WO2020156500A1 - 抗pd-l1抗体治疗头颈癌的用途 - Google Patents

抗pd-l1抗体治疗头颈癌的用途 Download PDF

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Publication number
WO2020156500A1
WO2020156500A1 PCT/CN2020/074083 CN2020074083W WO2020156500A1 WO 2020156500 A1 WO2020156500 A1 WO 2020156500A1 CN 2020074083 W CN2020074083 W CN 2020074083W WO 2020156500 A1 WO2020156500 A1 WO 2020156500A1
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seq
antibody
amino acid
chemotherapy
pharmaceutical composition
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English (en)
French (fr)
Inventor
张喜全
王训强
陈杰
赵伟
陈德培
朱漫杰
魏娇
陈飞洋
周雅倩
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
Nanjing Shunxin Pharmaceutical Co Ltd
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
Nanjing Shunxin Pharmaceutical Co Ltd
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Priority to CN202080011333.8A priority Critical patent/CN113365659B/zh
Publication of WO2020156500A1 publication Critical patent/WO2020156500A1/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 [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants

Definitions

  • the present application 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 precise specificity, so as to respond to various tumor antigens.
  • Emerging cancer immunotherapy enhances anti-tumor immune response through adoptive transfer of activated effector cells, immunization against related antigens, or the provision of non-specific immunostimulants.
  • researchers have worked hard to develop specific immune checkpoint inhibitors and hope to provide new immunotherapies for the treatment of cancer, including the development of antibodies that bind and inhibit CTLA-4 (Antibody) Ipilimumab ( Ipilimumab)( )
  • CTLA-4 Antibody Ipilimumab ( Ipilimumab)( )
  • PD-1 programmed death-1
  • PD-1 is a key immune checkpoint receptor expressed by activated T lymphocytes and B lymphocytes and mediates immune suppression. Its ligands include at least PD-L1 And PD-L2.
  • PD-L1 Programmed death-ligand 1
  • CD274 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 both consist 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) PNAS105:3011-3016).
  • PD-L1 contains a conserved short intracellular tail region (about 30 amino acids)
  • PD-1 contains two signal motifs based on cytoplasmic tyrosine, the immunoreceptor tyrosine-based inhibitory motif (ITIM ) And immunoreceptor tyrosine-based switching motifs (ITSM).
  • ITIM immunoreceptor tyrosine-based inhibitory motif
  • ITSM immunoreceptor tyrosine-based switching motifs
  • PD-L1 is not only widely distributed on white blood cells and non-hematopoietic cells in lymphoid and non-lymphoid tissues, but also widely distributed in various cancer cells. It is highly expressed on the surface of various tumor cells. Moreover, the malignancy of tumors and poor prognosis are related to The expression level of PD-L1 is closely related. There are clinical data showing that high tumor expression of PD-L1 is associated with increased tumor aggressiveness and poor prognosis.
  • the PD-1/PD-L1 complex forms a transmission inhibitory signal and negatively regulates the T cell immune response; it inhibits TCR-mediated T cell activation, cytokine production and T cell proliferation (Fife et al. (2011) Nature Immunology 10:1185- 1193); induce exhaustion or anergy in homologous antigen-specific T cells (Hofmeyer et al. (2011) Journal of Biomedicine and Biotechnology 2011: 1-9); promote Th1 cells to differentiate into Foxp3+ regulatory T cells (Armanath et al. (2011) Science TransMed 3:1-13; Francisco et al. (2009) J.Exp.Med.206:3015-3029); and induce the apoptosis of effector T cells.
  • Anti-PD-L1 antibodies can block the interaction of PD-L1 with PD-1 and CD80, so that related negative regulatory signals cannot be initiated and transmitted, thereby avoiding the inhibition of effector T cell activity in the tumor microenvironment , So that T cells can play the function of killing and inhibiting tumor cells. Because anti-PD-L1 antibody can directly act on tumor tissues, 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. ⁇ .
  • Head and neck cancers include oral, nasopharyngeal, oropharyngeal, and throat cancers, accounting for about 5% of global cancers (excluding non-melanoma skin cancers) (Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer Incidence and Morality Worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015; 136: E359-E386). In 2012, approximately 680,000 cases of head and neck cancer were newly diagnosed, and 370,000 patients died from the disease. Of these new cases reported, nearly 140,000 occurred in Europe, and more than 90% of the cases were histologically classified as squamous cell carcinoma.
  • Head and neck cancer is mainly squamous cell carcinoma.
  • Squamous cell carcinoma of the head and neck (SCCHN) involving the mouth, throat, oropharynx, and hypopharynx accounts for 75% of all SCCHN and is closely related to alcohol and tobacco use.
  • Oropharyngeal SCCHN is also closely related to human papillomavirus (HPV) type 16 infection.
  • HPV-positive oropharyngeal cancer has increased sharply, suggesting the important role of HPV infection in oropharyngeal cancer.
  • the prognosis of both recurrences is very poor, and only a few patients are suitable for potentially curative treatments for the recurrence of localized diseases, but the incidence is high.
  • the first-line treatment recommendation (1A) for recurrent and metastatic head and neck squamous cell carcinoma (1A) chemotherapy regimens include cisplatin/carboplatin + 5-FU, and the average OS (overall survival) of chemotherapy regimens It is 7.4-8.7 months.
  • the present application provides a method for treating, alleviating or ameliorating cancer in a subject, which comprises administering to the subject a therapeutically effective amount of an inhibitor of the interaction between PD-1 receptor and its ligand PD-L1, wherein The inhibitor is PD-L1 antibody.
  • the application also provides the use of anti-PD-L1 antibodies 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, Wherein, the inhibitor is an anti-PD-L1 antibody.
  • the application also provides the use of anti-PD-L1 antibodies in the preparation of drugs for treating, alleviating or improving cancer.
  • the application also provides anti-PD-L1 antibodies for the treatment, alleviation or amelioration of 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 A heavy chain CDR2 region with at least 80% homology to the amino acid sequence shown in NO: 2 or SEQ ID NO: 5; at least 80% homology to the amino acid sequence shown in SEQ ID NO: 3 or SEQ ID NO: 6
  • the heavy chain CDR3 region; the light chain CDR1 region having at least 80% homology with the amino acid sequence shown in SEQ ID NO: 7 or SEQ ID NO: 10; and the light chain CDR1 region with SEQ ID NO: 8 or SEQ ID NO: 11 The amino acid sequence shown has a light chain CDR2 region with at least 80% homology; and the amino acid sequence shown in SEQ ID NO: 9 or SEQ ID NO: 12 has a light chain CDR3 region with at least 80% homology.
  • the anti-PD-L1 antibody is administered 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
  • the dose per kg body weight is administered, and the administration is continued.
  • the anti-PD-L1 antibody is administered in one or more uniform doses that are effective in treating the cancer.
  • the uniform dose is in the range of about 20 mg to about 2000 mg of anti-PD-L1 antibody.
  • the uniform 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 of anti-PD-L1 antibody.
  • the anti-PD-L1 antibody is administered about every week (q1w), about every 2 weeks (q2w), about every 3 weeks (q3w), or about every 4 weeks (q4w). In some embodiments, a uniform dose of anti-PD-L1 antibody is administered to the patient approximately every 3 weeks. In some embodiments, the anti-PD-L1 antibody is administered at a dose of 1200 mg per patient, approximately once every 3 weeks, for 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 of about 1-2 hours, preferably about 1 hour of intravenous infusion.
  • the anti-PD-L1 antibody is a naked antibody, a complete antibody, or an antibody fragment containing an antigen binding region.
  • the method results in an objective response, preferably a complete response or a partial response.
  • the subject has not previously received systemic chemotherapy. In some protocols, the subject has previously received surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy. In some embodiments, the subject has not previously received systemic chemotherapy, but has received surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy. In some specific embodiments, the subject undergoes surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy, and disease progression occurs again after complete remission. In some specific embodiments, the subject fails to complete or partially relieve after surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy. In some embodiments, the subject undergoes surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy after cancer metastasis.
  • the cancer is squamous cell carcinoma of the head and neck (SCCHN).
  • SCCHN head and neck
  • the primary site of head and neck squamous cell carcinoma is the oropharynx, oral cavity, hypopharynx, and/or larynx.
  • the cancer is recurrent and/or metastatic head and neck squamous cell carcinoma.
  • the cancer is recurrent or metastatic head and neck squamous cell carcinoma.
  • the recurrent or metastatic head and neck squamous cell carcinoma is recurrent or metastatic head and neck squamous cell carcinoma without indications for local radical treatment.
  • the head and neck squamous cell carcinoma is recurrent.
  • the head and neck squamous cell carcinoma is metastatic.
  • the head and neck squamous cell carcinoma is refractory.
  • cancer treatment is the first-line treatment for recurrent or metastatic head and neck squamous cell carcinoma.
  • treatment is the first-line treatment of recurrent or metastatic head and neck squamous cell carcinoma combined with standard chemotherapy.
  • the standard chemotherapy includes administration of a chemotherapeutic agent to the patient.
  • the standard chemotherapy includes the administration of cisplatin and 5-fluorouracil to the patient.
  • the standard chemotherapy includes administration of carboplatin and 5-fluorouracil to the patient.
  • the anti-PD-L1 antibody and the chemotherapeutic agent are each in the form of a pharmaceutical composition, which can be administered simultaneously, sequentially or at intervals.
  • treatment takes 3 weeks (21 days) as a cycle.
  • D1 On the first day (D1) of each cycle, 1200 mg of anti-PD-L1 antibody is administered intravenously, and standard chemotherapy regimens are given after the anti-PD-L1 antibody infusion is completed.
  • the standard chemotherapy regimen is intravenous infusion of cisplatin 75mg/m 2 or intravenous infusion of carboplatin AUC5 on the first day (D1), and daily intravenous infusion on the first to fifth days (D1-D5) 5-Fluorouracil 750mg/m 2 was given as an infusion.
  • the standard chemotherapy regimen is cisplatin 75 mg/m 2 administered by intravenous infusion on the first day (D1), and 5-fluorouracil administered by intravenous infusion daily on the first to fifth days (D1-D5) 750mg/m 2 .
  • the standard chemotherapy regimen is carboplatin AUC5 administered by intravenous infusion on the first day (D1), and 5-fluorouracil 750 mg/m administered by intravenous infusion on the first to fifth days (D1-D5) 2 .
  • the application also provides a combined pharmaceutical composition for treating recurrent or metastatic head and neck squamous cell carcinoma, which includes an anti-PD-L1 antibody and a chemotherapeutic agent.
  • the combination pharmaceutical composition includes a pharmaceutical composition containing an anti-PD-L1 antibody and a pharmaceutical composition containing a chemotherapeutic agent.
  • the chemotherapeutic agent in the combination pharmaceutical composition may be cisplatin, carboplatin and/or 5-fluorouracil.
  • the combination pharmaceutical composition includes a pharmaceutical composition containing an anti-PD-L1 antibody.
  • the anti-PD-L1 antibody is stored in a container in a fixed dose, and the fixed dose is selected from approximately 300 mg, approximately 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 antibodies.
  • kits for the treatment of recurrent or metastatic head and neck squamous cell carcinoma includes an anti-PD-L1 antibody pharmaceutical composition and a chemotherapeutic agent, and a combination of an anti-PD-L1 antibody and a chemotherapeutic agent Instructions for the treatment of recurrent or metastatic head and neck squamous cell carcinoma.
  • This application provides a product including a container containing a fixed dose of anti-PD-L1 antibody.
  • the application also provides the use of the anti-PD-L1 antibody in the preparation of a product including a container of a fixed dose of the anti-PD-L1 antibody for the treatment of cancer.
  • 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 antibodies.
  • the article further includes a package insert or package insert that instructs the user to administer the fixed dose to a cancer patient.
  • the preparation includes one or more than one vial containing approximately 300 mg or 600 mg of anti-PD-L1 antibody. In some embodiments, the preparation includes 1 vial containing approximately 300 mg of anti-PD-L1 antibody. In some specific embodiments, the preparation includes 1 vial containing approximately 600 mg of anti-PD-L1 antibody.
  • This application provides a method for treating, relieving or improving a subject suffering from cancer or tumor, which comprises administering to the subject a therapeutically effective amount of the interaction between the PD-1 receptor and its ligand PD-L1 Inhibitor of action.
  • This application also provides a method for treating, relieving or improving 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 an antibody or its antigen binding portion that inhibits the activity of PD-L1.
  • PD-L1 programmed death ligand 1
  • the present application also provides a monotherapy or combination therapy for treating, alleviating or ameliorating a subject suffering from cancer or tumor.
  • the method comprises administering to the subject alone a therapeutically effective amount of: combined with programmed death ligand 1 (PD-L1) and/or an antibody or antigen binding portion thereof that inhibits the activity of PD-L1.
  • PD-L1 programmed death ligand 1
  • This application also provides a method for treating, alleviating or improving a subject suffering from cancer or tumor, the cancer or tumor is squamous cell carcinoma of the head and neck (SCCHN), the method includes: (i) measuring the The level of PD-L1 in a sample of a subject, wherein the subject is PD-L1 positive, and (ii) administering to the subject a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding portion thereof.
  • SCCHN head and neck
  • This application provides a method for treating, alleviating or improving a subject suffering from cancer or tumor.
  • the subject is a patient diagnosed with squamous cell carcinoma of the head and neck (SCCHN) by histopathology.
  • SCCHN head and neck
  • the primary site of head and neck squamous cell carcinoma can be the oropharynx, oral cavity, hypopharynx or larynx.
  • the patient’s cancer may be refractory, recurrent or metastatic head and neck squamous cell carcinoma, for example, in some patients, head and neck squamous cell carcinoma is recurrent; In some patients, the head and neck squamous cell carcinoma is metastatic; in some patients, the head and neck squamous cell carcinoma is refractory. In some aspects, the cancer is recurrent and/or metastatic head and neck squamous cell carcinoma. In some specific embodiments, the head and neck squamous cell carcinoma is recurrent SCCHN without indications for local radical treatment. In some specific embodiments, the head and neck squamous cell carcinoma is metastatic SCCHN without indications for local radical treatment.
  • the subject has previously received surgery, chemotherapy, and/or radiation therapy. In some embodiments, the subject recurs disease progression after achieving complete remission after surgery, chemotherapy, and/or radiation therapy. In some embodiments, the subject has not been completely relieved or failed to partially relieve after surgery, chemotherapy, and/or radiotherapy.
  • patients with head and neck squamous cell carcinoma may be patients who have not previously received systemic chemotherapy.
  • patients with head and neck squamous cell carcinoma have previously received surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy.
  • patients with squamous cell carcinoma of the head and neck are patients who have not previously received systemic chemotherapy, but have received surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy.
  • patients with squamous cell carcinoma of the head and neck are patients who have undergone surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy, and have recurred disease progression after achieving complete remission.
  • patients with squamous cell carcinoma of the head and neck are patients who have failed to complete or partially relieved after surgery, radiotherapy, induction chemotherapy, concurrent chemotherapy and/or adjuvant chemotherapy.
  • the cancer of the head and neck squamous cell carcinoma patient has metastasized.
  • the treatment is a first-line treatment for recurrent or metastatic head and neck squamous cell carcinoma.
  • the treatment is a first-line treatment for recurrent or metastatic head and neck squamous cell carcinoma combined with standard chemotherapy.
  • the standard chemotherapy includes administration of a chemotherapeutic agent to the patient.
  • the chemotherapeutic agent includes a platinum-containing chemotherapeutic agent.
  • the standard chemotherapy includes the administration of cisplatin and 5-fluorouracil to the patient, or the administration of carboplatin and 5-fluorouracil to the patient.
  • the standard chemotherapy includes the administration of platinum-containing dual chemotherapy to the patient.
  • the anti-PD-L1 antibody and the chemotherapeutic agent are each in the form of a pharmaceutical composition, which can be administered simultaneously, sequentially or at intervals.
  • the treatment takes 3 weeks (21 days) as a cycle, and each cycle gives the patient 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 Approximately 2400 mg of a uniform dose of anti-PD-L1 antibody.
  • the treatment takes 3 weeks (21 days) as a cycle, and 300 mg, about 600 mg, about 900 mg, about 1000 mg, about 1200 mg, about 1500 mg, about 1500 mg are administered intravenously on the first day (D1) of each cycle.
  • anti-PD-L1 antibody is given standard chemotherapy after infusion.
  • the treatment takes 3 weeks (21 days) as a cycle, and approximately 1200 mg of anti-PD-L1 antibody is administered intravenously on the first day (D1) of each cycle, and anti-PD-L1 antibody is administered after infusion Standard chemotherapy regimen.
  • the standard chemotherapy regimen includes: intravenous infusion of cisplatin 75-100mg/m 2 or intravenous infusion of carboplatin AUC5 on the first day (D1), and the first to fifth days (D1- D5) 5-Fluorouracil 750-1000mg/m 2 is administered intravenously every day.
  • the standard chemotherapy regimen includes: intravenous infusion of 75-100 mg/m 2 of cisplatin on the first day (D1), and daily intravenous infusion on the first to fifth days (D1-D5) Give 5-fluorouracil 750-1000mg/m 2 .
  • the standard chemotherapy regimen includes: carboplatin AUC5 administered by intravenous infusion on the first day (D1), and 5-fluorouracil 750 administered by intravenous infusion daily on the first to fifth days (D1-D5) -1000mg/m 2 .
  • the intravenous infusion of cisplatin 75-100mg / m 2 intravenous infusion is alternatively 75mg / m 2, 80mg / m 2, 85mg / m 2, 90mg / m 2 or 100mg / m 2, preferably infusion of 75mg / m 2, or intravenous infusion of 100mg / m 2;
  • the intravenous infusion of 5-fluorouracil 750-1000mg / m 2 intravenous infusion is alternatively 750mg / m 2, 800mg / m 2, 850mg /m 2 , 900 mg/m 2 or 1000 mg/m 2 , preferably intravenous infusion of 750 mg/m 2 or intravenous infusion of 1000 mg/m 2 .
  • This application also provides a combination therapy for the first-line treatment of subjects suffering from recurrent or metastatic head and neck squamous cell carcinoma, wherein the patient receives anti-PD-L1 antibody combined with standard chemotherapy regimen for 3 weeks (21 days) It is a cycle.
  • D1 On the first day (D1) of each cycle, 1200 mg of anti-PD-L1 antibody is administered intravenously.
  • the standard chemotherapy regimen is started: intravenous infusion on the first day of each cycle (D1) Infusion of cisplatin 75mg/m 2 , intravenous infusion of 5-fluorouracil 750mg/m 2 /d from day 1 to day 5 (D1-D5) of each cycle.
  • This application also provides a combination therapy for the first-line treatment of subjects suffering from recurrent or metastatic head and neck squamous cell carcinoma, wherein the patient receives anti-PD-L1 antibody combined with standard chemotherapy regimen for 3 weeks (21 days) It is a cycle.
  • D1 On the first day (D1) of each cycle, 1200 mg of anti-PD-L1 antibody is administered intravenously.
  • the standard chemotherapy regimen is started: intravenous infusion on the first day of each cycle (D1) Carboplatin AUC5 was injected, and 5-fluorouracil 750 mg/m 2 /d was infused intravenously from day 1 to day 5 (D1-D5) of each cycle.
  • the application also provides a combined pharmaceutical composition for treating recurrent or metastatic head and neck squamous cell carcinoma, which includes an anti-PD-L1 antibody and a chemotherapeutic agent.
  • the combination pharmaceutical composition includes a pharmaceutical composition containing an anti-PD-L1 antibody and a pharmaceutical composition containing a chemotherapeutic agent.
  • the chemotherapeutic agent includes a platinum-containing chemotherapeutic agent.
  • the chemotherapeutic agent in the combination pharmaceutical composition may be cisplatin, carboplatin and/or 5-fluorouracil.
  • the combination pharmaceutical composition includes a pharmaceutical composition containing an anti-PD-L1 antibody.
  • the anti-PD-L1 antibody is stored in a container in a fixed dose selected from the group consisting of 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 antibodies.
  • the combination pharmaceutical composition contains about 300 mg, about 600 mg, about 900 mg, or about 1200 mg of anti-PD-L1 antibody, and a therapeutically effective amount of cisplatin and 5-fluorouracil.
  • the combination pharmaceutical composition comprises about 300 mg, about 600 mg, or about 1200 mg of anti-PD-L1 antibody, and a therapeutically effective amount of carboplatin and 5-fluorouracil.
  • This application also provides a method for identifying a subject suffering from head and neck squamous cell carcinoma, the subject being suitable for anti-PD-L1 antibody therapy, the method comprising measuring a sample of the subject And wherein the subject is administered a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding portion thereof.
  • This application also provides a kit for treating a subject suffering from head and neck squamous cell carcinoma, the kit comprising: (a) an anti-PD-L1 antibody or an antigen binding portion thereof; (b) about treatment Instructions for the tumor.
  • the cancer is a primary cancer.
  • the cancer is metastatic or recurrent cancer.
  • the cancer is a relapsed or refractory cancer.
  • the cancer is head and neck squamous cell carcinoma.
  • the cancer is recurrent or metastatic head and neck squamous cell carcinoma.
  • the application also provides the use of an anti-PD-L1 antibody in the first-line treatment of head and neck squamous cell carcinoma.
  • the application also provides the use of an anti-PD-L1 antibody in the second-line treatment of head and neck squamous cell carcinoma.
  • the application also provides the use of an anti-PD-L1 antibody in the third-line treatment of head and neck squamous cell carcinoma.
  • the anti-PD-L1 antibody is used for the first-line treatment of recurrent or metastatic head and neck squamous cell carcinoma.
  • the subject is a human patient.
  • the subject has received another cancer treatment (for example, surgical treatment, radiation therapy, induction chemotherapy, concurrent chemotherapy and/or adjuvant chemotherapy), but the subject has been treated for such another cancer. Said to be resistant or refractory.
  • the subject is a human patient.
  • the subject has received another cancer treatment (for example, surgical treatment, radiation therapy, induction chemotherapy, concurrent chemotherapy and/or adjuvant chemotherapy), but the subject has been treated for such another cancer. Said to be recurrent or metastatic.
  • the application 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 application relates to a method of treating a subject suffering from a tumor, the tumor being recurrent or metastatic head and neck squamous cell carcinoma, the method comprising: (i) measuring the The level of PD-L1 in a sample of a 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 an antigen-binding portion thereof .
  • 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 Monoclonal antibody.
  • the anti-PD-L1 antibody competes with the 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%, at least about 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 PD-L1 expression level of the tumor is 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 antibodies, in situ mRNA hybridization, automated IHC and other methods, the PD-L1 expression level can be measured.
  • This application provides a method for treating, alleviating or improving a subject suffering from cancer or tumor, the method comprising administering to the subject a therapeutically effective amount of an anti-PD-L1 antibody or an antigen binding portion thereof, wherein the tumor sample obtained from the patient has been determined
  • the cells constituting about 1% or more (for example, about 1%, about 2%, about 3%, or about 4% or more) have a detectable expression level of PD-L1.
  • the tumor sample obtained from the patient has been determined to constitute about 1% to about 65% or more (e.g., about 1% to about 5%, about 5% to about 10%, about 10% to about 20%).
  • This application also provides a method for determining whether a patient suffering from head and neck squamous cell carcinoma is likely to respond to treatment with a therapeutic agent comprising an anti-PD-L1 antibody, the method comprising determining 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 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 application also provides a method for predicting the responsiveness of a patient suffering from head and neck squamous cell carcinoma to treatment with an anti-PD-L1 antibody-containing therapeutic agent, the method comprising determining 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 application also provides a method for selecting a therapy for a patient suffering from head and neck squamous cell carcinoma, the method comprising determining 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 PD-L1 expression level in the tumor cells of the tumor sample is the patient's choice of therapy containing the anti-PD-L1 antibody therapeutic agent.
  • a tumor sample obtained from the patient has been determined to have a detectable expression level 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 a detectable expression level of PD-L1 in tumor cells constituting at least about 10% of the tumor sample.
  • the application also provides a method for determining whether a patient suffering from head and neck squamous cell carcinoma is likely to respond to treatment with a therapeutic agent comprising an anti-PD-L1 antibody or an antigen-binding portion thereof, the method comprising a tumor sample obtained from the patient To determine the subtype of the tumor, where recurrent and/or metastatic head and neck squamous cell carcinoma indicates that the patient is likely to respond to treatment with a therapeutic agent containing an anti-PD-L1 antibody.
  • the present application provides a method for predicting the responsiveness of a patient suffering from head and neck squamous cell carcinoma to treatment with an anti-PD-L1 antibody-containing therapeutic agent, the method comprising determining the subgroup of the tumor based on a tumor sample obtained from the patient Type in which recurrent and/or metastatic head and neck squamous cell carcinoma indicates that the patient is likely to respond to treatment with a therapeutic agent containing an anti-PD-L1 antibody.
  • the present application provides a method for selecting a therapy for a patient suffering from head and neck squamous cell carcinoma, the method comprising determining the subtype of the tumor based on a tumor sample obtained from the patient, and determining that the tumor is recurrent and/ Or metastatic squamous cell carcinoma of the head and neck selects the treatment for the patient with a therapeutic agent containing an anti-PD-L1 antibody.
  • the method further comprises administering to the patient a therapeutically effective amount of an anti-PD-L1 antibody therapeutic agent based on the expression level of PD-L1 in tumor cells in the tumor sample.
  • the expression level of the molecular marker in the tumor sample or blood tissue sample obtained from the patient has been determined to have changed relative to the reference level of the at least one gene, such as an increase.
  • the expression level of microRNA in the tumor sample obtained from the patient has been determined to be changed relative to the reference level of the microRNA (microRNA), in some specific embodiments, the change is the expression level reduce.
  • the reference level is a non-tumor sample or blood tissue sample of a non-diseased subject as a reference. In some embodiments, the reference level is a patient's non-tumor sample as a reference.
  • the gene mutation level, gene modification level, transcription level and/or expression level of at least one of PD-L1, TMB, MSI, 9p24.1 in a tumor sample or blood tissue sample obtained from the patient has been It is determined that the reference level relative to the at least one gene has changed.
  • the reference level is a non-tumor sample or blood tissue sample of a non-diseased subject as a reference.
  • the reference level is a patient's non-tumor sample as a reference.
  • the objective response rate of a subject administered a therapeutically effective amount of anti-PD-L1 antibody is between about 10% to about 40% (e.g., about 10% to about 20%, about 20% to about 30%, Between about 30% and about 40%).
  • the objective response rate of a patient administered a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding portion thereof is between about 15% and about 25%.
  • the objective response rate of the patient administered a therapeutically effective amount of the anti-PD-L1 antibody therapeutic agent is at least about 15%.
  • the objective response rate of the patient administered a therapeutically effective amount of the anti-PD-L1 antibody therapeutic agent is at least about 20%.
  • the therapies of the application e.g., anti-PD-L1 antibodies
  • the anti-PD-L1 antibody therapy of the present application increases the duration of survival of the subject compared to standard-of-care therapy.
  • the therapies of the application increase 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 12 months after administration.
  • the duration of survival or overall survival of the subject is increased by at least about 5%, at least about 10%, at least about 15% when compared to another subject treated only with standard-of-care therapy , 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 overall survival of the subject is increased by at least about 1 month, at least about 2 months, or at least about 3 months when compared to another subject treated with only standard-of-care therapy. 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 application effectively increases the duration of progression-free survival of the subject. For example, when compared with another subject treated only with standard-of-care therapy, 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. 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 that is at least about 30%, 35%, 36%, 37%, 39% higher than the response rate after standard-of-care therapy is administered , 40%, 45% or 50% total 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 PD-L1 binding and inhibit the immunosuppression of PD-1 signal transmission pathways effect.
  • the anti-PD-1 or anti-PD-L1 "antibody” includes an antigen binding portion that binds to the PD-1 or PD-L1 receptor, respectively, and inhibits ligand binding and upregulates the immune system. It exhibits 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 regarding the treatment of a human subject, the antibody is a human antibody. Antibodies of 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 The proline residues replace the serine residues in the hinge region.
  • the mutation present in the monoclonal antibody prevents the exchange of the Fab arm with the endogenous IgG4 antibody, while retaining low affinity for activating 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 antibodies have been disclosed in WO2016022630, 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 - ⁇ .
  • the anti-PD-L1 antibody or fragment thereof cross-competes with 5G11 or 13C5 monoclonal antibody. In other embodiments, the anti-PD-L1 antibody or fragment thereof binds to the same or similar epitope as 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 or fragment thereof cross-competes with 5G11 or 13C5 monoclonal antibody 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 method of the invention 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 the 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 two Fab fragments connected by disulfide bonds in the hinge region; (iii) an Fd fragment composed of VH and CH1 domains; and (iv) a single-arm VL and Fv fragments (including, for example, scFv) composed of VH domains.
  • an anti-PD-L1 "antibody” includes an antigen that binds to a PD-L1 ligand and exhibits functional properties similar to those of a complete antibody in inhibiting receptor binding and upregulating the immune system Combine parts or fragments.
  • the anti-PD-L1 antibody or antigen-binding portion thereof cross-competes with 5G11 or 13C5 monoclonal antibody 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 IgG1, IgG2, IgG3 or IgG4 isotype can be used.
  • the anti-PD-L1 antibody used in the method can be replaced with another anti-PD-1 antagonist or anti-PD-L1 antagonist.
  • anti-PD-1 antibodies prevent the interaction between PD-1 and PD-L1, and thus play a similar role in the signal transmission pathway of PD-1
  • anti-PD-1 antibodies can replace anti-PD-L1 antibodies in Application in the method disclosed herein. Therefore, in one embodiment, the present application relates to a method for treating a subject suffering from a tumor that is recurrent or metastatic head and neck squamous cell carcinoma, the method comprising giving the subject A therapeutically effective amount of anti-PD-L1 antibody is administered.
  • 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 antigen-binding polypeptide is an antibody or an antigen-binding portion thereof that binds to programmed death ligand 1 (PD-L1) and/or inhibits the activity of PD-L1.
  • the antigen binding polypeptide is an anti-PD-L1 antibody.
  • the present application provides isolated antibodies or fragments thereof that bind PD-L1, wherein the antibodies can be produced by hybridomas selected from the group consisting of hybridomas referred to herein as 13C5, 5G11. Therefore, this application also includes hybridomas 13C5, 5G11, and any hybridoma that produces the antibodies disclosed herein.
  • the application also provides isolated polynucleotides encoding the antibodies and fragments thereof provided herein.
  • the application also includes an expression vector containing the isolated polynucleotide, and a host cell containing the expression vector.
  • This application provides an anti-PD-L1 antibody, which comprises a heavy chain complementarity determining region (CDR) selected from a 13C5 or 5G11 antibody, and a light chain complementarity determining region selected from a 13C5 or 5G11 antibody.
  • CDR heavy chain complementarity determining region
  • the present application provides an anti-PD-L1 antibody comprising a variable heavy chain selected from the group consisting of 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.
  • a variable heavy chain selected from the group consisting of ch5G11-hIgG1, ch5G11-hIgG4, ch13C5-hIgG1, ch13C5-hIgG4 chimeric antibody variable light chain.
  • the application provides an anti-PD-L1 antibody comprising a variable heavy chain selected from a humanized antibody of hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG4, and a humanized antibody selected from hu13C5- Variable light chain of hIgG1, hu13C5-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG4 humanized antibody.
  • the HCDR1 sequence of 13C5, ch13C5-hIgG1, ch13C5-hIgG4, hu13C5-hIgG1 or hu13C5-hIgG4 is SYGMS (SEQ ID NO: 4), and the HCDR2 sequence is SISSGGSTYYPDSVKG (SEQ 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); The HCDR1 sequence of 5G11, ch5G11-hIgG1, ch5G11-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG
  • 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 having the amino acid sequence shown in SEQ ID NO: 2
  • the heavy chain CDR2 region which has the amino acid sequence shown in SEQ ID NO: 3
  • the light chain CDR1 region which has the amino acid sequence shown in SEQ ID NO: 7, has the amino acid sequence shown in SEQ ID NO: 8
  • the light chain CDR2 region of the amino acid sequence shown 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 this application is a PD-L1Fc fusion protein.
  • the application administers a therapeutically effective amount of anti-PD-L1 antibody to the subject, wherein the anti-PD-L1 antibody is administered alone.
  • the separate administration 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 separate administration means that the anti-PD-L1 antibody may not be used in combination with chemotherapeutic drugs, and/or not be administered simultaneously with chemotherapeutic drugs.
  • the separate administration means that the anti-PD-L1 antibody may not be used in combination with other targeted drugs, and/or not be administered simultaneously with other targeted drugs.
  • the separate administration 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 separate administration means that the anti-PD-L1 antibody may not be used in combination with radiotherapy, and/or not administered simultaneously with radiotherapy.
  • the application administers a therapeutically effective amount of anti-PD-L1 antibodies to the subject, wherein the anti-PD-L1 antibodies are administered in combination.
  • immune checkpoint inhibitors eg, anti-PD-1 antibodies or anti-PD-L1 antibodies
  • the one or more anti-cancer The drug is administered to the subject.
  • the one or more anticancer drugs are not effective in treating the cancer.
  • the other anticancer agent is any anticancer agent described herein or known in the art.
  • an anti-PD-1 antibody or an anti-PD-L1 antibody can be combined with another immunotherapy.
  • immunotherapy involving blocking of immune checkpoints is administered as a monotherapy.
  • immunotherapy involving blockade of immune checkpoints is administered in combination with other therapies.
  • the therapeutic agent of the present application can be constituted in a composition, for example, a pharmaceutical composition containing an antibody and a pharmaceutically acceptable carrier.
  • “Pharmaceutically acceptable carrier” as used herein includes any and all solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic agents and absorption delaying agents that are physiologically compatible.
  • the carrier for the composition containing the antibody is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion), and is used to contain TKI (tyrosine
  • the carrier of the composition of acid kinase inhibitor) is suitable for non-parenteral (e.g., oral) administration.
  • the pharmaceutical composition of the present application 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 most suitable desired response, for example, maximum therapeutic response and/or minimum adverse effects.
  • the methods of the application can be used with uniform or weight-based dosages.
  • the anti-PD-1 antibody, anti-PD-L1 antibody or antigen binding portion thereof is administered as a uniform 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 following range: 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
  • 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, or 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 results in sustained receptor occupancy (RO) (based on the typical pharmacokinetic properties of antibodies).
  • RO sustained 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) , Approximately 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.
  • hu5G11-hIgG4 monoclonal antibody is administered to the subject.
  • the antibody is administered about once every 3 weeks.
  • the dosage and schedule can be changed during treatment.
  • the dosage regimen of the anti-PD-L1 antibody of the present application includes at least about 1 to at least about 30 mg/kg body weight, at least about 3 to at least about 20 mg/kg via intravenous administration 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 for up to about 6 weeks or about 12 weeks until a complete response or confirmed progress Sexual disease.
  • anti-PD-L1 monotherapy is administered at 3 mg/kg every 2 weeks until progressive disease or unacceptable toxicity. In other embodiments, anti-PD-L1 monotherapy is administered at 1200 mg every 3 weeks until progressive disease or unacceptable toxicity. In certain embodiments, the antibody therapy or any combination therapy disclosed herein lasts 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.
  • 13C5, ch13C5-hIgG1, ch13C5-hIgG4, hu13C5-hIgG1, hu13C5-hIgG4, 5G11, ch5G11-hIgG1, ch5G11-hIgG4, hu5G11-hIgG1 or hu5G11- which are lower than the typical 20mg/kg but not less than 0.001mg/kg
  • the dose of hIgG4 monoclonal antibody is a subtherapeutic dose.
  • the subtherapeutic dose of anti-PD-L1 antibody used in the methods herein is higher than 0.001 mg/kg and lower than 20 mg/kg. In certain embodiments, the subtherapeutic 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 10mg/kg body weight.
  • the subtherapeutic 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 subtherapeutic uniform dose is less than about 600 mg every 3 weeks, such as 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 application may be used in a uniform dose (the dose administered to the patient regardless of the weight of the patient).
  • the uniform 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 once every 3 weeks. In another embodiment, 1200 mg of the anti-PD-L1 antibody or antigen-binding fragment is administered once 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 can 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 results in sustained receptor occupancy (RO) (based on the typical pharmacokinetic properties of antibodies).
  • RO sustained 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 a month, about once every 3-6 months or longer Apply.
  • on the first day (D1) of each cycle receive intravenous infusion at a dose of about 3 mg/kg to about 30 mg/kg of the body weight, and about 21 days is a cycle, until the therapeutic effect is evaluated as disease progression and intolerable By the toxic reaction.
  • a dose of about 3 mg/kg to about 20 mg/kg of body weight is received intravenously, and about 21 days is a cycle, until the therapeutic effect is evaluated as disease progression and intolerable The toxic reaction.
  • a dose of 3 mg/kg is received intravenously, and about 21 days is a cycle, until the therapeutic effect is evaluated as disease progression and intolerable toxicity occurs.
  • the first day (D1) of each cycle receives an intravenous infusion at a dose of about 10 mg/kg body weight, and about 21 days is a cycle until the therapeutic effect is evaluated as disease progression and intolerable toxicity occurs.
  • a dose of about 15 mg/kg body weight is received intravenously, and about 21 days is a cycle until the therapeutic effect is evaluated as disease progression and intolerable toxicity occurs.
  • a dose of about 20 mg/kg body weight is received intravenously, and 21 days is a cycle until the efficacy is evaluated as disease progression and intolerable toxicity occurs.
  • the first day (D1) of each cycle receives an intravenous infusion at a dose of about 30 mg/kg body weight, and 21 days is a cycle until the therapeutic effect is assessed as disease progression and intolerable toxicity occurs. In certain embodiments, the first day (D1) of each cycle receives about 3mg/kg, 10mg/kg, 15mg/kg, 20mg/kg or 30mg/kg body weight intravenous infusion for about 2 weeks, about 3 weeks or About 4 weeks is a cycle, until the therapeutic effect is evaluated as disease progression and intolerable toxicity occurs.
  • the first day (D1) of each cycle receives a uniform dose of about 1200mg intravenous infusion, about 2 weeks, about 3 weeks, or about 4 weeks for 1 cycle, until the efficacy is evaluated as disease progression and intolerable By the toxic reaction.
  • a uniform dose of about 600 mg to about 1200 mg is received intravenously on the first day (D1) of each cycle, and about 21 days is a cycle until the efficacy is evaluated as disease progression and intolerable toxicity occurs.
  • a uniform dose of about 600 mg to about 900 mg is received intravenously, and about 21 days is a cycle until the therapeutic effect is evaluated as disease progression and intolerable toxicity occurs.
  • a uniform dose of 1200 mg is received intravenously 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 intolerable toxicity occurs.
  • a uniform dose of about 900 mg to about 1200 mg is received intravenously 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 intolerable toxicity occurs.
  • a uniform dose of 600 mg is received intravenously on the first day (D1) of each cycle, and 21 days is a cycle until the efficacy is evaluated as disease progression and intolerable toxicity occurs.
  • a uniform dose of 900 mg is received intravenously on day 1 (D1) of each cycle, and 21 days is a cycle until the therapeutic effect is evaluated as disease progression and intolerable toxicity occurs.
  • a uniform dose of 1200 mg is received intravenously on the first day (D1) of each cycle, and 21 days is a cycle until the efficacy is evaluated as disease progression and intolerable toxicity occurs.
  • the first day (D1) of each cycle receives a uniform dose of about 900mg intravenous infusion, about 2 weeks, about 3 weeks or about 4 weeks for 1 cycle, until the efficacy is evaluated as disease progression and intolerable By the toxic reaction.
  • the first day (D1) of each cycle receives a uniform dose of about 1200mg intravenous infusion, about 2 weeks, about 3 weeks, or about 4 weeks for 1 cycle, until the efficacy is evaluated as disease progression and intolerable By the toxic reaction.
  • 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 the pharmaceutical composition containing the second anticancer drug.
  • the actual dosage level of one or more active ingredients in the pharmaceutical composition of the present application can be changed, so as to obtain the amount of the active ingredient effective to achieve the desired therapeutic response for a specific patient, composition and mode of administration, and The patient has no undue toxicity.
  • the dosage level selected will depend on a variety of pharmacokinetic factors, including the activity of the specific composition used in the application, the route of administration, the time of administration, the excretion rate of the specific compound being used, the duration of treatment, and the specific
  • the 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 composition of the present application can be administered via one or more administration routes. The skilled person will understand that the route and/or mode of administration will vary with the desired result.
  • the purpose of the present application is at least to provide a pharmaceutical composition, characterized in that the pharmaceutical composition contains an antibody, and at least contains one of a buffer, an isotonicity regulator, a stabilizer, and/or a surfactant.
  • the pharmaceutical composition contains 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- 0.8 mg/mL surfactant, and the pH is about 4.5-6.8.
  • the concentration of anti-PD-L1 humanized monoclonal antibody is about 5-150 mg/mL in terms of w/v; preferably about 10-60 mg/mL; more preferably about 10-30 mg/mL.
  • the anti-PD-L1 humanized monoclonal antibody has a mass volume concentration of 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 70 mg /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 has a mass volume concentration of about 10 mg/mL. In other embodiments, the mass volume concentration of anti-PD-L1 humanized monoclonal antibody is about 30 mg/mL. In other embodiments, the mass volume concentration of anti-PD-L1 humanized monoclonal antibody is about 60 mg/mL.
  • the buffer is a histidine salt buffer.
  • the concentration of the histidine salt 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 5mM, about 10mM, about 15mM, about 20mM, about 25mM, or about 30mM.
  • the histidine salt buffer is about 10 mM.
  • the histidine salt buffer is about 15 mM.
  • the histidine salt buffer is about 20 mM.
  • the histidine salt buffer contains histidine and hydrochloric acid.
  • the isotonic regulator/stabilizer is about 20-150 mg/mL sucrose, preferably about 40-100 mg/mL sucrose, more preferably about 60-80 mg/mL 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 the sucrose is about 70 mg/mL.
  • the concentration of the sucrose is about 80 mg/mL.
  • the concentration of the sucrose is about 90 mg/mL.
  • the surfactant is selected from polysorbate 80, polysorbate 20, poloxamer 188; preferably polysorbate 80 or polysorbate 20; 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.
  • the surfactant is about 0.01-0.8 mg/mL of polysorbate 80 or polysorbate 20 in terms of w/v. In some specific solutions, the surfactant is about 0.05-0.6 mg/mL polysorbate 80, preferably about 0.1-0.4 mg/mL polysorbate 80, more preferably about 0.2-0.3 mg/mL Polysorbate 80 of about 0.2 mg/mL is most preferred.
  • 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 It is 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 some other embodiments, the content of polysorbate 80 in 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 content of polysorbate 80 in the pharmaceutical composition is about 0.4 mg/mL. In some embodiments, the content of polysorbate 80 in the pharmaceutical composition is about 0.5 mg/mL.
  • the pH value 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 solution of the pharmaceutical composition 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 is about 5.0.
  • the pH value of the aqueous pharmaceutical composition is about 5.2.
  • the pH of the aqueous pharmaceutical composition is about 5.4. In some embodiments, the pH of the aqueous pharmaceutical composition is about 5.5. In some embodiments, the pH of the aqueous pharmaceutical composition is about 5.6. In some embodiments, the pH of the aqueous pharmaceutical composition is about 5.8. In some embodiments, the pH of the aqueous pharmaceutical composition is about 6.0.
  • the application provides isolated antibodies or fragments thereof that bind PD-L1.
  • the anti-PD-L1 humanized monoclonal antibody provided in the present application comprises the following amino acid sequence: at least 80% (e.g., 81%, 82%, 83%, 83%, 81%, 82%, 83%, 81%, 82%, 83%), and 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% ) Homologous heavy chain CDR1 region; at least 80% (for example, 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%) homologous heavy
  • the anti-PD-L1 humanized monoclonal antibody provided in this application 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 SEQ ID NO: 2 or SEQ ID NO: 5 heavy chain CDR2 region; selected from SEQ ID NO: 3 or SEQ ID NO: 6 heavy chain CDR3 region; selected from SEQ ID NO: 7 or The light chain CDR1 region shown in SEQ ID NO: 10; selected from the light chain CDR2 region shown in SEQ ID NO: 8 or SEQ ID NO: 11; selected from the light chain CDR2 region shown in SEQ ID NO: 9 or SEQ ID NO: 12 CDR3 region of the light chain.
  • the anti-PD-L1 humanized monoclonal antibody provided in the present application 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% (for example, 81%, 82%, 83%, 84%, 85%) with 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
  • the anti-PD-L1 humanized monoclonal antibody provided in the present application includes the following amino acid sequence, such as the heavy chain variable region shown in SEQ ID NO: 13; and the light chain variable region shown in SEQ ID NO: 15 Chain variable region.
  • the anti-PD-L1 humanized monoclonal antibody provided in the present application 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 various CDR regions described herein and the various variants described above can specifically recognize and bind PD-L1, thereby effectively blocking the signal transduction between PD-L1 and PD-1.
  • the anti-PD-L1 humanized monoclonal antibody provided in the present application 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 in the present application 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 in the present application 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 in the present application comprises a monoclonal antibody selected from 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 containing the conservative substitution variant retains the ability to specifically recognize and bind to PD-L1.
  • the anti-PD-L1 humanized monoclonal antibody provided in this application 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) anti-PD-L1 humanized monoclonal antibody with a mass volume concentration of about 20 mg/mL, (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) optional amount of hydrochloric acid, and adjust 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, (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) optional amount of hydrochloric acid, and adjust the pH of the composition Approximately 5.5.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 humanized monoclonal antibody with a mass volume concentration of about 50 mg/mL, (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) optional amount of hydrochloric acid, and adjust the pH of the composition Approximately 5.5.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 humanized monoclonal antibody having a mass volume concentration of about 100 mg/mL, (b) a mass volume concentration of about 80 mg /mL of sucrose, (c) polysorbate 80 with a mass volume concentration of about 0.5 mg/mL, (d) histidine with a molar concentration of about 10 mM, (e) optional 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, (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) optional amount of hydrochloric acid, and adjust the pH of the composition Approximately 5.5.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 humanized monoclonal antibody with a mass volume concentration of about 60 mg/mL, (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) optional amount of hydrochloric acid, and adjust the pH of the composition Approximately 5.5.
  • 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 70 mg/mL 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) optional acetic acid, adjust 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 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) optional amount of hydrochloric acid, and adjust the pH of the composition Approximately 5.5.
  • the pharmaceutical composition is a water-soluble injection
  • the water-soluble injection includes, but is not limited to, a water-soluble preparation that has not been lyophilized or a water-soluble preparation reconstituted by a lyophilized powder.
  • the pharmaceutical composition is a lyophilized formulation.
  • the freeze-dried preparation refers to the preparation of an aqueous solution through a freeze-drying process. Freeze-drying 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 freeze-dried preparation of the present application can also be dried by other methods known in the art, such as spray drying and bubble drying.
  • the polymer does not exceed 1.1%, preferably does not exceed 0.9%, and more preferably does not exceed 0.5% when stored at 2-8°C or 25°C for at least 6 months.
  • This application 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 buffers, isotonic regulators/stabilizers and/or surfactants. One or more types are mixed.
  • the application also provides a method for treating, alleviating or improving neoplastic conditions in a subject, including administering the aforementioned pharmaceutical composition to the subject.
  • This application provides a product including a container containing a fixed dose of anti-PD-L1 antibody.
  • the application also provides the use of the anti-PD-L1 antibody in the preparation of a product including a container of a fixed dose of the anti-PD-L1 antibody for the treatment of cancer.
  • 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 antibodies.
  • the article further includes a package insert or package insert that instructs the user to administer the fixed dose to a cancer patient.
  • the preparation includes one or more than one vial containing approximately 300 mg or 600 mg of anti-PD-L1 antibody. In some embodiments, the preparation includes 1 vial containing approximately 300 mg of anti-PD-L1 antibody. In some embodiments, the product includes one or more vials, and each vial contains approximately 10 mL of a pharmaceutical composition containing an anti-PD-L1 antibody. In some embodiments, the preparation includes one or more than one vial, and each vial contains 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 isotonicity regulator/stabilizing And 0.01-0.8mg/mL surfactant, and the pH is about 4.5-6.8.
  • the product includes one or more than one vial, and each vial contains 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 product includes one or more than one vial, each vial contains 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.
  • 300 mg of anti-PD-L1 antibody can be placed in 1 container and 4 such containers can be combined into a product, or 600 mg of anti-PD-L1 antibody can be placed in 1 container and 2 such containers can be
  • the container constitutes a product, and optionally, the product further contains a therapeutically effective amount of cisplatin and/or 5-fluorouracil, or contains a therapeutically effective amount of carboplatin and/or 5-fluorouracil.
  • the substance in the product can be conveniently administered to the patient.
  • the term "antibody” refers to a binding protein having at least one antigen binding domain.
  • the antibodies and fragments of the present application may be whole antibodies or any fragments thereof. Therefore, the antibodies and fragments of the present application 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 can also include recombinant polypeptides, fusion proteins, and bispecific antibodies.
  • the anti-PD-L1 antibodies and fragments thereof disclosed herein may be of IgG1, IgG2, IgG3, or IgG4 isotype.
  • the term "isotype" refers to the antibody species encoded by the heavy chain constant region genes.
  • the anti-PD-L1 antibodies and fragments thereof disclosed herein are of the IgG1 or IgG4 isotype.
  • the PD-L1 antibodies and fragments thereof of the present application can be derived from any species, including but not limited to mice, rats, rabbits, primates, llamas and humans.
  • the PD-L1 antibody and its fragments can be chimeric antibodies, humanized antibodies or whole human antibodies.
  • the anti-PD-L1 antibody is an antibody produced by a hybridoma cell line derived from a mouse. 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.
  • Humanized antibodies are antibodies that contain complementarity determining regions (CDRs) derived from non-human antibodies; and framework regions and constant regions derived from human antibodies.
  • the anti-PD-L1 antibodies provided herein can 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 from which the CDR of the antibody is derived.
  • Exemplary humanized antibodies are provided herein. Additional anti-PD-L1 antibodies or variants thereof comprising the heavy chain CDRs and light chain CDRs provided herein can be produced using any human framework sequence and are also included in this application.
  • framework sequences suitable for use in this application include those framework sequences that are structurally similar to the framework sequences provided herein. Additional modifications can be made in the framework regions to improve the properties of the antibodies provided herein. Such additional framework modifications may include chemical modifications; point mutations to reduce immunogenicity or remove T cell epitopes; or revert 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 region of the VH and/or VL of the humanized antibody provided herein are backmutated to the corresponding amino acid in the parent murine antibody.
  • the amino acid at positions 53 and/or 60 and/or 67 of the light chain variable region is backmutated to the corresponding one found at that position in the mouse 5G11 or 13C5 light chain variable region Amino acids.
  • 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 Or the corresponding amino acid found at that 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, where 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 was mutated from Thr(T) to Asn(N), and the amino acid at position 83 was mutated from Thr(T) to Asn(N).
  • the humanized 13C5 antibody comprises a light chain variable region, wherein the amino acid at position 53 is mutated from Tyr (Y) to Lys (K); and a heavy chain variable region, wherein the amino acid at position 28
  • 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)
  • the amino acid at position 49 is mutated from Ser(S) to Ala(A)
  • the amino acid at position 94 was 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 properties of the antibodies.
  • the application also includes the following humanized antibodies that bind to PD-L1 and contain framework modifications corresponding to the exemplary modifications described herein relative to any suitable framework sequence, as well as other ways to improve the antibody Other frame modifications of characteristics.
  • isolated antibody means an antibody that does not substantially contain 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 Of the antigen). However, an isolated antibody that specifically binds 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 chemical substances.
  • 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 ) 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.
  • the "antigen-binding portion" (also referred to as “antigen-binding fragment”) of an antibody refers to one or more fragments of the antibody that retain the ability to specifically bind to 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 to the same epitope as the reference antibody or other binding protein.
  • the antibodies and antigen-binding fragments thereof disclosed herein are specific to PD-L1. In one embodiment, the antibody or fragments thereof are specific to PD-L1. In one embodiment, the antibodies and fragments provided herein bind to human or primate PD-L1, but not to PD-L1 from any other mammal. In another embodiment, the antibody or fragments thereof do not bind to mouse PD-L1.
  • the terms "human PD-L1”, “hPD-L1” and “huPD-L1” etc. are used interchangeably herein, and refer to human PD-L1 and human PD-L1 variants or isoforms. "Specific" means that the antibody and its fragments bind PD-L1 with a 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 and preventive or preventive measures.
  • Subjects in need of treatment include those who already have a disease or condition, as well as those who may have a disease or condition and whose purpose is to prevent, delay or attenuate the disease or condition.
  • systemic therapy refers to a treatment in which a drug substance is transported through the bloodstream to reach and affect cells throughout the body.
  • systemic chemotherapy refers to systemic chemotherapy that does not include chemotherapy for locally advanced disease as a part of multimodal therapy.
  • chemotherapy for locally advanced disease includes induction chemotherapy, concurrent chemotherapy with radiotherapy, and adjuvant Chemotherapy.
  • the term "subject” refers to mammals such as rodents, felines, canines, and primates.
  • the subject according to the present application is a human.
  • administering refers to the physical introduction of a composition containing a therapeutic agent to a subject using any of a variety of methods and delivery systems known to those skilled in the art.
  • the route of administration of immune checkpoint inhibitors includes intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral administration routes, such as by injection or infusion .
  • parenteral administration refers to modes of administration other than enteral and local administration usually performed by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, and lymphatic Intraductal, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspine, epidural and intrasternal injections and infusions Note, and electroporation in vivo.
  • the immune checkpoint inhibitor e.g., anti-PD-1 antibody or anti-PD-L1 antibody
  • a non-parenteral route e.g., anti-PD-1 antibody or anti-PD-L1 antibody
  • Other non-parenteral routes include topical, epidermal or mucosal routes of administration, for example, intranasal, vaginal, rectal, sublingual, or topical. Administration can also be performed, for example, once, multiple times, and/or over one or more extended periods of time.
  • AE adverse reaction
  • the adverse event may be related to the activation of the immune system or the expansion of immune system cells (e.g., T cells) in response to treatment.
  • Medical treatments can have one or more related AEs, and each AE can have the same or different severity levels.
  • the reference to a method capable of "changing adverse events” refers to a treatment plan that reduces the incidence and/or severity of one or more AEs related to the application of different treatment plans.
  • Dosing interval refers to the amount of time that elapses between multiple doses of the formulations disclosed herein that are administered to a subject. Thus the dosing interval can be indicated as a range.
  • dosing frequency means the frequency of administration of the dosage of the formulation disclosed herein at a given time.
  • the frequency of dosing can be indicated as the number of doses at a given time, for example, once a week or once every two weeks.
  • flat dose refers to the dose administered to a patient regardless of the weight or body surface area (BSA) of the patient. Therefore, the uniform dose is provided as an absolute amount of the agent (for example, anti-PD-L1 antibody), rather than as a mg/kg dose. For example, a 60 kg person and a 100 kg person will receive the same dose of antibody (e.g., 240 mg of 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 (e.g., mg) of the antibody.
  • 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.
  • 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 the dose calculated based on the weight of the patient and administered to the patient.
  • weight-based dose refers to the dose calculated based on the weight of the patient and administered to the patient.
  • a patient with a weight of 60 kg needs 3 mg/kg of anti-PD-1 antibody and 1 mg/kg of anti-CTLA-4 antibody, one can fix it from a 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 are 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 recurrence of the disease by a certain method including inducing, enhancing, suppressing or otherwise altering the immune response.
  • Treatment or “therapy” of a subject means any type of intervention or process performed on the subject, or administration of an active agent to the subject, with the purpose of reversing, alleviating, ameliorating, inhibiting, slowing down or preventing symptoms, complications or conditions Onset, progression, development, severity or recurrence of the disease, or biochemical indicators related to the disease.
  • PD-L1 positive can be used interchangeably with "at least about 1% 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 therefore 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” means that there are at least 100 cells expressing PD-L1 on the cell surface.
  • PD-1 Programmed death receptor-1
  • PD-1 is mainly expressed on previously activated T cells in the body and binds to two ligands, PD-L1 and PD-L2.
  • the term "PD-1” as used herein includes human PD-1 (hPD-1), variants, homologs and species homologs of hPD-1, and analogs that have 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 down-regulates 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 the onset of disease or promotes the regression of the disease when used alone or in combination with another therapeutic agent.
  • the regression of the disease is evidenced by a reduction in the severity of the disease symptoms, an increase in the frequency and duration of the symptom-free phase, or the prevention of injury or disability caused by the torture of the disease.
  • the ability of therapeutic agents to promote disease regression can be evaluated using a variety of methods known to skilled practitioners, 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 determined in the.
  • subtherapeutic dose refers to a dose of a therapeutic compound (e.g., antibody) that is lower than the usual or typical dose of the therapeutic compound when administered alone for the treatment of hyperproliferative diseases (e.g., cancer).
  • a therapeutic compound e.g., antibody
  • anticancer drugs promote the regression of cancer in the subject or prevent further tumor growth.
  • a therapeutically effective amount of the drug promotes cancer regression to the point of elimination.
  • Promote cancer regression refers to the administration of an effective amount of a drug alone or in combination with an antitumor agent, which results in a reduction in tumor growth or size, tumor necrosis, reduction in the severity of at least one disease symptom, and no disease symptoms The increase in the frequency and duration of the symptom phase, or the prevention of injury or disability caused by disease torment.
  • the terms “effective” and “effective” regarding treatment include pharmacological effectiveness and physiological safety. Pharmacological effectiveness refers to the ability of a drug to promote cancer regression in patients.
  • Physiological safety refers to the level of toxicity or other adverse physiological effects (adverse effects) at the cell, organ, and/or biological level caused by drug administration.
  • a therapeutically effective amount of anticancer drugs can inhibit cell growth or tumor growth 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 for a period of at least about 20 days, at least about 40 days, or at least about 60 days.
  • the "immune-related" response pattern refers to a clinical response pattern frequently observed in cancer patients treated with immunotherapeutic agents that produce anti-tumor effects by inducing cancer-specific immune responses or by altering innate immune processes.
  • This response pattern is characterized by a beneficial therapeutic effect after the initial increase in tumor burden or the appearance of new lesions, which will be classified as disease progression in the evaluation of traditional chemotherapeutics 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 antitumor agent to a subject at risk of developing cancer (for example, a subject with a pre-malignant 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 occurrence or recurrence of cancer, or completely preventing the occurrence or recurrence of cancer.
  • Recurrent cancer is cancer that regenerates at the original site or at a remote site after responding to an initial treatment (such as surgery).
  • "Locally recurrent” cancer is cancer that appears in the same place as the previously treated cancer after treatment.
  • Metalstatic cancer refers to cancer that has spread from one part of the body, such as the lungs, to another part of the body.
  • the term “about”, “approximately” or “substantially comprising” means a value or composition within the acceptable error range of a particular value or composition as determined by a person of ordinary skill in the art, which will depend in part on how the value is measured or determined. Composition, that is, the limits of the measurement system. For example, “about” or “substantially comprising” may mean within 1 or more than 1 standard deviation according to practice in the art. Alternatively, “about” or “substantially comprising” can refer to a range of at most 10% or 20% (ie, ⁇ 10% or ⁇ 20%), for example, within a given specific numerical range ⁇ 5% The fluctuation is preferably within a range of ⁇ 2%, and more preferably within a range of ⁇ 1%.
  • about 3 mg can include any number between 2.7 mg and 3.3 mg (for 10%) or 2.4 mg and 3.6 mg (for 20%).
  • a pH of about 5.5 means a pH of 5.5 ⁇ 5%, preferably a pH of 5.5 ⁇ 2%, and more preferably a pH of 5.5 ⁇ 1%.
  • the term can mean 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 administered in the sixth or twelfth week, respectively.
  • 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 (e.g., Monday) in the first week, and then in the sixth week or respectively.
  • the second dose was administered on the same day of the twelfth week (ie, Monday). Similar principles apply to phrases including, but not limited to, "about once every 2 weeks" and "about once a month.”
  • any concentration range, percentage range, ratio range, or integer range should be understood to include the value of any integer within the recited range, and where appropriate, a fraction thereof (such as one-tenth of an integer) And one percent), unless otherwise indicated.
  • This example discloses the test results of the pharmacodynamic study of anti-PD-L1 antibody in vitro and in mice.
  • hu5G11-hIgG1 (heavy chain amino acid sequence shown in SEQ ID NO.17, light chain amino acid sequence shown in SEQ ID NO.18) binds to human PD-L1 protein, and its EC50 is 21.3ng/mL; hu5G11-hIgG1 Human PD-L1 significantly induces the secretion of IFN- ⁇ in CD4+:DC cell MLR, and its effect is obviously dose-dependent, with an EC50 of 35.0 ⁇ 11.3ng/mL, indicating that after hu5G11-hIgG1 binds to PD-L1 expressed by DC, Inhibit PD-L1/PD-1 signaling pathway, thereby stimulating the secretion of IFN- ⁇ in CD4+ T cells.
  • the tumor 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 extended the intraperitoneal vaccination
  • the survival time of mouse MC-38/H-11 cell mice, the median survival time are all> 98 days, and the survival rate by the end of the experiment (D98) is 80% (p ⁇ 0.01, compared with human IgG 15mg/kg group ).
  • hu5G11-hIgG1 can prevent PD-L1 from binding to the PD-1 and B7.1 receptors on the surface of T cells, so that T cells can restore activity, thereby enhancing immune response and exerting anti-tumor effects. effect.
  • This example discloses the results of acute toxicity test and long-term toxicity test of anti-PD-L1 antibody in animals.
  • cynomolgus monkeys were used, divided into 2 groups, 3 in each group, both male and female.
  • the pharmaceutical composition of the present application containing hu5G11-hIgG1 at a concentration of 10 mg/mL was administered at doses of hu5G11-hIgG1 200 mg/kg and 400 mg/kg, respectively.
  • the day of administration was regarded as the first day of the test.
  • test results show that a single intravenous injection of 200mg/kg and 400mg/kg of this product by cynomolgus monkeys has no obvious findings in general observation, body weight, food intake, body temperature, electrocardiogram, blood pressure, hematology, blood biochemistry, urine routine and general anatomy. Abnormal, the maximum tolerated dose (MTD) is 400mg/kg.
  • the results of the long-term toxicity test showed that the cynomolgus monkeys were intravenously injected with the pharmaceutical composition of the present application containing hu5G11-hIgG1 for 4 weeks, and the drug was stopped and resumed for 4 weeks, and the NOAEL was 200 mg/kg.
  • This example discloses the preliminary results of the pharmacokinetics and tolerability of a single-center, open-ended, dose-escalating phase I clinical trial.
  • the clinical phase I tolerance and pharmacokinetic study included patients with advanced malignancies who had a clear diagnosis, failed standard treatment or lacked standard treatment, and observed the safety and tolerability of the pharmaceutical composition containing hu5G11-hIgG1 to determine the maximum tolerance responsible dose (MTD) and dose limiting toxicity (DLT).
  • MTD maximum tolerance responsible dose
  • DLT dose limiting toxicity
  • DLT Primary endpoint
  • MTD Primary endpoint
  • the safety and tolerability results showed that 1 mg/kg, 3 mg/kg, 10 mg/kg, 20 mg/kg, 30 mg/kg pharmaceutical compositions containing hu5G11-hIgG1 were administered to the enrolled patients. A cycle every 21 days, continuous administration. The results showed that the patients currently enrolled in the group were well tolerated during continuous administration, and none of the drug-related adverse reactions exceeded Grade II. The current dose can be tolerated; cytokine detection in the 1-10mg/kg dose group has not seen cytokine storm; and no serious immune-related adverse reactions have been found.
  • OS overall survival
  • Duration of remission For patients whose best remission is complete remission (CR) or partial remission (PR), it is defined as the time from the first appearance of CR or PR to recurrence or Progress (based on independent imaging assessment) or the time to death from various causes; for patients who reached remission, did not have disease progression before analysis, or tumor recurrence or death, DOR is the date of the last disease evaluation as termination.
  • PFS Progression-free survival
  • Objective response rate After receiving the study drug treatment, according to the RECIST1.1 standard evaluation, the objective response rate (ORR) is the percentage of complete response (CR) + partial response (PR).
  • DCR Disease control rate: the percentage of complete remission (CR) + partial remission (PR) + stable disease (SD).
  • PFS Progression-free survival
  • OS Overall survival: defined as the time from the first administration to death due to any cause. In terms of days, subjects who are lost to follow-up usually count the time of their last follow-up as the time of death.
  • Duration of remission 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 first administration of the subject to the first evaluation of CR or PR.
  • Safety evaluation indicators (1) The incidence of adverse events and serious adverse events in the treatment of the pharmaceutical composition containing hu5G11-hIgG1, the correlation with the test drug, and the severity. (2) Study the changes in vital signs, physical examination results and laboratory results before, during and after treatment. (3) To evaluate the immunogenicity (ADA) of the pharmaceutical composition containing hu5G11-hIgG1.
  • Exploratory research evaluation (1) Exploration of biomarkers related to efficacy, mechanism of action, safety and/or pathological mechanism.
  • biomarkers including but not limited to PD-L1 expression
  • tumor specimens were collected during the screening period.
  • Tumor tissue biomarkers including cells, deoxyribonucleic acid (DNA), ribonucleic acid (RNA), or protein, which may be related to the treatment of the pharmaceutical composition containing hu5G11-hIgG1 or the anti-tumor immune response and/or disease progression during standard chemotherapy Level.
  • PK pharmacokinetic
  • This experimental study is to evaluate the pharmaceutical composition containing hu5G11-hIgG1 combined with standard chemotherapy (cisplatin+5-fluorouracil or carboplatin+5-fluorouracil) compared with standard chemotherapy for recurrent or metastatic head and neck squamous cell carcinoma (R /M SCCHN)
  • standard chemotherapy cisplatin+5-fluorouracil or carboplatin+5-fluorouracil
  • R /M SCCHN metastatic head and neck squamous cell carcinoma
  • the experimental group received hu5G11-hIgG1 pharmaceutical composition combined with standard chemotherapy (cisplatin+5-fluorouracil or carboplatin+5-fluorouracil) regimen, and the control group received placebo combined chemotherapy (cisplatin+5-fluorouracil or carboplatin+5-fluorouracil) )
  • Program, 3 weeks (21 days) is 1 cycle, and the treatment period is a total of 6 cycles.
  • D1 On the first day of each cycle (D1), give hu5G11-hIgG1 pharmaceutical composition 1200mg/placebo intravenously.
  • Selection criteria Subjects must meet all of the following criteria to be selected: 1) Patients with squamous cell carcinoma of the head and neck (SCCHN) confirmed by histology or cytology, whose primary site is the oropharynx, oral cavity, hypopharynx or Larynx; 2) Recurrent/metastatic SCCHN without indications for local radical treatment; 3) At least one measurable lesion (assessed according to RECIST1.1); 4) Tumor tissue samples can be provided for PD-L1 expression detection , Prioritize selection of fresh biopsy tissue for testing.
  • SCCHN squamous cell carcinoma of the head and neck
  • biopsy tissue is not available for testing, archived tissue wax blocks can be provided for post-section testing; 5) The tumor expresses PD-L1 and the tumor proportion score (TPS) ⁇ 1%; 6) Age ⁇ 18 years old when signing informed consent; 7) Eastern Cooperative Oncology Group (ECOG) physical status: 0 to 1 point; 8) Expected survival time of more than 3 months; 9) Normal function of major organs.
  • TPS tumor proportion score
  • ECG Eastern Cooperative Oncology Group
  • Exclusion criteria (subjects who meet one or more of the following criteria will be excluded): 1) Have received systemic chemotherapy, but does not include chemotherapy for locally advanced disease as a part of multimodal treatment; for locally advanced disease
  • the chemotherapy includes: induction chemotherapy, concurrent chemotherapy with radiotherapy and adjuvant chemotherapy; 2) the treatment of locally advanced SCCHN is completed within 6 months of disease progression; 3) has received anti-PD-1, anti-PD-L1 antibodies, anti-PD -L2 antibody, anti-CD137 antibody or anti-CTLA-4 antibody or any other antibody or drug immunotherapy specifically targeted to T cell co-stimulation or immune checkpoint pathway; 4) Received Western medicine within 6 months before randomization Tuximab treatment; 5) The investigator believes that the patients are not suitable for enrollment due to other reasons.
  • Critical test suspension criteria The sponsor has the right to terminate the study at any time, but must notify the investigator, the ethics committee and the State Food and Drug Administration in advance, and explain the reasons.
  • Reasons for discontinuing the study include but are not limited to the following: 1. The number and severity of adverse events that occurred in this study suggest that continuing the study will cause significant harm to the subjects; 2. The research center’s enrollment speed is too slow to fail Complete the enrollment plan within a limited time; 3. The quality of the existing clinical data is not good, which is not conducive to continuing the follow-up research; 4. The research is terminated due to changes in the regulations and policies of the national drug administration.
  • Test drug A pharmaceutical composition containing hu5G11-hIgG1, 100mg/10mL, stored at 2 ⁇ 8°C under shading, and the validity period is tentatively scheduled for 24 months.
  • Manufacturer Zhengda Tianqing Pharmaceutical Group Co., Ltd.
  • Control drug placebo, 10mL.
  • hu5G11-hIgG1 pharmaceutical composition/placebo preparation method The principle of aseptic operation should be strictly observed during the preparation process. Draw the required dose of hu5G11-hIgG1 pharmaceutical composition/placebo from the glass bottle under aseptic conditions, and dilute it to 250 mL of polyvinyl chloride (PVC), polyethylene (PE) or polyethylene with sterile pyrogen-free normal saline. Polyolefin (PO) infusion bag. Mix the diluted solution by inversion gently without shaking. As an injection drug, it should be visually checked for particulate matter and discoloration before administration. The medicine is a clear to slightly opalescent, colorless to pale yellow liquid. If cloudiness, discoloration, or visible particles are present in the solution, it should be discarded. Do not shake the vial. This product contains no preservatives. Once prepared, administer immediately.
  • PVC polyvinyl chloride
  • PE polyethylene
  • PO polyolefin
  • Chemotherapeutic drug configuration method "Cisplatin” or “Carboplatin” and “5-Fluorouracil” in the standard chemotherapy regimen are configured with reference to the package instructions.
  • Test drug management According to the requirements of GCP, research drugs are kept, distributed, configured, used and recycled by hospital personnel. Used and partly used drug containers, residual liquid medicine, empty medicine bottles, infusion bags, and syringes can be destroyed on the spot according to the use guidelines and operating procedures established by the research center and local institutions. The outer packaging of the medicine must be recovered and returned to the sponsor . For unused drugs, unless the drug content has significant safety issues and needs to be destroyed immediately in accordance with local regulations, it must be returned to the sponsor. The issuance, configuration, use, and recovery of test drugs require complete records. Inspectors regularly check the use and recording of drugs, and monitor the recovery at any time.
  • Study treatment should start on the day of randomization, or as close as possible to the date of allocating treatment.
  • &hu5G11-hIgG1/placebo should be administered before standard chemotherapy, and the medication time should not exceed 96 weeks;
  • Platinum drugs cisplatin/carboplatin
  • the carboplatin dose should not exceed 800mg ;
  • Endpoint event disease progression, intolerable toxicity, or the investigator/subject's decision to withdraw from the study.
  • hu5G11-hIgG1/placebo use hu5G11-hIgG1/placebo, 1200mg/placebo, D1, intravenous drip on the first day (D1) of each cycle. 3 weeks (21 days) is a treatment cycle, and the medication time does not exceed 96 weeks until the disease progresses, intolerable toxicity or the investigator/subject decides to withdraw from the study.
  • Standard chemotherapeutics After the infusion of hu5G11-hIgG1/placebo is completed, standard chemotherapy regimens will be given from day 1 (D1) to day 5 (D5).
  • the standard chemotherapy regimen is as follows:
  • Cisplatin/Carboplatin Cisplatin 75mg/m 2 /Carboplatin AUC5, D1, intravenous infusion;
  • 5-Fluorouracil 750mg/m 2 , D1 ⁇ D5, intravenous infusion;
  • the dose of cisplatin should be calculated based on the subject's body surface area (BSA), and BSA should be calculated before each administration. For subjects with BSA>2.0m 2 , the dose is calculated according to 2.0m 2 .
  • the interval between the end of hu5G11-hIgG1/placebo infusion and the start of cisplatin infusion should be at least 1 hour.
  • Intravenous prehydration can be performed simultaneously with hu5G11-hIgG1/placebo infusion, but a separate infusion line must be used. Since cisplatin is highly emetic, it is necessary to prevent emesis in advance to prevent acute or delayed nausea and vomiting.
  • the dose of carboplatin is calculated according to the subject's renal function (creatinine clearance) using a formula, AUC 5, and the maximum dose is 800 mg.
  • 5-Fluorouracil is calculated based on the subject's body surface area (BSA), and BSA is calculated before each administration. 5-Fluorouracil should be administered after the cisplatin/carboplatin administration is completed, and the same infusion line can be used.
  • BSA body surface area
  • Subjects can stop chemotherapy and continue hu5G11-hIgG1/placebo alone. Similarly, subjects can stop hu5G11-hIgG1/placebo and continue chemotherapy alone (if appropriate) for the first 6 cycles.
  • Subjects will receive blinded hu5G11-hIgG1 1200mg (D1) or placebo (D1) combined with cisplatin 75mg/m 2 /carboplatin AUC 5(D1)+5-fluorouracil 750mg/m 2 (D1-D5)Q3W, A total of 6 cycles, and then receive blinded hu5G11-hIgG1 1200mg (D1) or placebo (D1) Q3W until the disease progression/treatment is completed.
  • hu5G11-hIgG1/placebo will be administered before chemotherapy.
  • the trial treatment should be administered on the first day of each cycle, after all procedures and evaluations are completed.
  • the trial treatment can be administered on the target day 1+3 of each cycle, and the first cycle can only be administered on the target day 1+3.
  • hu5G11-hIgG1/placebo administration time use an infusion set for administration, the infusion set is equipped with a sterile, pyrogen-free, low protein adsorption online filter (pore size: 0.2 ⁇ 0.22 ⁇ m), infusion is completed in 60 minutes . If the first infusion, the subject can tolerate it, and the subsequent medication can be completed in 30 minutes. Do not share the infusion set with other drugs.
  • the research center should make every effort to make the infusion time of the pharmaceutical composition/placebo containing hu5G11-hIgG1 as close as possible to 60 minutes. However, considering the variation of infusion pumps between different centers, a time window of -10 minutes to +20 minutes is allowed (ie, the infusion time is 50-80 minutes).
  • Cisplatin/carboplatin administration time According to local practice and instructions, cisplatin 75mg/m 2 will be administered through 60-120 minutes of intravenous infusion Q3W, a total of 6 cycles. Carboplatin AUC 5mg/mL/min was administered by intravenous infusion Q3W for 60 minutes, a total of 6 cycles.
  • 5-Fluorouracil administration time According to local practice and instructions, 5-Fluorouracil is 750mg/m 2 , 24 hours continuous infusion of intravenous infusion Q3W administration, a total of 6 cycles.
  • OS overall survival
  • DOR duration of remission
  • CR complete remission
  • PR partial remission
  • PFS Progression-free survival
  • ORR Objective response rate: After receiving study drug treatment, according to the RECIST1.1 standard evaluation, the objective response rate (ORR) is the percentage of complete response (CR) + partial response (PR).
  • DCR Disease control rate: the percentage of complete remission (CR) + partial remission (PR) + stable disease (SD).
  • the imaging examination in this study requires enhanced scanning with multiple detector CT (multiple detector CT).
  • the examination site is the whole body, including the neck, chest, abdomen and pelvis.
  • the test requires the same and consistent inspection method to be used for inspection.
  • MR magnetic resonance
  • the patient is allergic to CT contrast agents, magnetic resonance (MR) can be used as an imaging test instead of CT. Otherwise, please select the same inspection method as the baseline.
  • the investigator may decide to do other corresponding inspections. All experimental imaging data and related additional imaging examination data are required to be copied and archived for retrospective confirmation.
  • irRECIST is an adapted version of RECIST1.1, whose purpose is to explain the unique tumor remission of immunotherapy drugs.
  • the investigator will use irRECIST to assess tumor remission and progression, and make treatment decisions. If feasible, subjects should not discontinue treatment until the researcher’s imaging evaluation at the research center confirms disease progression. Considering that some subjects may have a temporary tumor outbreak in the first few months after starting immunotherapy, and then the disease will be remission, so the subjects are allowed to continue to receive treatment after the first imaging progress (PD). For subjects judged to be clinically unstable, there is no need to repeat tumor imaging tests to confirm PD.
  • Tumor outbreaks include any of the following conditions: 1) deterioration of the original target lesions; 2) deterioration of the original non-target lesions; 3) appearance of new lesions.
  • the main The researcher can determine whether to continue to give the subject research treatment until the imaging examination result is obtained again.
  • researchers in the research center make this clinical judgment based on the overall clinical condition of the subject, including physical fitness, clinical symptoms, and laboratory test results.
  • Subjects can continue to receive research treatment and receive tumor evaluation again after ⁇ 4 weeks so that the research center can confirm PD based on irRECIST.
  • clinical stability is as follows: 1) No clinically significant symptoms and signs (including deterioration of laboratory test values) that indicate disease progression. 2ECOG performance status score did not decrease. 3) No rapid disease progression. 4) There are no progressive tumors (such as spinal cord compression) in important anatomical parts that require other emergency medical intervention.
  • Subjects judged to be clinically unstable should discontinue the trial treatment from the first evaluation of PD imaging evidence, and there is no need to repeat imaging examinations to confirm PD.
  • the investigator of the research center should consider all target and non-target lesions, as well as any new lesions.
  • PD if all of the following conditions occur during repeated imaging examinations, PD cannot be confirmed: 1) The sum of the diameters of the target lesions increases by ⁇ 20% from the lowest value, or the absolute value increases by ⁇ 5mm. 2) The condition of the non-target lesions leading to the initial PD is stable or improved. 3) The condition of the new lesions leading to the initial PD is stable or improved. 4) There has been no increase in new lesions since the last evaluation. 5) New non-target lesions have not progressed since the last evaluation.
  • PD if any of the following occurs during repeated imaging examinations, it can be confirmed that PD has occurred: 1) The sum of the diameters of the target lesions is increased by ⁇ 20% from the lowest value, and the absolute value is increased by at least 5mm. 2) Deterioration of non-target lesions in the initial PD. 3) The condition of the new lesions that caused the initial PD to deteriorate. 4) New lesions have appeared since the last evaluation. 5) New non-target lesions have progressed again since the last evaluation. If any of the above conditions occurs during repeated imaging examinations, resulting in PD being confirmed, the subject will be discontinued from the study treatment.
  • This trial is a multi-center, randomized, double-blind study.
  • the primary endpoint is overall survival (OS), using Logrank difference test.
  • OS overall survival
  • the test drug hu5G11-hIgG1 combined with cisplatin/carboplatin+5-fluorouracil treatment is expected to be 12 months of mOS, which is relative to the control
  • PASS11 is used to calculate the sample size. In this study, at least 265 events need to be obtained, and the sample size is 334 (the test group and the control group each need to enter 167 cases).
  • Full analysis set All subjects who have been enrolled in the group and have used the trial medication at least once.
  • Per Protocol Set In the full analysis set, subjects who completed the medication according to the protocol, did not use illegal drugs, and did not seriously violate the protocol, and those who withdrew from the trial due to an endpoint event will be included in the PP set .
  • Safety Data Set Cases that have used the study drug at least once after being enrolled in the group, and have safety evaluation data.
  • ORR objective response rate
  • the analysis indicators of survival include: duration of response (DOR), progression-free survival (PFS), the Kaplan-Meier method is used to calculate the median survival time and its 95% CI, and the survival curve is drawn.
  • DOR duration of response
  • PFS progression-free survival
  • Kaplan-Meier method is used to calculate the median survival time and its 95% CI, and the survival curve is drawn.
  • ORR objective response rate
  • DCR disease control rate
  • the safety analysis population includes all patients who have received any dose of study drug and will be analyzed according to the treatment the subjects received.
  • study exposure will be summarized by treatment group, including the number of cycles received and the cumulative dose.
  • the first cycle of treatment (hu5G11-hIgG1 injection 1200mg; carboplatin 425mg; 5-FU1080mg/24 hours continuous infusion for 5 days) started on October 1, 2019; the second cycle of treatment began on October 23, 2019 (hu5G11 -hIgG1 injection 1200mg; carboplatin 478mg; 5-FU1035mg/24 hours continuous infusion for 5 days);
  • the subject received hu5G11-hIgG1 injection/placebo combined with carboplatin and fluorouracil for 21 days as a cycle and continued administration.
  • the target lesions in the initial tumor evaluation on November 11, 2019 were 39.4% smaller than the baseline ,
  • the efficacy evaluation is PR.
  • Subject No. 2 was pathologically diagnosed as (hypopharyngeal) moderately differentiated squamous cell carcinoma on April 23, 2018, and received radiotherapy from May 14, 2018 to July 10, 2018. Liver metastasis appeared in the review in June 2019.
  • the first cycle of treatment started on July 9, 2019 (hu5G11-hIgG1 injection 1200 mg; carboplatin 442.1 mg; 5-FU5625 mg/24 hours continuous infusion for 5 days); the second cycle of treatment started on July 31, 2019 (hu5G11-hIgG1 injection 1200mg; carboplatin 354.2mg; 5-FU5601mg/24 hours continuous instillation for 5 days); the third cycle of treatment started on August 21, 2019 (hu5G11-hIgG1 injection 1200mg; carboplatin 401.7mg ; 5-FU5577mg/24 hours continuous infusion for 5 days); September 12, 2019, the 4th cycle of treatment (hu5G11-hIgG1 injection 1200mg; carboplatin 385.5g; 5-
  • the subject received hu5G11-hIgG1 injection/placebo combined with carboplatin and fluorouracil, 21 days as a cycle, continuous administration, the initial tumor evaluation target lesions on August 19, 2019 were 38.4% smaller than the baseline , The efficacy evaluation is PR.
  • the target lesion was reduced by 46.9% by 80.4mm and the result was PR.
  • the subject received hu5G11-hIgG1 injection/placebo combined with carboplatin and fluorouracil, 21 days as a cycle, continuous administration, the initial tumor evaluation target lesions on August 21, 2019 decreased by 17% compared with the baseline , The efficacy evaluation was SD, the target lesion of the second efficacy evaluation was 64.3% smaller than the baseline on September 29, 2019, and the efficacy evaluation was PR.
  • the target lesion was reduced by 64.3% by 10mm and the result was PR.

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Abstract

本申请提供抗PD-L1抗体治疗头颈癌的用途，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抗体。

Description

抗PD-L1抗体治疗头颈癌的用途 技术领域
本申请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确的特异性，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 PCTCN2020074083-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 PCTCN2020074083-appb-000002
)和帕博利珠单抗(Pembrolizumab)(
Figure PCTCN2020074083-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查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CD274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)PNAS105:3011-3016)。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 Immunol 32:634-43)。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复合物形成传输抑制信号并负调控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。
头颈癌包括口腔、鼻咽、口咽和喉部癌症，占全球癌症(不包括非黑色素瘤皮肤癌)的5％左右(Ferlay J,Soerjomataram I,Dikshit R,et al.Cancer incidence and mortality worldwide:sources,methods and major patterns in GLOBOCAN 2012.Int J Cancer 2015；136:E359-E386)。2012年新诊断约68万例头颈癌，37万例患者死于该疾病。在报告的这些新病例中，近14万例出现在欧洲，超过90％的病例组织学分型为鳞状细胞癌。在美国，2016年估计有6.1万多人被诊断为头颈癌，将有超过1.3万人死于该癌症。头颈癌以鳞癌为主。累及口腔、喉、口咽和下咽部的头颈部鳞状细胞癌(SCCHN)占所有SCCHN的75％，并与酒精和烟草使用密切相关。口咽SCCHN还与人乳头状瘤病毒(HPV)16型感染密切相关。在过去的20年，HPV阳性口咽癌急剧增加，提示HPV感染在口咽癌中的重要作用。尽管HPV阴性SCCHN的发病率下降(符合全球烟草产品使用下降的趋势)，HPV阴性肿瘤的可治愈性仍未达到最佳。在新诊断的SCCHN患者中，约60％的患者为局部或区域晚期疾病。根据肿瘤部位、分期和可切除性，局部区域治疗失败率在35％-65％之间。该疾病的中位PFS(无进展生存期)是1.9年，报告3年PFS率为61.2％。接受过治疗的患者大部分最终局部复发，10％-30％的患者发生远隔转移。目前针对局部区域和远处复发的治疗选择有限。两种复发的预后都很差，只有少数患者适合接受针对局部区域疾病复发的潜在治愈性治疗，但发病率高。据CSCO头颈部肿瘤指南(2018.V1)，复发转移性头颈部鳞癌的一线治疗推荐(1A)化疗方案包括顺铂/卡铂+5-FU， 化疗方案平均OS(总生存期)为7.4-8.7个月。2016年8月5日和12月1日，PD-1抑制剂Keytruda(Pembrolizumab，默沙东)和Opdivo(Nivolumab，百时美施贵宝)分别获FDA批准用于复发或转移性治疗SCCHN治疗，目前用于二线治疗。
发明内容
本申请的概述
本申请提供治疗、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。
本申请也提供抗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。
本申请还提供抗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。
本申请还提供了用于治疗、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(q2w)、大约每3周(q3w)、或者大约每4周(q4w)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，主体先前未接受过系统化疗。在一些方案中，主体先前已接受手术治疗、放射治疗、诱导化疗、同期的化疗和/或辅助化疗。在一些具体实施方式中，主体先前未接受过系统化疗，但是接受过手术治疗、放射治疗、诱导化疗、同期的化疗和/或辅助化疗。在一些具体实施方式中，主体经手术治疗、放射治疗、诱导化疗、同期的化疗和/或辅助化疗后，获完全缓解后再次出现疾病进展。在一些具体实施方式中，主体经手术治疗、放射治疗、诱导化疗、同期的化疗和/或辅助化疗后，未能完全缓解或未能部分缓解。在一些具体实施方式中，主体经手术治疗、放射治疗、诱导化疗、同期的化疗和/或辅助化疗后癌症发生转移。
在一些方案中，癌症是头颈部鳞状细胞癌(SCCHN)。在一些实施方案中，头颈部鳞状细胞癌原发部位为口咽部、口腔、下咽和/或喉部。
在一些方案中，癌症是复发性和/或转移性头颈部鳞状细胞癌。
在一些方案中，癌症是复发性或转移性头颈部鳞状细胞癌。在一些具体实施方案中，所述复发性或转移性头颈部鳞状细胞癌是无局部根治性治疗指征的复发性或转移性头颈部鳞状细胞癌。
在一些方案中，所述头颈部鳞状细胞癌是复发性的。
在一些方案中，所述头颈部鳞状细胞癌是转移性的。
在一些方案中，所述头颈部鳞状细胞癌是难治性的。
在一些方案中，癌症治疗是对复发性或转移性头颈部鳞状细胞癌的一线治疗。
在一些方案中，治疗是联合标准化疗的对复发性或转移性头颈部鳞状细胞癌的一线治疗。在一些具体 实施方案中，所述标准化疗包括对患者施用化疗剂。在一些具体实施方案中，所述标准化疗包括对患者施用顺铂和5-氟尿嘧啶。在一些具体实施方案中，所述标准化疗包括对患者施用卡铂和5-氟尿嘧啶。在一些具体实施方案中，抗PD-L1抗体和化疗剂各自呈药物组合物形式，可同时、顺序或间隔给药。
在一些方案中，治疗以3周(21天)为一个周期，每个周期第一天(D1)静脉给予1200mg抗PD-L1抗体，抗PD-L1抗体输注完成后给予标准化疗方案。在一些方案中，标准化疗方案是第一天(D1)静脉输注给予顺铂75mg/m 2或静脉输注给予卡铂AUC5，并且第一天至第五天(D1-D5)的每天静脉输注给予5-氟尿嘧啶750mg/m 2。在一些具体实施方案中，标准化疗方案是第一天(D1)静脉输注给予顺铂75mg/m 2，并且第一天至第五天(D1-D5)的每天静脉输注给予5-氟尿嘧啶750mg/m 2。在一些具体实施方案中，标准化疗方案是第一天(D1)静脉输注给予卡铂AUC5，并且第一天至第五天(D1-D5)的每天静脉输注给予5-氟尿嘧啶750mg/m 2。
本申请还提供治疗复发性或转移性头颈部鳞状细胞癌的联用药物组合物，其包括抗PD-L1抗体和化疗剂。
在一些方案中，联用药物组合物包括含抗PD-L1抗体的药物组合物和含化疗剂的药物组合物。在一些具体实施方案中，联用药物组合物中的化疗剂可以是顺铂、卡铂和/或5-氟尿嘧啶。在一些具体实施方案中，联用药物组合物中包括含抗PD-L1抗体的药物组合物，具体地，抗PD-L1抗体以固定剂量存放于容器，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。
本申请还提供治疗复发性或转移性头颈部鳞状细胞癌的试剂盒，所述试剂盒包括抗PD-L1抗体的药物组合物和化疗剂，以及抗PD-L1抗体和化疗剂联合用于治疗复发性或转移性头颈部鳞状细胞癌的说明。
本申请提供包括含有固定剂量抗PD-L1抗体的容器的制品。本申请还提供抗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个管形瓶，所述管形瓶含有大约600mg抗PD-L1抗体。
本申请的详细内容及优选的实施方案
本申请提供了一种用于治疗、缓解或改善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。
本申请还提供了一种用于治疗、缓解或改善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。
本申请也提供了一种用于治疗、缓解或改善患有癌症或肿瘤的主体的单一疗法或联合疗法，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。
本申请也提供了一种治疗、缓解或改善患有癌症或肿瘤的主体的方法，所述癌症或肿瘤是头颈部鳞状细胞癌(SCCHN)，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。
本申请提供了一种用于治疗、缓解或改善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头颈部鳞状细胞癌(SCCHN)的患者。对于本申请所述患有癌症的患者，其头颈部鳞状细胞癌原发部位可以为口咽部、口腔、下咽或喉部。所述患者的癌症可能是难治性的、复发性的或转移性的头颈部鳞状细胞癌，例如，在某些患者中，其头颈部鳞状细胞癌是复发性的；在某些患者中，所述头颈部鳞状细胞癌是转移性的；在某些患者中，其头颈部鳞状细胞癌是难治性的。在一些方案中，所述癌症是复发性和/或转移性头颈部鳞状细胞癌。在一些具体实施方案中，所述头颈部鳞状细胞癌是无局部根治性治疗指征的复发性SCCHN。在一些具体实施方案中，所述头颈部鳞状细胞癌是无局部根治性治疗指征的转移性SCCHN。
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、化疗和/或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/或放射治疗后未能完全缓解或未能部分缓解。
在本申请的一些方案中，头颈部鳞状细胞癌患者可以是先前未接受过系统化疗的患者。在本申请的一 些方案中，头颈部鳞状细胞癌患者先前已接受手术治疗、放射治疗、诱导化疗、同期的化疗和/或辅助化疗。在一些具体实施方案中，头颈部鳞状细胞癌患者是先前未接受过系统化疗，但是接受过手术治疗、放射治疗、诱导化疗、同期的化疗和/或辅助化疗的患者。在本申请的一些方案中，头颈部鳞状细胞癌患者是经手术治疗、放射治疗、诱导化疗、同期的化疗和/或辅助化疗后，获完全缓解后再次出现疾病进展的患者。在本申请的一些方案中，头颈部鳞状细胞癌患者是经手术治疗、放射治疗、诱导化疗、同期的化疗和/或辅助化疗后，未能完全缓解或未能部分缓解的患者。在本申请的一些方案中，所述头颈部鳞状细胞癌患者的癌症已发生转移。
在本申请的一些方案中，所述治疗是对复发性或转移性头颈部鳞状细胞癌的一线治疗。在本申请的一些方案中，所述治疗是联合标准化疗的对复发性或转移性头颈部鳞状细胞癌的一线治疗。所述标准化疗包括对患者施用化疗剂。在一些具体实施方案中，化疗剂包括含铂的化疗药物。在一些具体实施方案中，所述标准化疗包括对患者施用顺铂和5-氟尿嘧啶，或者对患者施用卡铂和5-氟尿嘧啶。在一些具体实施方案中，所述标准化疗包括对患者实施含铂的双联化疗。在一些具体实施方案中，所述抗PD-L1抗体和化疗剂各自呈药物组合物的形式，可同时、顺序或间隔给药。在一些具体实施方案中，所述治疗以3周(21天)为一个周期，每个周期给予患者大约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统一剂量的抗PD-L1抗体。在一些具体实施方案中，所述治疗以3周(21天)为一个周期，每个周期第一天(D1)静脉给予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，抗PD-L1抗体输注后给予标准化疗方案。在另一些具体实施方案中，所述治疗以3周(21天)为一个周期，每个周期第一天(D1)静脉给予大约1200mg抗PD-L1抗体，抗PD-L1抗体输注后给予标准化疗方案。在一些方案中，所述标准化疗方案包括：第一天(D1)静脉输注给予顺铂75-100mg/m 2或静脉输注给予卡铂AUC5，并且第一天至第五天(D1-D5)每天静脉输注给予5-氟尿嘧啶750-1000mg/m 2。在一些具体实施方案中，所述标准化疗方案包括：第一天(D1)静脉输注给予顺铂75-100mg/m 2，并且第一天至第五天(D1-D5)每天静脉输注给予5-氟尿嘧啶750-1000mg/m 2。在一些具体实施方案中，所述标准化疗方案包括：第一天(D1)静脉输注给予卡铂AUC5，并且第一天至第五天(D1-D5)每天静脉输注给予5-氟尿嘧啶750-1000mg/m 2。其中，所述静脉输注给予顺铂75-100mg/m 2可选地是静脉输注75mg/m 2、80mg/m 2、85mg/m 2、90mg/m 2或100mg/m 2，优选为静脉输注75mg/m 2，或静脉输注100mg/m 2；所述静脉输注给予5-氟尿嘧啶750-1000mg/m 2可选地是静脉输注750mg/m 2、800mg/m 2、850mg/m 2、900mg/m 2或1000mg/m 2，优选为静脉输注750mg/m 2，或静脉输注1000mg/m 2。
本申请还提供了用于患有复发性或转移性头颈部鳞状细胞癌的主体的一线治疗的联合疗法，其中，患者接受抗PD-L1抗体联合标准化疗方案，3周(21天)为1个周期，每个周期第一天(D1)静脉给予抗PD-L1抗体1200mg，完成抗PD-L1抗体输注后，开始给予标准化疗方案：每个周期第一天(D1)静脉输注顺铂75mg/m 2，每个周期第一天至第五天(D1-D5)静脉输注5-氟尿嘧啶750mg/m 2/d。
本申请还提供了用于患有复发性或转移性头颈部鳞状细胞癌的主体的一线治疗的联合疗法，其中，患者接受抗PD-L1抗体联合标准化疗方案，3周(21天)为1个周期，每个周期第一天(D1)静脉给予抗PD-L1抗体1200mg，完成抗PD-L1抗体输注后，开始给予标准化疗方案：每个周期第一天(D1)静脉输注卡铂AUC5，每个周期第一天至第五天(D1-D5)静脉输注5-氟尿嘧啶750mg/m 2/d。
本申请还提供治疗复发性或转移性头颈部鳞状细胞癌的联用药物组合物，其包括抗PD-L1抗体和化疗剂。在一些方案中，联用药物组合物包括含抗PD-L1抗体的药物组合物和含化疗剂的药物组合物。在一些方案中，所述化疗剂包括含铂的化疗药物。在一些方案中，联用药物组合物中的化疗剂可以是顺铂、卡铂和/或5-氟尿嘧啶。在一些方案中，联用药物组合物中包括含抗PD-L1抗体的药物组合物，具体地，抗PD-L1抗体以固定剂量存放于容器，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。在一些具体实施方案中，联用药物组合物包含大约300mg、大约600mg、大约900mg、或大约1200mg的抗PD-L1抗体，以及治疗有效量的顺铂和5-氟尿嘧啶。在一些具体实施方案中，联用药物组合物包含大约300mg、大约600mg、或大约1200mg的抗PD-L1抗体，以及治疗有效量的卡铂和5-氟尿嘧啶。
本申请也提供了一种用于鉴别患有头颈部鳞状细胞癌的主体的方法，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。
本申请也提供了一种用于治疗患有头颈部鳞状细胞癌的主体的试剂盒，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。
本申请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，所述癌症是头颈部鳞状细胞癌。在一个实施方案中，所述癌症是复发性或转移性头颈部鳞状细胞癌。
本申请也提供一种抗PD-L1抗体在头颈部鳞状细胞癌一线治疗中的用途。本申请也提供一种抗PD-L1抗体在头颈部鳞状细胞癌二线治疗中的用途。本申请也提供一种抗PD-L1抗体在头颈部鳞状细胞癌三线治疗中的用途。在一些方案中，所述抗PD-L1抗体用于复发性或转移性头颈部鳞状细胞癌的一线治疗。
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，手术治疗、放射治疗、诱导化疗、同期的化疗和/或辅助化疗)，但是其对于这样的另一种癌症治疗来说是抗性的或难治的。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，手术治疗、放射治疗、诱导化疗、同期的化疗和/或辅助化疗)，但是其对于这样的另一种癌症治疗来说是后复发性的、或转移性的。
在某些实施方案中，本申请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，本申请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转移性的头颈部鳞状细胞癌，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％、至少约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。
本申请提供治疗、缓解或改善患有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。本申请也提供确定罹患头颈部鳞状细胞癌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。本申请还提供用于预测罹患头颈部鳞状细胞癌的患者对包含抗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。本申请还提供用于为罹患头颈部鳞状细胞癌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。本申请还提供用于确定罹患头颈部鳞状细胞癌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/或转移性的头颈部鳞状细胞癌指示该患者有可能响应包含抗PD-L1抗体的治疗剂的治疗。本申请提供用于预测罹患头颈部鳞状细胞癌的患者对包含抗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/或转移性的头颈部鳞状细胞癌指示该患者有可能响应包含抗PD-L1抗体的治疗剂的治疗。本申请提供用于为罹患头颈部鳞状细胞癌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/或转移性的头颈部鳞状细胞癌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分子标志物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。在其它实施方案中，自该患者获得的肿瘤样品中微小RNA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，本申请的疗法(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，本申请的抗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，本申请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，本申请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高至少约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，2014Cancer 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抗体或其片段与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-1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，本申请涉及一种用于治疗患有肿瘤的主体的方法，所述肿瘤是复发性或转移性的头颈部鳞状细胞癌，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)。
本申请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。
本申请提供了结合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，本申请还包括杂交瘤13C5、5G11，以及产生本文公开的抗体的任何杂交瘤。本申请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。本申请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。
本申请提供了抗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，本申请提供了抗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，本申请提供了抗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，在本申请中使用的免疫检查点抑制剂(例如，抗PD-L1拮抗剂)是PD-L1Fc融合蛋白。
在某些实施方案中，本申请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，本申请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。
可以将本申请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。本申请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，本申请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个月或更长时间一次的施用。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，本申请的抗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，本申请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。
可以改变本申请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，包括采用的本申请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申请的组合物。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。
本申请的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，所述蔗糖的浓度为约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含量为约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含量为约0.2mg/mL。在一些实施方案中，所述药物组合物中聚山梨酯80含量为约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含量为约0.4mg/mL。在一些实施方案中，所述药物组合物中聚山梨酯80含量为约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。
本申请提供了结合PD-L1的分离的抗体或其片段。本申请提供的抗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，本申请提供的抗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SEQ ID NO:9或SEQ ID NO:12示出的轻链CDR3区。
优选地，本申请提供的抗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，本申请提供的抗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，本申请提供的抗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，本申请提供的抗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，本申请提供的抗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，本申请提供的抗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，本申请提供的抗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。
本申请提供的抗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。
本申请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。
在本申请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。
在本申请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。
在本申请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。
在本申请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。
在本申请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。
在本申请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。
在本申请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量(初级干燥过程)，然后通过脱附作用降低溶剂量(二级干燥过程)，直到溶剂量为不再支持生物学活性或化学反应的值。本申请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)。
本申请提供的制剂，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％。
本申请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。
本申请还提供用于治疗、缓解或改善受试者中瘤形成病状的方法，包括给所述受试者施用前述的药物组合物。
本申请提供包括含有固定剂量抗PD-L1抗体的容器的制品。本申请还提供抗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。
在一些方案中，可以将300mg抗PD-L1抗体置于1个容器中并将4个这样的容器组成制品，或者，将600mg抗PD-L1抗体置于1个容器中并将2个这样的容器组成制品，可选地，所述制品中还包含治疗有效量的顺铂和/或5-氟尿嘧啶，或者包含治疗有效量的卡铂和/或5-氟尿嘧啶。可以方便地给患者施用制品中的物质。
定义和术语解释
为了可以更容易地理解本申请，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。本申请的抗体和其片段可以是整个抗体或其任何片段。因此，本申请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。本申请的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，并且也包括在本申请中。在一个实施方案中，适用于在本申请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。本申请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 其它哺乳动物的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“全身治疗”是指药物物质通过血流传送，到达并影响全身细胞的治疗。
如本文所用，术语“系统化疗”是指不包括作为多模式治疗的一个环节针对局部晚期疾病进行的化疗的全身化疗，其中，针对局部晚期疾病进行的化疗包括诱导化疗、放疗同期的化疗以及辅助化疗。
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，根据本申请的受试者是人。
“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药剂(例如，抗PD-L1抗体)的绝对量，而不是提供为mg/kg剂量。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)。
关于本申请的组合物的术语“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％。在本申请的其它实施方案中，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。
“复发性”癌症是在对初始治疗(例如手术)产生应答后，在初始部位或远处部位再生的癌症。“局部复发性”癌症是在治疗后，在与先前治疗的癌症相同的位置出现的癌症。
“不能切除的”癌症是无法通过手术去除的。
“转移性”癌症是指从身体的一部分(例如肺部)扩散到身体的另一部分的癌症。
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申请进行进一步的描述，然而，本申请中这些实施例仅用于阐明而不限制本申请的范围。同样，本申请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，对本申请技术特征所作的等同替换，或相应的改进，仍属于本申请的保护范围之内。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。
表1.缩略语表
Figure PCTCN2020074083-appb-000004
Figure PCTCN2020074083-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(重链氨基酸序列如SEQ ID NO.17所示，轻链氨基酸序列如SEQ ID NO.18所示)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 200mg/kg、400mg/kg的剂量给予浓度为10mg/mL的含hu5G11-hIgG1的本申请的药物组合物。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200mg/kg、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的本申请的药物组合物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1mg/kg、3mg/kg、10mg/kg、20mg/kg、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(1mg/kg、3mg/kg、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治疗复发性或转移性头颈部鳞状细胞癌(R/M SCCHN)的临床II期试验
主要目的：在接受研究者选择的标准化疗(顺铂+5-氟尿嘧啶或卡铂+5-氟尿嘧啶)的复发性或转移性头颈部鳞状细胞癌一线受试者中评价与安慰剂相比接受含hu5G11-hIgG1的药物组合物治疗的受试者的总生存期(OS)。
次要目的：在接受研究者选择的标准化疗(顺铂+5-氟尿嘧啶或卡铂+5-氟尿嘧啶)的复发性或转移性头颈部鳞状细胞癌一线受试者中：评价与安慰剂相比接受含hu5G11-hIgG1的药物组合物治疗的受试者的缓解持续时间(DOR)；评价与安慰剂相比接受含hu5G11-hIgG1的药物组合物治疗的受试者的无进展生存期(PFS)；评价与安慰剂相比接受含hu5G11-hIgG1的药物组合物治疗的受试者的客观缓解率(ORR)；评价与安慰剂相比接受含hu5G11-hIgG1的药物组合物治疗的受试者的疾病控制率(DCR)；评价含hu5G11-hIgG1的药物组合物治疗的安全性和免疫原性；评价含hu5G11-hIgG1的药物组合物治疗的受试者生活质量。
主要终点：总生存期(OS)：从随机分组至各种原因导致死亡的时间。
次要终点：(1)缓解持续时间(DOR)：对于最佳缓解为完全缓解(CR)或部分缓解(PR)的患者，定义为根据研究者评估，从首次出现CR或PR至疾病复发或进展(基于独立影像评估)或各种原因导致死亡的时间；对于达到缓解，在分析前没有出现疾病进展，或肿瘤复发或死亡的患者，DOR为至末次疾病评估的日期为终止。(2)无进展生存期(PFS)：指从随机分组至首次出现进展或复发或各种原因导致死亡的时间。(3)客观缓解率(ORR)：接受研究药物治疗后，按照RECIST1.1标准评价，客观缓解率(ORR)为完全缓解(CR)+部分缓解(PR)的百分比。(4)疾病控制率(DCR)：为完全缓解(CR)+部分缓解(PR)+疾病稳定(SD)的百分比。
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：(1)含hu5G11-hIgG1的药物组合物治疗中不良事件和严重不良事件的发生率、与试验药物相关性和严重程度。(2)研究治疗前、治疗期间和治疗之后，生命体征、体格检查结果和实验室结果的变化。(3)评价含hu5G11-hIgG1的药物组合物治疗的免疫原性(ADA)。
探索性研究评价：(1)与疗效、作用机制、安全性和/或病理机制相关的生物标志物的探索。为进行生物标志物(包括但不限于PD-L1表达)的测定，在筛选期收集肿瘤标本。可能与含hu5G11-hIgG1的药物组合物治疗或联合标准化疗期间抗肿瘤免疫应答和/或疾病进展有关的肿瘤组织生物标志物，包括细胞、脱氧核糖核酸(DNA)、核糖核酸(RNA)或蛋白水平。(2)描述顺铂/卡铂、5-氟尿嘧啶和含hu5G11-hIgG1的药物组合物联合用药后hu5G11-hIgG1的药代动力学(PK)特征。
本试验研究为评价含hu5G11-hIgG1的药物组合物联合标准化疗(顺铂+5-氟尿嘧啶或卡铂+5-氟尿嘧啶)对比标准化疗用于复发性或转移性头颈部鳞状细胞癌(R/M SCCHN)患者一线治疗的多中心、随机、双盲临床研究。试验组接受hu5G11-hIgG1药物组合物联合标准化疗(顺铂+5-氟尿嘧啶或卡铂+5-氟尿嘧啶)方案，对照组接受安慰剂联合化疗(顺铂+5-氟尿嘧啶或卡铂+5-氟尿嘧啶)方案，3周(21天)为1个周期，治疗期共6个周期。每个周期第一天(D1)静脉给予hu5G11-hIgG1药物组合物1200mg/安慰剂，完成hu5G11-hIgG1药物组合物/安慰剂输注后，开始给予标准化疗方案：顺铂75mg/m 2静脉输注(D1)，或卡铂AUC5静脉输注(D1)；5-氟尿嘧啶750mg/m 2静脉输注(D1-D5)，受试者将接受最多6个周期的hu5G11-hIgG1药物组合物/安慰剂联合标准化疗，之后继续进行hu5G11-hIgG1药物组合物/安慰剂维持治疗，3周(21天)为1个周期，hu5G11-hIgG1药物组合物/安慰剂用药时间不超过96周，直至疾病进展、不可耐受的毒性或研究者/受试者决定退出研究。
研究人群：复发性/转移性头颈部鳞状细胞癌(R/M SCCHN)患者。
入选标准(受试者必须符合下列所有标准才能入选)：1)经组织学或细胞学确诊的头颈部鳞状细胞癌患者(SCCHN)，原发部位为口咽部、口腔、下咽或喉部；2)无局部根治性治疗指征的复发性/转移性SCCHN；3)至少有一个可测量的病灶(根据RECIST1.1评估)；4)可提供肿瘤组织样本进行PD-L1表达检测，优先选择新鲜活检组织进行检测，如果不能提供活检组织进行检测，可提供存档的组织蜡块进行切片后检测；5)肿瘤表达PD-L1，且肿瘤比例评分(TPS)≥1％；6)签署知情同意时年龄≥18岁；7)美国东部肿瘤协作组(ECOG)体能状态：0～1分；8)预计生存期超过3个月；9)主要器官功能正常。
排除标准(符合一条或多条下列标准的受试者将被排除)：1)接受过系统化疗，但不包括作为多模式治疗的一个环节的针对局部晚期疾病进行的化疗；针对局部晚期疾病进行的化疗包括：诱导化疗、放疗同期的化疗以及辅助化疗；2)针对局部晚期的SCCHN的治疗完成6个月内疾病进展；3)既往接受过抗PD-1、抗PD-L1抗体、抗PD-L2抗体、抗CD137抗体或抗CTLA-4抗体或特别靶向作用于T细胞共同刺激或免疫检查点通路的任何其它抗体或药物的免疫治疗；4)随机分组前6个月内接受过西妥昔单抗治疗；5)研究者认为由于其它原因不适合入组的患者。
关键中止试验标准：申办方有权在任何时间终止本研究，但必须事先通知研究者、伦理委员会和国家食品药品监督管理总局，并阐明理由。终止研究的原因包括但不限于以下几点：1.在本研究发生的不良事件数量和严重程度提示继续该研究将对受试者带来显著伤害；2.研究中心入组速度过于缓慢，不能在限定时间内完成入组计划；3.已有临床数据质量不佳，不利于继续开展后续研究；4.因国家药品管理部门法规政策变化而终止研究。
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，生产商：正大天晴药业集团股份有限公司。
对照药物：安慰剂，规格10mL。
hu5G11-hIgG1药物组合物/安慰剂配置方法：配置过程中应严格遵守无菌操作原则。在无菌条件下从玻璃瓶中抽取所需剂量的hu5G11-hIgG1药物组合物/安慰剂，用无菌无热原的生理盐水稀释至250mL的聚氯乙烯(PVC)、聚乙烯(PE)或聚烯烃(PO)输液袋。轻轻倒置混合稀释溶液，不要摇晃。作为注射用药品，在给药前应该肉眼检查是否存在颗粒物质和变色。该药是一个澄清至微乳光，无色至淡黄色液体。如果观察到溶液时云雾状、变色，或有可见颗粒存在，则应弃用。勿摇晃小瓶。本品中不含防腐剂。一旦制备好，立即给药。
化疗药物配置方法：标准化疗方案中“顺铂”或“卡铂”和“5-氟尿嘧啶”参考各包装说明书进行配置。
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。
研究治疗
研究治疗应在随机分组当天开始，或尽可能接近分配治疗的日期。
分配治疗
受试者将接受以下两组(试验组和对照物)中的一种治疗(表2)：
表2分配治疗
Figure PCTCN2020074083-appb-000006
注：&hu5G11-hIgG1/安慰剂在标准化疗前给药，用药时间不超过96周；*铂类药物(顺铂/卡铂)可由研究者根据受试者情况自行选择，卡铂剂量不得超过800mg；#终点事件：疾病进展、不可耐受的毒性或研究者/受试者决定退出研究。
给药
剂量选择
hu5G11-hIgG1/安慰剂：每个周期第一天(D1)使用hu5G11-hIgG1/安慰剂，1200mg/安慰剂，D1，静脉滴注。3周(21天)为一个治疗周期，用药时间不超过96周，直至疾病进展、不可耐受的毒性或研究者/受试者决定退出研究。
标准化疗药物：hu5G11-hIgG1/安慰剂输注完成后，第1天(D1)至第5天(D5)给予标准化疗方案。
标准化疗方案如下：
顺铂/卡铂：顺铂75mg/m 2/卡铂AUC5，D1，静脉输注；
5-氟尿嘧啶：750mg/m 2，D1～D5，静脉输注；
顺铂
顺铂的剂量应按受试者的体表面积(BSA)计算，在每次给药前计算BSA。对于BSA＞2.0m 2的受试者按照2.0m 2计算剂量。
hu5G11-hIgG1/安慰剂输注结束和顺铂开始输注之间至少间隔1小时。静脉预水化可以和hu5G11-hIgG1/安慰剂输注同时进行，但必须使用独立的输注管道。由于顺铂具有高致吐性，必须要预防止吐，以防治急性或延迟性的恶心和呕吐。
卡铂
卡铂的剂量根据受试者的肾功能(肌酐清除率)使用公式进行计算，AUC 5，最大使用剂量为800mg。
hu5G11-hIgG1/安慰剂输注结束和卡铂开始输注之间至少间隔1小时。
5-氟尿嘧啶
5-氟尿嘧啶根据受试者的体表面积(BSA)计算，在每次给药前计算BSA。5-氟尿嘧啶应在顺铂/卡铂给药完成后进行，并可使用同一输注管道。
剂量调整
如果适合，研究者尽可能将每种毒性事件归因于单独的顺铂/卡铂、5-氟尿嘧啶或hu5G11-hIgG1/安慰剂，或联合治疗，并逐渐减少剂量。
受试者可以停止化疗，继续hu5G11-hIgG1/安慰剂单独治疗。同样，受试者可以停止hu5G11-hIgG1/ 安慰剂，在前6个周期继续单独的化疗(如适合)。
给药时间
受试者将接受盲态hu5G11-hIgG1 1200mg(D1)或安慰剂(D1)联合顺铂75mg/m 2/卡铂AUC 5(D1)+5-氟尿嘧啶750mg/m 2(D1-D5)Q3W，共6个周期，然后接受盲态hu5G11-hIgG1 1200mg(D1)或安慰剂(D1)Q3W，直至疾病进展/治疗完成。hu5G11-hIgG1/安慰剂将在化疗前给药。试验治疗应该在每个周期的第1天，在所有程序和评估完成后给药。试验治疗可以在每个周期的目标第1天+3天给药，第1周期只能在目标第1天+3天给药。
hu5G11-hIgG1/安慰剂给药时间：使用输液器进行给药，输液器带有一个无菌、无热原、低蛋白吸附的在线过滤器(孔径：0.2～0.22μm)，60分钟完成输注。如果首次输注，受试者可以耐受，后续用药可30分钟完成输注。不要和其它药物共用输液器。研究中心应尽全力使含hu5G11-hIgG1的药物组合物/安慰剂输注时间尽量接近60分钟。然而，考虑到不同中心之间输注泵的变化，允许-10分钟至+20分钟时间窗(即输注时间50-80分钟)。
顺铂/卡铂给药时间：根据当地实践和说明书要求，顺铂75mg/m 2将通过60-120分钟的静脉输注Q3W给药，共6个周期。卡铂AUC5mg/mL/min60分钟静脉输注Q3W给药，共6个周期。
5-氟尿嘧啶给药时间：根据当地实践和说明书要求，5-氟尿嘧啶750mg/m 2，24小时连续输注静脉输注Q3W给药，共6个周期。
有效性评价
主要疗效终点：总生存期(OS)：从入组至各种原因导致死亡的时间。
次要疗效终点：缓解持续时间(DOR)：对于最佳缓解为完全缓解(CR)或部分缓解(PR)的患者，定义为根据研究者评估，从首次出现CR或PR至疾病复发或进展(基于独立评估)或各种原因导致死亡的时间；对于达到缓解，在分析前没有出现疾病进展，或肿瘤复发或死亡的患者，DOR为至末次疾病评估的日期为终止。
无进展生存期(PFS)：指从入组至首次出现进展或复发或各种原因导致死亡的时间。
客观缓解率(ORR)：接受研究药物治疗后，按照RECIST1.1标准评价，客观缓解率(ORR)为完全缓解(CR)+部分缓解(PR)的百分比。
疾病控制率(DCR)：为完全缓解(CR)+部分缓解(PR)+疾病稳定(SD)的百分比。
影像学检查
本研究影像学检查要求为多排螺旋CT(multiple detector CT)增强扫描。检查部位为全身，包括颈部、胸部、腹部和盆腔。为了减少扫描仪间检测误差，试验要求采用相同一致的检查方法进行检查。当病人有CT造影剂过敏的情况下，核磁共振(MR)可作为替代CT的影像学检查。否则，请选择和基线相同的检查手段。研究期间，在常规的检查点及检查部位以外，如怀疑有新病灶，由研究者决定加做其它相应的检查。所有的试验影像学资料及相关的附加影像检查资料，均要求拷贝存档供回顾性确认。
疗效评价
本研究主要采用RECIST1.1标准进行疗效评价。
irRECIST是RECIST1.1的改编版本，其目的是为了解释免疫治疗药物的独特肿瘤缓解。研究中心的研究者影像学评价中将使用irRECIST评估肿瘤缓解和进展，并做出治疗决定。如果可行，受试者不应中止治疗，直至研究中心的研究者影像学评价证实发生疾病进展。考虑到部分受试者在开始接受免疫治疗后前几个月内可能会出现暂时性的肿瘤爆发，之后出现疾病缓解，所以允许受试者在首次出现影像学进展(PD)之后继续接受治疗。对于被判定为临床不稳定的受试者，不需要通过重复进行肿瘤影像学检查确证PD。
肿瘤爆发包括下列任何一种情况：1)原有目标病灶恶化；2)原有非目标病灶恶化；3)出现新的病灶对于根据RECIST1.1评价出现影像学PD初步证据的受试者，主要研究者可以自行判断是否继续给予受试者研究治疗，直至再次获得影像学检查结果。研究中心的研究者作出此临床判断时应依据受试者总体临床状况，包括体能状况、临床症状以及实验室检查结果。受试者可以继续接受研究治疗，并在≥4周之后再次接受肿瘤评估，以便研究中心根据irRECIST确证PD。
临床稳定的定义如下：1)未出现提示疾病进展的具有临床意义的症状和体征(包括实验室检查值恶化)。2ECOG体能状态评分未降低。3)未出现快速疾病进展。4)重要解剖学部位未出现需要其它紧急医疗干预的进展性肿瘤(如脊髓压迫)。
被判定为临床不稳定的受试者，应从首次评价的PD影像学证据开始中止试验治疗，而且不需要通过 重复进行影像学检查确证PD。
在依据irRECIST判断肿瘤负荷是否增加或降低时，研究中心的研究者应考虑所有的目标和非目标病灶，以及任何新出现的病灶。
按照irRECIST，如果在重复的影像学检查中，下列情况全部出现，则PD不能被确证：1)目标病灶的直径之和比最低值增加<20％，或者绝对值增加<5mm。2)导致最初PD的非目标病灶情况稳定或者改善。3)导致最初PD的新病灶情况稳定或者改善。4)自上次评价之后新病灶未增加。5)自上次评价之后新的非目标病灶未进展。
经研究中心研究者根据irRECIST评估，重复进行的影像学检查未确证PD，而且受试者的临床情况依然稳定，则可以继续给予研究治疗，并按照正常的计划进行影像学检查。
按照irRECIST，如果在重复的影像学检查中，发生了下列任何一种情况，则可以确证发生PD：1)目标病灶的直径之和比最低值增加≥20％，并且绝对值至少增加5mm。2)导致最初PD的非目标病灶情况恶化。3)导致最初PD的新病灶情况恶化。4)自上次评价之后又出现新病灶。5)自上次评价之后新的非目标病灶再次进展，如果在重复的影像学检查中出现上述的任何一种情况，导致PD被确认，则受试者将被中止研究治疗。
统计分析
样本量
本试验为多中心、随机、双盲研究，主要终点指标为总生存期(OS)，采用Logrank差异性检验。假设受试者接受顺铂/卡铂+5-氟尿嘧啶治疗的mOS为8.5个月，试验药物hu5G11-hIgG1联合顺铂/卡铂+5-氟尿嘧啶治疗的mOS预计为12个月，即相对于对照组标准化疗方案提高3.5个月(HR＝0.70)，按双侧α＝0.05，把握度(1-β)为80％，入组时间为18个月，随访时间为18个月，试验控制脱落率不超过15％，按照1:1分组比例，采用PASS11计算样本量，本研究至少需获得265例事件，入组样本量为334例(试验组和对照组各需入组167例)。
统计分析集
全分析集(FAS，Full analysis set)：所有入组、并至少使用过一次试验用药的受试者。
符合方案分析集(PPS，Per Protocol Set)：全分析集中，按照方案完成用药、没有使用违禁药物、无严重违反方案的受试者，因出现终点事件而退出试验的受试者将纳入PP集。
安全数据集(SS，Safety Set)：入组后至少使用过一次研究药物的病例，且有安全性评价数据的病例。
疗效分析
疗效分析将同时在FAS和PPS中进行。
在本研究的主要疗效指标总生存期(OS)，采用Kaplan-Meier法计算中位生存时间及其95％CI，并绘制生存曲线图。
客观缓解率(ORR)分析中，计算患者的ORR及其95％CI。
生存期的分析指标包括：反应持续时间(DOR)、无进展生存期(PFS)，采用Kaplan-Meier法计算中位生存时间及其95％CI，并绘制生存曲线图。客观缓解率(ORR)和疾病控制率(DCR)分析中，计算患者的ORR和DCR及其95％CI。
安全性分析
安全性分析人群包括所有接受了任何剂量的研究药物的患者，将依照受试者接受的治疗对其进行分析。
用MeDRA词典中相应的术语描述不良事件，并依照NCI CTCAE v5.0评定不良事件的级别。另外，还将对所有严重不良事件进行总结。
对在研究治疗期间报告的死亡以及完成治疗或终止治疗后随访期间报告的死亡病例将按治疗组进行总结。
导致治疗终止和提前退出研究的不良事件将按治疗组和退出原因进行总结。
此外，还将按治疗组对研究暴露情况进行总结，这包括接受的周期个数和累积剂量。
对超出正常范围的实验室数据将进行鉴定。按治疗组和NCI CTCAE v5.0分级对另外选择的实验室数据进行总结。具有临床意义的异常实验室数据将报告为不良事件，并总结在不良事件表中。
总结受试者中的免疫原性(ADA)的阳性率。
实施例5治疗复发性或转移性头颈部鳞状细胞癌(R/M SCCHN)的临床II期试验结果
1.①号受试者，2018年6月，术后经组织病理学确诊为咽喉鳞状细胞癌，病理组织获取途径为手术，发生淋巴结转移，术后于2018年8月-2018年10月进行顺铂化疗同步进行喉部及淋巴结区域放疗。2019年8月复发。2019年10月1日开始第1周期的治疗(hu5G11-hIgG1注射液1200mg；卡铂425mg；5-FU1080mg/24小时连续滴注5天)；2019年10月23开始第2周期的治疗(hu5G11-hIgG1注射液1200mg；卡铂478mg；5-FU1035mg/24小时连续滴注5天)；
疗效评估方面，该受试者接受hu5G11-hIgG1注射液/安慰剂联合卡铂及氟尿嘧啶，21天为1个周期，持续给药，2019年11月11日初次肿瘤评价靶病灶较基线缩小39.4％，疗效评估为PR。
病灶情况：
筛选期：靶病灶65mm
6周后：靶病灶39.4mm缩小39.4％结果为PR。
2.②号受试者，2018年4月23日病理诊断为(下咽)中等分化鳞状细胞癌，于2018年5月14日-2018年7月10日进行放疗。2019年6月复查出现肝转移。2019年7月9日开始第1周期的治疗(hu5G11-hIgG1注射液1200mg；卡铂442.1mg；5-FU5625mg/24小时连续滴注5天)；2019年7月31日开始第2周期的治疗(hu5G11-hIgG1注射液1200mg；卡铂354.2mg；5-FU5601mg/24小时连续滴注5天)；2019年8月21日开始第3周期的治疗(hu5G11-hIgG1注射液1200mg；卡铂401.7mg；5-FU5577mg/24小时连续滴注5天)；2019年9月12日开始第4周期的治疗(hu5G11-hIgG1注射液1200mg；卡铂385.5g；5-FU5601mg/24小时连续滴注5天)；2019年9月30日开始第5周期的治疗(hu5G11-hIgG1注射液1200mg；卡铂394.2mg；5-FU5601mg/24小时连续滴注5天)；2019年10月23日开始第6周期的治疗(hu5G11-hIgG1注射液1200mg；卡铂388.9mg；5-FU5553mg/24小时连续滴注5天)；2019年12月3日开始第7周期的治疗(hu5G11-hIgG1注射液1200mg)；
疗效评估方面，该受试者接受hu5G11-hIgG1注射液/安慰剂联合卡铂及氟尿嘧啶，21天为1个周期，持续给药，2019年8月19日初次肿瘤评价靶病灶较基线缩小38.4％，疗效评估为PR。
病灶情况：
筛选期：靶病灶151.5mm
6周后：靶病灶93.3mm缩小38.4％结果为PR
12周期后：靶病灶80.5mm缩小46.9％结果为PR
18周期后：靶病灶80.4mm缩小46.9％结果为PR。
3.③号受试者，2019年6月25日，喉镜活检病理学确诊为咽鳞状细胞癌，病理组织获取途径为喉镜活检，发生淋巴结转移，伴纵膈淋巴结转移。2019年7月11日开始第1周期的治疗(hu5G11-hIgG1注射液：1200mg；卡铂：800mg；5-FU：6558.75mg/24小时连续滴注5天)；2019年8月1开始第2周期的治疗(hu5G11-hIgG1注射液1200mg；卡铂800mg；5-FU 6558.75mg/24小时连续滴注5天)；
疗效评估方面，该受试者接受hu5G11-hIgG1注射液/安慰剂联合卡铂及氟尿嘧啶，21天为1个周期，持续给药，2019年08月21日初次肿瘤评价靶病灶较基线缩小17％，疗效评估为SD，2019年9月29日第二次疗效评估靶病灶较基线缩小64.3％，疗效评估为PR。
病灶情况：
筛选期：靶病灶28mm
6周后：靶病灶23mm缩小17％结果为SD
12周后：靶病灶10mm缩小64.3％结果为PR。
上述临床实验结果显示，hu5G11-hIgG1注射液能够有效抑制、治疗头颈部肿瘤，缩小靶病灶。
根据本申请所公开的内容，虽然根据优选实施方案对本申请的组合物和方法进行了描述，但对本领域技术人员而言，在不背离本申请的概念、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、程序上和其它的细节补充本文所述内容。

Claims (42)

  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，其中所述癌症是头颈部鳞状细胞癌(SCCHN)，并且其中所述抗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、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的方法，其中大约每周(q1w)、大约每2周(q2w)、大约每3周(q3w)、或者大约每4周(q4w)施用抗PD-L1抗体。
  5. 根据前述任一项权利要求的方法，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。
  7. 根据权利要求5-6任一项所述的方法，其中所述统一剂量在大约20mg至大约2400mg抗PD-L1抗体范围内。
  8. 根据权利要求5-7任一项的方法，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。
  9. 根据权利要求5-8任一项的方法，其中所述统一剂量选自大约1200mg抗PD-L1抗体。
  10. 根据权利要求5-9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. 根据权利要求1-4任一项的方法，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。
  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，其中所述主体先前未接受过系统化疗。
  17. 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手术治疗、放射治疗、诱导化疗、同期的化疗和/或辅助化疗。
  18. 根据前述任一项权利要求所述的方法，其中所述主体先前未接受过系统化疗，但是接受过手术治疗、放射治疗、诱导化疗、同期的化疗和/或辅助化疗。
  19. 根据前述任一项权利要求所述的方法，其中所述主体经手术治疗、放射治疗、诱导化疗、同期的化疗和/或辅助化疗后，获完全缓解后再次出现疾病进展。
  20. 根据前述任一项权利要求所述的方法，其中所述主体经手术治疗、放射治疗、诱导化疗、同期的化疗和/或辅助化疗后，未能完全缓解或未能部分缓解。
  21. 根据前述任一项权利要求所述的方法，其中所述主体的癌症已发生转移。
  22. 根据前述任一项权利要求所述的方法，其中所述头颈部鳞状细胞癌原发部位为口咽部、口腔、下咽和/或喉部。
  23. 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/或转移性头颈部鳞状细胞癌。
  24. 根据前述任一项权利要求所述的方法，其中所述复发性或转移性头颈部鳞状细胞癌是无局部根治性治疗指征的复发性或转移性头颈部鳞状细胞癌。
  25. 根据前述任一项权利要求所述的方法，其中所述头颈部鳞状细胞癌是难治性的。
  26. 根据前述任一项权利要求所述的方法，其中所述癌症的治疗是对复发性或转移性头颈部鳞状细胞癌的一线治疗。
  27. 根据前述任一项权利要求所述的方法，其中所述治疗是联合标准化疗的对复发性或转移性头颈部鳞状细胞癌的一线治疗。
  28. 根据权利要求27所述的方法，所述标准化疗包括对患者施用化疗剂。
  29. 根据权利要求27-28任一项所述的方法，所述标准化疗包括对患者施用顺铂和5-氟尿嘧啶，或者对患者施用卡铂和5-氟尿嘧啶。
  30. 根据权利要求29所述的方法，所述抗PD-L1抗体和化疗剂各自呈药物组合物的形式，可同时、顺序或间隔给药。
  31. 根据权利要求27-30任一项所述的方法，所述治疗3周(21天)为一个周期，每个周期第一天(D1)静脉给予1200mg抗PD-L1抗体，抗PD-L1抗体输注后给予标准化疗方案。
  32. 根据权利要求31所述的方法，所述标准化疗方案包括：第一天(D1)静脉输注给予顺铂75mg/m 2或静脉输注给予卡铂AUC 5，并且第一天至第五天(D1-D5)每天静脉输注给予5-氟尿嘧啶750mg/m 2。
  33. 根据权利要求31-32任一项所述的方法，所述标准化疗方案包括：第一天(D1)静脉输注给予顺铂75mg/m 2，并且第一天至第五天(D1-D5)静脉输注给予5-氟尿嘧啶750mg/m 2。
  34. 根据权利要求31-32任一项所述的方法，所述标准化疗方案包括：第一天(D1)静脉输注给予或静脉输注给予卡铂AUC 5，并且第一天至第五天(D1-D5)静脉输注给予5-氟尿嘧啶750mg/m 2。
  35. 治疗复发性或转移性头颈部鳞状细胞癌的联用药物组合物，其包括抗PD-L1抗体和化疗剂，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。
  36. 根据权利要求35所述的联用药物组合物，其中所述联用药物组合物包括含抗PD-L1抗体的药物组合物和含化疗剂的药物组合物。
  37. 根据权利要求35-36任一项的联用药物组合物，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。
  38. 根据权利要求35-37任一项的联用药物组合物，其中化疗剂选自顺铂、卡铂和/或5-氟尿嘧啶。
  39. 根据权利要求36-38任一项所述的联用药物组合物，其中含抗PD-L1抗体的药物组合物是存放于包括含有固定剂量抗PD-L1抗体的容器的制品，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。
  40. 根据权利要求39所述的联用药物组合物，其中所述制品包括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。
  41. 根据权利要求39-40任一项所述的联用药物组合物，其中所述制品还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。
  42. 治疗复发性或转移性头颈部鳞状细胞癌的试剂盒，所述试剂盒包括权利要求36-41任一项所述的含抗PD-L1抗体的药物组合物和化疗剂，以及抗PD-L1抗体和化疗剂联合用于治疗复发性或转移性头颈部鳞状细胞癌的说明。
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