CN117642181A

CN117642181A - Pharmaceutical composition for treating esophageal cancer

Info

Publication number: CN117642181A
Application number: CN202280049989.8A
Authority: CN
Inventors: 蒋淼; 于鼎; 王训强; 张喜全; 吴凤秀
Original assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Current assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority date: 2021-09-06
Filing date: 2022-09-06
Publication date: 2024-03-01
Also published as: WO2023030532A1

Abstract

A pharmaceutical combination for the treatment of esophageal cancer is provided comprising an anti-PD-L1 antibody and a chemotherapeutic agent, and optionally An Luoti n or a pharmaceutically acceptable salt thereof. In addition, the application of the pharmaceutical composition in preparing medicines for treating esophageal cancer is also provided.

Description

Pharmaceutical composition for treating esophageal cancer

Technical Field

The application belongs to the field of biological medicine, and in particular relates to a pharmaceutical composition for treating esophageal cancer.

Background

Esophageal cancer is a common malignant tumor in China, and has serious threat and influence on the health and life of people due to the characteristics of high incidence, strong invasiveness, poor prognosis and the like. According to the latest data published by world health organization, 60.4 cases of new esophageal cancer are globally developed in 2020, the morbidity is ranked at 8 th, the number of deaths is 54.4 tens of thousands, the number of deaths is 6 th, and 32.4 tens of thousands of new esophageal cancer are developed in China, the morbidity is ranked at 6 th, the number of deaths is 30.1 tens of thousands, the number of deaths is 4 th, and the average level of the deaths is higher than the average level in the world. About 95% of patients with esophageal cancer in china are esophageal squamous cell carcinoma (Esophageal Squamous Cell Carcinoma, ESCC) in terms of histological type. Since most ESCC patients have no obvious symptoms at early stage, approximately half of the patients' tumors have metastasized at the time of diagnosis.

At present, the operation treatment is one of the main radical treatment means of esophageal cancer, especially for early and middle stage patients, but the survival rate of the patients after the operation is only 20-30% in 5 years. Clinically advanced ESCC patients are still treated mainly by standard chemotherapy/radiotherapy, and the application of targeted drugs is still under exploration. According to NCCN guidelines, platinum-containing dual-drug chemotherapy is the preferred regimen for first-line treatment of advanced ESCC, and patients with better physical conditions can employ a platinum-containing triple-drug chemotherapy regimen. However, the current first-line treatment scheme has no curative effect meeting the treatment requirement, and further development of more novel treatment schemes with strong specificity, specific targets, small toxic and side effects and remarkable curative effect is required to achieve the expected treatment effect.

Disclosure of Invention

In one aspect, the present application provides a pharmaceutical combination for treating esophageal cancer comprising: anti-PD-L1 antibodies and chemotherapeutic agents.

In some embodiments of the present invention, in some embodiments, the chemotherapeutic drugs include but are not limited to platinum anti-tumor drugs (including but not limited to oxaliplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin, miboplatin, lobaplatin, picoplatin (picoplatin)), camptothecins anti-tumor drugs (including but not limited to camptothecins, hydroxycamptothecins, aminocamptothecins, irinotecan, topotecan, irinotecan, lubiptecan, lurotecan (lurotecan), gemfibrozil Ma Tikang, kartinitecin), taxane anti-tumor drugs (including but not limited to paclitaxel, paclitaxel liposomes, albumin-bound paclitaxel, docetaxel), nitrogen mustard anti-tumor drugs (including but not limited to cyclophosphamide, ifosfamide, chlorambucil, melphalan, bendamustine), and the like antimetabolite antitumor drugs (including but not limited to fluorouracil antitumor drugs (including but not limited to 5-fluorouracil, tegafur, capecitabine, tegafur), methotrexate, cytarabine, gemcitabine, fludarabine, azacytidine), anthracycline antitumor drugs (including but not limited to doxorubicin, epirubicin, pirarubicin, amrubicin, doxorubicin, idarubicin, daunorubicin, mitoxantrone), vincristine antitumor drugs (including but not limited to vinblastine, vincristine, vindesine and vinorelbine), podophyllone alkaloid antitumor drugs (including but not limited to etoposide, teniposide), hormones (including but not limited to prednisone, prednisolone, dexamethasone, methylprednisolone sodium succinate), methylbenzin, hexamethylenerimide, mitoxantrone, one or more of dacarbazine.

Further, the chemotherapeutic drug is selected from one or more of platinum anti-tumor drugs and taxane anti-tumor drugs. In some embodiments, the platinum-based antineoplastic agents include, but are not limited to, one or more of cisplatin, carboplatin, nedaplatin, dicycloplatin, picoplatin, oxaliplatin, miplatin, or lobaplatin. In some embodiments, the taxane antineoplastic agents include, but are not limited to, one or more of paclitaxel, paclitaxel liposomes, albumin-bound paclitaxel, docetaxel. In some embodiments, the chemotherapeutic agent is selected from one or more of a platinum-based anti-tumor agent and paclitaxel. In some embodiments, the chemotherapeutic agent is selected from one or more of cisplatin and taxane antineoplastic agents. In some embodiments, the chemotherapeutic agent is selected from one or more of cisplatin, nedaplatin, oxaliplatin, paclitaxel liposomes, albumin-bound paclitaxel, and docetaxel. In some embodiments, the chemotherapeutic agent is selected from one or more of cisplatin and paclitaxel. In some embodiments, the chemotherapeutic agent is cisplatin or paclitaxel.

In some embodiments, the pharmaceutical combination further comprises An Luoti ni or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical combination comprises an anti-PD-L1 antibody, an Luoti ni or a pharmaceutically acceptable salt thereof, a platinum-based anti-tumor drug, and a taxane-based anti-tumor drug. In some embodiments, the pharmaceutical combination comprises: an anti-PD-L1 antibody; an Luoti Ni or a pharmaceutically acceptable salt thereof; at least one selected from cisplatin, nedaplatin and oxaliplatin; and at least one selected from paclitaxel, paclitaxel liposome, albumin-bound paclitaxel, and docetaxel. In a specific embodiment, the pharmaceutical combination comprises an anti-PD-L1 antibody, an Luoti ni or a pharmaceutically acceptable salt thereof, cisplatin, and paclitaxel.

In another aspect, the present application provides a pharmaceutical combination for treating esophageal cancer comprising a first pharmaceutical combination, and optionally, a second pharmaceutical combination. In some embodiments, the pharmaceutical combination comprises a first pharmaceutical combination administered to a patient in need thereof during a first treatment phase, and optionally, a second pharmaceutical combination administered to a patient in need thereof during a second treatment phase. In some embodiments, the treatment period of the first treatment phase is from 1 to 10 treatment periods, preferably from 2 to 8 treatment periods, further preferably from 4 to 6 treatment periods, most preferably 6 treatment periods.

In some embodiments, the first pharmaceutical combination comprises an anti-PD-L1 antibody and a chemotherapeutic agent. In some embodiments, the first pharmaceutical combination comprises an anti-PD-L1 antibody and a chemotherapeutic agent, and An Luoti n or a pharmaceutically acceptable salt thereof.

In some embodiments, the second pharmaceutical combination comprises an anti-PD-L1 antibody. In some embodiments, the second pharmaceutical combination comprises an anti-PD-L1 antibody and An Luoti ni or a pharmaceutically acceptable salt thereof.

In a specific embodiment, the pharmaceutical combination comprises a first pharmaceutical combination administered to a patient in need thereof during a first treatment phase, and optionally, a second pharmaceutical combination administered to a patient in need thereof during a second treatment phase, the first pharmaceutical combination comprising an anti-PD-L1 antibody and a chemotherapeutic agent, the second pharmaceutical combination comprising an anti-PD-L1 antibody. In some embodiments, the treatment period of the first treatment phase is from 1 to 10 treatment periods, preferably from 2 to 8 treatment periods, further preferably from 4 to 6 treatment periods, most preferably 6 treatment periods.

In a specific embodiment, the pharmaceutical combination comprises a first pharmaceutical combination comprising an anti-PD-L1 antibody and a chemotherapeutic agent, and An Luoti ni or a pharmaceutically acceptable salt thereof, administered to a patient in need thereof during a first treatment phase, and optionally, a second pharmaceutical combination comprising an anti-PD-L1 antibody, and An Luoti ni or a pharmaceutically acceptable salt thereof, administered to a patient in need thereof during a second treatment phase. In some embodiments, the treatment period of the first treatment phase is from 1 to 10 treatment periods, preferably from 2 to 8 treatment periods, further preferably from 4 to 6 treatment periods, most preferably 6 treatment periods.

In some embodiments, the pharmaceutical combination further comprises a pharmaceutically acceptable carrier.

In some embodiments, for the pharmaceutical combinations described herein comprising an anti-PD-L1 antibody and a chemotherapeutic agent, wherein the anti-PD-L1 antibody and the chemotherapeutic agent are each in the form of a pharmaceutical composition, the administration may be simultaneous, sequential or sequential. In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition comprising an anti-PD-L1 antibody and a pharmaceutical composition comprising a chemotherapeutic agent. In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition comprising an anti-PD-L1 antibody and a pharmaceutical composition comprising a chemotherapeutic agent.

In some embodiments, for the pharmaceutical combinations described herein comprising an anti-PD-L1 antibody, a chemotherapeutic agent, and An Luoti ni or a pharmaceutically acceptable salt thereof, wherein the anti-PD-L1 antibody, chemotherapeutic agent, and An Luoti ni or a pharmaceutically acceptable salt thereof are each in the form of a pharmaceutical composition, can be administered simultaneously, sequentially, or sequentially. In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition comprising an anti-PD-L1 antibody, a pharmaceutical composition comprising a chemotherapeutic agent, and a pharmaceutical composition comprising An Luoti ni or a pharmaceutically acceptable salt thereof.

Further, the above-mentioned pharmaceutical combinations of the present application are packaged in the same kit, which also includes instructions for treating esophageal cancer.

In some embodiments, the present application provides a kit for treating esophageal cancer comprising: anti-PD-L1 antibodies and chemotherapeutic agents. In some embodiments, the anti-PD-L1 antibody is contained in a first compartment and the chemotherapeutic agent is contained in other compartments, optionally increasing the number of compartments in the kit depending on the type of chemotherapeutic agent, and may be administered to a patient in need thereof simultaneously, sequentially or in sequence. In some embodiments, the kit further comprises instructions for treating esophageal cancer in combination with an anti-PD-L1 antibody and a chemotherapeutic agent. In some embodiments, the kit comprises: a pharmaceutical composition comprising an anti-PD-L1 antibody; and pharmaceutical compositions containing chemotherapeutic agents.

In some embodiments, the present application provides a kit for treating esophageal cancer comprising: anti-PD-L1 antibodies and chemotherapeutic agents, an Luoti n or a pharmaceutically acceptable salt thereof. In some embodiments, the anti-PD-L1 antibody is contained in a first compartment, an Luoti ni or a pharmaceutically acceptable salt thereof is contained in a second compartment, and the chemotherapeutic agent is contained in other compartments, optionally increasing the number of compartments in the kit depending on the type of chemotherapeutic agent, which may be administered to a patient in need thereof simultaneously, sequentially or sequentially. In some embodiments, the kit further comprises instructions for the combined use of an anti-PD-L1 antibody, a chemotherapeutic agent, an Luoti ni or a pharmaceutically acceptable salt thereof, for the treatment of esophageal cancer. In some embodiments, the kit comprises: a pharmaceutical composition comprising an anti-PD-L1 antibody; and a pharmaceutical composition comprising a chemotherapeutic agent; and a pharmaceutical composition comprising An Luoti Ni or a pharmaceutically acceptable salt thereof.

Further, the above kit is a kit suitable for administration during a single treatment cycle (e.g., one treatment cycle of 21 days), including a pharmaceutical composition comprising 600 to 2400mg of an anti-PD-L1 antibody. In some embodiments, the kit is a kit suitable for administration over a single treatment cycle (e.g., one treatment cycle of 21 days), including a pharmaceutical composition comprising 600-2400 mg of an anti-PD-L1 antibody, and a pharmaceutical composition comprising 84-168 mg An Luoti ni or a pharmaceutically acceptable salt thereof. In some embodiments, one treatment cycle is every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks.

The amount of anti-PD-L1 antibody administered can be determined based on the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health status of the patient. For example, the daily dose of anti-PD-L1 antibody administered may be 600 to 2400mg, and in some embodiments, the daily dose of anti-PD-L1 antibody administered may be 600, 800, 1000, 1200, 1400, 1600, 1800, 2000, 2200, or 2400mg. In some embodiments, the anti-PD-L1 antibody is administered parenterally. In some embodiments, the anti-PD-L1 antibody is administered intravenously. In some embodiments, the concentration of anti-PD-L1 antibody in the anti-PD-L1 antibody-containing pharmaceutical composition is 10 to 60mg/mL. In some embodiments, the concentration of anti-PD-L1 antibody in the anti-PD-L1 antibody-containing pharmaceutical composition is 10, 20, 30, 40, 50, or 60mg/mL.

The dosage regimen of the anti-PD-L1 antibody can be determined comprehensively based on the activity, toxicity, tolerance of the patient, etc. In some embodiments, the anti-PD-L1 antibody is one treatment cycle every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, the anti-PD-L1 antibody is administered weekly, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, the dose of anti-PD-L1 antibody is 600-2400 mg per treatment cycle. In some embodiments, the dose of anti-PD-L1 antibody per treatment cycle is 1200mg. In some embodiments, the anti-PD-L1 antibody is administered once every 3 weeks at a dose of 600-2400 mg. In some embodiments, the An Luoti ni or pharmaceutically acceptable salt thereof is administered in a daily dose of 6mg, 8mg, 10mg, or 12mg, administered continuously for 2 weeks, at a dosing regimen of 1 week.

In some embodiments, the daily dose of paclitaxel may be 67.5 to 810mg, preferably 135 to 405mg. In some embodiments, the daily dose of cisplatin may be from 30 to 450mg, preferably from 60 to 225mg.

In some embodiments, the anti-PD-L1 antibody-and chemotherapeutic-containing pharmaceutical combinations described herein include anti-PD-L1 antibody-containing pharmaceutical compositions and chemotherapeutic-containing pharmaceutical compositions, wherein the anti-PD-L1 antibody-containing pharmaceutical compositions are prepared in unit dose or multi-dose form suitable for administration of 600-2400 mg of the anti-PD-L1 antibody to a patient upon first administration.

In some embodiments, the pharmaceutical combination described herein comprising an anti-PD-L1 antibody, a chemotherapeutic agent, and An Luoti ni or a pharmaceutically acceptable salt thereof comprises a pharmaceutical composition comprising an anti-PD-L1 antibody, and a pharmaceutical composition comprising An Luoti ni or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising a chemotherapeutic agent, wherein the pharmaceutical composition comprising an anti-PD-L1 antibody is prepared in a unit dose or multi-dose form suitable for administration of 600-2400 mg of the anti-PD-L1 antibody to a patient on first administration, and the pharmaceutical composition comprising An Luoti ni or a pharmaceutically acceptable salt thereof is prepared in a unit dose form suitable for administration of 6mg, 8mg, 10mg, and/or 12mg An Luoti ni or a pharmaceutically acceptable salt thereof to a patient for 14 consecutive days.

In some embodiments, a pharmaceutical combination comprising an anti-PD-L1 antibody and a chemotherapeutic agent described herein comprises: the anti-PD-L1 antibody concentration is 10-60 mg/mL. In some embodiments, a pharmaceutical combination comprising an anti-PD-L1 antibody, a chemotherapeutic agent, and An Luoti ni or a pharmaceutically acceptable salt thereof described herein comprises: the anti-PD-L1 antibody concentration is 10-60 mg/mL, and the unit dosage is 6mg, 8mg, 10mg and/or 12 mg.

In some embodiments, a pharmaceutical combination comprising an anti-PD-L1 antibody and a chemotherapeutic agent described herein comprises: pharmaceutical compositions comprising 1200mg of anti-PD-L1 antibody are provided in multi-dose form. In some embodiments, a pharmaceutical combination comprising an anti-PD-L1 antibody, a chemotherapeutic agent, and An Luoti ni or a pharmaceutically acceptable salt thereof described herein comprises: a pharmaceutical composition comprising 1200mg of an anti-PD-L1 antibody provided in a multi-dose form, and a pharmaceutical composition comprising An Luoti ni or a pharmaceutically acceptable salt thereof in unit dose of 8mg, 10mg and/or 12 mg.

Further, the pharmaceutical combinations described herein comprising an anti-PD-L1 antibody and a chemotherapeutic agent are formulations suitable for administration within a single treatment cycle (e.g., one treatment cycle of 21 days), including pharmaceutical compositions comprising 600-2400 mg of an anti-PD-L1 antibody.

In some embodiments, the pharmaceutical combination described herein comprising an anti-PD-L1 antibody, a chemotherapeutic agent, and An Luoti ni or a pharmaceutically acceptable salt thereof is a formulation suitable for administration over a single treatment cycle (e.g., one treatment cycle of 21 days), including pharmaceutical compositions comprising 600-2400 mg of the anti-PD-L1 antibody and pharmaceutical compositions comprising 84-168 mg An Luoti ni or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation suitable for administration over a single treatment period (e.g., one treatment period of 21 days) further comprises: a pharmaceutical composition containing 90-1350 mg, preferably 180-675 mg of cisplatin. In some embodiments, the formulation suitable for administration over a single treatment period (e.g., one treatment period of 21 days) further comprises: pharmaceutical compositions containing 67.5-810 mg, preferably 135-405 mg of paclitaxel.

Further, the pharmaceutical combination described herein comprising an anti-PD-L1 antibody, a chemotherapeutic agent and An Luoti Ni or a pharmaceutically acceptable salt thereof comprises an anti-PD-L1 antibody and An Luoti Ni in a weight ratio of (0.35-29): 1, preferably (3.5-29): 1, more preferably (3.5-14.5): 1, most preferably (7-14.5): 1. Wherein the anti-PD-L1 antibody and An Luoti can be packaged separately or together. And wherein An Luoti can be packaged in multiple aliquots (e.g., 2, 7, 14, 28, or more aliquots); anti-PD-L1 antibodies can be packaged in single aliquots or multiple aliquots (e.g., 2 aliquots, 4 aliquots, or more). In some embodiments, the pharmaceutical combinations described herein comprise an anti-PD-L1 antibody, an Luoti Ni or a pharmaceutically acceptable salt thereof, cisplatin, and paclitaxel, wherein the weight ratio of anti-PD-L1 antibody, an Luoti Ni or a pharmaceutically acceptable salt thereof, cisplatin, and paclitaxel is (600-2400): 84-168): 90-1350): 67.5-810, preferably (600-2400): 84-168): 180-675 (135-405). Preferably, the cisplatin and paclitaxel can be packaged in single or multiple aliquots (e.g., 2, 3, 6, or more aliquots).

In some embodiments, the chemotherapeutic agent is selected from one or more of a platinum-based anti-tumor agent and a taxane-based anti-tumor agent. In some embodiments, the chemotherapeutic agent is selected from one or more of a platinum-based anti-tumor agent and paclitaxel. In some embodiments, the chemotherapeutic agent is selected from one or more of cisplatin and taxane antineoplastic agents. In some embodiments, the chemotherapeutic agent is cisplatin or paclitaxel.

In yet another aspect, the present application also provides the use of a pharmaceutical combination of the present application, or a kit of the present application, for the manufacture of a medicament for treating esophageal cancer in a patient. Alternatively, the present application also provides a method of treating esophageal cancer comprising administering to a patient in need thereof an effective amount of a pharmaceutical combination of the present application, or a kit of the present application. Alternatively, the present application also provides the use of a pharmaceutical combination of the present application, or a kit of the present application, for treating esophageal cancer in a patient. Alternatively, the present application also provides a pharmaceutical combination of the present application, or a kit of the present application, for treating esophageal cancer in a patient.

In some embodiments, the methods of treating esophageal cancer provided herein comprise administering to a patient in need thereof a therapeutically effective amount of an anti-PD-L1 antibody and a chemotherapeutic agent. In some embodiments, the method of treatment comprises administering a first pharmaceutical combination to a patient in need thereof during a first treatment phase; and optionally, administering a second pharmaceutical combination to the patient in need thereof during a second treatment phase. In some embodiments, the first pharmaceutical combination comprises an anti-PD-L1 antibody, and a chemotherapeutic agent. In some embodiments, the second pharmaceutical combination comprises an anti-PD-L1 antibody.

In some embodiments, the methods of treating esophageal cancer provided herein comprise administering to a patient in need thereof a therapeutically effective amount of an anti-PD-L1 antibody, an Luoti ni or a pharmaceutically acceptable salt thereof, and a chemotherapeutic agent. In some embodiments, the method of treatment comprises administering a first pharmaceutical combination to a patient in need thereof during a first treatment phase; and optionally, administering a second pharmaceutical combination to the patient in need thereof during a second treatment phase. In some embodiments, the first pharmaceutical combination comprises an anti-PD-L1 antibody, an Luoti ni or a pharmaceutically acceptable salt thereof, and a chemotherapeutic agent. In some embodiments, the second pharmaceutical combination comprises an anti-PD-L1 antibody, and An Luoti ni or a pharmaceutically acceptable salt thereof.

In some embodiments, the treatment period of the first treatment phase is from 1 to 10 treatment periods, preferably from 2 to 8 treatment periods, further preferably from 4 to 6 treatment periods, most preferably 6 treatment periods.

In some embodiments, the chemotherapeutic agent is selected from one or more of a platinum-based anti-tumor agent and a taxane-based anti-tumor agent. In some embodiments, the chemotherapeutic agent is selected from one or more of a platinum-based anti-tumor agent and paclitaxel. In some embodiments, the chemotherapeutic agent is selected from one or more of cisplatin and taxane antineoplastic agents. In some embodiments, the chemotherapeutic agent is selected from one or more of cisplatin, nedaplatin, oxaliplatin, paclitaxel liposomes, albumin-bound paclitaxel, and docetaxel. In some embodiments, the chemotherapeutic agent is cisplatin or paclitaxel.

Further, the anti-PD-L1 antibody, an Luoti ni or a pharmaceutically acceptable salt thereof and the chemotherapeutic agent are each in the form of a pharmaceutical composition that can be administered simultaneously, sequentially or at intervals. Still further, the anti-PD-L1 antibody is administered weekly, every 2 weeks, every 3 weeks, or every 4 weeks; further, the anti-PD-L1 antibody is administered once every 3 weeks; preferably, the anti-PD-L1 antibody is administered at a dose of 600-2400 mg each time; further, the anti-PD-L1 antibody is administered at a dose of 1200mg each time. Still further, the An Luoti Ni is administered in a dose of 6mg, 8mg, 10mg or 12mg once daily, for 2 weeks, and for a dosing regimen of 1 week. In some embodiments, the paclitaxel is administered weekly, every 2 weeks, every 3 weeks, or every 4 weeks; further, the paclitaxel is administered once every 3 weeks; preferably, the paclitaxel is administered at a dose of 67.5 to 810mg, preferably 135 to 405mg, at a time. In some embodiments, the cisplatin is administered once daily in a regimen of continuous dosing for the first 3 days of each treatment cycle, with the rest of the time stopped; preferably, the cisplatin is administered at a dose of 30 to 450mg, preferably 60 to 225mg, at a time.

An Luoti Ni or a pharmaceutically acceptable salt thereof

An Luoti Ni has the chemical name 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine having the structural formula:

the pharmaceutically acceptable salts of An Luoti Ni include, but are not limited to, salts of An Luoti Ni with acids selected from the group consisting of: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, caproic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, p-toluenesulfonic acid, 3-phenylpropionic acid, trimethylacetic acid, t-butylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid; in some embodiments, the pharmaceutically acceptable salts are hydrochloride and maleate salts; in some embodiments, the pharmaceutically acceptable salt is a dihydrochloride salt.

The doses of An Luoti of the present application, or pharmaceutically acceptable salts thereof, are based on the molecular weight of An Luoti of the free base unless otherwise indicated.

An Luoti the drug or pharmaceutically acceptable salt thereof can be administered by a variety of routes including the gastrointestinal route of administration as well as the parenteral route of administration including, but not limited to, oral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intraadipose, intra-articular, intraperitoneal and intrathecal. In some particular embodiments, the administration is by oral administration. The amount of An Luoti Ni or a pharmaceutically acceptable salt thereof administered can be determined based on the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health of the patient. For example, the daily dose of An Luoti ni or a pharmaceutically acceptable salt thereof may be from 2 mg to 20 mg, and in some embodiments, the daily dose of An Luoti ni or a pharmaceutically acceptable salt thereof may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16 mg. An Luoti Ni or a pharmaceutically acceptable salt thereof can be administered one or more times daily. In some embodiments, an Luoti ni or a pharmaceutically acceptable salt thereof is administered once daily in an oral solid formulation.

The dosage regimen of An Luoti Ni or a pharmaceutically acceptable salt thereof can be determined comprehensively based on the activity, toxicity, tolerance of the patient, etc. of the drug. Preferably, an Luoti Ni or a pharmaceutically acceptable salt thereof is administered as a separate administration. The interval administration includes administration period and withdrawal period, and An Luoti Ni or pharmaceutically acceptable salt thereof can be administered once or more times daily during the administration period. For example, the ratio of the administration period to the withdrawal period in days is 2 (0.5 to 5), 2 (0.5 to 3), 2 (0.5 to 2), or 2 (0.5 to 1). In some embodiments, administration is stopped for 2 weeks following 2 weeks of administration. In some embodiments, administration is stopped for 1 week for 2 weeks. In some embodiments, administration is stopped for 2 days 5 days continuously. For example An Luoti Ni or a pharmaceutically acceptable salt thereof can be administered orally at a dose of 6mg, 8mg, 10mg or 12mg once daily for 2 weeks, and for 1 week.

Pharmaceutical composition containing An Luoti Ni or pharmaceutically acceptable salt thereof

In some embodiments of the present application, 6mg, 8mg, 10mg, or 12mg of An Luoti ni or a pharmaceutically acceptable salt thereof is included in a pharmaceutical composition comprising An Luoti ni or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition is provided in a single dose form. In some embodiments, the pharmaceutical composition comprising An Luoti ni or a pharmaceutically acceptable salt thereof is an oral solid formulation.

In some embodiments of the present application, the administration is in a regimen of 2 weeks of administration for 1 week, one treatment cycle every 3 weeks, with a total dose of 84-168 mg of An Luoti ni or a pharmaceutically acceptable salt thereof administered per treatment cycle. In some embodiments, the total dose of An Luoti Ni or a pharmaceutically acceptable salt thereof comprises a range selected from 84mg, 112mg, 140mg, 168mg, or any of the above. In some embodiments, the total dose of An Luoti Ni or a pharmaceutically acceptable salt thereof comprises 112mg to 168mg.

In some embodiments, the pharmaceutical compositions include, but are not limited to, formulations suitable for oral, parenteral, topical administration; in some embodiments, the pharmaceutical composition is a formulation suitable for oral administration; in some embodiments, the pharmaceutical composition is a solid formulation suitable for oral administration; in some embodiments, the pharmaceutical composition includes, but is not limited to, a tablet, a capsule.

Chemotherapeutic agents

In some embodiments of the present application, the chemotherapeutic agent includes, but is not limited to, one or more of cyclophosphamide, ifosfamide, vincristine, prednisone, prednisolone, anthracycline antitumor agents (including, but not limited to, doxorubicin, epirubicin, pirarubicin, amrubicin, doxorubicin, idarubicin, daunorubicin, mitoxantrone), platinum antitumor agents, camptothecins (including, but not limited to, camptothecins, hydroxycamptothecins, irinotecan, topotecan), taxane antitumor agents, dexamethasone, methotrexate, cytarabine, bendamustine, fludarabine, mitoxantrone, etoposide, procarbazine, gemcitabine, methylprednisolone sodium succinate, mesna, fluorouracil antitumor agents (including, but not limited to, 5-FU, capecitabine, tiglinide), azacytidine, dacarbazine, and risperidine.

Further, the chemotherapeutic agents include, but are not limited to, one or more of platinum-based antitumor agents and taxane-based antitumor agents. In some embodiments, the platinum-based antineoplastic agents include, but are not limited to, one or more of cisplatin, carboplatin, nedaplatin, dicycloplatin, picoplatin, oxaliplatin, miplatin, or lobaplatin. In some embodiments, the taxane antineoplastic agents include, but are not limited to, one or more of paclitaxel, paclitaxel liposomes, albumin-bound paclitaxel, docetaxel. In some embodiments, the chemotherapeutic agent is selected from one or more of a platinum-based anti-tumor agent and paclitaxel. In some embodiments, the chemotherapeutic agent is selected from one or more of cisplatin and taxane antineoplastic agents. In some embodiments, the chemotherapeutic agent is cisplatin or paclitaxel.

In some embodiments, paclitaxel is present at 135-175 mg/m ² Is preferably administered at a dose of 135mg/m ² Is administered in a dosage of (a). Wherein, as will be understood from the common knowledge of the person skilled in the art, mg/m ² Refers to the dosage of drug per square meter of body surface area of the subject.

In some embodiments, cisplatin is present at 50 to 100mg/m ² Is preferably administered in a dosage of 60 to 75mg/m ² Is administered in a dosage of (a). Wherein, as will be understood from the common knowledge of the person skilled in the art, mg/m ² Refers to the dosage of drug per square meter of body surface area of the subject.

anti-PD-L1 antibodies

In some embodiments of the present application, the anti-PD-L1 antibody is one or more of the antibodies disclosed in CN107001463 a.

In some embodiments of the present application, the anti-PD-L1 antibody is an isolated anti-PD-L1 antibody. In some embodiments of the present application, the anti-PD-L1 antibody is an anti-PD-L1 humanized monoclonal antibody. In some embodiments of the present application, the anti-PD-L1 antibody is an isolated anti-PD-L1 humanized monoclonal antibody. In some embodiments, the anti-PD-L1 antibody may be an IgG1 or IgG4 antibody. In some embodiments of the present application, the anti-PD-L1 antibody is an IgG1 antibody. In some embodiments, the anti-PD-L1 antibody is a glycosylated IgG1 antibody.

In some embodiments of the present application, the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain CDR1 region having at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the amino acid sequence set forth in SEQ ID No. 1 or SEQ ID No. 4; a heavy chain CDR2 region having at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the amino acid sequence shown in SEQ ID No. 2 or SEQ ID No. 5; a heavy chain CDR3 region having at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the amino acid sequence set forth in SEQ ID No. 3 or SEQ ID No. 6; a light chain CDR1 region having at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the amino acid sequence shown in SEQ ID No. 7 or SEQ ID No. 10; a light chain CDR2 region having at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the amino acid sequence shown in SEQ ID No. 8 or SEQ ID No. 11; a light chain CDR3 region having at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the amino acid sequence set forth in SEQ ID No. 9 or SEQ ID No. 12.

In some embodiments, the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain CDR1 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 1 or SEQ ID NO. 4; or a heavy chain CDR2 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 2 or SEQ ID NO. 5; or a heavy chain CDR3 region having at least 80% homology with the amino acid sequence shown in SEQ ID NO. 3 or SEQ ID NO. 6; or a light chain CDR1 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 7 or SEQ ID NO. 10; or a light chain CDR2 region having at least 80% homology with the amino acid sequence shown in SEQ ID NO. 8 or SEQ ID NO. 11; or a light chain CDR3 region having at least 80% homology with the amino acid sequence shown in SEQ ID NO. 9 or SEQ ID NO. 12.

In some embodiments, the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain CDR1 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 1 or SEQ ID NO. 4; a heavy chain CDR2 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 2 or SEQ ID NO. 5; a heavy chain CDR3 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 3 or SEQ ID NO. 6; a light chain CDR1 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 7 or SEQ ID NO. 10; a light chain CDR2 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 8 or SEQ ID NO. 11; a light chain CDR3 region having at least 80% homology with the amino acid sequence shown in SEQ ID NO. 9 or SEQ ID NO. 12.

In some embodiments of the present application, the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain CDR1 region selected from SEQ ID NO. 1 or SEQ ID NO. 4; a heavy chain CDR2 region selected from SEQ ID NO. 2 or SEQ ID NO. 5; a heavy chain CDR3 region selected from SEQ ID NO. 3 or SEQ ID NO. 6; a light chain CDR1 region selected from SEQ ID NO. 7 or SEQ ID NO. 10; a light chain CDR2 region selected from SEQ ID NO. 8 or SEQ ID NO. 11; a light chain CDR3 region selected from SEQ ID NO 9 or SEQ ID NO 12.

In some embodiments of the present application, an isolated anti-PD-L1 antibody described herein comprises: a heavy chain CDR1 region having the amino acid sequence shown in SEQ ID NO. 1, a heavy chain CDR2 region having the amino acid sequence shown in SEQ ID NO. 2, a heavy chain CDR3 region having the amino acid sequence shown in SEQ ID NO. 3; and a light chain CDR1 region having the amino acid sequence shown in SEQ ID NO. 7, a light chain CDR2 region having the amino acid sequence shown in SEQ ID NO. 8, and a light chain CDR3 region having the amino acid sequence shown in SEQ ID NO. 9.

Each CDR region described herein and the various variants thereof described above are capable of specifically recognizing and binding to PD-L1, thereby effectively blocking signaling between PD-L1 and PD-1.

In some embodiments of the present application, the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain variable region having at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the amino acid sequence shown in SEQ ID NO. 13 or SEQ ID NO. 14; a light chain variable region having at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the amino acid sequence shown in SEQ ID NO. 15 or SEQ ID NO. 16.

In some embodiments of the present application, the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain variable region as shown in SEQ ID NO. 13; the light chain variable region as shown in SEQ ID NO. 15.

In some embodiments of the present application, the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain variable region as shown in SEQ ID NO. 14; the light chain variable region as shown in SEQ ID NO. 16.

In some embodiments of the present application, the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain amino acid sequence as shown in SEQ ID NO. 17; the light chain amino acid sequence is shown as SEQ ID NO. 18.

In some embodiments of the present application, the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain amino acid sequence as shown in SEQ ID NO. 19; the light chain amino acid sequence is shown as SEQ ID NO. 20.

In some embodiments of the present application, the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain amino acid sequence as shown in SEQ ID NO. 21; the light chain amino acid sequence is shown as SEQ ID NO. 18.

In a specific embodiment, the anti-PD-L1 humanized monoclonal antibodies provided herein comprise conservative substitution variants of one or more selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO: 21. anti-PD-L1 humanized monoclonal antibodies comprising the conservative substitution variants retain the ability to specifically recognize and bind PD-L1.

In some embodiments of the present application, the anti-PD-L1 antibody comprises a heavy chain Complementarity Determining Region (CDR) selected from the group consisting of a 13C5 or 5G11 antibody, and a light chain complementarity determining region selected from the group consisting of a 13C5 or 5G11 antibody. In one embodiment, the anti-PD-L1 antibodies described herein comprise a variable heavy chain selected from the group consisting of a ch5G11-hIgG1, a ch5G11-hIgG4, a ch13C5-hIgG1, a ch13C5-hIgG4 chimeric antibody, and a variable light chain selected from the group consisting of a ch5G11-hIgG1, a ch5G11-hIgG4, a ch13C5-hIgG1, a ch13C5-hIgG4 chimeric antibody. In one embodiment, the anti-PD-L1 antibodies described herein comprise a variable heavy chain selected from the group consisting of hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1, or hu5G11-hIgG4 humanized antibodies, and a variable light chain selected from the group consisting of hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1, or hu5G11-hIgG4 humanized antibodies. Reference may be made to the description of patent document WO2016022630 or CN107001463 a: the HCDR1 sequence of 13C5, ch13C5-hIgG1, ch13C5-hIgG4, hu13C5-hIgG1, or hu13C5-hIgG4 is SYGMS (SEQ ID NO: 4), the HCDR2 sequence is SISSGGSTYYPDSVKG (SEQ ID NO: 5), the HCDR3 sequence is GYDSGFAY (SEQ ID NO: 6), the LCDR1 sequence is ASQSVSTSSSSFMH (SEQ ID NO: 10), the LCDR2 sequence is YASNLES (SEQ ID NO: 11), and the LCDR3 sequence is QHSWEIPYT (SEQ ID NO: 12); the HCDR1 sequence of 5G11, ch5G11-hIgG1, ch5G11-hIgG4, hu5G11-hIgG1, or hu5G11-hIgG4 is TYGVH (SEQ ID NO: 1), the HCDR2 sequence is VIWRGVTTDYNAAFMS (SEQ ID NO: 2), the HCDR3 sequence is LGFYAMDY (SEQ ID NO: 3), the LCDR1 sequence is KASQSVSNDVA (SEQ ID NO: 7), the LCDR2 sequence is YAANRY (SEQ ID NO: 8), and the LCDR3 sequence is QQDYTSPYT (SEQ ID NO: 9). In one embodiment, hu5G11-hIgG1 is 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.

In some embodiments of the present application, the anti-PD-L1 antibody in the pharmaceutical combination may be selected from one or more. As used herein, the term "plurality" may be more than one, for example, two, three, four, five or more. For example, in some embodiments of the present application, the anti-PD-L1 antibody is selected from the group consisting of comprising the heavy chain variable region as set forth in SEQ ID NO. 13 and the light chain variable region as set forth in SEQ ID NO. 15, or from the group consisting of the heavy chain variable region as set forth in SEQ ID NO. 14 and the light chain variable region as set forth in SEQ ID NO. 16, or from a combination of the foregoing. For another example, the anti-PD-L1 antibody is selected from the heavy chain amino acid sequence set forth in SEQ ID NO. 17 and the light chain amino acid sequence set forth in SEQ ID NO. 18, or from the heavy chain amino acid sequence set forth in SEQ ID NO. 19 and the light chain amino acid sequence set forth in SEQ ID NO. 20, or from the heavy chain amino acid sequence set forth in SEQ ID NO. 21 and the light chain amino acid sequence set forth in SEQ ID NO. 18, or from a combination of any of the foregoing.

Pharmaceutical composition containing anti-PD-L1 antibody

In some embodiments of the present application, the pharmaceutical composition comprising an anti-PD-L1 antibody contains 600 to 2400mg of the anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises an anti-PD-L1 antibody selected from 600mg, 900mg, 1200mg, 1500mg, 1800mg, 2100mg, 2400mg, or any range formed by any of the above. In some embodiments, the pharmaceutical composition contains 600-2100 mg, or 900-1500 mg, of anti-PD-L1 antibody; wherein the pharmaceutical composition comprising said anti-PD-L1 antibody may be present in a multi-dose or unit-dose form.

In some embodiments of the present application, the pharmaceutical composition comprises 300mg, 600mg, or 1200mg of the anti-PD-L1 antibody. In some embodiments of the present application, a pharmaceutical composition formulated as a unit dose containing 300mg, 600mg, or 1200mg of an anti-PD-L1 antibody is provided.

In a specific embodiment, the pharmaceutical composition comprising an anti-PD-L1 antibody is a solution for injection. In some embodiments, the pharmaceutical composition comprising an anti-PD-L1 antibody is an aqueous solution for injection. In some embodiments of the present application, the anti-PD-L1 antibody-containing pharmaceutical composition comprises one or more of a buffer, an isotonicity adjusting agent, a stabilizer, and/or a surfactant. In particular, the anti-PD-L1 antibody-containing pharmaceutical composition comprises 1 to 150mg/mL of an anti-PD-L1 antibody (e.g., monoclonal antibody), 3 to 50mM buffer, 2 to 150mg/mL of an isotonicity modifier/stabilizer, and 0.01 to 0.8mg/mL of a surfactant, and has a pH of 4.5 to 6.8.

In some embodiments of the present application, the anti-PD-L1 antibody-containing pharmaceutical composition has an anti-PD-L1 mab concentration of 5-150 mg/mL, calculated as w/v; in some embodiments the concentration is 10 to 60mg/mL; in some embodiments the concentration is 10 to 30mg/mL. In some embodiments, the anti-PD-L1 mab is at a mass volume concentration of 10mg/mL, 20mg/mL, 30mg/mL, 40mg/mL, 50mg/mL, 60mg/mL, 70mg/mL, 80mg/mL, 90mg/mL, 100mg/mL, 110mg/mL, or 120mg/mL; in some embodiments, the concentration is 10mg/mL, 20mg/mL, 30mg/mL, 40mg/mL, 50mg/mL, or 60mg/mL; in some embodiments, the concentration is 10mg/mL, 20mg/mL, or 30mg/mL. In some embodiments, the anti-PD-L1 mab is at a mass volume concentration of 10mg/mL. In other embodiments, the anti-PD-L1 mab is 30mg/mL in mass volume concentration. In other embodiments, the anti-PD-L1 mab is 60mg/mL in mass volume concentration.

In some embodiments of the present application, the buffer is a histidine salt buffer. The histidine salt buffer concentration is 5 to 30mM, in some embodiments, 10 to 25mM; in some embodiments, the concentration is 10 to 20mM; in some embodiments, the concentration is 10 to 15mM. In some embodiments, the histidine salt buffer concentration is 5mM, 10mM, 15mM, 20mM, 25mM or 30mM. In some embodiments, the histidine salt buffer concentration is 10mM. In other embodiments, the histidine salt buffer concentration is 15mM. In other embodiments, the histidine salt buffer concentration is 20mM. Wherein the histidine salt buffer comprises histidine and hydrochloric acid.

In some embodiments of the present application, the isotonicity modifier/stabilizer is from 20 to 150mg/mL sucrose, calculated as w/v; in some embodiments, the isotonicity modifier/stabilizer is 40 to 100mg/mL sucrose; in some embodiments, the isotonicity modifier/stabilizer is 60 to 80mg/mL sucrose. In some embodiments, the sucrose is at a concentration of 40mg/mL, 50mg/mL, 60mg/mL, 70mg/mL, 80mg/mL, 90mg/mL, or 100mg/mL. In some embodiments, the sucrose is at a concentration of 60mg/mL. In some embodiments, the sucrose is at a concentration of 70mg/mL. In some embodiments, the sucrose is at a concentration of 80mg/mL. In some embodiments, the sucrose is at a concentration of 90mg/mL.

In some embodiments of the present application, the surfactant is selected from polysorbate 80, polysorbate 20, poloxamer 188; in some embodiments, the surfactant is selected from polysorbate 80 or polysorbate 20; in some embodiments, the surfactant is selected from polysorbate 80. In some embodiments, the concentration of the surfactant is 0.05 to 0.6mg/mL calculated as w/v; in some embodiments, the concentration is 0.1 to 0.4mg/mL; in some embodiments, the concentration is 0.2 to 0.3mg/mL.

In some embodiments of the present application, the surfactant is polysorbate 80 or polysorbate 20 at 0.01 to 0.8mg/mL calculated as w/v. In some embodiments, the surfactant is polysorbate 80 at 0.05-0.6 mg/mL; in some embodiments, the surfactant is polysorbate 80 at 0.1-0.4 mg/mL; in some embodiments, the surfactant is polysorbate 80 at 0.2-0.3 mg/mL; in some embodiments, the surfactant is polysorbate 80 at 0.2mg/mL. In some embodiments, the polysorbate 80 content of the pharmaceutical composition is 0.1mg/mL, 0.2mg/mL, 0.3mg/mL, 0.4mg/mL, 0.5mg/mL, or 0.6mg/mL; in some embodiments, the polysorbate 80 content of the pharmaceutical composition is 0.2mg/mL, 0.3mg/mL, 0.4mg/mL, or 0.5mg/mL; in some embodiments, the polysorbate 80 content of the pharmaceutical composition is 0.2mg/mL, 0.3mg/mL, or 0.4mg/mL; in some embodiments, the polysorbate 80 content of the pharmaceutical composition is 0.2mg/mL. In some embodiments, the polysorbate 80 content of the pharmaceutical composition is 0.1mg/mL. In other embodiments, the polysorbate 80 content of the pharmaceutical composition is 0.2mg/mL. In some embodiments, the polysorbate 80 content of the pharmaceutical composition is 0.3mg/mL. In other embodiments, the polysorbate 80 content of the pharmaceutical composition is 0.4mg/mL. In some embodiments, the polysorbate 80 content of the pharmaceutical composition is 0.5mg/mL.

In some embodiments of the present application, the aqueous solution of the pharmaceutical composition has a pH value selected from 4.0 to 6.8; in some embodiments, the pH is 4.5 to 6.5; in some embodiments, the pH is from 5.5 to 6.0; in some embodiments, the pH is 5.5. In some embodiments, the aqueous pharmaceutical composition has a pH of 4.5, 4.8, 5.0, 5.2, 5.4, 5.5, 5.6, 5.8, or 6.0, in some embodiments, the pH is 5.0, 5.2, 5.4, 5.5, or 5.6; in some embodiments, the pH is 5.5. In some embodiments, the aqueous pharmaceutical composition has a pH of 5.0. In some embodiments, the aqueous pharmaceutical composition has a pH of 5.2. In some embodiments, the aqueous pharmaceutical composition has a pH of 5.4. In some embodiments, the aqueous pharmaceutical composition has a pH of 5.5. In some embodiments, the aqueous pharmaceutical composition has a pH of 5.6. In some embodiments, the aqueous pharmaceutical composition has a pH of 5.8. In some embodiments, the aqueous pharmaceutical composition has a pH of 6.0.

In some embodiments of the present application, the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody having a mass-volume concentration of 20mg/mL, (b) sucrose having a mass-volume concentration of 70mg/mL, (c) polysorbate 80 having a mass-volume concentration of 0.1mg/mL, (d) histidine having a molar concentration of 20mM, (e) optionally, an appropriate amount of hydrochloric acid, and adjusting the pH of the composition to 5.0. In a specific embodiment of the present application, the pharmaceutical composition comprises: (a) anti-PD-L1 monoclonal antibody with a mass volume concentration of 20mg/mL, (b) sucrose with a mass volume concentration of 70mg/mL, (c) polysorbate 80 with a mass volume concentration of 0.1mg/mL, (d) histidine with a molar concentration of 20mM, (e) optionally appropriate amount of hydrochloric acid, and adjusting the pH value of the composition to 5.0.

In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody having a mass-volume concentration of 10mg/mL, (b) sucrose having a mass-volume concentration of 80mg/mL, (c) polysorbate 80 having a mass-volume concentration of 0.2mg/mL, (d) histidine having a molar concentration of 10mM, (e) optionally, an appropriate amount of hydrochloric acid, and adjusting the pH of the composition to 5.5.

In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody having a mass-volume concentration of 50mg/mL, (b) sucrose having a mass-volume concentration of 80mg/mL, (c) polysorbate 80 having a mass-volume concentration of 0.3mg/mL, (d) histidine having a molar concentration of 10mM, (e) optionally, an appropriate amount of hydrochloric acid, and adjusting the pH of the composition to 5.5.

In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody having a mass-volume concentration of 100mg/mL, (b) sucrose having a mass-volume concentration of 80mg/mL, (c) polysorbate 80 having a mass-volume concentration of 0.5mg/mL, (d) histidine having a molar concentration of 10mM, (e) optionally, an appropriate amount of hydrochloric acid, and adjusting the pH of the composition to 5.5.

In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody having a mass-volume concentration of 30mg/mL, (b) sucrose having a mass-volume concentration of 80mg/mL, (c) polysorbate 80 having a mass-volume concentration of 0.2mg/mL, (d) histidine having a molar concentration of 10mM, (e) optionally, an appropriate amount of hydrochloric acid, and adjusting the pH of the composition to 5.5.

In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody having a mass-volume concentration of 60mg/mL, (b) sucrose having a mass-volume concentration of 80mg/mL, (c) polysorbate 80 having a mass-volume concentration of 0.2mg/mL, (d) histidine having a molar concentration of 10mM, (e) optionally, an appropriate amount of hydrochloric acid, and adjusting the pH of the composition to 5.5.

In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody having a mass-volume concentration of 10mg/mL, (b) sucrose having a mass-volume concentration of 70mg/mL, (c) polysorbate 80 having a mass-volume concentration of 0.4mg/mL, (d) histidine having a molar concentration of 20mM, (e) optionally, an appropriate amount of acetic acid, and adjusting the pH of the composition to 6.5.

In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) anti-PD-L1 monoclonal antibody with the mass volume concentration of 10mg/mL, (b) sucrose with the mass volume concentration of 80mg/mL, (c) polysorbate 80 with the mass volume concentration of 0.2mg/mL, (d) histidine with the molar concentration of 20mM, (e) optionally proper amount of hydrochloric acid, and adjusting the pH value of the composition to 5.5.

In another specific embodiment of the present application, the pharmaceutical composition is a water-soluble injection; in some embodiments, the water-soluble injection includes, but is not limited to, a water-soluble formulation that has not been lyophilized or a water-soluble formulation that has been reconstituted from a lyophilized powder. In other embodiments, the pharmaceutical composition is a lyophilized formulation. The lyophilized preparation refers to a preparation prepared by subjecting an aqueous solution to a lyophilization process in which a substance is first frozen, then the amount of solvent is reduced by sublimation (primary drying process) and then the amount of solvent is reduced by desorption (secondary drying process) until the amount of solvent is a value that no longer supports biological activity or chemical reaction. The lyophilized formulations of the present application may also be dried by other methods known in the art, such as spray drying and bubble drying (bubble drying).

Pharmaceutical combination

In one aspect, the present application provides a pharmaceutical combination for treating esophageal cancer comprising an anti-PD-L1 antibody and a chemotherapeutic agent. In some embodiments of the present application, the pharmaceutical combination comprising an anti-PD-L1 antibody and a chemotherapeutic agent is a fixed combination. In some embodiments, the fixed combination is in the form of a solid pharmaceutical composition or a liquid pharmaceutical composition. In some embodiments of the present application, the pharmaceutical combination comprising an anti-PD-L1 antibody and a chemotherapeutic agent is a non-fixed combination. In some embodiments, the anti-PD-L1 antibody and the chemotherapeutic agent in the non-fixed combination are each in the form of a pharmaceutical composition. In some embodiments, each of the anti-PD-L1 antibody and the chemotherapeutic agent in the non-fixed combination (e.g., one treatment cycle of 21 days) is in the form of a pharmaceutical composition.

In some embodiments of the present application, the pharmaceutical combination comprising an anti-PD-L1 antibody and a chemotherapeutic agent comprises:

i) An anti-PD-L1 antibody; in one embodiment, the anti-PD-L1 antibody comprises a heavy chain Complementarity Determining Region (CDR) selected from the group consisting of a 13C5 or 5G11 antibody, and a light chain complementarity determining region selected from the group consisting of a 13C5 or 5G11 antibody; in one embodiment, the anti-PD-L1 antibody comprises a variable heavy chain selected from the group consisting of a ch5G 11-igg 1, a ch5G 11-igg 4, a ch13C 5-igg 1, a ch13C 5-igg 4 chimeric antibody, and a variable light chain selected from the group consisting of a ch5G 11-igg 1, a ch5G 11-igg 4, a ch13C 5-igg 1, a ch13C 5-igg 4 chimeric antibody; in one embodiment, the anti-PD-L1 antibody comprises a variable heavy chain selected from the group consisting of hu13C 5-igg 1, hu13C 5-igg 4, hu5G 11-igg 1, or hu5G 11-igg 4 humanized antibodies, and a variable light chain selected from the group consisting of hu13C 5-igg 1, hu13C 5-igg 4, hu5G 11-igg 1, or hu5G 11-igg 4 humanized antibodies; in one embodiment, the anti-PD-L1 antibody is selected from the group consisting of complementarity determining regions comprising the following, as described in patent document WO2016022630 or CN107001463 a: 13C5, ch13C5-hIgG1, ch13C5-hIgG4, hu13C5-hIgG1, or hu13C5-hIgG4, the HCDR1 sequence is SYGMS, the HCDR2 sequence is SISSGGSTYYPDSVKG, HCDR, the LCDR1 sequence is ASQSVSTSSSSFMH, LCDR, the YASNLES, the LCDR3 sequence is QHSWEIPYT; the HCDR1 sequence of 5G11, ch5G11-hIgG1, ch5G11-hIgG4, hu5G11-hIgG1, or hu5G11-hIgG4 is TYGVH, the HCDR2 sequence is VIWRGVTTDYNAAFMS, HCDR sequence is LGFYAMDY, the LCDR1 sequence is KASQSVSNDVA, LCDR sequence is YAANRY, and the LCDR3 sequence is QQDYTSPYT;

ii) platinum-based antitumor agents, and/or taxane-based antitumor agents.

In some embodiments of the present application, the pharmaceutical combination comprising an anti-PD-L1 antibody and a chemotherapeutic agent comprises a pharmaceutical composition comprising 600-2400 mg of an anti-PD-L1 antibody. Wherein the pharmaceutical composition containing the anti-PD-L1 antibody is in single dose or multiple doses. In some embodiments of the present application, the pharmaceutical combination comprising an anti-PD-L1 antibody and a chemotherapeutic agent comprises a pharmaceutical composition comprising 1200mg of the anti-PD-L1 antibody provided in a multi-dose form.

In some embodiments of the present application, the anti-PD-L1 antibody-containing pharmaceutical combination with a chemotherapeutic agent comprises an anti-PD-L1 antibody-containing pharmaceutical composition having an anti-PD-L1 antibody concentration of 10-60 mg/mL. In some embodiments of the present application, the anti-PD-L1 antibody-and chemotherapeutic drug-containing pharmaceutical combination comprises an anti-PD-L1 antibody-containing pharmaceutical composition having an anti-PD-L1 antibody concentration of 30 mg/mL.

In some embodiments of the present application, the pharmaceutical combination is packaged in the same kit, which further includes instructions for the combined use of the PD-L1 antibody and a chemotherapeutic agent to treat esophageal cancer.

In some embodiments of the present application, the pharmaceutical combination comprises an anti-PD-L1 antibody, an Luoti ni or a pharmaceutically acceptable salt thereof, and a chemotherapeutic agent. In some embodiments of the present application, the pharmaceutical combination comprising an anti-PD-L1 antibody, an Luoti ni or a pharmaceutically acceptable salt thereof and a chemotherapeutic agent is a fixed combination. In some embodiments, the fixed combination is in the form of a solid pharmaceutical composition or a liquid pharmaceutical composition. In some embodiments of the present application, the pharmaceutical combination comprising an anti-PD-L1 antibody, an Luoti ni or a pharmaceutically acceptable salt thereof, and a chemotherapeutic agent is a non-fixed combination. In some embodiments, the anti-PD-L1 antibody, an Luoti ni or a pharmaceutically acceptable salt thereof and the chemotherapeutic agent in the non-fixed combination are each in the form of a pharmaceutical composition. In some embodiments, each of the anti-PD-L1 antibody, an Luoti ni or a pharmaceutically acceptable salt thereof, and the chemotherapeutic agent in the non-fixed combination is in the form of a pharmaceutical composition.

In some embodiments, a pharmaceutical combination is provided that includes an anti-PD-L1 antibody and An Luoti Ni in a weight ratio of (0.35-29): 1, preferably (3.5-29): 1, more preferably (3.5-14.5): 1, most preferably (7-14.5): 1. Wherein the anti-PD-L1 antibody and An Luoti can be packaged separately or together. And wherein An Luoti can be packaged in multiple aliquots (e.g., 2, 7, 14, 28, or more aliquots).

In some embodiments of the present application, the pharmaceutical combination comprising an anti-PD-L1 antibody, an Luoti ni or a pharmaceutically acceptable salt thereof and a chemotherapeutic agent comprises:

ii) An Luoti Ni or a pharmaceutically acceptable salt thereof;

iii) Platinum antitumor drugs, and/or taxane antitumor drugs.

In some embodiments of the present application, the pharmaceutical combination comprises an anti-PD-L1 antibody, an Luoti ni or a pharmaceutically acceptable salt thereof, and a chemotherapeutic agent; alternatively, it includes a pharmaceutical combination of the above anti-PD-L1 antibody, an Luoti ni or a pharmaceutically acceptable salt thereof, and a chemotherapeutic agent.

In some embodiments of the present application, the pharmaceutical combination comprising an anti-PD-L1 antibody, an Luoti ni or a pharmaceutically acceptable salt thereof, and a chemotherapeutic agent comprises a pharmaceutical composition comprising an anti-PD-L1 antibody, a pharmaceutical composition comprising An Luoti ni or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising a chemotherapeutic agent. In some embodiments of the present application, the pharmaceutical combination is packaged in the same kit, which further comprises instructions for the combined use of PD-L1 antibody, an Luoti ni or a pharmaceutically acceptable salt thereof and a chemotherapeutic agent for the treatment of esophageal cancer.

In some embodiments of the present application, the pharmaceutical combination comprising an anti-PD-L1 antibody, an Luoti ni or a pharmaceutically acceptable salt thereof, and a chemotherapeutic agent comprises: a pharmaceutical composition comprising 600-2400 mg of an anti-PD-L1 antibody, the single dose being 6mg, 8mg, 10mg and/or 12mg of An Luoti ni or a pharmaceutically acceptable salt thereof. Wherein the pharmaceutical composition containing the anti-PD-L1 antibody and the pharmaceutical composition containing An Luoti Ni or pharmaceutically acceptable salt thereof are in single dose or multiple doses. In some embodiments, the pharmaceutical combination comprises: a pharmaceutical composition comprising 1200mg of an anti-PD-L1 antibody provided in a multi-dose form, and a single dose of 6mg, 8mg, 10mg and/or 12mg of a pharmaceutical composition comprising An Luoti ni or a pharmaceutically acceptable salt thereof.

In some embodiments of the present application, the pharmaceutical combination comprising an anti-PD-L1 antibody, an Luoti ni or a pharmaceutically acceptable salt thereof, and a chemotherapeutic agent comprises: the anti-PD-L1 antibody concentration is 10-60mg/mL, and the single dose is 6mg, 8mg, 10mg and/or 12mg of the pharmaceutical composition containing An Luoti Ni or pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical combination comprises: a pharmaceutical composition comprising an anti-PD-L1 antibody at a concentration of 30mg/mL, and a single dose of 8mg, 10mg and/or 12mg of a pharmaceutical composition comprising An Luoti ni or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical combination comprises an anti-PD-L1 antibody and An Luoti Ni in a weight ratio of (0.35-29): 1, preferably (3.5-29): 1, more preferably (3.5-14.5): 1, most preferably (7-14.5): 1. Wherein the anti-PD-L1 antibody and An Luoti can be packaged separately or together. And wherein An Luoti can be packaged in multiple aliquots (e.g., 2, 7, 14, 28, or more aliquots).

In another aspect, the present application provides a pharmaceutical combination for treating esophageal cancer comprising a first pharmaceutical combination administered to a patient in need thereof during a first treatment phase, and optionally, a second pharmaceutical combination administered to a patient in need thereof during a second treatment phase. In some embodiments of the present application, the first pharmaceutical combination may be selected from one or more of the above-mentioned pharmaceutical combinations.

In some embodiments, the first pharmaceutical combination comprises an anti-PD-L1 antibody and a chemotherapeutic agent. In some embodiments, the first pharmaceutical combination comprises an anti-PD-L1 antibody, an Luoti ni or a pharmaceutically acceptable salt thereof, and a chemotherapeutic agent.

In some embodiments, the second pharmaceutical combination comprises an anti-PD-L1 antibody. In some embodiments, the second pharmaceutical combination comprises an anti-PD-L1 antibody, and An Luoti ni or a pharmaceutically acceptable salt thereof.

Kit for detecting a substance in a sample

In yet another aspect, the present application provides a kit for treating esophageal cancer comprising a pharmaceutical combination of an anti-PD-L1 antibody and a chemotherapeutic agent, and optionally An Luoti ni or a pharmaceutically acceptable salt thereof, and instructions for use in combination with treatment of esophageal cancer; in some embodiments, a kit for treating esophageal cancer is provided, the kit comprising a pharmaceutical composition comprising an anti-PD-L1 antibody, and/or a paclitaxel pharmaceutical composition and/or a cisplatin pharmaceutical composition, and optionally a pharmaceutical composition comprising An Luoti ni or a pharmaceutically acceptable salt thereof, and instructions for use in combination with treating esophageal cancer; alternatively, the kit comprises a pharmaceutical combination of the present application, and instructions for use in combination with treatment of esophageal cancer.

Use of the same

In yet another aspect, the present application also provides the use of a pharmaceutical combination of the present application, or a kit of the present application, for the manufacture of a medicament for treating esophageal cancer in a patient. The present application also provides a method of treating esophageal cancer in a patient comprising administering to a patient in need thereof an effective amount of a pharmaceutical combination of the present application, or a kit of the present application. The present application also provides the use of the pharmaceutical combination of the present application, or the kit of the present application, for treating esophageal cancer in a patient. The pharmaceutical combination, or kit, is as previously described. Alternatively, the application also provides a pharmaceutical combination of the application, or a kit of the application, for treating esophageal cancer in a patient.

In some embodiments of the present application, the anti-PD-L1 antibody and the chemotherapeutic agent, and optionally An Luoti ni or a pharmaceutically acceptable salt thereof, are each in a pharmaceutical composition for simultaneous, sequential or separate administration.

In some embodiments of the present application, the anti-PD-L1 antibody and the chemotherapeutic agent, and optionally An Luoti ni or a pharmaceutically acceptable salt thereof, are each administered as separate administrations. In some embodiments, the anti-PD-L1 antibody and the chemotherapeutic agent, and optionally An Luoti ni or a pharmaceutically acceptable salt thereof, are administered separately on the same or different dosing schedules. In some embodiments, the anti-PD-L1 antibody and the chemotherapeutic agent, and optionally An Luoti ni or a pharmaceutically acceptable salt thereof, are administered separately on different dosing schedules.

In some embodiments of the present application, the anti-PD-L1 antibody may be administered weekly (q 1 w), every 2 weeks (q 2 w), every 3 weeks (q 3 w), or every 4 weeks (q 4 w). In a specific embodiment, the anti-PD-L1 antibody is administered once every 3 weeks. In some embodiments, the anti-PD-L1 antibody is administered at a dose of 600-2400 mg per time.

In some embodiments of the present application, the An Luoti Ni or pharmaceutically acceptable salt thereof can be administered in a dose of 6mg, 8mg, 10mg, or 12mg once daily, for 2 weeks, with a dosing regimen of 1 week down. At this time, a dosing cycle was performed every 3 weeks.

In some embodiments of the present application, the chemotherapeutic agent may be administered according to known dosing regimens.

In some embodiments of the present application, the anti-PD-L1 antibody and the chemotherapeutic agent, and optionally An Luoti n or a pharmaceutically acceptable salt thereof, have the same or different dosing cycles, respectively. In some specific embodiments, the anti-PD-L1 antibody and the chemotherapeutic agent, and optionally An Luoti ni or a pharmaceutically acceptable salt thereof, have the same dosing period, e.g., one dosing period every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks.

In some embodiments of the present application, the dosing regimen of the pharmaceutical combination, or the use or method of treatment, is one dosing cycle for 21 days, the PD-L1 antibody and the chemotherapeutic agent are administered on the first day of each dosing cycle, wherein the chemotherapeutic agent may be administered according to a known dosing regimen, and optionally An Luoti ni or a pharmaceutically acceptable salt thereof, daily on days 1-14 of each cycle. In a specific embodiment, the PD-L1 antibody is administered once on the first day of each cycle, and/or paclitaxel is administered on day 1 of each cycle, and/or cisplatin is administered on days 1-3 of each cycle. In a specific embodiment, the PD-L1 antibody is administered once on the first day of each cycle, an Luoti ni or a pharmaceutically acceptable salt thereof once daily on days 1-14 of each cycle, and/or paclitaxel on day 1 of each cycle, and/or cisplatin on days 1-3 of each cycle.

In some embodiments of the present application, the use or method of treatment, wherein the anti-PD-L1 antibody may comprise a dose selected from the group consisting of 0.01 to 40mg/kg, 0.1 to 30mg/kg, 0.1 to 20mg/kg, 0.1 to 15mg/kg, 0.1 to 10mg/kg, 1 to 15mg/kg, 1 to 20mg/kg, 1 to 3mg/kg, 3 to 10mg/kg, 3 to 15mg/kg, 3 to 20mg/kg, 3 to 30mg/kg, 10 to 20mg/kg, or 15 to 20 mg/kg; or in a dosage of 60mg to 2400mg, 90mg to about 1800mg, 120mg to 1500mg, 300mg to 900mg, 600mg to 900mg, 300mg to 1200mg, 600mg to 1200mg, or 900mg to 1200 mg.

In some embodiments of the use or method of treatment, 21 days is a dosing cycle and 1200mg of PD-L1 antibody is administered on the first day of each cycle. In some embodiments, 21 days is a dosing cycle, and 6mg, 8mg, 10mg, and/or 12mg of An Luoti ni are administered daily on days 1-14 of each cycle.

In some embodiments of the present application, the anti-PD-L1 antibody and An Luoti ni are administered to the subject in a weight ratio of (0.35-29): 1, preferably (3.5-29): 1, more preferably (3.5-14.5): 1, most preferably (7-14.5): 1, in one treatment cycle every three weeks, wherein the anti-PD-L1 antibody and An Luoti ni are administered in a single dose and multiple dose, respectively.

In some embodiments of the present application, the dosing regimen of the pharmaceutical combination, or the use or method of treatment, comprises, in a repeat cycle, administering an anti-PD-L1 antibody and a chemotherapeutic agent for a first treatment phase; then, optionally, in a repeat cycle, an anti-PD-L1 antibody is administered for a second treatment phase. In some embodiments, the first treatment phase and the second treatment phase are each 21 days of a dosing cycle. In some embodiments, during the first treatment phase, PD-L1 antibody and a chemotherapeutic agent are administered on the first day of each dosing cycle, wherein the chemotherapeutic agent may be administered according to a known dosing regimen. In some embodiments, the chemotherapeutic agent is selected from one or more of a platinum-based anti-tumor agent and a taxane-based anti-tumor agent. In some embodiments, the chemotherapeutic agent is selected from cisplatin and paclitaxel. In a specific embodiment, the PD-L1 antibody is administered once on the first day of each cycle, and/or paclitaxel is administered on day 1 of each cycle, and/or cisplatin is administered on days 1-3 of each cycle. In some embodiments, the treatment period of the first treatment stage is from 1 to 10 treatment periods, further preferably from 4 to 6 treatment periods, most preferably 6 treatment periods.

In some embodiments, during the second treatment phase, PD-L1 antibody is administered on the first day of each dosing cycle.

In some embodiments of the present application, the dosing regimen of the pharmaceutical combination, or the use or method of treatment, comprises, in a repeat cycle, administering an anti-PD-L1 antibody, an Luoti ni or a pharmaceutically acceptable salt thereof, and a chemotherapeutic agent for a first treatment phase; then, optionally, in a repeat cycle, an anti-PD-L1 antibody, and An Luoti ni or a pharmaceutically acceptable salt thereof, are administered for a second treatment phase. In some embodiments, the first treatment phase and the second treatment phase are each 21 days of a dosing cycle. In some embodiments, during the first treatment phase, PD-L1 antibody is administered on the first day of each dosing cycle, an Luoti ni or a pharmaceutically acceptable salt thereof is administered daily on days 1-14 of each cycle, and chemotherapeutic agents may be administered according to known dosing schedules. In some embodiments, the chemotherapeutic agent is selected from one or more of a platinum-based anti-tumor agent and a taxane-based anti-tumor agent. In some embodiments, the chemotherapeutic agent is selected from cisplatin and paclitaxel. In a specific embodiment, the PD-L1 antibody is administered once on the first day of each cycle, an Luoti ni or a pharmaceutically acceptable salt thereof once daily on days 1-14 of each cycle, and/or paclitaxel on day 1 of each cycle, and/or cisplatin on days 1-3 of each cycle. In some embodiments, the treatment period of the first treatment stage is from 1 to 10 treatment periods, further preferably from 4 to 6 treatment periods, most preferably 6 treatment periods.

In some embodiments, paclitaxel is present at 135-175 mg/m ² Is preferably administered at a dose of 135mg/m ² Is administered in a dosage of (a).

In some embodiments, cisplatin is present at 50 to 100mg/m ² Is preferably administered in a dosage of 60 to 75mg/m ² Is administered in a dosage of (a).

In some embodiments, during the second treatment phase, PD-L1 antibody is administered on the first day of each dosing cycle, and An Luoti ni or a pharmaceutically acceptable salt thereof is administered daily on days 1-14 of each cycle.

Esophageal cancer

In some embodiments of the present application, the esophageal cancer is unresectable and/or advanced and/or recurrent and/or metastatic esophageal cancer; in some embodiments, the esophageal cancer is unresectable locally advanced esophageal cancer; in some embodiments, the esophageal cancer is unresectable recurrent esophageal cancer; in some embodiments, the esophageal cancer is unresectable metastatic esophageal cancer; in some embodiments, the esophageal cancer is refractory esophageal cancer.

In some embodiments of the present application, the esophageal cancer includes, but is not limited to, esophageal squamous cell carcinoma, esophageal adenocarcinoma, esophageal adenosquamous carcinoma. In some embodiments, the esophageal cancer is esophageal squamous cell carcinoma. In some embodiments, the esophageal cancer is unresectable locally advanced esophageal squamous cell carcinoma; in some embodiments, the esophageal cancer is unresectable recurrent or metastatic esophageal squamous cell carcinoma. In some embodiments, the esophageal cancer comprises primary unresectable recurrent or metastatic esophageal squamous cell carcinoma.

In some embodiments of the present application, the patient with esophageal cancer has not previously received systemic treatment.

In some embodiments, the patient with esophageal cancer has previously been treated with at least one chemotherapeutic agent; in some embodiments, the patient with esophageal cancer has previously received treatment with at least one chemotherapeutic agent and failed treatment; in some embodiments, the patient with esophageal cancer has previously received neoadjuvant/curative therapy. In some embodiments, the patient with esophageal cancer has previously received adjuvant/curative treatment. In some embodiments, the patient with esophageal cancer has previously relapsed after having received neoadjuvant/curative treatment. In some embodiments, the patient with esophageal cancer has relapsed after having received adjuvant/curative treatment. In some embodiments, the (neo) adjuvant/curative treatment includes, but is not limited to, chemotherapy, radiation therapy, surgical treatment.

Mode of administration

The following is not intended to limit the manner of administration of the pharmaceutical combinations of the present application.

The components of the pharmaceutical combinations of the present application may each be administered independently, or some or all of them together, in a suitable variety of ways, including, but not limited to, oral or parenteral (via intravenous, intramuscular, topical or subcutaneous routes). In some embodiments, the components of the pharmaceutical combinations of the present application may each be administered orally or by injection, e.g., intravenously or intraperitoneally, independently, or in combination with some or all of them.

The components of the pharmaceutical combinations of the present application may each independently, or some or all of them together, be in a suitable dosage form, including, but not limited to, tablets, troches, pills, capsules (e.g., hard, soft, enteric, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions, and dosage forms of sustained release formulations for oral or non-oral administration.

The components of the pharmaceutical combinations of the present application may each independently, or some or all of them together contain a pharmaceutically acceptable carrier and/or excipient.

Dosing regimen

For the drug combination of the present application, or the dosing regimen of the kit of the present application, the dosing regimen comprises a first treatment stage, optionally a second treatment stage.

The dosing regimen described herein is also applicable to the use of the medicaments described herein for the manufacture of a medicament for the treatment of esophageal cancer in a patient, a method of treating esophageal cancer in a patient, and a use for treating esophageal cancer in a patient.

In some embodiments of the present application, the first treatment phase comprises 1 to 10 treatment cycles, preferably comprises 2 to 8 treatment cycles, further preferably comprises 4 to 6 treatment cycles, most preferably comprises 6 treatment cycles.

In some embodiments of the present application, the second treatment phase comprises 2 to 20 treatment cycles. In some embodiments, the second treatment phase continues until clinical benefit is lost or toxicity is intolerable or efficacy is assessed as PD or the researcher deems it unsuitable for continued administration.

In some embodiments of the present application, the treatment period is 14 days to 42 days; in some embodiments, the treatment period is 14 days, 21 days, 28 days, 35 days, or 42 days; in some embodiments, the treatment period is 21 days. In some specific embodiments, the first treatment phase has the same treatment cycle as the second treatment phase. In some specific embodiments, the treatment period (e.g., a single treatment period) for both the first treatment phase and the second treatment phase is 21 days.

In some embodiments of the present application, the anti-PD-L1 antibody is administered once on days 1, 2, 3, 4, 5, 6, or 7 of each treatment cycle, preferably once on day 1 of each treatment cycle.

In some embodiments of the present application, the An Luoti Ni or pharmaceutically acceptable salt thereof is administered continuously on days 1-7, 7-14, 1-14, or 7-21 of each treatment cycle, preferably on days 1-14 of each treatment cycle.

In some embodiments of the present application, the taxane anti-tumor agent is administered once on days 1, 2, 3, 4, 5, 6, or 7 of each treatment cycle, preferably once on day 1 of each treatment cycle.

In some embodiments of the present application, the platinum-based anti-tumor agent is administered continuously on days 1-3, 1-4, 1-5, 1-6, 1-7, 2-4, 2-5, 2-6, 2-7, 3-5, 3-6, 3-7, 4-6, 4-7, or 5-7 of each treatment cycle, preferably continuously on days 1-3 of each treatment cycle.

In some embodiments of the present application, the dosing regimen of the first treatment stage comprises: 1) anti-PD-L1 antibody is administered once a day within days 1-7 of each treatment cycle; and optionally, 2) a taxane antitumor drug once a day within days 1-7 of each treatment cycle; and optionally, 3) a platinum anti-tumor agent is administered continuously on days 1-7 of each treatment cycle; and optionally 4) An Luoti Ni or a pharmaceutically acceptable salt thereof, is administered continuously on days 1-28 of each treatment cycle.

In some embodiments of the present application, the dosing regimen of the first treatment stage comprises: 1) anti-PD-L1 antibody is administered once on day 1 of each treatment cycle; and optionally, 2) a taxane antitumor drug is administered once on day 1 of each treatment cycle; and optionally, 3) platinum anti-tumor is administered continuously on days 1-3 of each treatment cycle; and optionally 4) An Luoti Ni or a pharmaceutically acceptable salt thereof, is administered continuously on days 1-14 of each treatment cycle.

In some embodiments of the present application, the dosing regimen of the first treatment stage comprises: 1) anti-PD-L1 antibody is administered once on day 1 of each treatment cycle; and optionally, 2) paclitaxel is administered once on day 1 of each treatment cycle; and optionally, 3) cisplatin is administered continuously on days 1-3 of each treatment cycle; and optionally 4) An Luoti Ni or a pharmaceutically acceptable salt thereof, is administered continuously on days 1-14 of each treatment cycle.

In some embodiments of the present application, the dosing regimen of the first treatment stage comprises: 1) anti-PD-L1 antibody is administered once on day 1 of each treatment cycle; and 2) taxane antitumor drug administration once on day 1 of each treatment cycle; and, 3) platinum anti-tumor drug is continuously administered on days 1-3 of each treatment cycle; and optionally 4) An Luoti Ni or a pharmaceutically acceptable salt thereof, is administered continuously on days 1-14 of each treatment cycle.

In some embodiments of the present application, the dosing regimen of the first treatment stage comprises: 1) anti-PD-L1 antibody is administered once on day 1 of each treatment cycle; and 2) paclitaxel is administered once on day 1 of each treatment cycle; and, 3) cisplatin is administered continuously on days 1-3 of each treatment cycle; and optionally 4) An Luoti Ni or a pharmaceutically acceptable salt thereof, is administered continuously on days 1-14 of each treatment cycle.

In some embodiments of the present application, the dosing regimen of the second treatment stage comprises: 1) anti-PD-L1 antibody is administered once a day within days 1-7 of each treatment cycle; optionally, 2) An Luoti ni or a pharmaceutically acceptable salt thereof is administered continuously on days 1-28 of each treatment cycle.

In some embodiments of the present application, the dosing regimen of the second treatment stage comprises: 1) anti-PD-L1 antibody is administered once on day 1 of each treatment cycle; and 2) An Luoti Ni or a pharmaceutically acceptable salt thereof, are administered continuously on days 1-14 of each treatment cycle.

In some embodiments of the present application, the dosing regimen of the second treatment stage comprises: 1) The anti-PD-L1 antibody hu5G11-hIgG1 was administered once on day 1 of each treatment cycle; 2) An Luoti the nim dihydrochloride is administered continuously on days 1-14 of each treatment cycle.

Technical effects

In some embodiments, the pharmaceutical combinations of the present application can safely and effectively treat esophageal cancer, particularly unresectable and/or advanced and/or recurrent and/or metastatic esophageal cancer. In some embodiments, the pharmaceutical combinations of the present application can safely and effectively treat esophageal squamous cell carcinoma, particularly unresectable and/or advanced and/or recurrent and/or metastatic esophageal squamous cell carcinoma. In some embodiments, the pharmaceutical combinations of the present application may provide a treatment with greater tolerability in a patient, with better anti-tumor effects, and/or fewer adverse reactions and/or complications than either or both of the drugs administered alone. In some embodiments, the pharmaceutical combinations of the present application exhibit superior anti-tumor synergy in the treatment of esophageal cancer.

In some embodiments, patients with esophageal cancer significantly lengthen the patient's median PFS (progression free survival) after receiving the drug combination therapy of the present application. In some embodiments, the median PFS of the patient reaches or exceeds 5.5 months after receiving the treatment; up to or exceeding 6 months; up to or exceeding 6.5 months; up to or exceeding 7 months; up to or exceeding 8 months; up to or exceeding 9 months.

In some embodiments, esophageal cancer patients significantly lengthen the ORR (objective remission rate) of the patient after receiving the drug combination therapy of the present application. In some embodiments, the ORR of the patient reaches or exceeds 20% after receiving the treatment; up to or exceeding 30%; up to or exceeding 35%; up to or exceeding 40%; up to or exceeding 50%; up to or exceeding 60%; up to or exceeding 70%; up to or exceeding 80%. In some embodiments, the patient with esophageal cancer has an ORR of 70% or more after receiving a drug combination therapy of the present application comprising an anti-PD-L1 antibody, an Luoti ni or a pharmaceutically acceptable salt thereof, and a chemotherapeutic; up to or exceeding 75%; up to or exceeding 80%; up to or exceeding 90%.

Definition and description

The following terms used in this application have the following meanings, unless otherwise indicated. A particular term, unless otherwise defined, shall not be construed as being ambiguous or otherwise unclear, but shall be construed in accordance with the ordinary meaning in the art. When trade names are present in the present application, it is intended to refer to their corresponding commercial products or active ingredients thereof.

Herein, unless otherwise indicated, references to the amount of An Luoti Ni or a pharmaceutically acceptable salt thereof refer to the amount of An Luoti Ni free base of the active ingredient.

The term "dose" refers to a dose administered to a patient irrespective of the weight or Body Surface Area (BSA) of the patient, unless otherwise indicated. For example, 60kg of humans and 100kg of humans will receive the same dose of antibody (e.g., 240mg of anti-PD-1 antibody).

Herein, "complete remission" (CR) refers to the disappearance of all target lesions.

Herein, "partial remission" (PR) refers to a reduction in the overall diameter of the target lesion by more than 30% from the baseline overall diameter.

Herein, "disease progression" (PD) refers to an increase in the overall diameter of a target lesion by 20% or more as compared to the minimum of the overall diameter present in the study (including the baseline overall diameter if it is the minimum in the study). In addition to a relative increase of more than 20%, the absolute value of the total diameter must also be increased by more than 5 mm. The appearance of one or more new lesions should also be considered as disease progression.

Herein, "disease stabilization" (SD) refers to a criterion of focal shrinkage, but insufficient PR; or increased lesions, but insufficient criteria for PD, with minimum diameter as a reference in the trial.

Herein, "optimal efficacy" refers to the best efficacy at all time points from the initial evaluation, through the last evaluation.

As used herein, the term "pharmaceutical combination" refers to a combination of two or more active ingredients administered simultaneously or sequentially (either as the respective active ingredients themselves or as derivatives, prodrugs or compositions of their respective pharmaceutically acceptable salts or esters). The active substances may each be administered to the patient simultaneously as a single formulation, or sequentially in any order, each as a single formulation.

As used herein, the term "antibody" refers to a binding protein having at least one antigen binding domain. The antibodies and fragments thereof of the present application may be whole antibodies or any fragment thereof. Thus, antibodies and fragments of the present application include monoclonal antibodies or fragments thereof and antibody variants or fragments thereof, as well as immunoconjugates. Examples of antibody fragments include Fab fragments, fab 'fragments, F (ab') 2 fragments, fv fragments, isolated CDR regions, single chain Fv molecules (scFv), fd fragments and other antibody fragments known in the art. Antibodies and fragments thereof may also include recombinant polypeptides, fusion proteins, and bispecific antibodies. The anti-PD-L1 antibodies and fragments thereof described herein may be of the IgG1, igG2, igG3 or IgG4 isotype. The term "isotype" refers to the type of antibody encoded by the heavy chain constant region gene. In one embodiment, the anti-PD-L1 antibodies and fragments thereof described herein are of the IgG1 or IgG4 isotype. The anti-PD-L1 antibodies and fragments thereof of the present application may be derived from any species including, but not limited to, mice, rats, rabbits, primates, llamas, and humans. The anti-PD-L1 antibody and fragments thereof may be chimeric, humanized or fully human antibodies. In one embodiment, the anti-PD-L1 antibody is an antibody produced by a mouse-derived hybridoma cell line. Thus, 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 the following antibodies: the antibodies contain Complementarity Determining Regions (CDRs) derived from a non-human antibody; and framework and constant regions derived from human antibodies. For example, an anti-PD-L1 antibody described herein can comprise CDRs derived from one or more murine antibodies as well as human framework and constant regions. Thus, in one embodiment, the humanized antibodies described herein bind to the same epitope on PD-L1 as the murine antibody from which the CDRs of the antibodies are derived. In some embodiments, the anti-PD-L1 antibody is a humanized antibody. Additional anti-PD-L1 antibodies or variants thereof comprising heavy and light chain CDRs provided herein can be generated using any human framework sequences and are also included in the present application. In one embodiment, framework sequences suitable for use in the present application include those framework sequences that are similar in structure to the framework sequences provided herein. Additional modifications may 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 to remove T cell epitopes; or reverting the mutation to a residue in the original germline sequence. In some embodiments, such modifications include those corresponding to the mutations exemplified herein, including back mutations to germline sequences. For example, in one embodiment, one or more amino acids in the human framework regions of VH and/or VL of a humanized antibody described herein are back mutated to corresponding amino acids in a parent murine antibody. For example, for the VH and VL of humanized 5G11 and humanized 13C5, several sites of framework amino acids of the above template human antibodies were back mutated to the corresponding amino acid sequences in the mouse 5G11 and 13C5 antibodies. In one embodiment, the amino acids at positions 53 and/or 60 and/or 67 of the light chain variable region are back mutated to the corresponding amino acids found at said positions in the mouse 5G11 or 13C5 light chain variable region. In another embodiment, the 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 back mutated to the corresponding amino acids found at said positions in the mouse 5G11 or 13C5 heavy chain variable region. In one embodiment, 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) to Tyr (Y); and a heavy chain variable region wherein the amino acid at position 24 is mutated from Phe (F) to Val (V), the amino acid at position 49 is mutated from Ala (a) to Gly (G), the amino acid at position 73 is mutated from Thr (T) to Asn (N), and the amino acid at position 83 is mutated from Thr (T) to Asn (N). In one embodiment, the humanized 13C5 antibody comprises a light chain variable region in which the amino acid at position 53 is mutated from Tyr (Y) to Lys (K); and a heavy chain variable region, wherein the amino acid at position 28 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), and the amino acid at position 94 is mutated from Tyr (Y) to Asp (D). Additional or alternative back mutations may be made in the framework regions of the humanized antibodies provided herein to improve the properties of the antibodies. The present application also includes humanized antibodies that bind PD-L1 and comprise framework modifications corresponding to the exemplary modifications described herein relative to any suitable framework sequence, as well as other framework modifications that otherwise improve the properties of the antibodies.

In the isolated antibodies or fragments thereof that bind PD-L1 described herein, the antibodies may be produced by a hybridoma selected from the group consisting of hybridomas referred to herein as 13C5, 5G 11. Thus, antibodies described herein also include hybridomas 13C5, 5G11, as well as any hybridomas that produce the antibodies disclosed herein. The present application also includes isolated polynucleotides encoding the antibodies and fragments thereof provided herein. The application also includes expression vectors comprising the isolated polynucleotides, and host cells comprising the expression vectors.

"isolated antibody" means an antibody that: which is substantially free of other antibodies having different antigen specificities (e.g., an isolated antibody that specifically binds PD-1 is substantially free of antibodies that specifically bind antigens other than PD-1). 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 antibodies may be substantially free of other cellular material and/or chemicals.

The term "monoclonal antibody" ("mAb") refers to a non-naturally occurring preparation of antibody molecules of single molecular composition (i.e., antibody molecules whose basic sequences are substantially identical and which exhibit a single binding specificity and affinity for a particular epitope). A mAb is one example of an isolated antibody. Mabs may be produced by hybridoma techniques, recombinant techniques, transgenic techniques, or other techniques known to those skilled in the art.

The antibodies and antigen binding fragments thereof described herein are specific for PD-L1. In one embodiment, the antibody or/and fragment thereof is specific for PD-L1. In one embodiment, the antibodies and fragments described herein bind to human or primate PD-L1, but do not bind to PD-L1 from any other mammal. In another embodiment, the antibody or fragment thereof does not bind to mouse PD-L1. The terms "human PD-L1", "hPD-L1" and "huPD-L1" and the like are used interchangeably herein and refer to human PD-L1 and variants or isoforms of human PD-L1. By "specific" is meant that the antibody and fragments thereof bind PD-L1 with greater affinity than any other target.

The term "treatment" generally refers to obtaining a desired pharmacological and/or physiological effect. The effect may be therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease. As used herein, "treatment" encompasses any treatment of a disease in a patient, including: (a) inhibiting the symptoms of the disease, i.e., arresting its development; or (b) alleviating a symptom of the disease, i.e., causing regression of the disease or symptom.

The term "effective amount" means an amount of a compound of the present application that (i) treats a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The amount of active agent (e.g., an antibody or compound of the present application) that comprises a "therapeutically effective amount" can vary depending on factors such as the disease state, age, sex, and weight of the individual, and the ability of the therapeutic agent or combination of therapeutic agents to elicit a desired response in the individual. An effective amount can also be routinely determined by one of ordinary skill in the art based on its own knowledge and disclosure.

The term "administering" means physically introducing a composition comprising a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those of skill in the art. Routes of administration of immune checkpoint inhibitors (e.g., anti-PD-1 antibodies or anti-PD-L1 antibodies) include parenteral routes of administration (including, but not limited to, intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration), for example, by injection or infusion. In some embodiments, the phrase "parenteral administration" or "parenteral administration" as used herein is used interchangeably and generally refers to modes of administration other than enteral and topical administration by injection and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, and in vivo electroporation. In certain embodiments, the immune checkpoint inhibitor (e.g., an anti-PD-1 antibody or an anti-PD-L1 antibody) is administered by a non-parenteral route; in certain embodiments, the oral administration; other non-parenteral routes include topical, epidermal or mucosal administration, e.g., intranasal, intravaginal, intrarectal, sublingual or topical administration. Administration may also be performed, for example, one, multiple times, and/or over one or more extended periods of time.

The term "pharmaceutically acceptable" is directed to those compounds, materials, compositions, and/or dosage forms which are suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response, or other problem or complication.

The term "pharmaceutically acceptable salts" includes salts of the free base with acids or salts of the acid with the free base, including for example, hydrochloride, hydrobromide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, fumarate, oxalate, maleate, citrate, succinate, methanesulfonate, benzenesulfonate or p-toluenesulfonate; in some embodiments, the pharmaceutically acceptable salt is a hydrochloride, hydrobromide, sulfate, formate, acetate, trifluoroacetate, fumarate, maleate, mesylate, p-toluenesulfonate, sodium, potassium, ammonium, amino acid salt, and the like. In this application, when a pharmaceutically acceptable salt is formed, the molar amount ratio of the acid to the free base is from 1:0.2 to 1:5; in some embodiments, the molar amount ratio is 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, or 1:8.

As used herein, "subject" or "patient" are used interchangeably. Herein, a "patient" is a mammal, and in some embodiments, the patient is a human. In some embodiments, the subject is a human.

The term "unit dose" refers to the smallest unit of packaging containing a quantity of a pharmaceutical product, e.g., a kit of seven capsules, each capsule being a unit dose; or each bottle of injection is in unit dosage. The terms "single dose" and "unit dose" have the same meaning and are used interchangeably herein.

The term "multi-dose" consists of a plurality of unit doses.

The term "pharmaceutical composition" refers to a mixture of one or more active ingredients of the present application or pharmaceutical combinations thereof and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present application or a pharmaceutical combination thereof to a patient.

In this document, the terms "comprises," "comprising," and "includes," or equivalents thereof, unless otherwise specified, are open ended and mean that other unspecified elements, components, and steps are contemplated in addition to those listed.

In this context, unless otherwise indicated, all numbers expressing quantities of ingredients, measurements, or reaction conditions used herein are to be understood as being modified in all instances by the term "about". The term "about" when used in connection with a percentage may mean, for example, ±0.1%, preferably, ±0.05%, more preferably, ±0.01%.

Unless the context clearly indicates otherwise, singular terms encompass the plural referents and vice versa. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise, and vice versa.

Herein, unless otherwise indicated, the term "optional" or "optionally" means that the subject or event to which it is modified is present or absent, or that it is occurring or absent, e.g. "the pharmaceutical combination comprises optionally An Luoti ni or a pharmaceutically acceptable salt thereof" means that the pharmaceutical combination may or may not comprise An Luoti ni or a pharmaceutically acceptable salt thereof.

All patents, patent applications, and other publications are expressly incorporated herein by reference for the purpose of description and disclosure. These publications are provided solely for their disclosure prior to the filing date of the present application. All statements as to the date or representation as to the contents of these documents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates or contents of these documents. Moreover, any reference to such publications in this document does not constitute an admission that the publications are part of the common general knowledge in the art, in any country.

Detailed Description

For clarity, the present application is further illustrated with examples, but the examples do not limit the scope of the present application. All reagents used in this application are commercially available and can be used without further purification. The anti-PD-L1 antibodies of the examples can be prepared as described in WO2016022630, and the eluate containing the antibodies can be obtained by conventional antibody purification methods after affinity chromatography.

Example 1 clinical trial

Subjects meeting the inclusion criteria were randomized to trial 1 or trial 2 and the treatment was divided into an initial treatment phase (i.e., the first treatment phase) and a maintenance treatment phase (i.e., the second treatment phase). After initial treatment (4-6 cycles, determined by the investigator in combination with patient tolerance, and as much as possible to let the patient receive 6 cycles of initial treatment), patients without disease progression (cr\pr\sd) are subjected to maintenance treatment until the end of the treatment when the efficacy is assessed as disease Progression (PD) or intolerance to the patient. Efficacy was evaluated every 2 cycles during the initial treatment phase and every 3 cycles during the maintenance treatment phase.

1.1 main inclusion criteria:

1) Histopathologically diagnosed unresectable locally advanced, recurrent or metastatic esophageal squamous carcinoma;

2) The patients who have not received systemic treatment or (new) adjuvant/curative treatment regimens (including curative surgery and curative radiotherapy and chemotherapy) ended for more than 6 months (note: including patients who have advanced or recurrent non-target lesions again following pure radiation therapy. Palliative treatment is performed for localized lesions (non-target lesions) from end time to time of group entry > 2 weeks);

3) According to the therapeutic effect evaluation standard RECIST version 1.1 of the solid tumor, at least one measurable focus is provided; the focus can be measured without local treatment such as radiotherapy (focus in previous radiotherapy area, if progress is confirmed, and meets RECIST 1.1 standard, target focus can be selected);

4) Age: 18-75 years old; ECOG PS score: 0-1 min; the expected lifetime is over 3 months.

1.2 test drug

anti-PD-L1 antibody hu5G11-hIgG1 injection: 1200mg of the anti-PD-L1 antibody injection (specification: 600mg/20 mL) was diluted to 250mL with physiological saline, and the infusion time was 60.+ -.10 min (the infusion time was the starting point of the infusion of the anti-PD-L1 antibody injection, the infusion of the anti-PD-L1 antibody injection was ended and the end point of the physiological saline (recommended 20mL physiological saline wash pipe) was the end point of the wash pipe). The anti-PD-L1 antibody injections were administered on the first day of each cycle, once every 21 days, i.e., 21 days for one treatment cycle (d 1/q3 w). The maximum use time is not more than 24 months.

An Luoti Ni hydrochloride capsule (An Luoti Ni dihydrochloride as active ingredient): 1 dose (10 mg) per day (oral administration before breakfast) 1 dose. The oral administration is continued for 2 weeks and stopped for 1 week, i.e. 21 days is a treatment period, and the administration is carried out on days 1-14 of each period. There is no special case, and it is recommended to take the medicine for a fixed time every day. Namely, an Luoti ni capsule of hydrochloric acid: 12mg/qd, d1-14/q3w.

Researchers can adjust the dosage of the An Luoti Ni capsule of hydrochloric acid according to the aspects of disease conditions, safety and the like, for example: 12mg, 10mg and 8mg.

Paclitaxel: according to 135mg/m ² Intravenous drip, administration of a hormone (dexamethasone, diphenhydramine, cimetidine, etc.) pre-treatment is given before administration of the drug every cycle d1, and 3 weeks is a treatment cycle.

Cisplatin: administration after paclitaxel is performed at a dosage of 60-75mg/m ² Intravenous drip, each cycle divided into d1-d3 doses, and 3 weeks is a treatment period.

Recommended body surface area calculation formula: 1. body surface area (m) ² ) =0.0061×height (cm) +0.0128×weight (kg) -0.1529;2. body surface area= (height + weight-60)/100, allowing the actual usage to be within + -10% of the calculated usage.

1.3 dosing regimen

Treatment is divided into an initial treatment phase (i.e., a first treatment phase) and a maintenance treatment phase (i.e., a second treatment phase).

The first treatment phase (4-6 treatment cycles, determined by the investigator in combination with patient tolerance, as much as possible to let the patient receive initial treatment for 6 treatment cycles):

test group 1: every 21 days is a treatment cycle.

anti-PD-L1 antibody injection: 1200 mg/dose, d1 dose per cycle, intravenous drip;

an Luoti Ni capsule of hydrochloric acid, 10 mg/time, 1 time daily, and d1-d14 every period, continuously taking medicine for 2 weeks, stopping taking medicine for 1 week, and taking orally;

paclitaxel: according to 135mg/m ² D1 is administered per cycle, hormone pretreatment is given before administration, and intravenous drip is performed;

cisplatin: administration after paclitaxel is performed at a dosage of 60-75mg/m ² Is administered by intravenous drip every cycle d1-d 3.

Test group 2: every 21 days is a treatment cycle.

The second treatment phase (end of dosing until efficacy is assessed as disease Progression (PD) or intolerance to the patient):

test group 1: every 21 days is a treatment cycle.

an Luoti Ni capsule of hydrochloric acid, 10 mg/time, 1 time daily, and d1-d14 every period, and stopping for 1 week for 2 weeks continuously, and taking orally.

Test group 2: every 21 days is a treatment cycle.

anti-PD-L1 antibody injection: 1200 mg/dose, d1 dose per cycle, intravenous drip.

1.4 evaluation criteria

Safety evaluation criteria: the severity of adverse events was judged using the NCI-CTC AE 5.0 standard.

Validity evaluation criteria: disease states were determined using RECIST 1.1, irec criteria. The evaluation standard RECIST 1.1 is used as the main and the iRECIST standard is used as the auxiliary. I.e., patients who were judged to be disease Progression (PD) according to RECIST 1.1 criteria were further confirmed according to the irec criteria to determine whether to further observe medication.

1.5 study endpoint

The main indexes are as follows: disease progression-free survival PFS;

secondary index: (1) Progression free survival (iPFS, irec assessment), objective remission rate (orr=cr+pr), disease control rate (dcr=cr+pr+sd), duration of remission (DOR), quality of life score; (2) Incidence and severity of Adverse Events (AEs) and Severe Adverse Events (SAE), as well as abnormal laboratory inspection indicators;

Exploratory index: biomarker, PD-L1 expression and efficacy relationship.

1.6 test results

On a statistical day of the cut-off data, 36 subjects were evaluated for efficacy at least once in trial group 1, with 1 subject fully relieved (CR achieved), 26 subjects partially relieved (PR achieved), 9 subjects stable (SD achieved), objective Remission Rate (ORR) up to 75%, and Disease Control Rate (DCR) up to 100%. Of the 36 subjects, 16 subjects had received more than 6 treatment cycles, with some subjects having received a maximum of more than 14 treatment cycles. PFS of the subject reached more than 8 months; the PFS of some subjects even reached or exceeded 9.8 months.

The best efficacy of 36 subjects over the first 6 treatment cycles was counted, and found that 1 subject was completely relieved (CR was reached), 26 subjects were partially relieved (PR was reached), 9 subjects were stable in disease (SD was reached), objective Remission Rate (ORR) was 75%, and Disease Control Rate (DCR) was 100%.

In addition, the incidence of AE (adverse events) of the subject is significantly reduced, the incidence of AE of three or more levels is significantly reduced, and the incidence of SAE (serious adverse events) is significantly reduced.

Preliminary researches show that the combination drug combination can safely and effectively treat the esophageal cancer. Subjects hopefully achieve more significant clinical benefit than traditional first line standard chemotherapy regimens, receiving both trial 1 and trial 2 regimens. The subjects of test group 1 and test group 2 were both improved in PFS and ORR.

Those skilled in the art will recognize that the scope of the present application is not limited to the various embodiments and examples described above, but is capable of various modifications, substitutions, or rearrangements without departing from the spirit of the application, which are intended to be within the scope of the present application.

Claims

Use of a pharmaceutical combination comprising an anti-PD-L1 antibody and a chemotherapeutic agent in the manufacture of a medicament for the treatment of esophageal cancer.
The use of claim 1, wherein the pharmaceutical combination further comprises An Luoti ni or a pharmaceutically acceptable salt thereof.
The use of claim 1 or 2, wherein the pharmaceutical combination comprises a first pharmaceutical combination, and optionally, a second pharmaceutical combination; wherein the first pharmaceutical combination comprises an anti-PD-L1 antibody and a chemotherapeutic agent, optionally An Luoti ni or a pharmaceutically acceptable salt thereof.
The use of claim 3, wherein the second pharmaceutical combination comprises an anti-PD-L1 antibody, and optionally An Luoti ni or a pharmaceutically acceptable salt thereof.
The use of claim 3 or 4, wherein the first pharmaceutical combination is administered to a patient in need thereof during a first treatment phase, and optionally the second pharmaceutical combination is administered to a patient in need thereof during a second treatment phase.
Use according to claim 5, wherein the treatment period of the first treatment phase is 1 to 10 treatment periods, preferably 4 to 6 treatment periods, most preferably 6 treatment periods.
The use according to any one of claims 1 to 6, wherein the chemotherapeutic is selected from one or more of platinum-based antitumor drugs and taxane-based antitumor drugs.
The use of claim 7, wherein the platinum-based anti-tumor drug is selected from one or more of cisplatin, carboplatin, nedaplatin, dicycloplatin, picoplatin, oxaliplatin, miplatin, or lobaplatin.
The use according to claim 7 or 8, wherein the taxane antitumor drug is selected from one or more of paclitaxel, paclitaxel liposome, albumin-bound paclitaxel, docetaxel.
The use according to any one of claims 1-9, wherein the chemotherapeutic agent is selected from paclitaxel and/or cisplatin.
The use of any one of claims 1-10, wherein the daily dose of the anti-PD-L1 antibody is 600, 800, 1000, 1200, 1400, 1600, 1800, 2000, 2200, or 2400mg.
The use according to any one of claims 2-11, wherein the daily dose of An Luoti ni or a pharmaceutically acceptable salt thereof is 6mg-12mg, or 6mg, 8mg, 10mg or 12mg.
The use according to any one of claims 9-12, wherein the paclitaxel is at 135-175 mg/m ² Is preferably administered at a dose of 135mg/m ² Is administered in a dosage of (a).
The use according to any one of claims 8 to 13, wherein the cisplatin is present at a concentration of 50 to 100mg/m ² Is preferably administered in a dosage of 60-75mg/m ² Is administered in a dosage of (a).
The use of any one of claims 1-14, wherein the anti-PD-L1 antibody and the chemotherapeutic agent, and optionally An Luoti ni or a pharmaceutically acceptable salt thereof, are each in the form of a pharmaceutical composition for simultaneous, sequential or sequential administration.
The use of any one of claims 1-15, wherein one treatment cycle is every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks.
The use of any one of claims 1-16, wherein one treatment cycle is every 3 weeks, the anti-PD-L1 antibody is administered on day 1 of each cycle, and optionally An Luoti ni or a pharmaceutically acceptable salt thereof is administered on days 1-14 of each cycle.
The use according to any one of claims 10-17, wherein one treatment cycle is every 3 weeks, paclitaxel is administered on day 1 of each cycle, and cisplatin is administered on days 1-3 of each cycle.
The use according to any one of claims 2-18, wherein the pharmaceutical combination is a formulation suitable for administration in a single treatment cycle, comprising a pharmaceutical composition comprising 600-2400 mg of an anti-PD-L1 antibody; a pharmaceutical composition comprising 84-168 mg An Luoti Ni or a pharmaceutically acceptable salt thereof; a pharmaceutical composition comprising 90-1350 mg cisplatin; and a pharmaceutical composition containing 67.5-810 mg of paclitaxel.
The use of any one of claims 2-19, wherein the pharmaceutical combination comprises an anti-PD-L1 antibody, an Luoti ni or a pharmaceutically acceptable salt thereof, cisplatin, and paclitaxel, and the weight ratio of the anti-PD-L1 antibody, an Luoti ni or a pharmaceutically acceptable salt thereof, cisplatin, and paclitaxel is (600-2400): 84-168): 90-1350): 67.5-810.
The use according to any one of claims 1-20, wherein the esophageal cancer is unresectable and/or advanced and/or recurrent and/or metastatic esophageal cancer;

alternatively, the esophageal cancer is esophageal squamous cell carcinoma.
The use of any one of claims 1-21, wherein the patient with esophageal cancer has not previously received systemic treatment.

Alternatively, the patient with esophageal cancer has previously been treated with at least one chemotherapeutic agent.
A method of treating esophageal cancer comprising: administering to a patient in need thereof a therapeutically effective amount of an anti-PD-L1 antibody and a chemotherapeutic agent.
The method of claim 23, further comprising administering to a patient in need thereof a therapeutically effective amount of An Luoti ni or a pharmaceutically acceptable salt thereof.
The method of claim 23 or 24, comprising administering a first pharmaceutical combination to a patient in need thereof during a first treatment phase; and optionally, administering a second pharmaceutical combination to the patient in need thereof in a second treatment phase, wherein the first pharmaceutical combination comprises an anti-PD-L1 antibody and a chemotherapeutic agent, and optionally An Luoti ni or a pharmaceutically acceptable salt thereof.
The method of claim 25, wherein the second pharmaceutical combination comprises an anti-PD-L1 antibody, and optionally An Luoti ni or a pharmaceutically acceptable salt thereof.
The method according to claim 25 or 26, wherein the treatment period of the first treatment phase is 1 to 10 treatment periods, preferably 4 to 6 treatment periods, most preferably 6 treatment periods.
The method of any one of claims 23-27, wherein the chemotherapeutic agent is selected from one or more of a platinum-based anti-tumor agent and a taxane-based anti-tumor agent.
The method of any one of claims 23-28, wherein the chemotherapeutic agent is selected from paclitaxel and/or cisplatin.
The method of any one of claims 23-29, wherein the anti-PD-L1 antibody and the chemotherapeutic agent, and optionally An Luoti n or a pharmaceutically acceptable salt thereof, are each in the form of a pharmaceutical composition for simultaneous, sequential or sequential administration.
The method of any one of claims 23-30, wherein the daily dose of anti-PD-L1 antibody is 600-2400 mg or 600, 800, 1000, 1200, 1400, 1600, 1800, 2000, 2200, or 2400mg.
The method of any one of claims 24-31, wherein the daily dose of An Luoti ni or a pharmaceutically acceptable salt thereof is 6mg-12mg, or 6mg, 8mg, 10mg or 12mg.
The method of any one of claims 29-32, wherein paclitaxel is present at 135-175 mg/m ² Is preferably administered at a dose of 135mg/m ² Is administered in a dosage of (a).
The method of any one of claims 29-33, wherein cisplatin is present at 50-100 mg/m ² Is preferably administered in a dosage of 60-75mg/m ² Is administered in a dosage of (a).
The method of any one of claims 23-34, wherein one treatment cycle is every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks.
The method of any one of claims 23-35, wherein one treatment cycle is every 3 weeks, the anti-PD-L1 antibody is administered on day 1 of each cycle, and optionally An Luoti ni or a pharmaceutically acceptable salt thereof is administered on days 1-14 of each cycle.
The method of any one of claims 29-36, wherein each 3 weeks is a treatment cycle, paclitaxel is administered on day 1 of each cycle, and cisplatin is administered on days 1-3 of each cycle.
The method according to any one of claims 23-37, wherein the esophageal cancer is unresectable and/or advanced and/or recurrent and/or metastatic esophageal cancer;

alternatively, the esophageal cancer is esophageal squamous cell carcinoma.
The method of any one of claims 23-38, wherein the patient with esophageal cancer has not previously received systemic treatment;

alternatively, the patient with esophageal cancer has previously been treated with at least one chemotherapeutic agent.
A pharmaceutical combination for treating esophageal cancer, comprising: anti-PD-L1 antibodies and chemotherapeutic agents.
The pharmaceutical combination of claim 40, further comprising An Luoti Ni or a pharmaceutically acceptable salt thereof.
The pharmaceutical combination of claim 40 or 41, wherein the pharmaceutical combination comprises a first pharmaceutical combination, and optionally, a second pharmaceutical combination, wherein the first pharmaceutical combination comprises an anti-PD-L1 antibody and a chemotherapeutic agent, and optionally An Luoti ni or a pharmaceutically acceptable salt thereof.
The pharmaceutical combination of claim 42, wherein the second pharmaceutical combination comprises an anti-PD-L1 antibody, and optionally An Luoti ni or a pharmaceutically acceptable salt thereof.
The pharmaceutical combination according to any one of claims 40-43, wherein the chemotherapeutic agent is selected from one or more of a platinum-based anti-tumor agent and a taxane-based anti-tumor agent, preferably the chemotherapeutic agent is selected from paclitaxel and/or cisplatin.
The pharmaceutical combination according to any one of claims 40-44, wherein the anti-PD-L1 antibody and the chemotherapeutic agent, and optionally An Luoti ni or a pharmaceutically acceptable salt thereof and the chemotherapeutic agent, are each in the form of a pharmaceutical composition.
The pharmaceutical combination according to any one of claims 41-45, wherein the pharmaceutical combination is a formulation suitable for administration within a single treatment cycle, comprising a pharmaceutical composition comprising 600-2400 mg of an anti-PD-L1 antibody; a pharmaceutical composition comprising 84-168 mg An Luoti Ni or a pharmaceutically acceptable salt thereof; a pharmaceutical composition comprising 90-1350 mg cisplatin; and a pharmaceutical composition containing 67.5-810 mg of paclitaxel.
The pharmaceutical combination according to any one of claims 41-46, wherein the pharmaceutical combination comprises anti-PD-L1 antibody, an Luoti Ni or a pharmaceutically acceptable salt thereof, cisplatin and paclitaxel, wherein the weight ratio of anti-PD-L1 antibody, an Luoti Ni or a pharmaceutically acceptable salt thereof, cisplatin and paclitaxel is (600-2400): 84-168): 90-1350): 67.5-810.
The pharmaceutical combination according to any one of claims 40-47, wherein the esophageal cancer is unresectable and/or advanced and/or recurrent and/or metastatic esophageal cancer; alternatively, the esophageal cancer is esophageal squamous cell carcinoma.
The use of any one of claims 1-22, or the method of any one of claims 23-39, or the pharmaceutical combination of any one of claims 40-48, wherein the anti-PD-L1 antibody comprises the amino acid sequence: a heavy chain CDR1 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 1 or SEQ ID NO. 4; a heavy chain CDR2 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 2 or SEQ ID NO. 5; a heavy chain CDR3 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 3 or SEQ ID NO. 6; a light chain CDR1 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 7 or SEQ ID NO. 10; a light chain CDR2 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 8 or SEQ ID NO. 11; a light chain CDR3 region having at least 80% homology with the amino acid sequence shown in SEQ ID NO. 9 or SEQ ID NO. 12.
The use of any one of claims 1-22, or the method of any one of claims 23-39, or the pharmaceutical combination of any one of claims 40-48, wherein the anti-PD-L1 antibody comprises the amino acid sequence: a heavy chain CDR1 region selected from SEQ ID NO. 1 or SEQ ID NO. 4; a heavy chain CDR2 region selected from SEQ ID NO. 2 or SEQ ID NO. 5; a heavy chain CDR3 region selected from SEQ ID NO. 3 or SEQ ID NO. 6; a light chain CDR1 region selected from SEQ ID NO. 7 or SEQ ID NO. 10; a light chain CDR2 region selected from SEQ ID NO. 8 or SEQ ID NO. 11; a light chain CDR3 region selected from SEQ ID NO 9 or SEQ ID NO 12.
The use of any one of claims 1-22, or the method of any one of claims 23-39, or the pharmaceutical combination of any one of claims 40-48, wherein the anti-PD-L1 antibody comprises: a heavy chain CDR1 region having the amino acid sequence shown in SEQ ID NO. 1, a heavy chain CDR2 region having the amino acid sequence shown in SEQ ID NO. 2, a heavy chain CDR3 region having the amino acid sequence shown in SEQ ID NO. 3; and a light chain CDR1 region having the amino acid sequence shown in SEQ ID NO. 7, a light chain CDR2 region having the amino acid sequence shown in SEQ ID NO. 8, and a light chain CDR3 region having the amino acid sequence shown in SEQ ID NO. 9.
The use of any one of claims 1-22, or the method of any one of claims 23-39, or the pharmaceutical combination of any one of claims 40-48, wherein the anti-PD-L1 antibody comprises the amino acid sequence: a heavy chain variable region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 13 or SEQ ID NO. 14; a light chain variable region having at least 80% homology with the amino acid sequence shown in SEQ ID NO. 15 or SEQ ID NO. 16.
The use of any one of claims 1-22, or the method of any one of claims 23-39, or the pharmaceutical combination of any one of claims 40-48, wherein the anti-PD-L1 antibody comprises: a variable heavy chain selected from the group consisting of hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1, or hu5G11-hIgG4 humanized antibodies, and a variable light chain selected from the group consisting of hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1, or hu5G11-hIgG4 humanized antibodies.