore, in one embodiment, the humanized antibody provided herein binds to the same epitope on PD-L1 as the murine antibody derived from the CDR of the antibody.
  • Exemplary humanized antibodies are provided herein. Additional anti-PD-L1 antibodies or variants comprising the heavy chain CDRs and light chain CDRs provided herein can be generated using any human framework sequence and are also included in the present invention.
  • framework sequences suitable for use in the present invention include those structurally similar to those provided herein. Additional modifications can be made in the framework region to improve the characteristics of the antibodies provided herein. Such additional framework modifications may include chemical modifications; point mutations to reduce immunogenicity or remove T cell epitopes; or reversion of mutations to residues in the original germline sequence. In some embodiments, such modifications include those corresponding to the mutations exemplified herein, including back mutations to the germline sequence. For example, in one embodiment, one or more amino acids in the human framework regions of the VH and/or VL of the humanized antibodies provided herein are back-mutated to the corresponding amino acids in the parent murine antibody.
  • amino acids at positions 24 and/or 28 and/or 30 and/or 49 and/or 73 and/or 83 and/or 94 of the heavy chain variable region are backmutated to 5G11 in mouse Or the corresponding amino acid found at said position in the variable region of the 13C5 heavy chain.
  • the humanized 5G11 antibody comprises a light chain variable region in which the amino acid at position 60 is mutated from Ser(S) to Asp(D), and the amino acid at position 67 is mutated from Ser(S) Is Tyr(Y); and the heavy chain variable region in which the amino acid at position 24 is mutated from Phe(F) to Val(V), and the amino acid at position 49 is mutated from Ala(A) to Gly(G),
  • the amino acid at position 73 is mutated from Thr(T) to Asn(N), and the amino acid at position 83 is mutated from Thr(T) to Asn(N).
  • the humanized 13C5 antibody comprises a light chain variable region in which the amino acid at position 53 is mutated from Tyr(Y) to Lys(K); and a heavy chain variable region in which the The amino acid is mutated from Thr(T) to Ile(I), the amino acid at position 30 is mutated from Ser(S) to Arg(R), and the amino acid at position 49 is mutated from Ser(S) to Ala(A), and The amino acid at position 94 is mutated from Tyr(Y) to Asp(D). Additional or alternative back mutations can be made in the framework regions of the humanized antibodies provided herein to improve the characteristics of the antibody.
  • the invention also includes humanized antibodies that bind to PD-L1 and include framework modifications corresponding to the exemplary modifications described herein with respect to any suitable framework sequence, as well as otherwise improving the antibody Features other frame modifications.
  • isolated antibody means an antibody that contains substantially no other antibodies with different antigen specificities (for example, an isolated antibody that specifically binds PD-1 does not substantially contain specific binding other than PD-1 Antibody to the antigen). However, isolated antibodies that specifically bind PD-1 may have cross-reactivity with other antigens, such as PD-1 molecules from different species. In addition, the isolated antibody may be substantially free of other cellular materials and/or chemicals.
  • mAb refers to an antibody molecule composed of a single molecule (ie, an antibody molecule whose basic sequence is substantially the same, and which exhibits a single binding specificity and affinity for a specific epitope ) Of non-naturally occurring preparations.
  • mAb is an example of an isolated antibody.
  • the mAb can be produced by hybridoma technology, recombinant technology, transgenic technology or other technologies known to those skilled in the art.
  • an “antigen-binding portion” (also referred to as an “antigen-binding fragment”) of an antibody refers to one or more fragments of an antibody that retain the ability to specifically bind the antigen bound by the intact antibody.
  • the term "derived" when used to refer to a molecule or polypeptide relative to a reference antibody or other binding protein means a molecule or polypeptide capable of specifically binding the same epitope as the reference antibody or other binding protein.
  • the antibodies and antigen-binding fragments disclosed herein are specific for PD-L1.
  • the antibody or fragment thereof is specific for PD-L1.
  • the antibodies and fragments provided herein bind human or primate PD-L1, but not PD-L1 from any other mammal.
  • the antibody or fragment thereof does not bind to mouse PD-L1.
  • the terms "human PD-L1", “hPD-L1” and “huPD-L1” are used interchangeably herein and refer to variants or isoforms of human PD-L1 and human PD-L1. "Specific" means that the antibody and fragments thereof bind PD-L1 with greater affinity than any other target.
  • EC50 refers to the effective concentration, 50% of the maximum response of the antibody.
  • IC50 refers to the inhibitory concentration, 50% of the maximum response of the antibody. Both EC50 and IC50 can be measured by ELISA or FACS analysis or any other method known in the art.
  • treatment refers to therapeutic treatment as well as prophylactic or preventative measures.
  • Subjects in need of treatment include those who already have the disease or condition, as well as those who may have the disease or condition and whose purpose is to prevent, delay or reduce the disease or condition.
  • the term "subject” refers to mammals such as rodents, felines, canines, and primates.
  • the subject according to the invention is a human.
  • administering means using any of a variety of methods and delivery systems known to those skilled in the art to physically introduce a composition containing a therapeutic agent into the subject.
  • Routes of administration of immune checkpoint inhibitors include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral routes of administration, such as by injection or infusion .
  • parenteral administration refers to modes of administration other than enteral and topical administration that are usually performed by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, lymphatic Intraductal, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and transfusion Note, and in vivo electroporation.
  • the immune checkpoint inhibitor (eg, anti-PD-1 antibody or anti-PD-L1 antibody) is administered by a parenteral route, and in certain embodiments, is administered orally.
  • parenteral routes include topical, epidermal or mucosal routes of administration, for example, intranasally, vaginally, rectally, sublingually or locally. Administration can also be performed, for example, once, multiple times, and/or in one or more extended periods of time.
  • AE adverse reaction
  • an adverse event may be related to activation of the immune system in response to treatment or expansion of immune system cells (eg, T cells).
  • Medical treatments can have one or more related AEs, and each AE can have the same or different severity levels.
  • Reference to a method capable of "altering adverse events” refers to a treatment plan that reduces the incidence and/or severity of one or more AEs associated with the use of different treatment plans.
  • dose interval refers to the amount of time elapsed between multiple doses of the formulation disclosed herein administered to a subject.
  • the administration interval can be indicated as a range.
  • administration frequency means the frequency of administration of the formulation disclosed herein at a given time.
  • the frequency of administration can be indicated as the number of doses per given time, for example, once a week or once every 2 weeks.
  • flat dose refers to the dose administered to a patient regardless of the patient's weight or body surface area (BSA). Therefore, the uniform dose is provided as a mg/kg dose, rather than as an absolute amount of the agent (eg, anti-PD-L1 antibody). For example, a 60 kg human and a 100 kg human will receive the same dose of antibody (eg, 240 mg anti-PD-L1 antibody).
  • BSA body surface area
  • fixed dose means that two or more different antibodies in a single composition are present in the composition in a specific (fixed) ratio to each other.
  • the fixed dose is based on the weight of the antibody (eg, mg).
  • the fixed dose is based on the concentration of the antibody (eg, mg/mL).
  • the ratio of mg first antibody:mg second antibody is at least about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1: 6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, about 1:40, about 1:50, about 1: 60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:120, about 1:140, about 1:160, about 1:180, about 1:200, about 200: 1.About 180:1, about 160:1, about 140:1, about 120:1, about 100:1, about 90:1, about 80:1, about 70:1, about 60:1, about 50: 1.
  • a 3:1 ratio of the first antibody and the second antibody may mean that the bottle may contain about 240 mg of the first antibody and 80 mg of the second antibody, or about 3 mg/mL of the first antibody and 1 mg/mL of the second antibody.
  • weight-based dose refers to a dose administered to a patient calculated based on the weight of the patient.
  • a patient with 60 kg body weight requires 3 mg/kg of anti-PD-1 antibody and 1 mg/kg of anti-CTLA-4 antibody, one can fix from the 3:1 ratio of anti-PD-1 antibody and anti-CTLA-4 antibody
  • An appropriate amount of anti-PD-1 antibody (i.e., 180 mg) and anti-CTLA-4 antibody (i.e., 60 mg) were drawn from the dosage formulation at one time.
  • immunotherapy refers to the treatment of a subject suffering from a disease or at risk of infection or suffering from a recurrence of the disease by a method that includes inducing, enhancing, inhibiting or otherwise modifying the immune response.
  • Treatment or “therapy” of the subject means any type of intervention or process performed on the subject, or administration of the active agent to the subject, with the purpose of reversing, alleviating, improving, inhibiting, slowing or preventing symptoms, complications or conditions The onset, progression, development, severity or recurrence of the disease, or biochemical indicators associated with the disease.
  • PD-L1 positive can be used interchangeably with “at least about 1% of PD-L1 expression”.
  • PD-L1 expression can be used by any method known in the art.
  • PD-L1 expression is measured by automated IHC.
  • PD-L1 positive tumors may thus have at least about 1%, at least about 2%, at least about 5%, at least about 10%, or at least about 20% of tumor cells expressing PD-L1, as measured by automated IHC .
  • “PD-L1 positive” refers to the presence of at least 100 cells that express PD-L1 on the cell surface.
  • PD-1 Programmed death receptor-1
  • PD-1 is mainly expressed on previously activated T cells in vivo and binds two ligands PD-L1 and PD-L2.
  • the term "PD-1” as used herein includes human PD-1 (hPD-1), variants, homologs and species homologues of hPD-1, and analogs having at least one common epitope with hPD-1.
  • P-L1 Programmed death ligand-1 (PD-L1) is one of two cell surface glycoprotein ligands for PD-1 (the other is PD-L2), which downregulates T cells after binding to PD-1 Activation and cytokine secretion.
  • Subject includes any human or non-human animal.
  • non-human animal includes, but is not limited to vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs.
  • the subject is human.
  • the terms “subject” and “patient” are used interchangeably in certain contexts herein.
  • a “therapeutically effective amount” or “therapeutically effective dose” of a drug or therapeutic agent is any amount of a drug that protects the subject from disease onset or promotes regression of the disease when used alone or in combination with another therapeutic agent, said Disease regression is evidenced by a reduction in the severity of disease symptoms, an increase in the frequency and duration of stages without disease symptoms, or prevention of injury or disability caused by disease torture.
  • a variety of methods known to skilled practitioners can be used to evaluate the therapeutic agent's ability to promote disease regression, such as in human subjects during clinical trials, in animal model systems that predict efficacy in humans, or by in vitro assays The activity of the agent is measured in.
  • sub-therapeutic dose refers to a dose of a therapeutic compound (eg, antibody) that is lower than the usual or typical dose of a therapeutic compound when administered alone for the treatment of hyperproliferative diseases (eg, cancer).
  • a therapeutic compound eg, antibody
  • hyperproliferative diseases eg, cancer
  • anti-cancer drugs promote cancer regression in the subject or prevent further tumor growth.
  • a therapeutically effective amount of the drug promotes cancer regression to the point of eliminating the cancer.
  • Promote cancer regression means that an effective amount of the drug is administered alone or in combination with an anti-tumor agent, resulting in a reduction in tumor growth or size, tumor necrosis, a reduction in the severity of at least one disease symptom, and no disease symptoms Increased frequency and duration of symptoms, or prevention of injury or disability caused by disease.
  • the terms “effective” and “effectiveness” regarding treatment include pharmacological effectiveness and physiological safety. Pharmacological effectiveness means the ability of a drug to promote cancer regression in patients.
  • Physiological safety refers to toxicity levels or other adverse physiological effects (adverse effects) at the cell, organ and/or organism level caused by drug administration.
  • a therapeutically effective amount of anticancer drugs can inhibit cell growth or tumor growth by at least About 10%, at least about 20%, at least about 40%, at least about 60%, or at least about 80%.
  • tumor regression can be observed and lasts for a period of at least about 20 days, at least about 40 days, or at least about 60 days.
  • Immunotherapeutic response patterns represent the clinical response patterns often observed in cancer patients treated with immunotherapeutic agents that produce antitumor effects by inducing cancer-specific immune responses or by altering the innate immune process.
  • This response pattern is characterized by a beneficial therapeutic effect after the initial increase in tumor burden or the appearance of a new lesion, which will be classified as disease progression in the evaluation of traditional chemotherapeutic agents and will be synonymous with drug failure. Therefore, proper evaluation of immunotherapeutic agents may require long-term monitoring of the effects of these agents on target diseases.
  • a therapeutically effective amount of a drug includes a "prophylactically effective amount", which is when administered alone or in combination with an anti-tumor agent to a subject at risk of developing cancer (eg, a subject with a pre- worsening condition) or a subject at risk of cancer recurrence
  • the amount of any drug that inhibits the occurrence or recurrence of cancer In certain embodiments, the prophylactically effective amount completely prevents the occurrence or recurrence of cancer.
  • “Inhibiting" the occurrence or recurrence of cancer refers to reducing the possibility of the occurrence or recurrence of cancer, or preventing the occurrence or recurrence of cancer completely.
  • the term “about”, “approximately” or “substantially encompass” means a value or composition that is within an acceptable error range for a particular value or composition determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined or Composition, that is, the limitations of the measurement system. For example, “about” or “substantially encompasses” may refer to within 1 or more than 1 standard deviation as practiced in the art. Alternatively, “about” or “substantially encompass” may refer to a range of up to 10% or 20% (ie, ⁇ 10% or ⁇ 20%), for example, within a specified numerical range of ⁇ 5% The fluctuation is preferably within a range of ⁇ 2%, and more preferably within a range of ⁇ 1%.
  • about 3 mg may include any number between 2.7 mg to 3.3 mg (for 10%) or 2.4 mg to 3.6 mg for 20%).
  • a pH value of about 5.5 means that the pH is 5.5 ⁇ 5%, preferably the pH is 5.5 ⁇ 2%, and more preferably the pH is 5.5 ⁇ 1%.
  • the term may refer to up to an order of magnitude or up to 5 times the value.
  • a dosing interval of about once every 6 weeks or about once every 12 weeks means that the first dose can be administered on any day of the first week, and then can be on the sixth or twelfth week, respectively On any day of the day.
  • a dosing interval of about once every 6 weeks or about once every 12 weeks means that the first dose is administered on a specific day of the first week (eg, Monday), and then on the sixth week or The second dose is administered on the same day of the twelfth week (ie, Monday). Similar principles apply to phrases including "about once every 2 weeks", "about once a month” and other phrases.
  • any concentration range, percentage range, ratio range, or integer range should be understood to include any integer value within the enumerated range, and where appropriate, its fraction (such as one-tenth of the integer And one percent) unless otherwise noted.
  • the present invention will be further described below in conjunction with specific embodiments. However, the embodiments of the present invention are only used to clarify and do not limit the scope of the present invention. Likewise, the invention is not limited to any specifically preferred embodiments described herein. Those skilled in the art should understand that equivalent replacements or corresponding improvements made to the technical features of the present invention still fall within the protection scope of the present invention.
  • the reagents used in the following examples are all commercially available products, and the preparation of the solution may use conventional techniques in the art.
  • the anti-PD-L1 humanized monoclonal antibody was prepared according to the method described in WO2016022630. After affinity chromatography, the eluate containing the antibody was obtained according to the conventional antibody purification method.
  • This example discloses the test results of pharmacodynamic studies of anti-PD-L1 antibodies in vitro and in vivo in mice.
  • hu5G11-hIgG1 binds to human PD-L1 protein and its EC50 is 21.3ng/mL; hu5G11-hIgG1 and human PD-L1 significantly induce the secretion of IFN- ⁇ in MLR of CD4+:DC cells, and its effect is obviously dose-dependent,
  • the EC50 is 35.0 ⁇ 11.3 ng/mL, indicating that hu5G11-hIgG1 binds to PD-L1 expressed by DC, inhibits the PD-L1/PD-1 signaling pathway, and thereby stimulates the secretion of IFN- ⁇ in CD4+ T cells.
  • the inhibition rate of hu5G11-hIgG1 (15mg/kg, IP, Q2D ⁇ 11) on MC-38/H-11 mice subcutaneously transplanted tumors was 91.7% (all calculated based on the median tumor volume), and significantly prolonged the intraperitoneal vaccination.
  • the survival time of mouse MC-38/H-11 cells and the median survival time were all >98 days, and the survival rate to the end of the experiment (D98) was 80% (p ⁇ 0.01, compared with the human IgG 15mg/kg group) ).
  • hu5G11-hIgG1 can prevent PD-L1 from binding to PD-1 and B7.1 receptors on the surface of T cells, restore T cell activity, thereby enhancing immune response and exerting anti-tumor effects. effect.
  • This example discloses the results of acute toxicity tests and long-term toxicity tests of anti-PD-L1 antibodies in animals.
  • the pharmaceutical composition of the present invention containing hu5G11-hIgG1 at a concentration of 10 mg/mL is administered at a dose of 200 and 400 mg/kg of hu5G11-hIgG1, respectively. Take the day of dosing as the first day of the test.
  • test results show that: the cynomolgus monkey intravenous injection of 200,400mg/kg of this product, the general observation, weight, food intake, body temperature, electrocardiogram, blood pressure, hematology, blood biochemistry, urine routine and gross anatomy have no obvious abnormalities,
  • the maximum tolerated dose (MTD) is 400mg/kg.
  • the long-term toxicity test results show that the cynomolgus monkey intravenously injects the pharmaceutical composition of the present invention containing hu5G11-hIgG1 for 4 weeks, withdraws for 4 weeks, and the NOAEL is 200 mg/kg.
  • This example discloses the preliminary pharmacokinetics and tolerability results of a single-center, open-label, dose-escalation clinical phase I trial.
  • MTD Subject to dose
  • DLT dose-limiting toxicity
  • DLT Primary endpoint
  • MTD Primary endpoint
  • the safety and tolerability results showed that the enrolled patients were given 1, 3, 10, 20, 30 mg/kg of the pharmaceutical composition containing hu5G11-hIgG1. Every 21 days a cycle, continuous administration. The results showed that the currently enrolled patients were well tolerated during the continuous administration, and the drug-related adverse reactions did not exceed Grade II. The current dose can be tolerated; cytokine detection in the 1-10mg/kg dose group, no cytokine storm; no serious adverse reactions related to immunity have been found.
  • the preliminary pharmacokinetic evaluation showed that after the first intravenous infusion of different doses (1, 3, 10 mg/kg) of the test drug, the serum drug exposure level of the currently enrolled patients was significantly dose-dependent, showing linear pharmacokinetics feature.
  • This example discloses the results of preliminary efficacy evaluation of patients with classic Hodgkin lymphoma enrolled in the clinical phase I trial.
  • 2 classic Hodgkin lymphoma subjects have been enrolled, including: Subject No. 3, who was diagnosed as classic Hodgkin lymphoma by histopathology, and the pathological tissue acquisition method was surgery , With lymph node metastasis, previously undergoing surgical treatment, radiation therapy, and chemotherapy; subject No. 6, a patient diagnosed with classic Hodgkin's lymphoma by histopathology, whose pathological tissue was obtained by tissue biopsy, pleural and local chest wall metastasis occurred , Previously undergoing chemotherapy.
  • Subject No. 3 received a dose of 3 mg/kg body weight, 21 days as a cycle, and continued to administer. After 9 weeks, the initial tumor evaluation target lesion was 73% smaller than baseline, and after 18 weeks, the target lesion was smaller than baseline. 76%.
  • Subject No. 6 received a dose of 10 mg/kg body weight, 21 days as a cycle, and continued dosing. After 9 weeks, the initial tumor evaluation target lesions were reduced by 55% from baseline, and after 18 weeks, the target lesions were reduced by 75% from baseline. It is suggested that the pharmaceutical composition containing hu5G11-hIgG1 is effective for the treatment of patients with classic Hodgkin lymphoma.
  • Example 5 Phase II clinical trial for the treatment of relapsed or refractory classic Hodgkin lymphoma
  • This trial used a single-arm, open, multi-center phase II trial design. Objective efficacy indicators were evaluated by the independent imaging evaluation committee using Lugano 2014 efficacy evaluation standards.
  • ORR Objective remission rate
  • ORR objective remission rate
  • This trial used objective remission rate (ORR) as the main efficacy index.
  • ORR objective remission rate
  • "Guidelines for clinical trials of anti-tumor drugs” pointed out that ORR is the initial reliable basis for anti-tumor activity of reactive drugs, and ORR is the most commonly used alternative endpoint in FDA accelerated approval. In one-arm studies, ORR observations can be used to provide evidence to support accelerated approval. Therefore, this trial chose ORR as the primary efficacy endpoint.
  • CRR complete remission rate
  • OS overall survival
  • DOR sustained remission time
  • PFS progression-free survival
  • TTR Remission time
  • CRR complete remission rate
  • PFS Progression-free survival
  • OS Overall survival
  • Continuous remission time defined as the time from the first evaluation of CR or PR to the first evaluation of PD or death.
  • Time to remission the time from the start of the first medication to the first evaluation of CR or PR.
  • Safety evaluation indicators adverse reactions, adverse events and serious adverse events, weight, vital signs, physical examination, ECOG score, laboratory examination, electrocardiogram examination, echocardiography examination, and early withdrawal due to safety or tolerance reasons Situation etc.
  • Study population Patients with relapsed or refractory classic Hodgkin lymphoma.
  • At least one measurable lesion (longer diameter of lymph node lesion> 15mm and shorter diameter> 5mm, longer and shorter diameter of extranodal lesion> 10mm), and corresponding to 18FDG-PET-CT scan is high Ingestion of the lesion; 6. ECOG PS score: 0 to 2 points; 7. The expected survival period is more than 3 months.
  • Nodular lymphocytes are mainly Hodgkin’s lymphoma or gray area lymphoma; 2. The central nervous system is violated, including cerebral parenchyma, meningeal invasion, or spinal cord compression; etc. Or currently have other malignant tumors at the same time; 4. Those with severe allergic diseases, severe drug allergies, known to be allergic to macromolecular protein preparations; 5. Previously received PD-1 antibody, anti-PD-L1 antibody, anti- PD-L2 antibody; 6. May receive other systemic anti-tumor treatment during treatment; 7. Patients known to have active tuberculosis; 8. Pregnant and lactating women; 9. According to the judgment of the investigator, there is serious harm Patients with concomitant diseases that affect patient safety or affect the completion of the study.
  • Critical suspension test criteria The termination of the trial means that the clinical trial has not been completed as planned and all trials will be stopped halfway. The main purpose is to protect the rights and interests of the subjects, ensure the quality of the experiment, and avoid unnecessary economic losses. 1. Serious safety problems occurred during the test; 2. The efficacy was found to be too poor during the test, and there is no need to continue the test; 3. During the test, the clinical trial program was found to have major errors, which was difficult to evaluate the drug effect, or occurred during implementation Major deviations, it is difficult to evaluate the efficacy of the drug if it continues; 4. The State Drug Administration of China ordered to cancel the test for some reason.
  • Test drug a pharmaceutical composition containing hu5G11-hIgG1, 100mg/10mL, stored at 2-8°C in the shade, and the validity period is tentatively 24 months.
  • Trial drug management According to the requirements of GCP, the research medication is kept, distributed, configured, used and recycled by the hospital staff. Used and partially used medicine containers, residual medicine liquids, empty medicine bottles, infusion bags and syringes can be destroyed in situ according to the usage guidelines and operating procedures established by the research center and local institutions, and the outer packaging of medicines must be recovered and returned to the sponsor . For unused drugs, unless the contents of the drug have significant safety issues that need to be destroyed immediately in accordance with local regulations, they need to be returned to the sponsor. The issuance, configuration, use and recovery of test drugs require complete records. The inspectors regularly check the use and records of drugs, and monitor the recovery at any time.
  • Dosage Subjects received hu5G11-hIgG1 monotherapy and received a uniform dose of 1200 mg intravenously on the first day of each cycle (D1). Every 21 days is a cycle until the effect evaluation is disease progression, an intolerable toxic reaction occurs, or the investigator/subject decides to withdraw from the clinical trial.
  • the test drug can be used for up to 96 weeks. If the subject does not show disease progression after 96 weeks of treatment, the investigator judges that the subject is still benefiting from the study drug and needs to sign an additional informed consent before continuing treatment. Except for the first cycle, the dosing time of subsequent cycles should be calculated based on the actual dosing time of the previous cycle, and the dosing window period is ⁇ 3 days of the calculated time.
  • CRR complete response rate
  • PFS progression-free survival
  • OS overall survival
  • DOR duration of remission
  • TTR time to remission
  • ORR Objective response rate: CR+PR cases/total cases. Contains cases of complete remission (CR) and partial remission (PR).
  • CRR Complete remission rate
  • PFS Progression-free survival
  • Tumor remission duration (DOR): the time from the first CR or PR acquisition to the progression of the disease in subjects who obtained CR or PR.
  • OS Overall survival
  • Time to remission defined as the time from the first dose to the first evaluation as PR or CR, whichever occurs first. Only applicable to subjects who obtained CR or PR.
  • Imaging evaluation CT/MRI examination, PET-CT examination
  • the imaging evaluation of this study will be carried out in each research center, and the imaging department researchers will complete the imaging evaluation form, and the researchers will conduct a comprehensive evaluation of the efficacy.
  • this study will use an independent imaging evaluation committee to conduct an independent imaging evaluation to review the evaluation results of the sub-centers, and to evaluate the main research endpoints of this study.
  • independent imaging evaluation will not be used as a basis for researchers' medical decisions.
  • Biomarkers include, but are not limited to: PD-L1, tumor mutation load (TMB), MSI, 9p24.1.
  • PD-L1 It is a molecule that appears on the surface of tumor cells. Clinical studies have shown that the expression level of PD-L1 may be related to the anti-tumor activity of PD-L1/PD-1 antibody drugs in specific tumor types. By detecting the expression of PD-L1 protein in the sample, the use of the corresponding drugs can be guided.
  • TMB It is the total number of mutations per megabase of cell substitutions and insertions and deletions in tumor tissues. Popularly speaking, it is the mutation density of tumor genes. For predicting the efficacy of tumor immunotherapy and determining which patients can benefit from immunotherapy, TMB is a new biomarker with good prospects.
  • 9p24.1 At the specific position of p24.1 on chromosome 9, there are two genes, PD-L1 and PD-L2. Many Hodgkin lymphomas carry a special chromosomal change, called 9p24.1 amplification, which restricts immune cells by overexpressing PD-L1 and PD-L2 and activating PD-1 signaling pathways. Testing 9p24.1 can determine which patients can benefit from immunotherapy and is a brand new biomarker with good prospects.
  • Adverse events refer to any adverse medical events that occur when a subject is treated with study medication, but are not necessarily causally related to treatment. Therefore, AE can be any adverse and unintended signs (including abnormal laboratory findings), symptoms, or disease that are related in time to the use of the study drug, regardless of whether it is related to the drug.
  • AE also includes the complications caused by the medical interventions prescribed in the protocol, for example, the complications caused by invasive procedures such as tissue biopsy; the abnormalities caused by the diagnosis or treatment required by the protocol during the screening period, and the researchers believe that the pre-existing diseases are in AE Those that deteriorated during the reporting period (except for tumor progression) are also considered to be AE, but disease progression is not AE.
  • the researcher should record in detail any adverse events that occurred to the patient.
  • the records of adverse events include: description of the adverse event and all related symptoms, time of occurrence, severity, duration, measures taken and outcomes.
  • SAS version 9.4 is used for all statistical analysis. For continuous variables, the number of subjects, mean, standard deviation, median, minimum, and maximum will be listed. For categorical variables, they will be listed in the form of frequency tables (frequency and percentage). Percentages will retain 2 decimal places.
  • Cloper-Pearson method to estimate the 95% confidence interval of the ORR, if the subject ensures at least 68 cases, if the subject's lower ORR confidence limit is greater than 40%, the drug can be considered effective.
  • the Clopper-Pearson method was used to estimate the 95% confidence interval of CRR; the Kaplan-Meier method was used to estimate the median and 95% confidence intervals of PFS, OS, DOR, and TTR, and the corresponding survival curves were drawn.
  • Logistic regression model was used to analyze the factors affecting ORR.
  • Safety indicators include adverse reactions, adverse events and serious adverse events, weight, vital signs, physical examination, ECOG score, laboratory Examination, electrocardiogram examination, echocardiography examination, and early withdrawal due to safety or tolerance reasons.
  • the ECOG score, laboratory examination, and electrocardiogram examination were used to describe the normal and abnormal changes before and after treatment.
  • the abnormal inspection items after treatment will be listed in the form of a list.
  • the examination indexes of normal before treatment, abnormal after treatment and aggravated abnormality after treatment are listed.
  • the mean and standard deviation, maximum value, minimum value, and median value of blood routine and blood biochemistry were used to describe the measured and changed values before and after treatment, and paired t test was used if necessary.
  • PK Pharmacokinetic data analysis
  • Blood drug concentration analysis is based on PK concentration set (PKCS).
  • the analysis of PK parameters is based on the PK parameter analysis set (PKPS). Descriptive analysis was performed using statistics such as mean, standard deviation, median, minimum, maximum, geometric mean, and geometric standard error. Summarize the changes of blood drug concentration at various time points and its relative baseline.
  • the main pharmacokinetic parameters include peak time Tmax, peak concentration Cmax, area under blood concentration-time curve AUC, elimination half-life t1/2, steady-state peak concentration Css-max, steady-state valley concentration Css-min, average stability State plasma concentration Css-av and so on.
  • Example 6 Results of a clinical phase II trial for the treatment of relapsed or refractory classic Hodgkin lymphoma
  • PET-CT showed on October 30, 2017: 1. Confirmed Hodgkin's lymphoma in May, suggesting that the left side of the neck, the left clavicle, the right clavicle, the right and left clavicle, and the longitudinal prostatic lymph nodes are active Lymphoma lesions. 2. Fibrous foci of left lower lobe. 3. The benign hypertrophy of the bilateral lower posterior pleura. 4. Double breast calcification. 5. F18-FDG PET-CT whole body examination (cranial brain to upper femoral segment) showed no other obvious abnormalities. Tumor marker: carbohydrate antigen CA-72416.96U/mL. 2017-10-30Rheumatism series: anti-nuclear antibody determination is weak positive ( ⁇ ). Bone marrow cytology and flow cytometry were not abnormal.
  • In situ hybridization EBER(-). After excluding the contraindications to chemotherapy, the ABVD regimen was given for 6 cycles of chemotherapy from November 09, 2017 to May 23, 2018. The process was smooth and the patient was tolerated. On July 24, 2018, PET-CT showed: HLC supraclavicular lymph node biopsy confirmed; after 6 cycles of chemotherapy and local neck radiotherapy, compared with PET-CT on June 23, 2017, the original mediastinum and the left side of the neck III The volume of residual lymph node lesions in the area was not obvious, but there was no obvious FOG metabolic activity.
  • Pulmonary bullae in right middle lobe double breast calcification: F18-FDG PET-CT whole body examination (cranium to upper femoral segment) without any other obvious abnormalities. Excluding the contraindications to chemotherapy, the CHOP regimen was given for 1 cycle of chemotherapy on November 29, 2018, and the chemotherapy was poorly tolerated. The patient refused other second-line chemotherapy, and the COP regimen was given for 2 cycles on March 15, 2019. Review of PET-CT on April 25, 2019: After HL radiotherapy and chemotherapy, compared with (2018-11-07) PET-CT images, the original mediastinal lesions were larger than before and the FDG metabolic level increased, suggesting that the treatment effect is not good .
  • PET-CT results are as follows:
  • Baseline mediastinal blood pool SUV value 1.8; liver blood pool SUV value 2.6; lesion SUV value 6.2; score 5 points
  • C4D21 mediastinal blood pool SUV value 1.7; liver blood pool SUV value 1.8; lesion SUV value 1.7; score 2 points
  • C8D21 mediastinal blood pool SUV value 1.7; liver blood pool SUV value 3.2; lesion SUV value 4.1; score 4 points
  • PET-CT results showed that the tumor invaded the anterior mediastinal pleura and pericardium and the opening of the left upper lobe bronchus, left parotid gland, bilateral neck (area II-IV), double Multiple hypermetastatic enlarged lymph nodes in the supraclavicular area, bilateral armpits, mediastinum (groups 2-7), bilateral hilar, bilateral costal septum, cardiac septal angle, and splenic hilar area, multiple metastatic tumors of the pancreas and spleen, Subcutaneous high metabolic foci in the left anterior chest wall, considering metastases, multiple bone metastases throughout the body, suspected lymphoma.
  • ABVD chemotherapy (doxorubicin liposome 30mg d1, d15, vincristine 2mg d1, d15, bleomycin 1.5g d1, d15, dacarbazine 550mg d1, d15) treatment, a total of 8 courses, the best efficacy PR.
  • PET-CT was reviewed to consider tumor recurrence.
  • the last course of treatment was: June 5, 2018.
  • Cyclophosphamide + etoposide mobilization chemotherapy was performed to collect stem cells.
  • ESHAP chemotherapy etoposide 80mg, d1-4, cisplatin 30mg, d1-4, methylprednisolone 0.5g, d1-5) from June 28, 2018 to July 26, 2018 Cytarabine 3gd5) 2 courses, PCR (prednisone 20mg, cyclophosphamide 50mg, lenalidomide 10mg) chemotherapy from September 25, 2018 to April 6, 2019, December 7, 2018 PET-CT indicates disease progression. Because there is no other chemotherapy option, the patient continues to take oral chemotherapy drugs.
  • the patient started treatment with hu5G11-hIgG1 injection on May 16, 2019, a 21-day cycle, June 6, 2019, June 27, 2019, July 18, 2019, August 8, 2019, 2019 A total of 10 courses of treatment will be given on August 29, September 19, 2019, October 10, 2019, October 31, 2019, and November 21, 2019.
  • the patient was well tolerated during treatment and continued medication.
  • target lesion 1672 mm 2
  • non-target lesion non-CR/non-PD
  • efficacy evaluation SD At the end of the second cycle: target lesion: 1672 mm 2 , non-target lesion: non-CR/non-PD; efficacy evaluation SD.
  • End of cycle 4 target lesion: 1596 mm 2 , non-target lesion: non-CR/non-PD; efficacy evaluation SD.
  • End of cycle 6 target lesion: 1596 mm 2 , non-target lesion: non-CR/non-PD; efficacy evaluation SD.
  • PET-CT results are as follows (according to Lugano2014):
  • End of cycle 8 CR for efficacy evaluation.
  • lymph node biopsy report on March 7, 2018 (right cervical lymph node) classic Hodgkin lymphoma (mixed cell type), immunohistochemistry: tumor cells CD30 (+), CD15 (+), PAX5 (scattered weak +), CD20(-), CD79a(-), OCT-2(+), Bob.1(-), LCA(-), MUM1(+), ALK1(-) , EBER(-), CD3(-).
  • PET-CT multiple lymph nodes (right cervical area IV, bilateral supraclavicular, 2R, 3A, 4R, 6, 7, 8, right diaphragmatic foot, left adrenal area, spleen and stomach space, pancreas Posterior and paraabdominal aorta) increased and swollen, increased metabolism; enlarged spleen, increased uneven metabolism; increased metabolism of the left clavicle and sternum; the above considerations are lymphoma infiltration foci. 3 courses of ABVD chemotherapy from March 15, 2018 to May 31, 2018, the first day of the fourth course of ABVD chemotherapy on June 14, 2018, and PET-CY on June 14, 2018, the best effect PR. From July 20, 2018 to July 24, 2018, 2 courses of ESHAP chemotherapy, the efficacy is unknown.
  • Autologous hematopoietic stem cell transplantation stimulating factor mobilization on July 26, 2018, autologous stem cells were collected from August 1 to August 2, 2018, and entered the transplantation warehouse from September 7 to September 13 for BEAM chemotherapy pretreatment, 9 Autotransfusion of autologous hematopoietic stem cells on September 14th, leukocyte transplantation on September 25, platelet transplantation on September 29, PET-CT on December 26, 2018, 5 points, best efficacy PR, June 25, 2019 PET-CT progressed earlier.
  • the drip rate is 250mL/1h, and it will be halved from the second cycle to the seventh cycle at a low rate to 250mL/2h, 2019.8 Hospitalization of herpes zoster occurred from June 6 to September 2019.
  • the trial medication in the third cycle was delayed after 15 days of recovery. There was no other complaint during or after the medication.
  • PET-CT results are as follows:
  • target lesions 1. 5 points for lymph nodes in the space between the liver and stomach, 2. 5 points for retroperitoneal lymph nodes;
  • Week06 Target lesions: 1. Hepatic-gastric space lymph node 2 points, 2. retroperitoneal lymph node 2 points, efficacy CR;
  • Week12 Target lesions: 1. Hepatic and gastric interstitial lymph nodes 3 points, 2. Retroperitoneal lymph nodes 3 points, curative effect CR.
  • target lesions 1. Hepatogastric space lymph nodes 21.68 ⁇ 19.65mm, 2. retroperitoneal lymph nodes 16.80 ⁇ 10.66mm, non-target lesions: residual lesions/no enlargement;
  • Week06 Target lesions: 1. Hepatogastric space lymph nodes 15.64 ⁇ 10.50mm, 2. Retroperitoneal lymph nodes 10.43 ⁇ 5.23mm, non-target lesions: residual lesion/no enlargement; efficacy PR;
  • Target lesions 1. Hepatogastric space lymph nodes 17.31 ⁇ 10.82mm, 2. Retroperitoneal lymph nodes 13.13 ⁇ 5.90mm, non-target lesions: residual lesions/no enlargement; efficacy PR.
  • PET CT results are as follows:
  • target lesion Deauville score 1 point non-target lesion: non-CR/non-PD
  • target lesion Deauville score 1 point non-target lesion: non-CR/non-PD
  • target lesion 882.04 non-target lesion: non-CR/non-PD
  • target lesion 653.08 non-target lesion: non-CR/non-PD.
  • compositions and methods of the present invention have been described according to preferred embodiments, for those skilled in the art, without departing from the concept, spirit and scope of the present invention, The composition and/or method described herein and the steps or sequence of steps of the method are changed.

Abstract

本申请提供抗PD-L1单克隆抗体治疗癌症的用途，其包括向所述主体施用治疗有效量的PD-1受体和其配体PD-L1之间的相互作用的抑制剂，其中抑制剂是抗PD-L1单抗。

Description

抗PD-L1单克隆抗体治疗癌症的用途 技术领域
本发明提供治疗主体中的癌症的方法，其包括向所述主体施用治疗有效量的PD-1受体和其配体PD-L1之间的相互作用的抑制剂。
背景技术
包含T淋巴细胞的天然免疫系统具有强大的抗癌能力，其具有广泛的能力和精细的特异性，从而对各种肿瘤抗原做出响应。新兴的癌症免疫疗法通过激活的效应细胞的过继转移、针对相关抗原的免疫接种或提供非特异性免疫刺激剂来增强抗肿瘤免疫应答。在过去的十余年中，研究者努力开发特异性免疫检查点抑制剂并期望提供用于治疗癌症的新免疫治疗方案，包括开发结合并抑制CTLA-4的抗体(Antibody)伊匹单抗(Ipilimumab)
Figure PCTCN2019127891-appb-000001
用于治疗具有晚期黑素瘤的患者(Hodi等人(2010)N Engl J Med 363:711-23)，和开发抗体诸如纳武利尤单抗(Nivolumab)
Figure PCTCN2019127891-appb-000002
和帕博利珠单抗(Pembrolizumab)
Figure PCTCN2019127891-appb-000003
它们特异性地结合程序性死亡受体-1(PD-1)并阻断抑制性PD-1/PD-1配体途径(Topalian等人(2012a)N Engl J Med 366:2443-54)。其中，PD-1(programmed death-1，PD-1)是一种由活化的T淋巴细胞和B淋巴细胞表达的关键免疫检验点受体并介导免疫抑制，其配体至少包括PD-L1和PD-L2。
PD-L1(Programmed death-ligand 1)又称为CD247和B7-H1，是由CD274基因编码的40kDa的1型跨膜蛋白，是PD-1的一个配体。PD-L1和PD-1两者都属于免疫球蛋白超家族并且都由两个细胞外Ig结构域，即N末端V结构域和C末端恒定结构域组成。PD-L1与程序性死亡受体-1(PD-1)和B7-1(CD80)的结合界面是在IgV样结构域上(Lin等(2008)PNAS 105:3011-3016)。虽然PD-L1含有保守的短的细胞内尾区(约30个氨基酸)，但PD-1含有两个基于细胞质酪氨酸的信号基序，即基于免疫受体酪氨酸的抑制基序(ITIM)和基于免疫受体酪氨酸的转换基序(ITSM)。在T细胞刺激之后，PD-1将酪氨酸磷酸酶SHP-2募集到其胞质尾区内的ITSM基序，导致参与CD3T细胞信号传导级联的效应分子(诸如CD3ζ、PKCθ和ZAP70)的去磷酸化(Freeman等(2000)J Exp Med 192:1027-34；Latchman等(2001)Nat Immunol 2:261-8；Carter等(2002)Eur J Immunol32:634-43)。PD-L1不仅在淋巴和非淋巴组织中的白细胞和非造血细胞上广泛分布，而且还在各种癌细胞中广泛分布，在多种肿瘤细胞表面高表达，而且肿瘤的恶性程度以及不良预后与PD-L1的表达水平密切相关。有临床数据表明PD-L1的高肿瘤表达与增加的肿瘤侵袭性和较差的预后相关联。PD-1/PD-L1复合物的形成传输抑制信号并负调节T细胞免疫应答；它抑制TCR介导的T细胞活化、细胞因子产生和T细胞增殖(Fife等(2011)Nature Immunology 10:1185-1193)；诱导同源抗原特异性T细胞之中的衰竭或无反应性(Hofmeyer等(2011)Journal of Biomedicine and Biotechnology 2011:1-9)；促进Th1细胞分化成Foxp3+调节性T细胞(Armanath等(2011)Science TransMed 3:1-13；Francisco等(2009)J.Exp.Med.206:3015-3029)；并诱导效应T细胞的凋亡。PD-L1基因的破坏导致上调的T细胞应答和自身反应性T细胞的产生(Latchman等(2004)PNAS 101:10691-10696)。PD-1或PD-L1的抗体阻断导致增加的抗肿瘤免疫性(Iwai等(2002)PNAS99:12293-12297)。
抗PD-L1抗体可以通过阻断PD-L1与PD-1及CD80的相互作用，使得相关的负调控信号不能被启动与传导，从而避免了在肿瘤微环境中的效应T细胞的活性被抑制，使T细胞可以发挥杀伤和抑制肿瘤细胞的功能。由于抗PD-L1抗体能够直接作用于肿瘤组织，因而具有较高的特异性和安全性。目前主要的抗PD-L1单抗药物产品包括罗氏的Atezolizumab、阿斯利康的Durvalumab和默克&辉瑞的Avelumab等。专利WO2016022630也公开了抗PD-L1抗体，对PD-L1具有较高的亲和力，能够显著抑制细胞表面的PD-L1和PD-1的相互作用，并显著促进T细胞分泌IL-2和IFN-γ。
恶性淋巴瘤是中国最常见的十种肿瘤之一，根据《中国肿瘤登记年报》公布的数据，2003年至2013年，恶性淋巴瘤的发病率约为每10万人5例。霍奇金淋巴瘤(英语：Hodgkin’s lymphoma)又称霍奇氏金淋巴瘤、霍奇金氏病、何杰金氏病，或何杰金氏淋巴瘤，为淋巴瘤的一种类型，是一种淋巴细胞的癌变(Bower,Mark；Waxman,Jonathan.Lecture Notes:Oncology 2.John Wiley&Sons.2011:195.ISBN 978-1118293003.)，症状包含发烧、夜间盗汗，以及体重减轻，常见颈部、上臂，以及鼠蹊部淋巴结无痛肿大，患者同时也可能会感到疲惫或搔痒(Adult Hodgkin Lymphoma Treatment
Figure PCTCN2019127891-appb-000004
-Patient Version.NCI.August 3,2016)。约半数的霍奇金淋巴瘤是因EB病毒引起，其它危险因子包含家族有相关病史，或是个人曾受HIV感染(World Cancer Report 2014.World Health Organization.2014:Chapter 2.4.ISBN 928320429-8.)。霍奇金淋巴瘤主要分为经典型霍奇金淋巴瘤(classical Hodgkin lymphoma)及结节样淋巴细胞为主型霍奇金淋巴瘤两种(SEER Stat Fact Sheets:Hodgkin Lymphoma.NCI.April 2016)，其中cHL约占95％，可以借由寻找淋巴结中的霍奇金淋巴细胞协助诊断，例如RS细胞。霍奇金淋巴瘤可以借由化学疗法、放射线疗法，以及骨髓移植治疗，治疗的选择一般借由疾病的进展程度，以及其特性进行判断。一般来说，早期霍奇金淋巴瘤采用联合治疗策略，先给予缩减疗程的化疗，然后给予病灶部位放疗；晚期霍奇金淋巴瘤一般采用更长疗 程的化疗。但化疗药物和放疗可能增加日后罹患其它癌症、心血管疾病，以及肺部疾病的风险。在疾病初期，治愈率通常较高(Armitage,JO.Early-stage Hodgkin’s Lymphoma.N.Engl.J.Med.August 2010,363(7):653-62.PMID 20818856.)，在美国，此疾病的五年生存率约为86％，20岁以下的患者存活率更高达97％(Ward,E；DeSantis,C；Robbins,A；Kohler,B；Jemal,A.Childhood and adolescent cancer statistics,2014.CA:A Cancer Journal for Clinicians.2014,64(2):83-103.PMID 24488779)。尽管首次治疗的治愈率高，但大约5-10％的霍奇金淋巴瘤患者将会出现原发性难治性疾病，10％-30％的患者在首次获得CR后出现复发。复发性难治性疾病的治疗包括高剂量化疗(HDT)和自体造血干细胞移植(ASCT)，在HDT/ASCT中获得完全消退、部分消退和发生耐药的患者中五年生存率分别为79％、59％和17％(Ansell SM.Hodgkin Lymphoma:2012 update on diagnosis,risk-stratification,and management.Am Jhematol 2012；87(12):1097-103.)。
发明内容
本发明的概述
本发明提供治疗、缓解或改善主体中的癌症的方法，其包括向所述主体施用治疗有效量的PD-1受体和其配体PD-L1之间的相互作用的抑制剂，其中，所述抑制剂是PD-L1抗体。
本发明也提供抗PD-L1抗体治疗、缓解或改善癌症的用途，其包括向所述主体施用治疗有效量的PD-1受体和其配体PD-L1之间的相互作用的抑制剂，其中，所述抑制剂是抗PD-L1抗体。
本发明还提供抗PD-L1抗体在制备用于治疗、缓解或改善癌症的药物中的用途。
本发明还提供了用于治疗、缓解或改善主体中的癌症的抗PD-L1抗体。
在一些方案中，所述抗PD-L1抗体包含如下氨基酸序列：与SEQ ID NO:1或SEQ ID NO:4所示的氨基酸序列有至少80％同源性的重链CDR1区；与SEQ ID NO:2或SEQ ID NO:5所示的氨基酸序列有至少80％同源性的重链CDR2区；与SEQ ID NO:3或SEQ ID NO:6所示的氨基酸序列有至少80％同源性的重链CDR3区；与SEQ ID NO:7或SEQ ID NO:10所示的氨基酸序列有至少80％同源性的轻链CDR1区；与SEQ ID NO:8或SEQ ID NO:11所示的氨基酸序列有至少80％同源性的轻链CDR2区；与SEQ ID NO:9或SEQ ID NO:12所示的氨基酸序列有至少80％同源性的轻链CDR3区。
在一些方案中，所述抗PD-L1抗体以1mg/kg、2mg/kg、3mg/kg、5mg/kg、6mg/kg、9mg/kg、10mg/kg、15mg/kg、20mg/kg、30mg/kg体重的剂量施用，持续给药。
在一些方案中，所述抗PD-L1抗体以可以有效治疗所述癌症的一个或多个统一剂量施用。在一些具体实施方式中，其中所述统一剂量在大约20mg至大约2000mg抗PD-L1抗体范围内。在一些具体实施方式中，其中所述统一剂量选自大约300mg、大约600mg、大约900mg、大约1000mg、大约1200mg、大约1500mg、大约1800mg、大约2100mg或大约2400mg抗PD-L1抗体。在一些具体实施方式中，所述统一剂量选自大约1200mg抗PD-L1抗体。
在一些方案中，大约每周(q1w)、大约每2周(q1w)、大约每3周(q1w)、或者大约每4周(q1w)施用抗PD-L1抗体。在一些具体实施方式中，大约每3周为病人施用统一剂量的抗PD-L1抗体。在一些具体实施方式中，所述抗PD-L1抗体以每个患者1200mg的剂量施用，大约每3周施用一次，持续施用。
在一些方案中，所述抗PD-L1抗体作为静脉输注施用。在一些具体实施方式中，所述抗PD-L1抗体作为约1-2小时静脉输注施用，优选约1小时静脉输注施用。
在一些方案中，所述抗PD-L1抗体为裸抗体、完整抗体或包含抗原结合区的抗体片段。
在一些方案中，所述方法导致客观反应，优选完全反应或部分反应。
在一些方案中，所述主体先前已接受手术、化疗和/或放射治疗。在一些具体实施方式中，所述主体经手术后获完全缓解后再次出现疾病进展。在一些具体实施方式中，所述主体经手术后未能完全缓解或未能部分缓解。在一些具体实施方式中，所述主体经化疗后获完全缓解后再次出现疾病进展。在一些具体实施方式中，所述主体经化疗后未能完全缓解或未能部分缓解。在一些具体实施方式中，所述主体经放射治疗后获完全缓解后再次出现疾病进展。在一些具体实施方式中，所述主体经放射治疗后未能完全缓解或未能部分缓解。在一些方案中，所述主体先前已接受手术和化疗。在一些具体实施方式中，所述主体经手术和化疗后获完全缓解后再次出现疾病进展。在一些具体实施方式中，所述主体经手术和化疗后未能完全缓解或未能部分缓解。在一些方案中，所述主体先前已接受手术和放射治疗。在一些具体实施方式中，所述主体经手术和放射治疗后获完全缓解后再次出现疾病进展。在一些具体实施方式中，所述主体经手术和放射治疗后未能完全缓解或未能部分缓解。在一些方案中，所述主体先前已接受化疗和放射治疗。在一些具体实施方式中，所述主体经化疗和放射治疗后获完全缓解后再次出现疾病进展。在一些具体实施方式中，所述主体经化疗和放射治疗后未能完全缓解或未能部分缓解。在一些方案中，所述主体先前已接受手术、化 疗和放射治疗。在一些具体实施方式中，所述主体经手术、化疗和放射治疗后获完全缓解后再次出现疾病进展。在一些具体实施方式中，所述主体经手术、化疗和放射治疗后未能完全缓解或未能部分缓解。
在一些方案中，所述主体接受手术、化疗和/或放射治疗后接受过自体干细胞移植。在一些具体实施方式中，所述主体经手术、化疗和/或自体干细胞移植后获完全缓解后再次出现疾病进展。在一些具体实施方式中，所述主体经手术、化疗和/或自体干细胞移植后未能完全缓解或未能部分缓解。在一些方案中，所述主体接受手术后接受过自体干细胞移植。在一些具体实施方式中，所述主体经手术和自体干细胞移植后获完全缓解后再次出现疾病进展。在一些具体实施方式中，所述主体经手术和自体干细胞移植后未能完全缓解或未能部分缓解。在一些方案中，所述主体接受化疗后接受过自体干细胞移植。在一些具体实施方式中，所述主体经化疗和自体干细胞移植后获完全缓解后再次出现疾病进展。在一些具体实施方式中，所述主体经化疗和自体干细胞移植后未能完全缓解或未能部分缓解。在一些方案中，所述主体接受放射治疗后接受过自体干细胞移植。在一些具体实施方式中，所述主体经放射治疗和自体干细胞移植后获完全缓解后再次出现疾病进展。在一些具体实施方式中，所述主体经放射治疗和自体干细胞移植后未能完全缓解或未能部分缓解。在一些方案中，所述主体接受手术和化疗后接受过自体干细胞移植。在一些具体实施方式中，所述主体经手术、化疗和自体干细胞移植后获完全缓解后再次出现疾病进展。在一些具体实施方式中，所述主体经手术、化疗和自体干细胞移植后未能完全缓解或未能部分缓解。在一些方案中，所述主体接受手术和放射治疗后接受过自体干细胞移植。在一些具体实施方式中，所述主体经手术、放射治疗和自体干细胞移植后获完全缓解后再次出现疾病进展。在一些具体实施方式中，所述主体经手术、放射治疗和自体干细胞移植后未能完全缓解或未能部分缓解。在一些方案中，所述主体接受化疗和放射治疗后接受过自体干细胞移植。在一些具体实施方式中，所述主体经化疗、放射治疗和自体干细胞移植后获完全缓解后再次出现疾病进展。在一些具体实施方式中，所述主体经化疗、放射治疗和自体干细胞移植后未能完全缓解或未能部分缓解。
在一些方案中，所述主体接受手术后接受过自体干细胞移植。在一些具体实施方式中，所述主体经自体干细胞移植后获完全缓解后再次出现疾病进展。在一些具体实施方式中，所述主体经自体干细胞移植后未能完全缓解或未能部分缓解。
在一些方案中，所述癌症是霍奇金淋巴瘤(Hodgkin’s lymphoma)。在一些具体实施方式中，所述癌症是经典型霍奇金淋巴瘤(cHL)。在一些具体实施方式中，所述经典型霍奇金淋巴瘤在化疗和/或放射治疗后已进展。在一些具体实施方式中，所述癌症是复发性或难治性经典型霍奇金淋巴瘤。在一些具体实施方式中，所述经典型霍奇金淋巴瘤是复发性的。在一些具体实施方式中，所述经典型霍奇金淋巴瘤是难治性的。在一些具体实施方式中，所述经典型霍奇金淋巴瘤是转移性的。在一些具体实施方式中，所述癌症治疗是复发性或难治性经典型霍奇金淋巴瘤的三线治疗。在一些具体实施方式中，所述癌症治疗是转移性经典型霍奇金淋巴瘤的三线治疗。在一些具体实施方式中，所述复发性或难治性经典型霍奇金淋巴瘤在完成一线化疗期间和/或放射治疗之后没有进展。在一些具体实施方式中，所述转移性经典型霍奇金淋巴瘤在完成一线化疗期间和/或放射治疗之后没有进展。在一些具体实施方式中，所述复发性或难治性经典型霍奇金淋巴瘤在化疗和/或放射治疗后已进展。在一些具体实施方式中，所述转移性经典型霍奇金淋巴瘤在化疗和/或放射治疗后已进展。
本发明提供包括含有固定剂量抗PD-L1抗体的容器的制品。本发明还提供抗PD-L1抗体在制备用于治疗癌症的包括固定剂量的抗PD-L1抗体的容器的制品中的用途。在一些具体实施方式中，所述容器是管形瓶。所述固定剂量选自大约300mg、大约600mg、大约900mg、大约1000mg、大约1200mg、大约1500mg、大约1800mg、大约2100mg和大约2400mg的抗PD-L1抗体。在一些具体实施方式中，所述制品进一步包括指导用户为癌症病人施用所述固定剂量的包装插页或药品说明书。在一些具体实施方式中，所述制品包括1个或1个以上的管形瓶，所述管形瓶含有大约300mg或600mg抗PD-L1抗体。在一些具体实施方式中，所述制品括1个管形瓶，所述管形瓶含有大约300mg抗PD-L1抗体。在一些具体实施方式中，所述制品包括1个管形瓶，所述管形瓶含有大约600mg抗PD-L1抗体。
本发明的详细内容及优选的实施方案
本发明提供了一种用于治疗患有癌症或肿瘤的主体的方法，其包括向所述主体施用治疗有效量的PD-1受体和其配体PD-L1之间的相互作用的抑制剂。
本发明还提供了一种用于治疗患有癌症或肿瘤的主体的方法，所述方法包括给所述主体施用治疗有效量的：结合程序性死亡配体1(PD-L1)和/或抑制PD-L1活性的抗体或其抗原结合部分。
本发明也提供了一种用于治疗患有癌症或肿瘤的主体的单一疗法，所述方法包括给所述主体单独施用治疗有效量的：结合程序性死亡配体1(PD-L1)和/或抑制PD-L1活性的抗体或其抗原结合部分。
本发明也提供了一种治疗患有癌症或肿瘤的主体的方法，所述癌症或肿瘤是经典型霍奇金淋巴瘤，所 述方法包括：(i)测量所述主体的样品中的PD-L1水平，其中所述主体是PD-L1阳性的，和(ii)给所述主体施用治疗有效量的抗PD-L1抗体或其抗原结合部分。
本发明提供了一种用于治疗患有癌症或肿瘤的主体的方法。在某些实施方案中，所述主体是经组织病理学确诊为霍奇金淋巴瘤的患者。在另一些实施方案中，所述主体是经组织病理学确诊为经典型霍奇金淋巴瘤(cHL)的患者。在另一些实施方案中，所述主体是复发性或难治性的经典型霍奇金淋巴瘤(cHL)的患者，例如，是a)挽救化疗和/或放射治疗后接受自体干细胞移植之后复发或进展的患者，或者是b)第一线化疗为全身多药联合化疗，后续化疗至少有一线化疗为全身多药联合化疗的患者，或者是c)难治患者，例如疗程≥2周期未达到部分缓解(PR)或者疗程≥4周期未达到完全缓解(CR)的患者，如果最佳疗效或在先治疗结束原因为疾病进展(PD)则疗程数不作要求，或者是d)复发患者，例如复发前近期内至少接受过二线化疗的患者。在另一些实施方案中，所述主体是复发或难治性的经典型霍奇金淋巴瘤(cHL)的患者。在另一些实施方案中，所述主体是复发性经典型霍奇金淋巴瘤(cHL)的患者，所述复发性是指经治疗获完全缓解后再次出现疾病进展。在另一些实施方案中，所述主体是难治性经典型霍奇金淋巴瘤(cHL)的患者，所述难治性是指经治疗后未能获得完全缓解或部分缓解。在另一些实施方案中，所述主体是转移性经典型霍奇金淋巴瘤(cHL)的患者。在一些具体实施方案中，所述转移性是淋巴结转移。在另一些具体实施方案中，所述转移性是胸膜和/或局部胸壁转移。
在一些方案中，所述主体是复发和难治性的经典型霍奇金淋巴瘤(cHL)的患者。在一些方案中，所述主体是转移性的复发性和难治性的经典型霍奇金淋巴瘤(cHL)的患者。在一些方案中，所述主体是转移性的复发性或难治性的经典型霍奇金淋巴瘤(cHL)的患者。
经典型霍奇金淋巴瘤的一线化疗方案可能包括但不限于ABVD(多柔比星、博来霉素、长春花碱、达卡巴嗪)，剂量递增的BEACOPP(博来霉素、依托泊苷、阿霉素、环磷酰胺、长春新碱、甲基苄肼、强的松)或StanfordV(多柔比星、长春花碱、氮芥、依托泊苷、长春新碱、博来霉素、强的松)等等。经典型霍奇金淋巴瘤的二线化疗方案可能包括但不限于本妥昔单抗(Brentuximab vedotin)，DHAP(地塞米松、顺铂、阿糖胞苷)，ESHAP(依托泊苷、甲基强的松龙、阿糖胞苷、顺铂)，吉西他滨，苯达莫司汀，长春瑞滨，GVD(吉西他滨、长春瑞滨、脂质体多柔比星)，ICE(异环磷酰胺、卡波、依托泊苷)，IGEV(异环磷酰胺、吉西他滨和长春瑞滨)，或其组合。
本发明也提供了一种用于鉴别患有经典型霍奇金淋巴瘤的主体的方法，所述主体对于抗PD-L1抗体疗法而言是适合的，所述方法包括测量所述主体的样品中的PD-L1水平，且其中给所述主体施用治疗有效量的抗PD-L1抗体或其抗原结合部分。
本发明也提供了一种用于治疗患有经典型霍奇金淋巴瘤的主体的试剂盒，所述试剂盒包含：(a)抗PD-L1抗体或其抗原结合部分；(b)关于治疗所述肿瘤的说明书。
本发明提供了使用一种或多种免疫检查点抑制剂(例如抗PD-L1抗体或其抗原结合部分、或者抗PD-1抗体或其抗原结合部分)治疗癌症的方法。在一个实施方案中，所述癌症是原发癌。在一个实施方案中，所述癌症是转移性或复发性癌症。在一个实施方案中，所述癌症是复发性或难治性癌症。在一个实施方案中，所述癌症是霍奇金淋巴瘤。在一个实施方案中，所述癌症是复发或难治性霍奇金淋巴瘤。
本发明也提供一种抗PD-L1抗体在经典型霍奇金淋巴瘤一线治疗中的用途。本发明也提供一种抗PD-L1抗体在经典型霍奇金淋巴瘤二线治疗中的用途。本发明也提供一种抗PD-L1抗体在经典型霍奇金淋巴瘤三线治疗中的用途。在一些方案中，所述抗PD-L1抗体用于复发性或难治性经典型霍奇金淋巴瘤的二线治疗。在一些方案中，所述抗PD-L1抗体用于复发性或难治性经典型霍奇金淋巴瘤的三线治疗。在一些方案中，所述抗PD-L1抗体单独用于复发性或难治性经典型霍奇金淋巴瘤的三线治疗。在一些方案中，所述抗PD-L1抗体用于复发性或难治性经典型霍奇金淋巴瘤的后续治疗。在一些具体实施方式中，所述抗PD-L1抗体单独用于复发性或难治性经典型霍奇金淋巴瘤患者的三线治疗，所述患者先前接受过包括但不限于ABVD(多柔比星、博来霉素、长春花碱、达卡巴嗪)，ABVD联合放射治疗(例如ISRT)，剂量递增的BEACOPP(博来霉素、依托泊苷、阿霉素、环磷酰胺、长春新碱、甲基苄肼、强的松)，剂量递增的BEACOPP继以ABVD和放射治疗(例如ISRT)，或Stanford V(多柔比星、长春花碱、氮芥、依托泊苷、长春新碱、博来霉素、强的松)等的一线治疗。在一些具体实施方式中，所述抗PD-L1抗体单独用于复发性或难治性经典型霍奇金淋巴瘤患者的三线治疗，所述患者先前接受过包括但不限于本妥昔单抗(Brentuximab vedotin)，DHAP(地塞米松、顺铂、阿糖胞苷)，ESHAP(依托泊苷、甲基强的松龙、阿糖胞苷、顺铂)，吉西他滨，苯达莫司汀，长春瑞滨，GVD(吉西他滨、长春瑞滨、脂质体多柔比星)，ICE(异环磷酰胺、卡波、依托泊苷)，IGEV(异环磷酰胺、吉西他滨和长春瑞滨)，或其组合等的二线治疗。
在某些实施方案中，所述主体是人患者。在某些实施方案中，所述主体已经接受另一种癌症治疗(例如，化学疗法)，但是对于这样的另一种癌症而言是治疗抗性的或难治的。
在某些实施方案中，本发明提供了一种用于治疗患有肿瘤的主体的方法，所述方法包括给所述主体施用治疗有效量的免疫检查点抑制剂，例如，抗PD-L1抗体。在某些实施方案中，本发明涉及一种治疗患有肿瘤的主体的方法，所述肿瘤是复发性或难治性的经典型霍奇金淋巴瘤，所述方法包括：(i)测量所述主体的样品中的PD-L1水平，其中所述主体表达PD-L1，和(ii)给所述主体施用治疗有效量的免疫检查点抑制剂，例如，抗PD-L1抗体或其抗原结合部分。在某些实施方案中，所述抗PD-L1抗体是13C5、5G11、ch13C5-hIgG1、ch13C5-hIgG4、ch5G11-hIgG1、ch5G11-hIgG4、hu13C5-hIgG1、hu13C5-hIgG4、hu5G11-hIgG1或hu5G11-hIgG4单抗。在其它实施方案中，所述抗PD-L1抗体与5G11单抗竞争结合。
在一些方案中，所述癌症或肿瘤表达PD-L1。在施用任何组合物或利用本文公开的任何方法之前，可以测量主体中肿瘤的PD-L1表达水平。在一个实施方案中，肿瘤的PD-L1表达水平是至少约0.5％、至少约0.6％、至少约0.7％、至少约0.8％、至少约0.9％、1％、至少约2％、至少约3％、至少约4％、至少约5％、至少约6％、至少约7％、至少约8％、至少约9％、至少约10％、至少约11％、至少约12％、至少约13％、至少约14％、至少约15％、至少约20％或大于至少约20％。在另一个实施方案中，肿瘤的PD-L1表达水平是至少约1％。在其它实施方案中，主体的PD-L1表达水平是至少约5％。在一个特定实施方案中，肿瘤的PD-L1表达水平是至少约10％。使用抗体、原位mRNA杂交、自动化的IHC等方法，可以执行PD-L1表达水平的测量。
本发明提供治疗癌症或肿瘤的主体的方法，该方法包含对该主体施用治疗有效量的抗PD-L1抗体或其抗原结合部分，其中自该患者获得的肿瘤样品已经确定构成约1％或更多(例如约1％，约2％，约3％，或约4％或更多)的细胞中具有可检测的PD-L1的表达水平。在一些实施方案中，自该患者获得的肿瘤样品已经确定构成约1％至约65％或更多(例如约1％至约5％，约5％至约10％，约10％至约20％，约20％至约30％，约30％至约40％，约40％至约50％，或约50％至约65％)的细胞中具有可检测的PD-L1的表达水平。本发明也提供确定罹患经典型霍奇金淋巴瘤的患者是否有可能响应包含抗PD-L1抗体的治疗剂的治疗的方法，该方法包含测定自该患者获得的肿瘤样品中的肿瘤细胞中PD-L1的表达水平，其中构成约1％或更多的该肿瘤样品的细胞中可检测的PD-L1的表达水平指示该患者有可能响应包含抗PD-L1抗体的治疗剂的治疗。本发明还提供用于预测罹患经典型霍奇金淋巴瘤的患者对包含抗PD-L1抗体的治疗剂的治疗的响应性的方法，该方法包含测定自该患者获得的肿瘤样品中的细胞中PD-L1的表达水平，其中构成约1％或更多的该肿瘤样品的肿瘤细胞中可检测的PD-L1的表达水平指示该患者有可能响应包含抗PD-L1抗体的治疗剂的治疗。本发明还提供用于为罹患经典型霍奇金淋巴瘤的患者选择疗法的方法，该方法包含测定自该患者获得的肿瘤样品中的肿瘤细胞中PD-L1的表达水平，和基于构成约1％或更多的该肿瘤样品的肿瘤细胞中可检测的PD-L1的表达水平为该患者选择包含抗PD-L1抗体的治疗剂的疗法。在一些实施方案中，自该患者获得的肿瘤样品已经确定构成约5％或更多的该肿瘤样品的肿瘤细胞中具有可检测的PD-L1的表达水平。在一些实施方案中，自该患者获得的肿瘤样品已经确定构成至少约10％的该肿瘤样品的肿瘤细胞中具有可检测的PD-L1的表达水平。本发明还提供用于确定罹患经典型霍奇金淋巴瘤的患者是否有可能响应包含抗PD-L1抗体或其抗原结合部分的治疗剂治疗的方法，该方法包含根据自该患者获得的肿瘤样品确定该肿瘤的亚型，其中复发性的和/或难治性的经典型霍奇金淋巴瘤指示该患者有可能响应包含抗PD-L1抗体的治疗剂的治疗。本发明提供用于预测罹患经典型霍奇金淋巴瘤的患者对包含抗PD-L1抗体的治疗剂的治疗的响应性的方法，该方法包含根据自该患者获得的肿瘤样品确定该肿瘤的亚型，其中复发性的和/或难治性的经典型霍奇金淋巴瘤指示该患者有可能响应包含抗PD-L1抗体的治疗剂的治疗。本发明提供用于为罹患经典型霍奇金淋巴瘤的患者选择疗法的方法，该方法包含根据自该患者获得的肿瘤样品确定该肿瘤的亚型，和基于该肿瘤确定是复发性的和/或难治性的经典型霍奇金淋巴瘤为该患者选择包含抗PD-L1抗体的治疗剂的疗法。在一些具体实施方案中，该方法进一步包含基于该肿瘤样品中的肿瘤细胞中PD-L1的表达水平对该患者施用治疗有效量的抗PD-L1抗体的治疗剂。
在某些实施方案中，自该患者获得的肿瘤样品或血液组织样品中CD15、CD30、PAX5、CD20、EBV-EBER、CCL17和/或CCL22至少一项的表达水平已经确定相对于该至少一种基因的参照水平发生改变，所述改变例如是发生升高；和/或，自该患者获得的肿瘤样品中CD15、CD45、CD20、CD99和/或CD3至少一项的表达水平已经确定相对于该至少一种基因的参照水平发生改变，所述改变例如是降低。在其它实施方案中，自该患者获得的肿瘤样品中miR135a的表达水平已经确定相对于该微小RNA(micro RNA)的参照水平发生改变，在一些具体实施例中，所述改变是表达水平的降低。在一些具体实施方式中，所述参照水平是以非患病主体的非肿瘤样品或血液组织样品作为参照。在一些具体实施方式中，所述参照水平是以患者的非肿瘤样品作为参照。
在某些实施方案中，自该患者获得的肿瘤样品或血液组织样品中PD-L1、TMB、MSI、9p24.1至少一项的基因突变水平、基因修饰水平、转录水平和/或表达水平已经确定相对于该至少一种基因的参照水平发生改变。在一些具体实施方式中，所述参照水平是以非患病主体的非肿瘤样品或血液组织样品作为参照。 在一些具体实施方式中，所述参照水平是以患者的非肿瘤样品作为参照。
在某些实施方案中，施用治疗有效量的抗PD-L1抗体的主体的客观响应率介于约10％至约40％(例如约10％至约20％，约20％至约30％，约30％至约40％)之间。在还有另一个实施方案中，施用治疗有效量的抗PD-L1抗体或其抗原结合部分的患者的客观响应率介于约15％至约25％之间。在其它实施方案中，施用治疗有效量的抗PD-L1抗体的治疗剂的患者的客观响应率是至少约15％。在其它实施方案中，施用治疗有效量的抗PD-L1抗体的治疗剂的患者的客观响应率是至少约20％。
在某些实施方案中，本发明的疗法(例如，抗PD-L1抗体)有效地增加主体的存活的持续时间。在某些实施方案中，与护理标准疗法相比，本发明的抗PD-L1抗体疗法增加主体的存活的持续时间。在某些实施方案中，本发明的疗法增加主体的总存活。在某些实施方案中，所述主体表现出在施用以后至少约6个月、7个月、8个月、9个月、10个月、至少约11个月、至少约12个月、至少约13个月、至少约14个月至少约15个月、至少约16个月、至少约17个月、至少约18个月、至少约19个月、至少约20个月、至少约21个月、至少约22个月、至少约23个月、至少约2年、至少约3年、至少约4年或至少约5年的总存活。在某些实施方案中，当与另一位仅用护理标准疗法治疗的主体对比时，所述主体的存活或总存活的持续时间增加了至少约5％、至少约10％、至少约15％、至少约20％、至少约25％、至少约30％、至少约40％、至少约50％或至少约75％。在其它实施方案中，当与另一位仅用护理标准疗法治疗的主体对比时，所述主体的存活或总存活的持续时间增加了至少约1个月、至少约2个月、至少约3个月、至少约4个月、至少约6个月、至少约1年、至少约18个月、至少约2年、至少约3年、至少约4年或至少约5年。
在某些实施方案中，本发明的疗法有效地增加主体的无进展存活的持续时间。例如，与另一位仅用护理标准疗法治疗的主体对比时，主体的无进展存活增加了至少约2周、至少约1个月、至少约2个月、至少约3个月、至少约4个月、至少约6个月或至少约1年。在某些实施方案中，在施用抗PD-L1抗体疗法以后，所述主体表现出与施用护理标准疗法以后的应答率相比至少约30％、35％、36％、37％、39％、40％、45％或50％的总应答率。
适合用在公开的方法中的免疫检查点抑制剂包括抗PD-L1抗体，其以高特异性和亲和力结合PD-L1、阻断PD-L1的结合和抑制PD-1信号传递途径的免疫抑制作用。在本文公开的任何治疗方法中，抗PD-1或抗-PD-L1“抗体”包括抗原结合部分，其分别结合PD-1或PD-L1受体，并在抑制配体结合和上调免疫系统中表现出与完整抗体的功能性质类似的功能性质。在一些实施方案中，所述抗PD-1抗体、抗PD-L1抗体或其抗原结合部分是嵌合的、人源化的或人的单克隆抗体或其部分。在某些关于治疗人主体的实施方案中，所述抗体是人源化抗体。在其它关于治疗人主体的实施方案中，所述抗体是人抗体。可以使用IgG1、IgG2、IgG3或IgG4同种型的抗体。
在某些实施方案中，所述抗PD-1抗体、抗PD-L1抗体或其抗原结合部分包含人IgG1或IgG4同种型的重链恒定区。在某些其它实施方案中，抗PD-1抗体、抗PD-L1抗体或其抗原结合部分的IgG4重链恒定区的序列含有S228P突变，其用通常在IgG1同种型抗体的对应位置处发现的脯氨酸残基替代铰链区中的丝氨酸残基。存在于单抗中的该突变阻止与内源性IgG4抗体的Fab臂交换，同时保留低亲和力用于活化与野生型IgG4抗体有关的Fc受体(Wang等人，2014 Cancer Immunol Res.2(9):846-56)。在其它实施方案中，所述抗体包含轻链恒定区，其为人κ或λ恒定区。在其它实施方案中，所述抗PD-1抗体、抗PD-L1抗体或其抗原结合部分是mAb或其抗原结合部分。
在WO2016022630中已经公开了抗PD-L1抗体，对PD-L1具有较高的亲和力，能够显著抑制细胞表面的PD-L1和PD-1的相互作用，并显著促进T细胞分泌IL-2和IFN-γ。
在某些实施方案中，所述抗PD-L1抗体或其片段与5G11或13C5单抗交叉竞争。在其它实施方案中，所述抗PD-L1抗体或其片段与5G11或13C5单抗结合相同或相近的表位。在某些实施方案中，所述抗PD-L1抗体具有与5G11或13C5单抗相同的CDR。
在某些实施方案中，所述抗PD-L1抗体与5G11或13C5单抗交叉竞争对人PD-L1的相同表位区域的结合。对于施用给人主体，这些交叉竞争性抗体是嵌合抗体或人源化抗体或人抗体。这样的嵌合、人源化或人mAb可以通过本领域众所周知的方法制备和分离。
在公开的发明方法中有用的抗PD-L1抗体还包括上述抗体的抗原结合部分。已经充分证实，抗体的抗原结合功能可以由全长抗体的片段执行。被术语抗体的“抗原结合部分”包含的结合片段的例子包括：(i)Fab片段，即由VL、VH、CL和CH1结构域组成的单价片段；(ii)F(ab')2片段，即包含2个Fab片段的二价片段，所述Fab片段在铰链区通过二硫键连接；(iii)由VH和CH1结构域组成的Fd片段；和(iv)由抗体的单臂的VL和VH结构域组成的Fv片段(包括例如scFv)。
适合用于所公开的组合物中的抗PD-L1抗体是以高特异性和亲和力结合PD-L1、阻断PD-1的结合并 抑制PD-L1/PD-1信号传递途径的免疫抑制作用的抗体。在本文公开的任何组合物或方法中，抗PD-L1“抗体”包括结合PD-L1配体并在抑制受体结合和上调免疫系统中表现出与完整抗体的功能性质类似的功能性质的抗原结合部分或片段。在某些实施方案中，所述抗PD-L1抗体或其抗原结合部分与5G11或13C5单抗交叉竞争对人PD-L1的结合。在其它实施方案中，所述抗PD-L1抗体或其抗原结合部分是嵌合、人源化或人单克隆抗体或其部分。在某些实施方案中，所述抗体是人源化抗体。在其它实施方案中，所述抗体是人抗体。可以使用IgG1、IgG2、IgG3或IgG4同种型的抗体。
在某些实施方案中，在所述方法中使用的抗PD-L1抗体可以用另一种抗PD-1拮抗剂或抗PD-L1拮抗剂替换。例如，因为抗PD-L1抗体阻止PD-1和PD-L1之间的相互作用，由此对PD-1的信号传递途径发挥类似的作用，抗PD-1抗体可以替代抗PD-L1抗体在本文公开的方法中的应用。因此，在一个实施方案中，本发明涉及一种用于治疗患有肿瘤的主体的方法，所述肿瘤是经典型霍奇金淋巴瘤，所述方法包括给所述主体施用治疗有效量抗PD-L1抗体。
在某些实施方案中，所述抗PD-L1抗体或其抗原结合片段是13C5、5G11、ch13C5-hIgG1、ch13C5-hIgG4、ch5G11-hIgG1、ch5G11-hIgG4、hu13C5-hIgG1、hu13C5-hIgG4、hu5G11-hIgG1或hu5G11-hIgG4单克隆抗体或其抗原结合片段(参见WO2016022630或CN107001463A)。
本发明提供了用于治疗癌症或肿瘤的抗原结合多肽或包含抗原结合多肽的药物组合物。在一些方案中，所述抗原结合多肽是结合程序性死亡配体1(PD-L1)和/或抑制PD-L1活性的抗体或其抗原结合部分。在一些方案中，所述抗原结合多肽是抗PD-L1抗体。
本发明提供了结合PD-L1的分离的抗体或其片段，其中所述抗体可以由杂交瘤产生，所述杂交瘤选自由本文称为13C5、5G11的杂交瘤组成的组。因此，本发明还包括杂交瘤13C5、5G11，以及产生本文公开的抗体的任何杂交瘤。本发明还提供了编码本文提供的抗体和其片段的分离的多核苷酸。本发明还包括包含分离的多核苷酸的表达载体，和包含所述表达载体的宿主细胞。
本发明提供了抗PD-L1抗体，其包含选自13C5或5G11抗体的重链互补决定区(CDR)，和选自13C5或5G11抗体的轻链互补决定区。在一个实施方案中，本发明提供了抗PD-L1抗体，其包含选自ch5G11-hIgG1、ch5G11-hIgG4、ch13C5-hIgG1、ch13C5-hIgG4嵌合抗体的可变重链，和选自ch5G11-hIgG1、ch5G11-hIgG4、ch13C5-hIgG1、ch13C5-hIgG4嵌合抗体的可变轻链。在一个实施方案中，本发明提供了抗PD-L1抗体，其包含选自hu13C5-hIgG1、hu13C5-hIgG4、hu5G11-hIgG1或hu5G11-hIgG4人源化抗体的可变重链，和选自hu13C5-hIgG1、hu13C5-hIgG4、hu5G11-hIgG1或hu5G11-hIgG4人源化抗体的可变轻链。可以参考专利文献WO2016022630或CN107001463A的记载：13C5、ch13C5-hIgG1、ch13C5-hIgG4、hu13C5-hIgG1或hu13C5-hIgG4的HCDR1序列为SYGMS(SEQ ID NO:4)，HCDR2序列为SISSGGSTYYPDSVKG(SEQ ID NO:5)，HCDR3序列为GYDSGFAY(SEQ ID NO:6)，LCDR1序列为ASQSVSTSSSSFMH(SEQ ID NO:10)，LCDR2序列为YASNLES(SEQ ID NO:11)，LCDR3序列为QHSWEIPYT(SEQ ID NO:12)；5G11、ch5G11-hIgG1、ch5G11-hIgG4、hu5G11-hIgG1或hu5G11-hIgG4的HCDR1序列为TYGVH(SEQ ID NO:1)，HCDR2序列为VIWRGVTTDYNAAFMS(SEQ ID NO:2)，HCDR3序列为LGFYAMDY(SEQ ID NO:3)，LCDR1序列为KASQSVSNDVA(SEQ ID NO:7)，LCDR2序列为YAANRYT(SEQ ID NO:8)，LCDR3序列为QQDYTSPYT(SEQ ID NO:9)。
在某些实施方案中，本文所述的分离的抗PD-L1抗体包含：具有以SEQ ID NO:1示出的氨基酸序列的重链CDR1区，具有以SEQ ID NO:2示出的氨基酸序列的重链CDR2区，具有以SEQ ID NO:3示出的氨基酸序列的重链CDR3区；以及具有以SEQ ID NO:7示出的氨基酸序列的轻链CDR1区，具有以SEQ ID NO:8示出的氨基酸序列的轻链CDR2区，具有以SEQ ID NO:9示出的氨基酸序列的轻链CDR3区。
在某些实施方案中，在本发明中使用的免疫检查点抑制剂(例如，抗PD-L1拮抗剂)是PD-L1 Fc融合蛋白。
在某些实施方案中，本发明向主体施用治疗有效量的抗PD-L1抗体，其中，抗PD-L1抗体是单独施用。在一些具体实施方案中，所述单独施用是指抗PD-L1抗体可以不与其它抗癌药物联用，和/或不与其它抗癌药物同时施用。在一些具体实施方案中，所述单独施用是指抗PD-L1抗体可以不与化疗药物联用，和/或不与化疗药物同时施用。在一些具体实施方案中，所述单独施用是指抗PD-L1抗体可以不与其它靶向药物联用，和/或不与其它靶向药物同时施用。在一些具体实施方案中，所述单独施用是指抗PD-L1抗体可以不与其它抗癌抗体联用，和/或不与其它抗癌抗体同时施用。在一些具体实施方案中，所述单独施用是指抗PD-L1抗体可以不与放射治疗联用，和/或不与放射治疗同时施用。
在某些实施方案中，本发明向主体施用治疗有效量的抗PD-L1抗体，其中，抗PD-L1抗体是联合施用。
在某些实施方案中，与一种或多种其它抗癌药联合施用免疫检查点抑制剂(例如，抗PD-1抗体或抗 PD-L1抗体)。在某些实施方案中，在抗PD-1抗体或抗PD-L1抗体的施用之前或与抗PD-1抗体或抗PD-L1抗体的组合之前，已经将所述一种或多种抗癌药施用给所述主体。在某些实施方案中，所述一种或多种抗癌药在治疗所述癌症中不是有效的。在某些实施方案中，所述其它抗癌药是本文描述的或本领域已知的任何抗癌药。
在某些实施方案中，可以将抗PD-1抗体或抗PD-L1抗体与另一种免疫疗法组合。在某些实施方案中，将涉及免疫检查点的阻断的免疫疗法作为单一疗法来施用。在其它实施方案中，将涉及免疫检查点的阻断的免疫疗法与其它疗法联合施用。
可以将本发明的治疗剂构成在组合物中，例如，含有抗体和药学上可接受的载体的药物组合物。本文中使用的“药学上可接受的载体”包括生理学上相容的任意的和所有的溶剂、分散介质、包衣剂、抗细菌剂和抗真菌剂、等渗剂和吸收延迟剂等。在一个实施方案中，用于含有抗体的组合物的载体适合静脉内、肌肉内、皮下、胃肠外、脊柱或表皮施用(例如，通过注射或输注)，而用于含有TKI(酪氨酸激酶抑制剂)的组合物的载体适合非胃肠外(例如，口服)施用。本发明的药物组合物可以包括一种或多种药学上可接受的盐、抗氧化剂、水性和非水性载体，和/或佐剂，诸如防腐剂、润湿剂、乳化剂和分散剂。
调节剂量方案以提供最适期望应答，例如，最大治疗应答和/或最小不良作用。在某些实施方案中，本发明的方法可以与统一剂量或基于重量的剂量一起使用。在其它实施方案中，将所述抗PD-1抗体、抗PD-L1抗体或其抗原结合部分作为统一剂量施用。在其它实施方案中，将所述抗PD-1抗体、抗PD-L1抗体或其抗原结合部分作为基于重量的剂量施用。为了施用抗PD-L1抗体(作为单一疗法或与另一种抗癌药组合)，所述剂量可以在以下范围内：约0.01至约40mg/kg，约0.1至约30mg/kg，约0.1至约20mg/kg，约0.1至约15mg/kg，约0.1至约10mg/kg，约1至约15mg/kg，约1至约20mg/kg，约1至约3mg/kg，约3至约10mg/kg，约3至约15mg/kg，约3至约20mg/kg，约3至约30mg/kg，约10至约20mg/kg，或约15至约20mg/kg主体体重，或约60mg至至少约2400mg，约90mg至至少约1800mg，约120mg至至少约1500mg，约300mg至至少约9000mg，约600mg至至少约900mg，约300mg至至少约1200mg，约600mg至至少约1200mg，或约900mg至至少约1200mg。例如，剂量可以是约0.1、约1、约2、约3、约5、约6、约9、约10、约15、约20或约30mg/kg体重；或约30mg、约60mg、约120mg、约150mg、约180mg、约300mg、约600mg、约900mg、约1200mg、约1800mg、约2100mg或约2400mg。通常设计给药计划以实现导致持续受体占用(RO)的暴露(基于抗体的典型药代动力学性质)。一种示例性治疗方案需要约每周一次(q1w)、约每2周一次(q2w)、约每3周一次(q3w)、约每4周一次(q4w)、约1个月一次(q1m)、约每3-6个月或更长一次的施用。在某些实施方案中，约每2周一次将抗PD-L1抗体诸如13C5、ch13C5-hIgG1、ch13C5-hIgG4、hu13C5-hIgG1、hu13C5-hIgG4、5G11、ch5G11-hIgG1、ch5G11-hIgG4、hu5G11-hIgG1或hu5G11-hIgG4单抗施用给主体。在其它实施方案中，约每3周一次施用所述抗体。所述剂量和调度可以在治疗过程中变化。考虑到IgG4抗体通常具有2-3周的半衰期，本发明的抗PD-L1抗体的剂量方案包含经由静脉内施用的至少约1至至少约30mg/kg体重、至少约3至至少约20mg/kg体重、至少约10至至少约15mg/kg体重、或至少约300至至少约1200mg，所述抗体在多达约6周或约12周周期中每约14-21天施用直到完全应答或证实进行性疾病。在某些实施方案中，每2周以3mg/kg施用抗PD-L1单一疗法直到进行性疾病或不可接受的毒性。在其它实施方案中，每3周以1200mg施用抗PD-L1单一疗法直到进行性疾病或不可接受的毒性。在某些实施方案中，所述抗体治疗或本文公开的任意组合治疗持续至少约1个月、至少约3个月、至少约6个月、至少约9个月、至少约1年、至少约18个月、至少约24个月、至少约3年、至少约5年或至少约10年。
当与其它癌症药剂联合使用时，抗PD-L1抗体的剂量可以相对于单一疗法剂量降低。低于典型的20mg/kg，但是不小于0.001mg/kg的13C5、ch13C5-hIgG1、ch13C5-hIgG4、hu13C5-hIgG1、hu13C5-hIgG4、5G11、ch5G11-hIgG1、ch5G11-hIgG4、hu5G11-hIgG1或hu5G11-hIgG4单抗的剂量是亚治疗剂量。在本文方法中使用的抗PD-L1抗体的亚治疗剂量高于0.001mg/kg且低于20mg/kg。在某些实施方案中，亚治疗剂量是约0.001mg/kg至约3mg/kg，约0.01mg/kg至约3mg/kg，约0.001mg/kg至约10mg/kg，或约0.01mg/kg至约10mg/kg体重。在某些实施方案中，所述亚治疗剂量是至少约0.001mg/kg、至少约0.005mg/kg、至少约0.01mg/kg、至少约0.05mg/kg、至少约0.1mg/kg、至少约0.5mg/kg、至少约1.0mg/kg体重或至少约3.0mg/kg体重。在某些实施方案中，亚治疗统一剂量是每3周小于约600mg，例如每3周约300mg或约120mg。在某些实施方案中，3mg/kg给药可以允许足够的暴露以导致最大生物学活性。
在某些实施方案中，抗PD-L1抗体或抗PD-1抗体的剂量是药物组合物中的固定剂量。在其它实施方案中，本发明的方法可以以统一剂量(不考虑患者的体重施用给患者的剂量)使用。例如，13C5、ch13C5-hIgG1、ch13C5-hIgG4、hu13C5-hIgG1、hu13C5-hIgG4、5G11、ch5G11-hIgG1、ch5G11-hIgG4、hu5G11-hIgG1或hu5G11-hIgG4单抗的统一剂量可以是约1200mg。在某些实施方案中，以约1200mg的剂量施用所述抗PD-L1抗体或其抗原结合部分。在某些实施方案中，以约900mg的剂量施用所述抗PD-L1 抗体或其抗原结合部分。在某些实施方案中，以约600mg的剂量施用所述抗PD-L1抗体或其抗原结合部分。在一个实施方案中，每3周一次施用900mg所述抗PD-L1抗体或抗原结合片段。在另一个实施方案中，每4周一次施用1200mg所述抗PD-L1抗体或抗原结合片段。
为了施用抗PD-L1抗体(作为单一疗法或与另一种抗癌药组合)，所述剂量可以在以下范围内：约0.01至约20mg/kg，约0.1至约10mg/kg，约0.1至约5mg/kg，约3至约5mg/kg，约3至约10mg/kg，约3至约15mg/kg，或约0.1至约30mg/kg主体体重或约80mg至至少约800mg，约80mg至至少约700mg，约80mg至至少约600mg，约80mg至至少约500mg，约80mg至至少约400mg，约80mg至至少约300mg，约100mg至至少约300mg，或约200mg至约300mg。例如，剂量可以是约0.1、约0.3、约1、约2、约3、约5或约10mg/kg体重，或约0.3、约1、约2、约3或约5mg/kg体重；或约80mg、约100mg、约160mg、约200mg、约240mg、约300mg、约320mg、约400mg、约500mg、约600mg、约700mg或约800mg。通常设计给药计划以实现导致持续受体占用(RO)的暴露(基于抗体的典型药代动力学性质)。一种示例性治疗方案需要约每周一次、约每2周一次、约每3周一次、约每4周一次、约每个月1次、约每3-6个月或更长时间一次的施用。
在某些实施方案中，每周期第1天(D1)接受约3mg/kg至约30mg/kg主体体重剂量静脉滴注，约21天为1个周期，直至疗效评估为疾病进展、出现不可耐受的毒性反应。在某些实施方案中，每周期第1天(D1)接受约3mg/kg至约20mg/kg体重剂量静脉滴注，约21天为1个周期，直至疗效评估为疾病进展、出现不可耐受的毒性反应。在某些实施方案中，每周期第1天(D1)接受3mg/kg剂量静脉滴注，约21天为1个周期，直至疗效评估为疾病进展、出现不可耐受的毒性反应。在某些实施方案中，每周期第1天(D1)接受约10mg/kg体重剂量静脉滴注，约21天为1个周期，直至疗效评估为疾病进展、出现不可耐受的毒性反应。在某些实施方案中，每周期第1天(D1)接受约15mg/kg体重剂量静脉滴注，约21天为1个周期，直至疗效评估为疾病进展、出现不可耐受的毒性反应。在某些实施方案中，每周期第1天(D1)接受约20mg/kg体重剂量静脉滴注，21天为1个周期，直至疗效评估为疾病进展、出现不可耐受的毒性反应。在某些实施方案中，每周期第1天(D1)接受约30mg/kg体重剂量静脉滴注，21天为1个周期，直至疗效评估为疾病进展、出现不可耐受的毒性反应。在某些实施方案中，每周期第1天(D1)接受约3mg/kg、10mg/kg、15mg/kg、20mg/kg或30mg/kg体重剂量静脉滴注，约2周、约3周或者约4周为1个周期，直至疗效评估为疾病进展、出现不可耐受的毒性反应。在某些实施方案中，每周期第1天(D1)接受约1200mg统一剂量静脉滴注，约2周、约3周或者约4周为1个周期，直至疗效评估为疾病进展、出现不可耐受的毒性反应。
在某些实施方案中，每周期第1天(D1)接受约600mg至约1200mg统一剂量静脉滴注，约21天为1个周期，直至疗效评估为疾病进展、出现不可耐受的毒性反应。在某些实施方案中，每周期第1天(D1)接受约600mg至约900mg统一剂量静脉滴注，约21天为1个周期，直至疗效评估为疾病进展、出现不可耐受的毒性反应。在某些实施方案中，每周期第1天(D1)接受1200mg统一剂量静脉滴注，约21天为1个周期，直至疗效评估为疾病进展、出现不可耐受的毒性反应。在某些实施方案中，每周期第1天(D1)接受约900mg至约1200mg统一剂量静脉滴注，约21天为1个周期，直至疗效评估为疾病进展、出现不可耐受的毒性反应。在某些实施方案中，每周期第1天(D1)接受600mg统一剂量静脉滴注，21天为1个周期，直至疗效评估为疾病进展、出现不可耐受的毒性反应。在某些实施方案中，每周期第1天(D1)接受900mg统一剂量静脉滴注，21天为1个周期，直至疗效评估为疾病进展、出现不可耐受的毒性反应。在某些实施方案中，每周期第1天(D1)接受1200mg统一剂量静脉滴注，21天为1个周期，直至疗效评估为疾病进展、出现不可耐受的毒性反应。在某些实施方案中，每周期第1天(D1)接受约900mg统一剂量静脉滴注，约2周、约3周或者约4周为1个周期，直至疗效评估为疾病进展、出现不可耐受的毒性反应。在某些实施方案中，每周期第1天(D1)接受约1200mg统一剂量静脉滴注，约2周、约3周或者约4周为1个周期，直至疗效评估为疾病进展、出现不可耐受的毒性反应。
在某些实施方案中，抗PD-L1抗体或抗PD-1抗体的剂量是在药物组合物中的固定剂量。
在某些实施方案中，抗PD-L1抗体或抗PD-1抗体的剂量是含有第二种抗癌药的药物组合物中的固定剂量。
可以改变本发明的药物组合物中的一种或多种活性成分的实际剂量水平，从而获得对于特定患者、组合物和施用模式而言有效地实现期望的治疗应答的活性成分的量，而对患者没有不适当毒性。选择的剂量水平将取决于多种药代动力学因素，包括采用的本发明的特定组合物的活性，施用途径，施用时间，正在采用的特定化合物的排泄速率，治疗的持续时间，与所用特定组合物联合使用的其它药物、化合物和/或材料，所治疗的患者的年龄、性别、重量、状况、一般健康和先前医疗史，和医学领域中众所周知的类似因素。使用本领域众所周知的多种方法中的一种或多种，可以经由一种或多种施用途径施用本发明的组合物。技术人员将理解，施用的途径和/或模式将随所期望的结果而变化。
本发明目的至少还在于提供一种药物组合物，其特征在于：所述药物组合物包含抗体，并至少包含缓冲液、等渗调节剂、稳定剂和/或表面活性剂中的一种或几种。特别地，所述药物组合物包含1-150mg/mL抗PD-L1人源化单克隆抗体(单抗)、3-50mM缓冲液、2-150mg/mL等渗调节剂/稳定剂和0.01-0.8mg/mL表面活性剂，且pH为约4.5-6.8。
在一些方案中，以w/v计算，抗PD-L1人源化单抗浓度约为5-150mg/mL；优选为约10-60mg/mL；更优选为约10-30mg/mL。在一些具体方案中，抗PD-L1人源化单抗质量体积浓度为约10mg/mL、约20mg/mL、约30mg/mL、约40mg/mL、约50mg/mL、约60mg/mL、约70mg/mL、约80mg/mL、约90mg/mL、约100mg/mL、约110mg/mL或约120mg/mL，优选为约10mg/mL、约20mg/mL、约30mg/mL、约40mg/mL、约50mg/mL或约60mg/mL，更优选为约10mg/mL、约20mg/mL或约30mg/mL。在一些实施方案中，抗PD-L1人源化单抗质量体积浓度为约10mg/mL。在另一些实施方案中，抗PD-L1人源化单抗质量体积浓度为约30mg/ml。在另一些实施方案中，抗PD-L1人源化单抗质量体积浓度为约60mg/mL。
在一些方案中，所述缓冲液为组氨酸盐缓冲液。所述组氨酸盐缓冲液浓度约为5-30mM，优选约为10-25mM，更优选约为10-20mM，最优选约为10-15mM。在一些具体方案中，所述组氨酸盐缓冲液为约5mM、约10mM、约15mM、约20mM、约25mM或约30mM。在一些实施方案中，所述组氨酸盐缓冲液为约10mM。在另一些实施方案中，所述组氨酸盐缓冲液为约15mM。在另一些实施方案中，所述组氨酸盐缓冲液为约20mM。其中，所述组氨酸盐缓冲液包含组氨酸和盐酸。
在一些方案中，以w/v计算，所述等渗调节剂/稳定剂为约20-150mg/mL的蔗糖，优选约为40-100mg/mL的蔗糖，更优选约为60-80mg/mL的蔗糖。在一些具体方案中，所述蔗糖的浓度约为40mg/mL、50mg/mL、60mg/mL、70mg/mL、80mg/mL、90mg/mL或100mg/mL。在一些具体实施方案中，所述蔗糖的浓度约60mg/mL。在一些具体实施方案中，所述蔗糖的浓度为约70mg/mL。在一些具体实施方案中，所述蔗糖的浓度为约80mg/mL。在一些具体实施方案中，所述蔗糖的浓度为约90mg/mL。
在一些方案中，所述表面活性剂选自聚山梨酯80、聚山梨酯20、泊洛沙姆188；优选聚山梨酯80或聚山梨酯20；更优选为聚山梨酯80。在一些方案中，以w/v计算，所述表面活性剂的浓度约为0.05-0.6mg/mL，优选约为0.1-0.4mg/mL，更优选约为0.2-0.3mg/mL。
在一些具体方案中，以w/v计算，所述表面活性剂为约0.01-0.8mg/mL的聚山梨酯80或聚山梨酯20。在一些具体方案中，所述表面活性剂为约0.05-0.6mg/mL的聚山梨酯80，优选约为0.1-0.4mg/mL的聚山梨酯80，更优选约为0.2-0.3mg/mL的聚山梨酯80，最优选约为0.2mg/mL的聚山梨酯80。在一些实施方案中，所述药物组合物中聚山梨酯80含量约为0.1mg/mL、0.2mg/mL、0.3mg/mL、0.4mg/mL、0.5mg/ml或0.6mg/mL；优选地，所述药物组合物中聚山梨酯80含量约为0.2mg/mL、0.3mg/mL、0.4mg/mL或0.5mg/mL；更优地，所述药物组合物中聚山梨酯80含量约为0.2mg/mL、0.3mg/mL或0.4mg/mL；最优地，所述药物组合物中聚山梨酯80含量约为0.2mg/mL。在一些实施方案中，所述药物组合物中聚山梨酯80含量约为0.1mg/mL。在另一些实施方案中，所述药物组合物中聚山梨酯80含量约为0.2mg/mL。在一些实施方案中，所述药物组合物中聚山梨酯80含量约为0.3mg/mL。在另一些实施方案中，所述药物组合物中聚山梨酯80含量约为0.4mg/mL。在一些实施方案中，所述药物组合物中聚山梨酯80含量约为0.5mg/mL。
在一些方案中，所述药物组合物的水溶液pH值选自4.0-6.8；优选为4.5-6.5；更优选为5.5-6.0；最优选5.5。在一些实施方案中，药物组合物水溶液的pH值为约4.5、约4.8、约5.0、约5.2、约5.4、约5.5、约5.6、约5.8或约6.0，优选为约5.0、约5.2、约5.4、约5.5或约5.6，更优选为约5.5。在一些实施方案中，药物组合物水溶液的pH值为约5.0。在一些实施方案中，药物组合物水溶液的pH值为约5.2。在一些实施方案中，药物组合物水溶液的pH值为约5.4。在一些实施方案中，药物组合物水溶液的pH值为约5.5。在一些实施方案中，药物组合物水溶液的pH值为约5.6。在一些实施方案中，药物组合物水溶液的pH值为约5.8。在一些实施方案中，药物组合物水溶液的pH值为约6.0。
本发明提供了结合PD-L1的分离的抗体或其片段。本发明提供的抗PD-L1人源化单抗包含如下氨基酸序列：与SEQ ID NO:1或SEQ ID NO:4所示的氨基酸序列有至少80％(例如81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)同源性的重链CDR1区；与SEQ ID NO:2或SEQ ID NO:5所示的氨基酸序列有至少80％(例如81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)同源性的重链CDR2区；与SEQ ID NO:3或SEQ ID NO:6所示的氨基酸序列有至少80％(例如81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)同源性的重链CDR3区；与SEQ ID NO:7或SEQ ID NO:10所示的氨基酸序列有至少80％(例如81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)同源性的轻链CDR1区；与SEQ ID NO:8或SEQ ID NO:11所示的氨基 酸序列有至少80％(例如81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)同源性的轻链CDR2区；与SEQ ID NO:9或SEQ ID NO:12所示的氨基酸序列有至少80％(例如81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)同源性的轻链CDR3区。
在一个具体实施方案中，本发明提供的抗PD-L1人源化单抗包含如下氨基酸序列：选自以SEQ ID NO:1或SEQ ID NO:4示出的重链CDR1区；选自以SEQ ID NO:2或SEQ ID NO:5示出的重链CDR2区；选自以SEQ ID NO:3或SEQ ID NO:6示出的重链CDR3区；选自以SEQ ID NO:7或SEQ ID NO:10示出的轻链CDR1区；选自以SEQ ID NO:8或SEQ ID NO:11示出的轻链CDR2区；选自以SEQID NO:9或SEQ ID NO:12示出的轻链CDR3区。
优选地，本发明提供的抗PD-L1人源化单抗包含如下氨基酸序列：与SEQ ID NO:13或SEQ IDNO:14所示的氨基酸序列有至少80％(例如81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)同源性的重链可变区；与SEQ ID NO:15或SEQ ID NO:16所示的氨基酸序列有至少80％(例如81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)同源性的轻链可变区。
在一个具体实施方案中，本发明提供的抗PD-L1人源化单抗包含如下氨基酸序列，如SEQ ID NO:13所示的重链可变区；如SEQ ID NO:15所示的轻链可变区。
在另一个具体实施方案中，本发明提供的抗PD-L1人源化单抗包含如下氨基酸序列，如SEQ ID NO:14所示的重链可变区；如SEQ ID NO:16所示的轻链可变区。本文所述的各CDR区及其上述的各种变体能够特异性地识别并结合PD-L1，从而有效地阻断PD-L1和PD-1之间的信号传导。
在一个具体实施方案中，本发明提供的抗PD-L1人源化单抗包含如SEQ ID NO.17所示的重链氨基酸序列，和SEQ ID NO.18所示的轻链氨基酸序列。
在另一个具体实施方案中，本发明提供的抗PD-L1人源化单抗包含如SEQ ID NO.19所示的重链氨基酸序列，和SEQ ID NO.20所示的轻链氨基酸序列。
在另一个具体实施方案中，本发明提供的抗PD-L1人源化单抗包含如SEQ ID NO.21所示的重链氨基酸序列，和SEQ ID NO.18所示的轻链氨基酸序列。
在一个具体实施方案中，本发明提供的抗PD-L1人源化单抗包含选自SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO.17、SEQ ID NO.18、SEQ ID NO.19、SEQ ID NO.20、SEQ ID NO.21中的一个或多个的保守置换变体。包含所述保守置换变体的抗PD-L1人源化单抗保留了特异性地识别并结合PD-L1的能力。
本发明提供的抗PD-L1人源化单抗可为IgG1或IgG4抗体，优选地，所述抗PD-L1人源化单抗为IgG1抗体，更优选为糖基化的IgG1抗体。
本发明的一个具体实施方案中，所述药物组合物包含：(a)质量体积浓度为约20mg/mL的抗PD-L1人源化单抗，(b)质量体积浓度为约70mg/mL的蔗糖，(c)质量体积浓度为约0.1mg/mL的聚山梨酯80，(d)摩尔浓度为约20mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为约5.0。
在本发明的另一个具体实施方案中，所述药物组合物包含：(a)质量体积浓度为约10mg/mL的抗PD-L1人源化单抗，(b)质量体积浓度为约80mg/mL的蔗糖，(c)质量体积浓度为约0.2mg/mL的聚山梨酯80，(d)摩尔浓度为约10mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为约5.5。
在本发明的还一个具体实施方案中，所述药物组合物包含：(a)质量体积浓度为约50mg/mL的抗PD-L1人源化单抗，(b)质量体积浓度为约80mg/mL的蔗糖，(c)质量体积浓度为约0.3mg/mL的聚山梨酯80，(d)摩尔浓度为约10mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为约5.5。
在本发明的又一个更加具体实施方案中，所述药物组合物包含：(a)质量体积浓度为约100mg/mL的抗PD-L1人源化单抗，(b)质量体积浓度为约80mg/mL的蔗糖，(c)质量体积浓度为约0.5mg/mL的聚山梨酯80，(d)摩尔浓度为约10mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为约5.5。
在本发明的还一个具体实施方案中，所述药物组合物包含：(a)质量体积浓度为约30mg/mL的抗PD-L1人源化单抗，(b)质量体积浓度为约80mg/mL的蔗糖，(c)质量体积浓度为约0.2mg/mL的聚山梨酯80，(d)摩尔浓度为约10mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为约5.5。
在本发明的又一个具体实施方案中，所述药物组合物包含：(a)质量体积浓度为约60mg/mL的抗PD-L1人源化单抗，(b)质量体积浓度为约80mg/mL的蔗糖，(c)质量体积浓度为约0.2mg/mL的聚山梨酯80， (d)摩尔浓度为约10mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为约5.5。
在本发明的再一个具体实施方案中，所述药物组合物包含：(a)质量体积浓度为约10mg/mL的抗PD-L1人源化单抗，(b)质量体积浓度为约70mg/mL的蔗糖，(c)质量体积浓度为约0.4mg/mL的聚山梨酯80，(d)摩尔浓度为约20mM的组氨酸，(e)任选醋酸适量，调节组合物的pH值为约6.5。
在本发明的还一个具体实施方案中，所述药物组合物包含：(a)质量体积浓度为约10mg/mL的抗PD-L1人源化单抗，(b)质量体积浓度为约80mg/mL的蔗糖，(c)质量体积浓度为约0.2mg/mL的聚山梨酯80，(d)摩尔浓度为约20mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为约5.5。
在一些方案中，药物组合物为水溶性注射液，所述水溶性注射液包括但不限于未经冻干的水溶性制剂或冻干粉重构的水溶性制剂。在另一些方案中，药物组合物为冻干制剂。所述冻干制剂是指水溶液经历冻干过程制备制剂，冻干是一个稳定化过程，其中物质首先被冷冻，然后先通过升华降低溶剂数量(初级干燥过程)，然后通过脱附作用降低溶剂数量(二级干燥过程)，直到溶剂数量为不再支持生物学活性或化学反应的值。本发明的冻干制剂还可以通过本领域已知的其它方法干燥，如喷雾干燥和鼓泡干燥(bubble drying)。
本发明提供的制剂，其在2-8℃或25℃保存至少6个月的情况下聚合物不超过1.1％，优选地不超过0.9％，更优选为不超过0.5％。
本发明还提供制备前述的药物组合物的方法，包括将抗PD-L1人源化单抗与其它试剂相混合，例如与缓冲液、等渗调节剂/稳定剂和/或表面活性剂中的一种或几种相混合。
本发明还提供用于治疗受试者中的瘤形成病状的方法，包括给所述受试者施用前述的药物组合物。
本发明提供包括含有固定剂量抗PD-L1抗体的容器的制品。本发明还提供抗PD-L1抗体在制备用于治疗癌症的包括固定剂量的抗PD-L1抗体的容器的制品中的用途。在一些具体实施方式中，所述容器是管形瓶。所述固定剂量选自大约300mg、大约600mg、大约900mg、大约1000mg、大约1200mg、大约1500mg、大约1800mg、大约2100mg和大约2400mg的抗PD-L1抗体。在一些具体实施方式中，所述制品进一步包括指导用户为癌症病人施用所述固定剂量的包装插页或药品说明书。在一些具体实施方式中，所述制品包括1个或多于1个的管形瓶，所述管形瓶含有大约300mg或600mg抗PD-L1抗体。在一些具体实施方式中，所述制品包括1个管形瓶，所述管形瓶含有大约300mg抗PD-L1抗体。在一些具体实施方式中，所述制品包括1个或多于1个的管形瓶，每个所述管形瓶含有大约10mL含抗PD-L1抗体的药物组合物。在一些具体实施方式中，所述制品包括1个或多于1个的管形瓶，每个所述管形瓶含有大约20mL含抗PD-L1抗体的药物组合物。在一些具体实施方式中，所述药物组合物包含1-150mg/mL抗PD-L1人源化单克隆抗体(单抗)、3-50mM缓冲液、2-150mg/mL等渗调节剂/稳定剂和0.01-0.8mg/mL表面活性剂，且pH为约4.5-6.8。在一些具体实施方式中，所述制品包括1个或多于1个的管形瓶，每个所述管形瓶含有大约10mL含抗PD-L1抗体的药物组合物，其中所述药物组合物包含30mg/mL抗PD-L1人源化单克隆抗体。在一些具体实施方式中，所述制品包括1个或多于1个的管形瓶，每个所述管形瓶含有大约20mL含抗PD-L1抗体的药物组合物，其中所述药物组合物包含30mg/mL抗PD-L1人源化单克隆抗体。在一些具体实施方式中，所述药物组合物是本文中提供的任意一种药物组合物。
定义和术语解释
为了可以更容易地理解本发明，定义某些术语。如在本申请中使用的，除了在本文中另外明确地提供以外，下述术语中的每一个应当具有下述的含义。另外的定义在本申请中阐述。
如本文所用，术语“抗体”是指具有至少一个抗原结合结构域的结合蛋白。本发明的抗体和其片段可以是整个抗体或其任何片段。因此，本发明的抗体和片段包括单克隆抗体或其片段和抗体变体或其片段，以及免疫缀合物。抗体片段的实例包括Fab片段、Fab'片段、F(ab')2片段、Fv片段、分离的CDR区、单链Fv分子(scFv)、Fd片段和本领域已知的其它抗体片段。抗体和其片段还可以包括重组多肽、融合蛋白和双特异性抗体。本文公开的抗PD-L1抗体和其片段可以是IgG1、IgG2、IgG3或IgG4同种型。术语“同种型”是指由重链恒定区基因编码的抗体种类。在一个实施方案中，本文公开的抗PD-L1抗体和其片段是IgG1或IgG4同种型。本发明的PD-L1抗体和其片段可以衍生自任何物种，其包括但不限于小鼠、大鼠、兔、灵长类动物、美洲驼和人。PD-L1抗体和其片段可以是嵌合抗体、人源化抗体或完整的人抗体。在一个实施方案中，抗PD-L1抗体是由源自小鼠的杂交瘤细胞系产生的抗体。因此，在一个实施方案中，抗PD-L1抗体是鼠类抗体。在另一个实施方案中，抗PD-L1抗体是嵌合抗体。在另一个实施方案中，嵌合抗体是小鼠-人嵌合抗体。在另一个实施方案中，抗体是人源化抗体。在另一个实施方案中，抗体衍生自鼠类抗体并且是人源化的。
“人源化抗体”是下述抗体：所述抗体含有衍生自非人抗体的互补决定区(CDR)；和衍生自人抗体的框架区以及恒定区。例如，本文提供的抗PD-L1抗体可以包含衍生自一种或多种鼠类抗体的CDR以及 人框架区和恒定区。因此，在一个实施方案中，本文提供的人源化抗体与所述抗体的CDR所衍生自的鼠类抗体结合PD-L1上的相同表位。本文提供了示例性人源化抗体。包含本文提供的重链CDR和轻链CDR的另外的抗PD-L1抗体或其变体可以使用任何人框架序列产生，并且也包括在本发明中。在一个实施方案中，适用于在本发明中使用的框架序列包括在结构上与本文提供的框架序列类似的那些框架序列。可以在框架区中进行另外修饰以改进本文提供的抗体的特性。此类另外的框架修饰可以包括化学修饰；点突变以降低免疫原性或去除T细胞表位；或使突变回复为原始种系序列中的残基。在一些实施方案中，此类修饰包括对应于本文示例的突变的那些修饰，包括对种系序列的回复突变。例如，在一个实施方案中，本文提供的人源化抗体的VH和/或VL的人框架区中的一个或多个氨基酸被回复突变为亲本鼠类抗体中对应的氨基酸。例如，对于人源化5G11和人源化13C5的VH和VL，上述模板人抗体的框架氨基酸的几个位点被回复突变为小鼠5G11和13C5抗体中对应的氨基酸序列。在一个实施方案中，轻链可变区的位置53和/或60和/或67处的氨基酸被回复突变为在小鼠5G11或13C5轻链可变区中的所述位置处发现的对应的氨基酸。在另一个实施方案中，重链可变区的位置24和/或28和/或30和/或49和/或73和/或83和/或94处的氨基酸被回复突变为在小鼠5G11或13C5重链可变区中的所述位置处发现的对应的氨基酸。在一个实施方案中，人源化5G11抗体包含轻链可变区，其中在位置60处的氨基酸从Ser(S)突变为Asp(D)，并且在位置67处的氨基酸从Ser(S)突变为Tyr(Y)；以及重链可变区，其中在位置24处的氨基酸从Phe(F)突变为Val(V)，在位置49处的氨基酸从Ala(A)突变为Gly(G)，在位置73处的氨基酸从Thr(T)突变为Asn(N)，并且在位置83处的氨基酸从Thr(T)突变为Asn(N)。在一个实施方案中，人源化13C5抗体包含轻链可变区，其中在位置53处的氨基酸从Tyr(Y)突变为Lys(K)；以及重链可变区，其中在位置28处的氨基酸从Thr(T)突变为Ile(I)，在位置30处的氨基酸从Ser(S)突变为Arg(R)，在位置49处的氨基酸从Ser(S)突变为Ala(A)，并且在位置94处的氨基酸从Tyr(Y)突变为Asp(D)。另外的或另选的回复突变可以在本文提供的人源化抗体的框架区中进行以改进抗体的特性。本发明还包括下述人源化抗体，所述人源化抗体结合PD-L1并且包含对应于本文所述的相对于任何合适的框架序列的示例性修饰的框架修饰，以及以其它方式改进抗体特性的其它框架修饰。
“分离的抗体”表示这样的抗体：其基本上不含有具有不同抗原特异性的其它抗体(例如，分离的特异性地结合PD-1的抗体基本上不含有特异性地结合除PD-1以外的抗原的抗体)。但是，分离的特异性地结合PD-1的抗体可以具有与其它抗原(诸如来自不同物种的PD-1分子)的交叉反应性。此外，分离的抗体可以基本上不含有其它细胞材料和/或化学物质。
术语“单克隆抗体”(“mAb”)表示单一分子组成的抗体分子(即，这样的抗体分子：其基本序列是基本上相同的，并且其表现出对特定表位的单一结合特异性和亲和力)的非天然存在的制备物。mAb是分离的抗体的一个例子。通过本领域技术人员已知的杂交瘤技术、重组技术、转基因技术或其它技术，可以生产mAb。
抗体的“抗原结合部分”(也称为“抗原结合片段”)表示抗体的一个或多个片段，其保留特异性地结合被完整抗体结合的抗原的能力。
如本文所用，术语“衍生的”当用于指相对于参考抗体或其它结合蛋白的分子或多肽时，意指能够与参考抗体或其它结合蛋白特异性地结合相同表位的分子或多肽。
本文公开的抗体和其抗原结合片段对PD-L1是特异性的。在一个实施方案中，抗体或和其片段对PD-L1是特异性的。在一个实施方案中，本文提供的抗体和片段结合人或灵长类动物PD-L1，但不结合来自任何其他哺乳动物的PD-L1。在另一个实施方案中，抗体或和其片段不结合小鼠PD-L1。术语“人PD-L1”、“hPD-L1”和“huPD-L1”等在本文中可互换使用，并且是指人PD-L1和人PD-L1的变体或同种型。“特异性”意指抗体和其片段以比任何其它靶标更大的亲和力结合PD-L1。
如本文所用，术语“EC50”是指有效浓度，抗体的50％最大应答。如本文所用，术语“IC50”是指抑制浓度，抗体的50％最大应答。EC50和IC50两者均可以通过ELISA或FACS分析或本领域已知的任何其它方法进行测量。
如本文所用，术语“治疗(treatment或treating)”是指治疗性治疗以及防范性或预防性措施。需要治疗的受试者包括那些已经患有疾病或病状的受试者，以及可能患疾病或病状并且其目的是预防、延迟或减弱疾病或病状的受试者。
如本文所用，术语“受试者”表示哺乳动物，诸如啮齿动物、猫科动物、犬科动物和灵长类动物。优选地，根据本发明的受试者是人。
“施用”表示，使用本领域技术人员已知的多种方法和递送系统中的任一种，向主体物理引入包含治疗剂的组合物。免疫检查点抑制剂(例如，抗PD-1抗体或抗PD-L1抗体)的施用途径包括静脉内、肌肉内、皮下、腹膜内、脊柱或其它胃肠外施用途径，例如通过注射或输注。本文中使用的短语“胃肠外施用” 是指，通常通过注射进行的除了肠内和局部施用以外的施用模式，且包括、但不限于，静脉内、肌肉内、动脉内、鞘内、淋巴管内、病灶内、囊内、眶内、心内、真皮内、腹膜内、经气管、皮下、表皮下、关节内、囊下、蛛网膜下、脊柱内、硬膜外和胸骨内注射和输注、以及体内电穿孔。在某些实施方案中，所述免疫检查点抑制剂(例如，抗PD-1抗体或抗PD-L1抗体)通过非胃肠外途径施用，在某些实施方案中，口服施用。其它非胃肠外途径包括局部、表皮或粘膜施用途径，例如，鼻内地、阴道地、直肠地、舌下地或局部地。还可以执行施用，例如，一次、多次，和/或在一个或多个延长的时间段中。
本文中使用的“不良反应”(AE)是与医学治疗的应用有关的任何不利的和通常非故意的或不希望的迹象(包括异常的实验室发现)、征状或疾病。例如，不利事件可以与响应于治疗的免疫系统的激活或免疫系统细胞(例如，T细胞)的扩增相关。医学治疗可以具有一种或多种相关的AE，并且每种AE可以具有相同或不同的严重性水平。对能够“改变不利事件”的方法的提及是指降低与不同治疗方案的应用相关的一种或多种AE的发生率和/或严重性的治疗方案。
本文中使用的“给药间隔”是指在施用给主体的本文公开的制剂的多个剂量之间逝去的时间的量。因而可以将给药间隔指示为范围。
本文中使用的术语“给药频率”表示在给定时间中本文公开的制剂的施用剂量的频率。可以将给药频率指示为每个给定时间的剂量的数目，例如，每周1次或2周1次。
术语“统一剂量(flat dose)”的应用是指，不考虑患者的重量或体表面积(BSA)施用给患者的剂量。因此将统一剂量提供为mg/kg剂量，而不是提供为药剂(例如，抗PD-L1抗体)的绝对量。例如，60kg人和100kg人将接受相同剂量的抗体(例如，240mg抗PD-L1抗体)。
关于本发明的组合物的术语“固定剂量”的应用是指，单一组合物中的两种或更多种不同抗体彼此以特定(固定)比率存在于所述组合物中。在某些实施方案中，所述固定剂量是基于所述抗体的重量(例如，mg)。在某些实施方案中，所述固定剂量是基于所述抗体的浓度(例如，mg/mL)。在某些实施方案中，所述mg第一抗体:mg第二抗体的比率是至少约1:1、约1:2、约1:3、约1:4、约1:5、约1:6、约1:7、约1:8、约1:9、约1:10、约1:15、约1:20、约1:30、约1:40、约1:50、约1:60、约1:70、约1:80、约1:90、约1:100、约1:120、约1:140、约1:160、约1:180、约1:200、约200:1、约180:1、约160:1、约140:1、约120:1、约100:1、约90:1、约80:1、约70:1、约60:1、约50:1、约40:1、约30:1、约20:1、约15:1、约10:1、约9:1、约8:1、约7:1、约6:1、约5:1、约4:1、约3:1或约2:1。例如，第一抗体和第二抗体的3:1比率可以是指，瓶可以含有约240mg第一抗体和80mg第二抗体，或约3mg/mL的第一抗体和1mg/mL的第二抗体。
本文提及的术语“基于重量的剂量”是指基于患者的重量计算出的、施用给患者的剂量。例如，当具有60kg体重的患者需要3mg/kg的抗PD-1抗体和1mg/kg的抗CTLA-4抗体时，人们可以从抗PD-1抗体和抗CTLA-4抗体的3:1比率固定剂量制剂中一次性抽取适当量的抗PD-1抗体(即，180mg)和抗CTLA-4抗体(即，60mg)。
术语“免疫疗法”表示通过一定方法治疗患有疾病或处于感染或遭受疾病复发的风险的主体，所述方法包括诱导、增强、抑制或以其它方式改变免疫应答。主体的“治疗”或“疗法”表示在主体上执行的任何类型的干预或过程，或给主体施用活性剂，目的在于逆转、减轻、改善、抑制、减慢或阻止征状、并发症或病症的发作、进展、发展、严重程度或复发，或与疾病相关的生化指标。
本文中使用的“PD-L1阳性的”可以与“至少约1％的PD-L1表达”互换使用。在一个实施方案中，通过本领域已知的任意方法可以使用PD-L1表达。在另一个实施方案中，通过自动化的IHC测量PD-L1表达。PD-L1阳性的肿瘤因而可以具有至少约1％、至少约2％、至少约5％、至少约10％或至少约20％的表达PD-L1的肿瘤细胞，如通过自动化的IHC测得的。在某些实施方案中，“PD-L1阳性的”是指，存在至少100个在细胞表面上表达PD-L1的细胞。
“程序性死亡受体-1(PD-1)”表示属于CD28家族的免疫抑制性受体。PD-1主要在体内先前活化的T细胞上表达，并且结合两种配体PD-L1和PD-L2。本文使用的术语“PD-1”包括人PD-1(hPD-1)，hPD-1的变体、同种体和物种同系物，以及与hPD-1具有至少一个共同表位的类似物。
“程序性死亡配体-1(PD-L1)”是针对PD-1的两种细胞表面糖蛋白配体(另一种是PD-L2)之一，其在结合PD-1后下调T细胞活化和细胞因子分泌。
“主体”包括任何人或非人动物。术语“非人动物”包括、但不限于脊椎动物诸如非人灵长类动物、绵羊、狗，和啮齿类动物诸如小鼠、大鼠和豚鼠。在某些实施方案中，所述主体是人。术语“主体”和“患者”在本文中的某些语境下可互换地使用。
药物或治疗剂的“治疗有效量”或“治疗上有效的剂量”是当单独使用或与另一种治疗剂联合使用时保护主体免于疾病发作或促进疾病消退的药物的任何量，所述疾病消退通过疾病征状的严重程度的降低、无疾病征状阶段的频率和持续时间的增加、或由疾病折磨引起的损伤或失能的预防来证明。使用熟练的从 业人员已知的多种方法可以评价治疗剂的促进疾病消退的能力，诸如在临床试验期间在人主体中，在预测对于人类的效力的动物模型系统中，或通过在体外测定法中测定所述药剂的活性。
本文中使用的“亚治疗剂量”是指，当单独施用用于治疗过度增殖性疾病(例如，癌症)时低于治疗性化合物的常用或典型剂量的治疗性化合物(例如，抗体)的剂量。
作为例子，“抗癌药”促进主体中的癌症消退或阻止进一步的肿瘤生长。在某些实施方案中，治疗有效量的药物将癌症消退促进至消除癌症的点。“促进癌症消退”是指，单独地或与抗肿瘤剂联合施用有效量的药物，导致肿瘤生长或大小的减小、肿瘤的坏死、至少一种疾病征状的严重程度的降低、无疾病征状阶段的频率和持续时间的增加、或由疾病折磨引起的损伤或失能的预防。此外，关于治疗的术语“有效的”和“有效性”包括药理学有效性和生理学安全性。药理学有效性表示药物在患者中促进癌症消退的能力。生理学安全性表示由药物施用引起的在细胞、器官和/或生物体水平的毒性水平或其它不利的生理效应(不良作用)。
作为用于治疗肿瘤的例子，相对于未治疗的主体，或者，在某些实施方案中，相对于用护理标准疗法治疗的患者，治疗有效量的抗癌药可以将细胞生长或肿瘤生长抑制至少约10％、至少约20％、至少约40％、至少约60％或至少约80％。在本发明的其它实施方案中，可以观察到肿瘤消退并持续至少约20天、至少约40天或至少约60天的时间段。尽管存在治疗有效性的这些最终测量，免疫治疗药物的评价还必须考虑“免疫相关的”应答模式。
“免疫相关的”应答模式表示在用免疫治疗剂治疗的癌症患者中经常观察到的临床应答模式，所述免疫治疗剂通过诱导癌症特异性免疫应答或通过改变天然免疫过程而产生抗肿瘤作用。该应答模式的特征在于在肿瘤负荷的初始增加或新病变出现之后的有益的治疗效果，其在传统化学治疗剂的评价中将被分类为疾病进展并且将与药物失效同义。因此，免疫治疗剂的适当评价可以需要长期监测这些药剂对靶疾病的影响。
药物的治疗有效量包括“预防有效量”，其为当单独地或与抗肿瘤剂联合施用给处于发生癌症的风险的主体(例如，具有恶化前病症的主体)或具有癌症复发的风险的主体时，抑制癌症的发生或复发的任何药物量。在某些实施方案中，预防有效量完全阻止癌症的发生或复发。“抑制”癌症的发生或复发是指减少癌症的发生或复发的可能性，或完全阻止癌症的发生或复发。
备选方案(例如，“或”)的应用应当被理解为是指备选方案中的任一个、两个或它们的任意组合。本文中使用的不定冠词“一个”或“一种”应当理解为表示任何列举或枚举的组分中的“一个或多个/一种或多种”。
术语“约”、“大约”或“基本上包含”表示在本领域普通技术人员确定的特定值或组成的可接受误差范围内的值或组成，其将部分地取决于如何测量或测定值或组成，即，测量系统的限制。例如，“约”或“基本上包含”可以是指按本领域中的实践，在1个或超过1个标准差内。可替换地，“约”或“基本上包含”可以是指至多10％或20％(即，±10％或±20％)的范围，例如在所给定的具体数值范围±5％范围内波动，优选在±2％范围内波动，更优选在±1％范围内波动。例如，约3mg可以包括2.7mg至3.3mg之间(对于10％)或2.4mg至3.6mg)对于20％)之间的任何数字。例如pH值为约5.5表示pH为5.5±5％，优选pH为5.5±2％，更优选pH为5.5±1％。此外，特别是关于生物学系统或过程，该术语可以是指直到一个数量级或直到数值的至多5倍。当在本申请和权利要求中提供特定值或组成时，除非另有说明，否则“约”或“基本上包含”的含义应当假定在该特定值或组成的可接受误差范围内。
本文中使用的术语“约每周一次”、“约每两周一次”或任意其它类似的给药间隔术语是指近似值。“约每周一次”可以包括每7天±1天，即，每6天至每8天。“约每两周一次”可以包括每14天±3天，即，每11天至每17天。类似的近似值适用于，例如，约每3周一次，约每4周一次，约每5周一次，约每6周一次，和约每12周一次。在某些实施方案中，约每6周一次或约每12周一次的给药间隔是指，可以在第一周的任意天施用第一剂，然后可以分别在第六周或第十二周的任意天施用第二剂。在其它实施方案中，约每6周一次或约每12周一次的给药间隔是指，在第一周的特定天(例如，星期一)施用第一剂，并然后分别在第六周或第十二周的相同天(即，星期一)施用第二剂。类似的原则适用于包括、但不限于“约每2周1次”，“约每月1次”等短语。
如本文中所述的，任何浓度范围、百分比范围、比率范围或整数范围应当理解为包括在列举的范围内的任意整数的值，且当适当时，包括其分数(诸如整数的十分之一和百分之一)，除非另外指出。
在本文中，除非另有说明，否则术语“包含、包括和含有(comprise、comprises和comprising)”或等同物为开放式表述，意味着除所列出的要素、组分和步骤外，还可涵盖其它未指明的要素、组分和步骤。
为了描述和公开的目的，以引用的方式将所有的专利、专利申请和其它已确定的出版物在此明确地并入本文。这些出版物仅因为它们的公开早于本申请的申请日而提供。所有关于这些文件的日期的声明或这 些文件的内容的表述是基于申请者可得的信息，并且不构成任何关于这些文件的日期或这些文件的内容的正确性的承认。而且，在任何国家，在本中对这些出版物的任何引用并不构成关于该出版物成为本领域的公知常识的一部分的认可。
具体实施方式
下面结合具体实施例对本发明进行进一步的描述，然而，本发明中这些实施例仅用于阐明而不限制本发明的范围。同样，本发明不限于本文描述的任何具体优选的实施方案。本领域技术人员应该理解，对本发明技术特征所作的等同替换或相应的改进仍属于本发明的保护范围之内。除特别说明的以外，以下实施例采用的试剂均为市售产品，溶液的配制可以采用本领域常规技术。实施例中抗PD-L1人源化单抗按WO2016022630中所述方法制得，经亲和层析后，按常规的抗体纯化方法得到含有该抗体的洗脱液。
Figure PCTCN2019127891-appb-000005
实施例1 临床前药效学试验
本实施例披露了抗PD-L1抗体在体外和小鼠体内的药效学研究的试验结果。
hu5G11-hIgG1与人PD-L1蛋白结合，其EC50为21.3ng/mL；hu5G11-hIgG1与人PD-L1显著诱导CD4+:DC细胞MLR中IFN-γ的分泌，其作用呈明显的剂量依赖性，EC50为35.0±11.3ng/mL，说明hu5G11-hIgG1与DC表达的PD-L1结合后，抑制PD-L1/PD-1信号通路，从而刺激CD4+T细胞中IFN-γ的分泌。
hu5G11-hIgG1(15mg/kg，IP，Q2D×11)对MC-38/H-11小鼠皮下移植瘤的抑瘤率为91.7％(均根据中位肿瘤体积计算)，并明显延长腹腔接种小鼠MC-38/H-11细胞小鼠的存活时间，中位存活时间均>98天，至实验结束时(D98)的存活率为80％(p<0.01，与人IgG 15mg/kg组比较)。
由此可见，体内外药效学试验均证实hu5G11-hIgG1能够阻止PD-L1与T细胞表面的PD-1和B7.1受体结合，使T细胞恢复活性，从而增强免疫应答，发挥抗肿瘤作用。
实施例2.临床前毒理学试验
本实施例披露了抗PD-L1抗体在动物体内的急性毒性试验和长期毒性试验结果。
使用食蟹猴6只，分为2组，每组3只，雌雄兼有。分别按照hu5G11-hIgG1 200、400mg/kg的剂量给予浓度为10mg/mL的含hu5G11-hIgG1的本发明的药物组合物。以给药当天为试验第1天。给药后连续14天观察各组食蟹猴一般状况；给药前及试验第4、9、14天测定体重；试验第2～3、8～9、12～13天测定摄食量；给药当日给药前、给药后约0～1小时及试验第14天测定体温、II导联心电图和血压；试验第4、14天进行血液学、血生化检测；试验第15天对各组所有食蟹猴麻醉后施以安乐死，进行解剖观察。试验结果显示：食蟹猴单次静脉注射200、400mg/kg的本品，一般观察、体重、摄食、体温、心电图、血压、血液学、血生化、尿常规及大体解剖均未见明显异常，最大耐受剂量(MTD)为400mg/kg。
长期毒性试验结果显示食蟹猴静脉注射含hu5G11-hIgG1的本发明的药物组合物4周，停药恢复4周，无毒性反应剂(NOAEL)为200mg/kg。
实施例3.临床I期试验方案和安全性、耐受性结果
本实施例披露了单中心、开放式、剂量递增临床I期试验的药代动力学及耐受性初步疗效结果。
临床I期耐受性和药代动力学研究纳入诊断明确、经标准治疗失败或缺乏标准治疗的晚期恶性肿瘤患者，观察使用含hu5G11-hIgG1的药物组合物安全性和耐受性，确定最大耐受剂量(MTD)和剂量限制性毒性(DLT)。
主要终点：DLT；MTD。
次要终点：药代动力学评价；初步考察抗肿瘤治疗效果。
安全性和耐受性结果显示，给予入组患者1、3、10、20、30mg/kg含hu5G11-hIgG1的药物组合物。每21天一个周期，连续给药。结果显示，当前已入组的患者在连续给药期间耐受性良好，与药物相关的不良反应均不超过II级。目前剂量均可以耐受；1-10mg/kg剂量组细胞因子检测，未见细胞因子风暴；也暂未发现与免疫相关严重不良反应。
初步药代动力学评估显示，首次静脉滴注不同剂量(1、3、10mg/kg)受试药物后，当前已入组患者的血清药物暴露水平呈明显剂量依赖，表现出线性药代动力学特征。
实施例4.针对经典型霍奇金淋巴瘤患者的治疗结果
本实施例披露了临床I期试验中入组的经典型霍奇金淋巴瘤患者的初步疗效评估结果。
截止2018年7月已入组2名经典型霍奇金淋巴瘤受试者，包括：3号受试者，经组织病理学确诊为经典型霍奇金淋巴瘤患者，病理组织获取途径为手术，发生淋巴结转移，先前经受手术治疗、放射治疗和化疗；6号受试者，经组织病理学确诊为经典型霍奇金淋巴瘤患者，病理组织获取途径为组织活检，发生胸膜及局部胸壁转移，先前经受化疗。
疗效评估方面，3号受试者接受3mg/kg体重剂量，21天为1个周期，持续给药，在9周后初次肿瘤评价靶病灶较基线缩小73％，18周后靶病灶较基线缩小76％。6号受试者接受10mg/kg体重剂量，21天为1个周期，持续给药，在9周后初次肿瘤评价靶病灶较基线缩小55％，18周后靶病灶较基线缩小75％。提示含hu5G11-hIgG1的药物组合物对该经典型霍奇金淋巴瘤患者治疗有效。
实施例5 治疗复发性或难治性经典型霍奇金淋巴瘤的临床II期试验
主要目的：评估含hu5G11-hIgG1的药物组合物在复发性或难治性经典型霍奇金淋巴瘤患者中的客观缓解率(ORR)，由独立影像评估委员会采用Lugano 2014疗效评价标准进行评价。
次要目的：评价含hu5G11-hIgG1的药物组合物在复发性或难治性经典型霍奇金淋巴瘤患者中的完全缓解率(CRR)、无进展生存期(PFS)、总生存期(OS)、持续缓解时间(DOR)、至缓解时间(TTR)、免疫原性、安全性、药代动力学(PK)特征。
探索性目的：探索生物标志物(PD-L1、TMB、MSI、9p24.1等)与含hu5G11-hIgG1的药物组合物疗效的相关性。
本试验采用单臂、开放、多中心的II期试验设计。客观疗效指标由独立影像评估委员会采用Lugano 2014疗效评价标准进行评价。
主要疗效指标：客观缓解率(ORR)，即CR+PR例数/总例数，本试验采用客观缓解率(ORR)作为主要疗效指标。《抗肿瘤药物的临床试验技术指导原则》指出，ORR是反应药物具有抗肿瘤活性的初步可靠依据，在FDA加速审批中ORR是最常用的替代终点指标。在单臂研究中可采用ORR的观察提供依据来支持加速审批。因此，本试验选择ORR作为主要疗效终点。
次要疗效指标：(1)完全缓解率(CRR)；(2)总生存期(OS)；(3)持续缓解时间(DOR)；(4)无进展生存期(PFS)；(5)至缓解时间(TTR)；完全缓解率(CRR)：CR例数/总例数。
无进展生存期(PFS)：定义为从首次给药直至肿瘤客观进展或死亡时间。
总生存期(OS)：定义为首次给药开始至因任何原因引起死亡的时间。以天数计，失访的受试者，通常将最后一次随访时间计算为死亡时间。
持续缓解时间(DOR)：定义为从第一次评价为CR或者PR开始至第一次评价为PD或死亡的时间。
至缓解时间(TTR)：为受试者首次用药开始至第一次评价为CR或者PR的时间。
安全性评价指标：不良反应、不良事件与严重不良事件、体重、生命体征、体格检查、ECOG评分、实验室检查、心电图检查、超声心动图检查，以及因安全性或耐受性原因而提前退出的情况等。
研究人群：复发性或难治性经典型霍奇金淋巴瘤患者。
关键入选标准：1、患者自愿参加本次研究，签署知情同意书；2、经组织病理学确诊为经典型霍奇金淋巴瘤(cHL)；3、受试者必须为复发或难治性的cHL，并且符合下列要求：挽救化疗后接受自体干细胞移植，之后复发或进展；对于未接受自体干细胞移植的受试者，则要求：第一线化疗必须为全身多药联合化疗，后续化疗要求至少有一线化疗为全身多药联合化疗；对于难治患者，指疗程≥2周期未达到部分缓解(PR)或者疗程≥4周期未达到完全缓解(CR)，如最佳疗效或结束原因为疾病进展(PD)，则疗程数不做要求；对于复发患者，复发前近期内至少接受过二线化疗；难治性：经最近的治疗后未能获得完全缓解或部分缓解；4、18周岁≤年龄≤75周岁，性别不限；5、至少有一个可测量病灶(淋巴结病灶长径＞15mm且短径＞5mm，结外病灶长、短径均＞10mm)，且对应18FDG-PET-CT扫描为高摄取病灶；6、ECOG PS评分：0～2分；7、预计生存期超过3个月。
关键排除标准：1、结节性淋巴细胞为主型霍奇金淋巴瘤或灰区淋巴瘤；2、中枢神经系统受侵犯，包括脑实质、脑膜侵犯或脊髓压迫等；3、5年内出现过或当前同时患有其它恶性肿瘤；4、有严重过敏性疾病、严重药物过敏史，已知对大分子蛋白制剂过敏者；5、既往曾接受过PD-1抗体，抗PD-L1抗体、抗PD-L2抗体；6、在治疗期间可能会接受其它全身抗肿瘤治疗；7、已知患有活动性肺结核的患者；8、妊娠及哺乳期妇女；9、根据研究者的判断，有严重危害患者安全或影响患者完成研究的伴随疾病者。
关键中止试验标准：试验中止是指临床试验尚未按方案结束，中途停止全部试验。主要目的是为了保护受试者权益，保证试验质量，避免不必要的经济损失。1、试验中发生严重安全性问题；2、试验过程中发现疗效太差，无继续进行试验的必要；3、在试验中发现临床试验方案有重大失误，难以评价药物效应，或在实施中发生重大偏差，再继续下去难以评价药物疗效；4、中国国家药品监督管理局因某种原因勒令撤销试验。
试验用药：含hu5G11-hIgG1的药物组合物，100mg/10mL，2～8℃遮光保存，有效期暂定24个月。
试验药物管理：根据GCP的要求，研究用药由医院专人保管、发放、配置、使用和回收。已经使用过的及部分使用的药物容器、残余药液、空药瓶、输液袋和注射器可根据研究中心、当地机构建立的使用指南及操作程序就地销毁，药品外包装需回收并返还申办方。对于未使用的药物除非药物内容物有显著的安全性问题需要按照当地法规立即销毁外，则需返还申办方。试验药品的发放、配置、使用及回收都需要完整的记录。由监查员定期检查药品的使用和记录情况，并对回收情况随时监查。
给药剂量：受试者接受hu5G11-hIgG1单药治疗，每周期第1天(D1)接受统一剂量1200mg静脉滴注。每21天为1个周期，直至疗效评估为疾病进展、出现不可耐受的毒性反应或研究者/受试者决定退出临床试验，试验药物最长能使用96周。如果受试者在接受96周治疗后没有出现疾病进展，经研究者判断，受试者仍然处于研究药物的获益中，需签署额外的知情同意书后可继续接受治疗。除第1周期外，后续周期的给药时间应根据上一周期实际给药时间进行计算，给药窗口期为计算时间的±3天。
疗效评价标准及确认
在方案规定的时间点进行影像学检查和/或骨髓检查。采用Lugano 2014疗效评价标准对受试者治疗疗效进评价。
主要疗效评价指标：客观缓解率(ORR)。
次要疗效评价指标：完全缓解率(CRR)、无进展生存(PFS)、总生存期(OS)、持续缓解时间(DOR)、至缓解时间(TTR)。
客观缓解率(ORR)：CR+PR例数/总例数。包含完全缓解(CR)和部分缓解(PR)的病例。
完全缓解率(CRR)：CR例数/总例数。
无进展生存期(PFS)：受试者首次给药开始至出现疾病进展或者死亡的时间。
肿瘤缓解持续时间(DOR)：获得CR或PR的受试者从首次获得CR或PR开始至出现疾病进展的时间。
总生存期(OS)：受试者从首次给药开始到死亡的时间。至数据分析截止日仍存活或失访的受试者， 生存以该受试者最后已知的存活时间为准。
至缓解时间(TTR)：定义为从首次给药开始至第一次评估为PR或CR的时间，以先出现者为准。只适用于取得CR或PR的受试者。
影像学评估：CT/MRI检查、PET-CT检查
根据lugano 2014修订后评效标准第一次判定为疾病进展(初次疾病进展)的受试者如果研究者判断可继续接受含hu5G11-hIgG1的药物组合物治疗，需要符合下列标准：
研究者认为继续接受研究治疗可能有临床获益，疾病没有快速进展；
能够耐受研究药物；
ECOG评分稳定；
不会延误需要迫切干预的严重并发症的处理；
继续用含hu5G11-hIgG1的药物组合物治疗之前，受试者需要充分知情，研究者需要详细阐明所有可预见的风险或不适以及其它可选的治疗方法。
在满足以上标准的前提下，进展后继续治疗需要研究者与申办方讨论决定，并记录在研究记录中。
本研究的影像学评估将在各研究中心进行，并由影像科研究者填写影像评估表，由研究者进行综合疗效评估。同时，本研究将使用独立影像评估委员会进行独立的影像学评估以对分中心评估结果进行复核，并以此评价本研究的主要研究终点。但独立的影像学评估将不作为研究者医疗决策的依据。
生物标志物分析
本研究需探索生物标志物包括但不限于PD-L1、TMB、MSI、9p24.1等与疗效的相关性。生物标志物包括但不限于：PD-L1、肿瘤突变负荷(TMB)、MSI、9p24.1。
PD-L1：是一种出现在肿瘤细胞表面的分子，临床研究显示，PD-L1的表达水平可能与PD-L1/PD-1抗体类药物在特定肿瘤类型中的抗肿瘤活性有关。通过检测样本中PD-L1蛋白的表达情况，可指导相应药物的使用。
TMB：是肿瘤组织每兆碱基体细胞碱基替换及插入缺失突变的突变总数，通俗的讲就是肿瘤基因的突变密度。对于预测肿瘤免疫治疗的疗效，确定哪些患者能够受益于免疫治疗而言，TMB是一个具有良好前景的全新生物标志物。
9p24.1：9号染色体上的p24.1这个特定位置，存在PD-L1和PD-L2这两个基因。很多霍奇金淋巴瘤都携带一种特别的染色体变化，称为9p24.1扩增，通过高表达PD-L1和PD-L2，激活PD-1信号通路来限制免疫细胞。检测9p24.1能够为确定哪些患者能够受益于免疫治疗，是一个具有良好前景的全新生物标志物。
安全性评价
不良事件：不良事件(AE)指受试者接受研究药物治疗时出现的任何不良的医学事件，但不一定与治疗有因果关系。因此，AE可以是与使用研究药物在时间上相关的任何不利的和非意求的征兆(包括异常的实验室发现)、症状或疾病，而不管其是否与药物有关。
AE也包括方案规定的医学干预导致的并发症，例如，组织活检等有创操作导致的并发症；筛选期按方案要求诊察或处理所导致的异常情况，以及研究者认为之前存在的疾病在AE报告期间出现恶化(肿瘤进展除外)的，也认为是AE，但疾病进展不是AE。
研究人员应详细记录患者所发生的任何不良事件。不良事件的记录包括：不良事件及所有相关症状的描述，发生的时间，严重程度，持续时间，采取的措施和转归情况。
不良事件性质和严重程度的评价标准遵照美国国立癌症研究所的常见毒性反应标准[CTC AE v5.0]进行。
统计分析方法
所有统计分析均用SAS 9.4版本。对于连续型变量，将列出受试者例数、均数、标准差、中位数、最小值和最大值。对于分类变量，将以频数表的形式(频数和百分数)列出。百分数将保留2位小数。
基于全分析集，对受试者入组的情况、各分析集人数、完成试验的情况、退出原因、人口学特征、疾病的基线情况、方案偏离、既往史、既往用药和合并用药、用药暴露和剂量调整情况以及用药依从性等进行总结描述。既往史采用MedDRA(21.0中文版)进行编码，既往用药和合并用药采用WHOdrug(2018版)进行编码。基于全分析集和符合方案集，通过评价受试者的ORR、CRR、PFS、OS、DOR、TTR来评估含hu5G11-hIgG1的药物组合物的有效性。采用Clopper-Pearson法估计ORR的95％置信区间，在受试者确保至少68例的情况下，如果受试者的ORR置信下限大于40％，可认为本药有效。此外，采用 Clopper-Pearson法估计CRR的95％置信区间；采用Kaplan-Meier法估计PFS、OS、DOR、TTR的中位数及其95％置信区间，并绘制相应的生存曲线。本研究采用Logistic回归模型对影响ORR的因素进行分析。
基于安全性数据集，对临床观察得到的安全性指标进行安全性和耐受性评估，安全性指标包括不良反应、不良事件与严重不良事件、体重、生命体征、体格检查、ECOG评分、实验室检查、心电图检查、超声心动图检查，以及因安全性或耐受性原因而提前退出的情况等。
利用MedDRA(21.0中文版)对试验过程中发生的所有不良事件进行医学标准编码，并根据系统器官分类(SOC)/首选术语(PT)分类详细列举所有不良事件/不良反应和严重不良事件/严重不良反应的发生例数与例次，并计算不良事件/不良反应和严重不良事件/严重反应的发生率。另外，在系统器官分类(SOC)/首选术语(PT)分类基础上根据毒性等级(NCI CTCAE V5.0版)列举不良事件/不良反应，导致提前退出或/和导致死亡不良事件/不良反应等。
对ECOG评分、实验室检查、心电图检查采用交叉分类表描述治疗前后正常、异常的变化情况。治疗后异常的检查项目将以清单形式列出。对于实验室检查列出治疗前正常、治疗后异常和治疗后异常加重的检查指标。另外，血常规、血生化采用均数±标准差、最大值、最小值、中位数描述治疗前后的测量值和变化值，必要时采用配对t检验。
对生命体征、体格检查、体重和超声心动图检查采用均数±标准差、最大值、最小值、中位数描述治疗前后的测量值和变化值，必要时采用配对t检验。采用率或构成比对免疫原性检测结果进行统计描述。列出因安全性或耐受性原因而提前退出的情况。
探索生物标志物(PD-L1、TMB、9p24.1等)与含hu5G11-hIgG1的药物组合物疗效的相关性。
药代动力学(PK)数据分析：血药浓度分析基于PK浓度集(PKCS)。PK参数的分析基于PK参数分析集(PKPS)。采用平均值、标准差、中位值、最小值、最大值、几何均值和几何标准误等统计量进行描述性分析。总结血药浓度在各个时间点及其相对基线的变化。主要药代动力学参数有达峰时间Tmax、峰浓度Cmax、血药浓度-时间曲线下面积AUC、消除半衰期t1/2、稳态峰浓度Css-max、稳态谷浓度Css-min、平均稳态血浆浓度Css-av等。
实施例6.治疗复发性或难治性经典型霍奇金淋巴瘤的临床II期试验结果
(1)43岁女性，患者于2017年10月因颈部淋巴结无痛性肿大就诊，2017年10月25日给予颈部淋巴结穿刺活检示：结节硬化型霍奇金淋巴瘤。
2017年10月30日PET-CT显示：1.确认霍奇金淋巴瘤近5月，提示颈部左侧、左侧锁骨上、右侧锁骨上、右侧锁骨上下及纵脯淋巴结为活动性淋巴瘤病灶。2.左肺下叶纤维灶。3.双侧下后壁胸膜良性肥厚。4.双乳钙化灶。5.F18-FDG PET-CT全身检查(颅脑至股上段)无其它明显异常发现。肿瘤标志物：糖类抗原CA-72416.96U/mL。2017-10-30风湿系列：抗核抗体测定弱阳性(±)。骨髓细胞学、流式细胞学等未见异常。
2017年11月04日，骨髓染色体核型分析：可见20个中期22号染色体随体大。颈部淋巴结穿刺病理：(左颈部)结合免疫组化，符合结节硬化型霍奇金淋巴瘤，2级。免疫组化：CD30(+)、CD15(-)、CD79a(-)、CD20(-)、PAX-5少量细胞弱(+)、PAX-8弱(+)、LCA部分(+)、OCT-2部分(+)、GATA-3(+)、BoB.1(-)、C04(--)、CD7(-)、CD2(-)、CD3(-)、CD43(-)、EMA(-)、ALK(-)、Ki67大细胞阳性率较高。原位杂交：EBER(-)。排除化疗禁忌后，2017年11月09日至2018年05月23日给予ABVD方案化疗6周期，过程顺利，患者耐受可。2018年07月24日PET-CT显示：HLC锁骨上淋巴结活检确诊；6周期化疗及颈部局部放疗后，与2017年6月23日的PET-CT比较，原纵隔内及颈部左侧III区残留淋巴结病灶体积变化不明显，但均无明显FOG代谢活性，扫描野内未见明确新发活动性淋巴瘤病灶：提示治疗效果良好：右肺中叶肺大瘤，左肺下野纤维灶：双乳钙化灶；F18-FDGPET-CT全身检查无其它明显异常发现。患者6个月前出现双侧肩肝骨区疼痛，2018年11月07日复查PET-CT:HL放化疗后。与上次(2018-07-23)PET-CT图像相比，原纵隔内残余病灶较前增大、FDG代谢水平明显增高，提示病情反复：扫描野内脊柱、骨盆等多骨髓/髓摄取FDG弥漫性增高。右肺中叶肺大泡：双乳钙化灶：F18-FDG PET-CT全身检查(颅脑至股上段)无其它明显异常发现。排除化疗禁忌，于2018年11月29日给予CHOP方案化疗1周期，化疗耐受差，患者拒绝其它二线化疗方案，于2019年3月15日行COP方案化疗2周期。2019年04月25日复查PET-CT：HL放化疗后，与(2018-11-07)PET-CT图像相比，原纵隔内病灶较前增大、FDG代谢水平增高，提示治疗效果欠佳。
2019年4月30日给予hu5G11-hIgG1注射液1200mg ivdrip q3w进行治疗，每21天为1周期，持续给药。在4周后初次肿瘤评价靶病灶较基线缩小38.2％，6周后靶病灶较基线缩小66％。
PET-CT结果如下：
基线：纵隔血池SUV值1.8；肝血池SUV值2.6；病灶SUV值6.2；评分5分
C4D21：纵隔血池SUV值1.7；肝血池SUV值1.8；病灶SUV值1.7；评分2分
C8D21：纵隔血池SUV值1.7；肝血池SUV值3.2；病灶SUV值4.1；评分4分
CT结果如下：
基线：SPD：952mm 2
C2D21：SPD：588mm 2
C6D21：SPD：324mm 2
C6D21：SPD：324mm 2
(2)38岁女性患者，2017年7月18日，PET-CT结果显示肿瘤侵犯前纵膈胸膜及心包及左上叶支气管开口，左侧腮腺、双侧颈部(II-IV区)、双侧锁骨上区、双侧腋窝、纵膈(2-7组)、双侧肺门、双侧肋隔脚、心隔角及脾门区多发高代谢肿大淋巴结，胰腺、脾脏多发转移瘤，左前胸壁皮下高代谢灶，考虑转移瘤，全身多发骨转移，怀疑淋巴瘤。2017年8月2日经脾肺穿刺病理学诊断为经典型霍奇金淋巴瘤，结节硬化型，IVB期。2017年8月9日-2018年3月27日行ABVD化疗(多柔比星脂质体30mg d1、d15，长春新碱2mg d1、d15,博来霉素1.5g d1、d15，达卡巴嗪550mg d1、d15)治疗，共8个疗程，最佳疗效PR。
2018年4月进行PET-CT复查，考虑肿瘤复发，最后一疗程用药时间为：2018年6月5日进行环磷酰胺+依托泊苷动员化疗，采集干细胞，期间患者反复发热，考虑肿瘤热可能性大，未进行干细胞移植，于2018年6月28日至2018年7月26日行ESHAP化疗(依托泊苷80mg d1-4，顺铂30mg d1-4，甲强龙0.5g d1-5，阿糖胞苷3g d5)2疗程，2018年9月25日至2019年4月6日进行PCR(强的松20mg，环磷酰胺50mg，来那度胺10mg)化疗，2018年12月7日PET-CT提示疾病进展，因无其它化疗方案选择，患者仍继续口服化疗药。
患者2019年5月16日开始进行hu5G11-hIgG1注射液治疗，21天一个周期，2019年6月6日、2019年6月27日、2019年7月18日、2019年8月8日、2019年8月29日、2019年9月19日、2019年10月10日、2019年10月31日、2019年11月21日共行10疗程治疗。患者治疗期间整体耐受性良好，继续用药治疗中。
CT结果如下：
第2周期末：靶病灶：1672mm 2，非靶病灶：非CR/非PD；疗效评估SD。
第4周期末：靶病灶：1596mm 2，非靶病灶：非CR/非PD；疗效评估SD。
第6周期末：靶病灶：1596mm 2，非靶病灶：非CR/非PD；疗效评估SD。
PET-CT结果如下(根据Lugano2014)：
第4周期末：疗效评估CR。
第8周期末：疗效评估CR。
(3)28岁男性，2018年3月7日获得淋巴结活检报告：(右侧颈部淋巴结)经典型霍奇金淋巴瘤(混合细胞型)，免疫组化：瘤细胞CD30(+)，CD15(+)，PAX 5(散在弱+)，CD20(-)，CD79a(-)，OCT-2(+)，Bob.1(-)，LCA(-)，MUM1(+)，ALK1(-)，EBER(-)，CD3(-)。2018.3.16进行PET-CT：多处淋巴结(右侧颈部IV区、双侧锁骨上、2R、3A、4R、6、7、8、右侧膈肌脚、左侧肾上腺区、脾胃间隙、胰腺后方、腹主动脉旁)增多并肿大，代谢增高；脾脏增大，代谢不均匀增高；左侧锁骨、胸骨代谢增高；上述考虑淋巴瘤浸润灶。2018年3月15日-2018年5月31日进行ABVD化疗3个疗程，2018年6月14日进行ABVD化疗第4疗程第1天，2018年6月14日进行PET-CY，最佳疗效PR。2018年7月20日-2018年7月24日ESHAP化疗2个疗程，疗效未知。自体造血干细胞移植：2018年7月26日刺激因子动员，2018年8月1日-8月2日采集自体干细胞，9月7日-9月13日进入移植仓予BEAM方案化疗预处理，9月14日回输自体造血干细胞，9月25日白细胞植活，9月29日血小板植活，2018年12月26日行PET-CT，5分，最佳疗效PR，2019年6月25日行PET-CT，较前进展。
2019年7月10日开始hu5G11-hIgG1注射液第1周期用药(1200mg，每21天一次)，滴速250mL/1h,从第2周期-第7周期低速减半至250mL/2h，2019年8月6日-2019年9月发生带状疱疹住院，第3周期试验用药延迟15天后恢复，用药期间及用药后未诉其他不适。
PET-CT结果如下：
基线：靶病灶：1.肝胃间隙淋巴结5分，2.腹膜后淋巴结5分；
Week06：靶病灶：1.肝胃间隙淋巴结2分，2.腹膜后淋巴结2分，疗效CR；
Week12：靶病灶：1.肝胃间隙淋巴结3分，2.腹膜后淋巴结3分，疗效CR。
CT结果如下：
基线：靶病灶：1.肝胃间隙淋巴结21.68×19.65mm，2.腹膜后淋巴结16.80×10.66mm，非靶病灶：残余病灶/没有增大；
Week06：靶病灶：1.肝胃间隙淋巴结15.64×10.50mm，2.腹膜后淋巴结10.43×5.23mm，非靶病灶：残余病灶/没有增大；疗效PR；
Week18：靶病灶：1.肝胃间隙淋巴结17.31×10.82mm，2.腹膜后淋巴结13.13×5.90mm，非靶病灶：残余病灶/没有增大；疗效PR。
(4)45岁男性，2017年1月5日，术后病理诊断为经典型霍奇金淋巴瘤、混合细胞型。入院接受ABVD化疗，2017年1月11日至2018年1月19日期间进行6周期化疗，2018年2月26日示出疾病进展。2018年3月15日至2018年10月16日期间进行6周期BEACOPP化疗，2019年9月3日示出疾病进展。
2019年9月12日，开始输注1200mg固定剂量的hu5G11-hIgG1注射液，每三周为一个治疗周期，每周期第一天给药，直至疾病进展或不耐受。患者服药期间整体性良好，可继续用药。
PET CT结果如下：
第一周期给药后：靶病灶：多维尔评分1分非靶病灶：非CR/非PD
第三周期给药后：靶病灶：多维尔评分1分非靶病灶：非CR/非PD
CT结果如下：
第一周期给药后：靶病灶：882.04非靶病灶：非CR/非PD
第三周期给药后：靶病灶：653.08非靶病灶：非CR/非PD。
上述(1)-(4)例临床实验结果显示，hu5G11-hIgG1治疗经典型霍奇金淋巴瘤能够达到完全缓解。
根据本发明所公开的内容，虽然根据优选实施方案对本发明的组合物和方法进行了描述，但对本领域技术人员而言，在不背离本发明的概念、精神和范围的情况下，可对在此所述的组合物和/或方法以及所述方法的步骤或步骤的顺序进行改变。
本文所引用的所有文献的公开内容通过引用结合于此，引用程度为，它们提供示例性的、程序上和其他的细节补充本文所述内容。

Claims (36)

  1. 治疗、缓解或改善主体中的癌症的方法，其包括向所述主体施用治疗有效量的作为PD-1受体和其配体PD-L1之间的相互作用的抑制剂的抗PD-L1抗体，其中所述抗PD-L1抗体包含如下氨基酸序列：与SEQ ID NO:1或SEQ ID NO:4所示的氨基酸序列有至少80％同源性的重链CDR1区；与SEQ ID NO:2或SEQ ID NO:5所示的氨基酸序列有至少80％同源性的重链CDR2区；与SEQ ID NO:3或SEQ ID NO:6所示的氨基酸序列有至少80％同源性的重链CDR3区；与SEQ ID NO:7或SEQ ID NO:10所示的氨基酸序列有至少80％同源性的轻链CDR1区；与SEQ ID NO:8或SEQ ID NO:11所示的氨基酸序列有至少80％同源性的轻链CDR2区；与SEQ ID NO:9或SEQ ID NO:12所示的氨基酸序列有至少80％同源性的轻链CDR3区。
  2. 根据权利要求1所述的方法，其中所述抗PD-L1抗体包含选自SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO.17、SEQ ID NO.18、SEQ ID NO.19、SEQ ID NO.20和SEQ ID NO.21中的一个或多个的保守置换变体，并且所述抗PD-L1抗体保留了特异性地识别并结合PD-L1的能力。
  3. 根据权利要求1或2所述的方法，其中所述抗PD-L1抗体包含：具有以SEQ ID NO:1示出的氨基酸序列的重链CDR1区，具有以SEQ ID NO:2示出的氨基酸序列的重链CDR2区，具有以SEQ ID NO:3示出的氨基酸序列的重链CDR3区；以及具有以SEQ ID NO:7示出的氨基酸序列的轻链CDR1区，具有以SEQ ID NO:8示出的氨基酸序列的轻链CDR2区，以及具有以SEQ ID NO:9示出的氨基酸序列的轻链CDR3区。
  4. 根据前述任一项权利要求所述的方法，其中所述抗PD-L1抗体以1mg/kg、3mg/kg、10mg/kg、15mg/kg、20mg/kg、25mg/kg、30mg/kg体重的剂量施用，持续给药。
  5. 根据前述任一项权利要求所述的方法，其中所述抗PD-L1抗体以有效治疗所述癌症的一个或多个统一剂量施用。
  6. 根据前述任一项权利要求所述的方法，其中所述统一剂量在大约20mg至大约2000mg抗PD-L1抗体范围内。
  7. 根据前述任一项权利要求所述的方法，其中所述统一剂量选自大约300mg、大约600mg、大约900mg、大约1000mg、大约1200mg、大约1500mg、大约1800mg、大约2100mg或大约2400mg抗PD-L1抗体。
  8. 根据前述任一项权利要求所述的方法，其中所述统一剂量选自大约1200mg抗PD-L1抗体。
  9. 根据前述任一项权利要求所述的方法，其中大约每周(q1w)、大约每2周(q1w)、大约每3周(q1w)、或者大约每4周(q1w)施用抗PD-L1抗体。
  10. 根据前述项中任一项的方法，其中所述抗PD-L1抗体以每个患者大约1200mg的剂量施用，大约每3周施用一次，持续施用。
  11. 根据前述任一项权利要求所述的方法，其中大约每3周为病人施用统一剂量的抗PD-L1抗体。
  12. 根据前述任一项权利要求所述的方法，其中所述抗PD-L1抗体作为静脉输注施用。
  13. 根据前述任一项权利要求所述的方法，其中所述抗PD-L1抗体作为1-2小时静脉输注施用，优选1小时静脉输注施用。
  14. 根据前述任一项权利要求所述的方法，其中所述抗PD-L1抗体为裸抗体、完整抗体或包含抗原结合区的抗体片段。
  15. 根据前述任一项权利要求所述的方法，其中所述方法导致客观反应，优选完全反应或部分反应。
  16. 根据前述任一项权利要求所述的方法，其中所述主体先前已接受化疗和/或放射治疗。
  17. 根据前述任一项权利要求所述的方法，其中所述主体接受化疗和/或放射治疗后接受过自体干细胞移植。
  18. 根据前述任一项权利要求所述的方法，其中所述主体经化疗和/或自体干细胞移植后获完全缓解后再次出现疾病进展。
  19. 根据前述任一项权利要求所述的方法，其中所述主体经化疗和/或自体干细胞移植后未能完全缓解或未能部分缓解。
  20. 根据前述任一项权利要求所述的方法，其中所述癌症是经典型霍奇金淋巴瘤。
  21. 根据前述任一项权利要求所述的方法，其中所述经典型霍奇金淋巴瘤在化疗后已进展。
  22. 根据前述任一项权利要求所述的方法，其中所述癌症是复发性和/或难治性经典型霍奇金淋巴瘤。
  23. 根据前述任一项权利要求所述的方法，其中所述癌症治疗是复发性或难治性经典型霍奇金淋巴瘤的三线治疗。
  24. 根据前述任一项权利要求所述的方法，其中所述复发性或难治性经典型霍奇金淋巴瘤在完成一线化疗期间或之后没有进展。
  25. 根据前述任一项权利要求所述的方法，其中所述复发性或难治性经典型霍奇金淋巴瘤在化疗后已进 展。
  26. 根据前述任一项权利要求所述的方法，其中所述经典型霍奇金淋巴瘤是转移性的。
  27. 根据前述任一项权利要求所述的方法，其中所述癌症治疗是转移性经典型霍奇金淋巴瘤的三线治疗。
  28. 根据前述任一项权利要求所述的方法，其中所述转移性经典型霍奇金淋巴瘤在完成一线化疗期间或之后没有进展。
  29. 根据前述任一项权利要求所述的方法，其中所述转移性经典型霍奇金淋巴瘤在化疗后已进展。
  30. 根据前述任一项权利要求所述的方法，其中所述癌症是转移性的复发性和/或难治性经典型霍奇金淋巴瘤。
  31. 包括含有固定剂量抗PD-L1抗体的容器的制品，其中所述固定剂量选自大约300mg、大约600mg、大约900mg、大约1000mg、大约1200mg、大约1500mg、大约1800mg、大约2100mg和大约2400mg的抗PD-L1抗体。
  32. 根据前述任一项权利要求所述的制品，其中所述抗PD-L1抗体包含如下氨基酸序列：与SEQ ID NO:1或SEQ ID NO:4所示的氨基酸序列有至少80％同源性的重链CDR1区；与SEQ ID NO:2或SEQ ID NO:5所示的氨基酸序列有至少80％同源性的重链CDR2区；与SEQ ID NO:3或SEQ ID NO:6所示的氨基酸序列有至少80％同源性的重链CDR3区；与SEQ ID NO:7或SEQ ID NO:10所示的氨基酸序列有至少80％同源性的轻链CDR1区；与SEQ ID NO:8或SEQ ID NO:11所示的氨基酸序列有至少80％同源性的轻链CDR2区；与SEQ ID NO:9或SEQ ID NO:12所示的氨基酸序列有至少80％同源性的轻链CDR3区。
  33. 根据前述任一项权利要求所述的制品，其进一步包括指导用户为癌症病人施用所述固定剂量的包装插页或药品说明书。
  34. 根据前述任一项权利要求所述的制品，其包括1个或多于1个的管形瓶，所述管形瓶含有大约300mg或600mg抗PD-L1抗体。
  35. 根据前述任一项权利要求所述的制品，其包括1个管形瓶，所述管形瓶含有大约300mg抗PD-L1抗体。
  36. 根据前述任一项权利要求所述的制品，其包括1个管形瓶，所述管形瓶含有大约600mg抗PD-L1抗体。
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