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WO2020156500A1 - Utilisation d'un anticorps anti-pd-l1 dans le traitement du cancer de la tête et du cou - Google Patents

Utilisation d'un anticorps anti-pd-l1 dans le traitement du cancer de la tête et du cou 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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Prior art keywords
seq
antibody
amino acid
chemotherapy
pharmaceutical composition
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PCT/CN2020/074083
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English (en)
Chinese (zh)
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
Original Assignee
正大天晴药业集团股份有限公司
正大天晴药业集团南京顺欣制药有限公司
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Application filed by 正大天晴药业集团股份有限公司, 正大天晴药业集团南京顺欣制药有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to CN202080011333.8A priority Critical patent/CN113365659B/zh
Publication of WO2020156500A1 publication Critical patent/WO2020156500A1/fr

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

Definitions

  • the present 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

La présente invention concerne l'utilisation d'un anticorps anti-PD-L1 dans le traitement du cancer de la tête et du cou. Une quantité thérapeutiquement efficace d'un inhibiteur de l'interaction entre un récepteur PD -1 et un ligand de celui-ci, PD-L1, est administrée à un sujet, l'inhibiteur étant un anticorps anti-PD-L1.
PCT/CN2020/074083 2019-01-31 2020-01-31 Utilisation d'un anticorps anti-pd-l1 dans le traitement du cancer de la tête et du cou WO2020156500A1 (fr)

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