CN112168961A - Combined pharmaceutical composition for treating colorectal cancer - Google Patents
Combined pharmaceutical composition for treating colorectal cancer Download PDFInfo
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- CN112168961A CN112168961A CN202010636341.3A CN202010636341A CN112168961A CN 112168961 A CN112168961 A CN 112168961A CN 202010636341 A CN202010636341 A CN 202010636341A CN 112168961 A CN112168961 A CN 112168961A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
Abstract
The invention belongs to the field of biomedicine, and relates to a combined pharmaceutical composition for treating colorectal cancer, which has good anti-colorectal cancer activity.
Description
Technical Field
The application belongs to the field of biomedicine and relates to a combined pharmaceutical composition for treating colorectal cancer.
Background
Tyrosine kinases are a group of enzymes catalyzing phosphorylation of tyrosine residues of proteins, play important roles in signal transduction in cells, participate in regulation, signal transmission and development of normal cells, and are closely related to proliferation, differentiation, migration and apoptosis of tumor cells. Many receptor tyrosine kinases are involved in tumor formation and are classified into Epidermal Growth Factor Receptor (EGFR), platelet-derived growth factor receptor (PDGFR), Vascular Endothelial Growth Factor Receptor (VEGFR), Fibroblast Growth Factor Receptor (FGFR), and the like according to their extracellular domain structure.
PD-L1(Programmed death-ligand I), also known as CD247 and B7-H1, is a ligand for the Programmed death molecule I (PD-1). PD-L1 is highly expressed on the surface of various tumor cells, and the malignancy degree and poor prognosis of tumors are closely related to the expression level of PD-L1. In a tumor microenvironment, PD-L1 on the surface of a cancer cell inhibits the activation and proliferation of T cells, promotes effector T cells to enter a failure or non-response state, induces the apoptosis of the T cells, stimulates the differentiation of helper T cells into regulatory T cells through the combination with PD-1 or CD80 on the surface of the T cells, thereby preventing the killing effect of the T cells on the tumor cells. The anti-PD-L1 antibody can block the interaction of PD-L1 with PD-1 and CD80, so that the related negative regulation signals can not be started and conducted, thereby preventing the activity of effector T cells in a tumor microenvironment from being inhibited, and enabling the T cells to play the functions of killing and inhibiting the tumor cells. The anti-PD-L1 antibody can directly act on tumor tissues, so that the antibody has high specificity and safety.
Colorectal cancer (CRC) is one of the common malignant tumors of the digestive tract, and has high incidence and mortality.
WO2016022630 discloses a PD-L1 antibody, which has high affinity for PD-L1, can obviously inhibit the interaction between PD-L1 and PD-1 on the cell surface, and can obviously promote IL-2 and INF-gamma secretion of T cells.
Despite the many treatment options available for patients with proliferative diseases (cancer), there is a need for more effective therapeutic agents for clinical use, especially in combination with more than one drug.
Summary of The Invention
In one aspect, the present application provides a combination pharmaceutical combination comprising an anti-PD-L1 antibody and erlotinib.
In another aspect, the present application provides a combination pharmaceutical composition for the treatment of colorectal cancer comprising an anti-PD-L1 antibody and nilotinib.
Further, the nilotinib is in the free base form, or in the form of a pharmaceutically acceptable salt thereof. For example, the pharmaceutically acceptable salt of the nilotinib can be the hydrochloride salt or the dihydrochloride salt.
Further, 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 set forth 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 set forth 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 set forth 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 set forth 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 set forth in SEQ ID NO. 8 or SEQ ID NO. 11; a light chain CDR3 region having at least 80% homology to the amino acid sequence set forth in SEQ ID NO. 9 or SEQ ID NO. 12. Still further, 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. Still further, 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. Still further, 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 set forth 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. Still further, the anti-PD-L1 antibody comprises: a variable heavy chain of a humanized antibody selected from hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1, or hu5G11-hIgG4, and a variable light chain of a humanized antibody selected from hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1, or hu5G11-hIgG 4.
Further, the above-mentioned combination pharmaceutical composition of the present application is packaged in the same kit, which further comprises instructions for the combined use of PD-L1 antibody and erlotinib for the treatment of colorectal cancer.
Further, the application provides a combined medicine composition which comprises a medicine composition containing 600-2400 mg of the anti-PD-L1 antibody and a medicine composition with a single dose of 6mg, 8mg, 10mg and/or 12mg of the aniotinib. Wherein the pharmaceutical composition comprising the anti-PD-L1 antibody is in a single dose or multiple doses.
Further, the application provides a pharmaceutical combination composition, which comprises a pharmaceutical composition containing 600-2400 mg of the anti-PD-L1 antibody provided in a multi-dose form and a pharmaceutical composition with a single dose of 6mg, 8mg, 10mg and/or 12mg of aniotinib.
Further, the present application provides a combination pharmaceutical composition which is a formulation suitable for administration within a single treatment cycle (e.g., one treatment cycle of 21 days), comprising a pharmaceutical composition comprising 600-2400 mg of the anti-PD-L1 antibody and a pharmaceutical composition comprising 84-168 mg of the aniotinib.
Further, the present application provides a pharmaceutical combination composition comprising an anti-PD-L1 antibody and anitinib 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 the erlotinib are packaged separately or together. And wherein the nilotinib can be packaged in multiple aliquots (e.g., 2 aliquots, 7 aliquots, 14 aliquots, 28 aliquots, or more); the anti-PD-L1 antibody can be packaged in single or multiple aliquots (e.g., 2 aliquots, 4 aliquots, or more).
In another aspect, the present application also provides the use of a combination pharmaceutical composition for the manufacture of a medicament for the treatment of colorectal cancer. The present application also provides a method of treating colorectal cancer comprising administering to an individual in need thereof an effective amount of a combination pharmaceutical composition of the present application. The application also provides the use of the combination pharmaceutical composition for the treatment of colorectal cancer. The combination pharmaceutical composition comprises an anti-PD-L1 antibody and an nilotinib.
In another aspect, the application also provides the use of an anti-PD-L1 antibody in combination with nilotinib for the manufacture of a medicament for the treatment of colorectal cancer. The present application also provides a method of treating colorectal cancer comprising administering to an individual in need thereof an effective amount of an anti-PD-L1 antibody and erlotinib. The application also provides the use of an anti-PD-L1 antibody in combination with aniotinib for the treatment of colorectal cancer. Alternatively, the present application also provides a combination of an anti-PD-L1 antibody and erlotinib for use in the treatment of colorectal cancer.
Further, the anti-PD-L1 antibody and the aniotinib are each in the form of a pharmaceutical composition that can be administered simultaneously, sequentially, or at intervals. Further, the anti-PD-L1 antibody is administered once a week, every 2 weeks, every 3 weeks, or every 4 weeks; preferably, the anti-PD-L1 antibody is administered at a dose of 600-2400 mg each time. Further, the nilotinib is administered at a dose of 6mg, 8mg, 10mg, or 12mg once daily for 2 weeks, with a dosing regimen of 1 week off.
In addition, the present application provides kits for treating colorectal cancer, the kits comprising a pharmaceutical composition of an anti-PD-L1 antibody and a pharmaceutical composition of aniotinib, and instructions for the combined use of an anti-PD-L1 antibody and aniotinib for treating colorectal cancer.
Further, the kit is a kit suitable for administration within a single treatment cycle (e.g., one treatment cycle of 21 days), comprising a pharmaceutical composition comprising 600-2400 mg of the anti-PD-L1 antibody and a pharmaceutical composition comprising 84-168 mg of Arotinib.
Disclosure of Invention
In one aspect, the present application provides a combination pharmaceutical combination comprising an anti-PD-L1 antibody and erlotinib.
In another aspect, the present application provides a combination pharmaceutical composition for the treatment of colorectal cancer comprising an anti-PD-L1 antibody and nilotinib.
In some embodiments of the present application, the combination pharmaceutical composition comprises a pharmaceutical composition of an anti-PD-L1 antibody and a pharmaceutical composition of anitinib.
In some embodiments of the present application, the combination pharmaceutical composition is packaged in the same kit, which further comprises instructions for the combined use of the PD-L1 antibody and the nilotinib for the treatment of colorectal cancer.
In some embodiments, a pharmaceutical composition for use in combination for the treatment of colorectal cancer is provided, comprising a pharmaceutical composition comprising 600-2400 mg of an anti-PD-L1 antibody and 6-12 mg of aniotinib. Wherein the pharmaceutical composition is a single dose or multiple doses.
In some embodiments, a combination pharmaceutical composition for the treatment of colorectal cancer is provided, comprising a pharmaceutical composition comprising 600-2400 mg of an anti-PD-L1 antibody and a pharmaceutical composition comprising 6mg, 8mg, 10mg and/or 12mg of antrotanib in a single dose form. Wherein the pharmaceutical composition of the anti-PD-L1 antibody is in a single dose or multiple doses.
In some embodiments, a combination pharmaceutical composition for the treatment of colorectal cancer is provided, comprising a pharmaceutical composition comprising 600-2400 mg of an anti-PD-L1 antibody in a multiple dose form and a pharmaceutical composition comprising 6mg, 8mg, 10mg, and/or 12mg of antrotanib in a single dose form.
In some embodiments, a combination pharmaceutical composition for the treatment of colorectal cancer is provided, comprising an anti-PD-L1 antibody and antrodia 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 the erlotinib are packaged separately or together. And wherein the nilotinib can be packaged in multiple aliquots (e.g., 2 aliquots, 7 aliquots, 14 aliquots, 28 aliquots, or more).
In some embodiments, a combination pharmaceutical composition for the treatment of colorectal cancer is provided, comprising a pharmaceutical composition of an anti-PD-L1 antibody and a pharmaceutical composition of aniotinib, wherein the anti-PD-L1 antibody is prepared suitable for administering 600-2400 mg of the anti-PD-L1 antibody to an individual in need thereof in a single dose or in multiple doses at each administration, and the pharmaceutical composition of aniotinib is prepared suitable for administering 6mg, 8mg, 10mg, and/or 12mg of aniotinib to the individual in need thereof in a single dose for 14 consecutive days.
In some embodiments, a combination pharmaceutical composition for the treatment of colorectal cancer is provided, comprising an anti-PD-L1 antibody pharmaceutical composition having an anti-PD-L1 antibody concentration of 10-60mg/mL and a pharmaceutical composition containing 6mg, 8mg, 10mg, and/or 12mg of apratinib in a single dose form.
In some embodiments, a combination pharmaceutical composition for the treatment of colorectal cancer is provided, comprising an anti-PD-L1 antibody pharmaceutical composition having an anti-PD-L1 antibody concentration of 10mg/mL and a pharmaceutical composition in single dose form comprising 8mg and/or 10mg and/or 12mg of antrostinib.
In some embodiments, a combination pharmaceutical composition for the treatment of colorectal cancer is provided, comprising a pharmaceutical composition comprising 1200mg of an anti-PD-L1 antibody in multiple dose form and a pharmaceutical composition comprising 8mg and/or 10mg and/or 12mg of antrovinib in a single dose form.
In another aspect, the present application also provides the use of a combination pharmaceutical composition for the manufacture of a medicament for the treatment of colorectal cancer. The present application also provides a method of treating colorectal cancer comprising administering to an individual in need thereof an effective amount of a combination pharmaceutical composition of the present application. The application also provides the use of the combination pharmaceutical composition for the treatment of colorectal cancer. The combined pharmaceutical composition comprises an anti-PD-L1 humanized monoclonal antibody and an nilotinib.
In another aspect, the application also provides the use of a composition of an anti-PD-L1 antibody and antrotinib in the manufacture of a medicament for the treatment of colorectal cancer. The present application also provides a method of treating colorectal cancer comprising administering to an individual in need thereof an effective amount of a composition of an anti-PD-L1 antibody and erlotinib. The application also provides use of a composition of an anti-PD-L1 antibody and antrotinib to treat colorectal cancer.
In another aspect, the application also provides the use of an anti-PD-L1 antibody and nilotinib for the manufacture of a medicament for the treatment of colorectal cancer. The present application also provides a method of treating colorectal cancer comprising administering to an individual in need thereof an effective amount of an anti-PD-L1 antibody and erlotinib. The application also provides the use of an anti-PD-L1 antibody and erlotinib for the treatment of colorectal cancer.
In yet another aspect, the present application provides a kit for treating colorectal cancer, the kit comprising a pharmaceutical composition of an anti-PD-L1 antibody and a pharmaceutical composition of aniotinib, and instructions for the use of an anti-PD-L1 antibody in combination with aniotinib to treat colorectal cancer.
In yet another aspect, the application also provides an anti-PD-L1 antibody for use in treating colorectal cancer. The present application also provides a method of treating colorectal cancer comprising administering to an individual in need thereof an effective amount of an anti-PD-L1 antibody of the present application. The application also provides the use of an anti-PD-L1 antibody for the treatment of colorectal cancer. The application also provides the use of an anti-PD-L1 antibody in the manufacture of a medicament for the treatment of colorectal cancer.
Administration/treatment regimen of combination pharmaceutical compositions
In one aspect, the present invention provides a combination pharmaceutical composition comprising an anti-PD-L1 antibody and nilotinib.
In some embodiments of the present application, the above uses or methods of treatment, the anti-PD-L1 antibody and the erlotinib are each in a pharmaceutical composition, which can be administered simultaneously, sequentially or at intervals.
In some embodiments of the present application, the above use or method of treatment, the anti-PD-L1 antibody and erlotinib are each administered in a spaced dosing regimen. In some embodiments the antibody and the anitinib are each administered on the same or different dosing regimen. In some embodiments, the administration is performed separately in different dosing regimens.
In some embodiments of the application, the use or method of treatment, the anti-PD-L1 antibody may be administered once weekly (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4 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 each time.
The aritinib may be administered at a dose of 6mg, 8mg, 10mg or 12mg once daily for 2 weeks on a 1-week off schedule.
In some embodiments, the anti-PD-L1 antibody and the erlotinib each have the same or different treatment cycles. In some specific embodiments, the anti-PD-L1 antibody and the erlotinib have the same treatment cycle, e.g., one treatment cycle every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks.
In some embodiments of the application, the use or method of treatment wherein 21 days is one treatment cycle, the PD-L1 antibody is administered on the first day of each cycle and the nilotinib is administered 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 the nilotinib is administered once daily on days 1-14 of each cycle.
In some embodiments of the present application, the use or method of treatment, wherein the anti-PD-L1 antibody can 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 20mg/kg administered to an individual in need thereof; or administered to an individual in need thereof at a dose 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 treatment cycle, 1200mg of PD-L1 antibody is administered on the first day of each cycle, and 6mg, 8mg, 10mg, and/or 12mg of aritinib is administered daily on days 1-14 of each cycle.
In some embodiments of the present application, the anti-PD-L1 antibody and the nilotinib are administered to an individual in need thereof 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, during one treatment cycle every three weeks, wherein the anti-PD-L1 antibody and the nilotinib are administered in single and multiple doses, respectively.
anti-PD-L1 antibody pharmaceutical composition
In some embodiments of the present application, the single dose or single dose form of the anti-PD-L1 antibody pharmaceutical composition comprises 300mg or 600mg of the anti-PD-L1 antibody.
In some embodiments of the present application, the total dose of the anti-PD-L1 antibody pharmaceutical composition is 600-2400 mg. In a partial regimen, the total dose of the anti-PD-L1 antibody pharmaceutical composition includes an anti-PD-L1 antibody selected from 600mg, 900mg, 1200mg, 1500mg, 1800mg, 2100mg, 2400mg, or a range formed by any of the values above. In some embodiments, the total dose of the anti-PD-L1 antibody pharmaceutical composition is preferably 600-2100 mg, or 900-1500 mg of the anti-PD-L1 antibody.
In some embodiments of the present application, the anti-PD-L1 antibody 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 pharmaceutical composition comprises 1-150mg/mL anti-PD-L1 antibody (mab), 3-50mM buffer, 2-150mg/mL isotonicity modifier/stabilizer, and 0.01-0.8mg/mL surfactant, and has a pH of about 4.0-6.8.
In some embodiments of the present application, the anti-PD-L1 antibody pharmaceutical composition has an anti-PD-L1 mab concentration of about 5-150mg/mL, calculated as w/v; preferably about 10-60 mg/mL; more preferably about 10-30 mg/mL. In some embodiments, the anti-PD-L1 mab is at a mass-volume concentration of about 10mg/mL, about 20mg/mL, about 30mg/mL, about 40mg/mL, about 50mg/mL, about 60mg/mL, about 70mg/mL, about 80mg/mL, about 90mg/mL, about 100mg/mL, about 110mg/mL, or about 120mg/mL, preferably about 10mg/mL, about 20mg/mL, about 30mg/mL, about 40mg/mL, about 50mg/mL, or about 60mg/mL, more preferably about 10mg/mL, about 20mg/mL, or about 30 mg/mL. In some embodiments, the anti-PD-L1 mab is at a mass-volume concentration of about 10 mg/mL. In other embodiments, the anti-PD-L1 monoclonal antibody is present at a mass volume concentration of about 30 mg/mL. In other embodiments, the anti-PD-L1 monoclonal antibody is present at a mass volume concentration of about 60 mg/mL.
In some embodiments of the present application, the buffer is a histidine salt buffer. The histidine salt buffer is present at a concentration of about 5 to about 30mM, preferably about 10 to about 25mM, more preferably about 10 to about 20mM, and most preferably about 10 to about 15 mM. In some embodiments, the histidine salt buffer is about 5mM, about 10mM, about 15mM, about 20mM, about 25mM, or about 30 mM. In some embodiments, the histidine salt buffer is about 10 mM. In other embodiments, the histidine salt buffer is about 15 mM. In other embodiments, the histidine salt buffer is about 20 mM. Wherein the histidine salt buffer comprises histidine and hydrochloric acid.
In some embodiments of the present application, the isotonicity adjusting/stabilizing agent is about 20-150mg/mL sucrose, preferably about 40-100mg/mL sucrose, more preferably about 60-80mg/mL sucrose, calculated as w/v. In some embodiments, the sucrose is at a concentration of about 40mg/mL, 50mg/mL, 60mg/mL, 70mg/mL, 80mg/mL, 90mg/mL, or 100 mg/mL. In some embodiments, the sucrose is at a concentration of about 60 mg/mL. In some embodiments, the sucrose is at a concentration of about 70 mg/mL. In some embodiments, the sucrose is at a concentration of about 80 mg/mL. In some embodiments, the sucrose is at a concentration of about 90 mg/mL.
In some embodiments of the present application, the surfactant is selected from polysorbate 80, polysorbate 20, poloxamer 188; preferably polysorbate 80 or polysorbate 20; more preferably polysorbate 80. In some embodiments, the surfactant is present at a concentration of about 0.05 to about 0.6mg/mL, preferably about 0.1 to about 0.4mg/mL, and more preferably about 0.2 to about 0.3mg/mL, w/v.
In some embodiments of the present application, the surfactant is about 0.01-0.8mg/mL polysorbate 80 or polysorbate 20, calculated as w/v. In some embodiments, the surfactant is about 0.05-0.6mg/mL polysorbate 80, preferably about 0.1-0.4mg/mL polysorbate 80, more preferably about 0.2-0.3mg/mL polysorbate 80, and most preferably about 0.2mg/mL polysorbate 80. In some embodiments, polysorbate 80 is present in the pharmaceutical composition at about 0.1mg/mL, 0.2mg/mL, 0.3mg/mL, 0.4mg/mL, 0.5mg/mL, or 0.6 mg/mL; preferably, the pharmaceutical composition has polysorbate 80 at a level of about 0.2mg/mL, 0.3mg/mL, 0.4mg/mL, or 0.5 mg/mL; more preferably, the pharmaceutical composition comprises polysorbate 80 at a level of about 0.2mg/mL, 0.3mg/mL, or 0.4 mg/mL; most preferably, the pharmaceutical composition has polysorbate 80 at a level of about 0.2 mg/mL. In some embodiments, the polysorbate 80 content of the pharmaceutical composition is about 0.1 mg/mL. In other embodiments, the pharmaceutical composition comprises polysorbate 80 at a level of about 0.2 mg/mL. In some embodiments, the polysorbate 80 content of the pharmaceutical composition is about 0.3 mg/mL. In other embodiments, the pharmaceutical composition comprises polysorbate 80 at a level of about 0.4 mg/mL. In some embodiments, the polysorbate 80 content of the pharmaceutical composition is about 0.5 mg/mL.
In some embodiments of the present application, the pharmaceutical composition is an aqueous solution. In some embodiments, the aqueous solution pH is selected from 4.0 to 6.8; preferably 4.5 to 6.5; more preferably 5.5 to 6.0; most preferably 5.5. In some embodiments, the pH of the aqueous solution is about 4.5, about 4.8, about 5.0, about 5.2, about 5.4, about 5.5, about 5.6, about 5.8, or about 6.0, preferably about 5.0, about 5.2, about 5.4, about 5.5, or about 5.6, more preferably about 5.5. In some embodiments, the pH of the aqueous solution is about 5.0. In some embodiments, the pH of the aqueous solution is about 5.2. In some embodiments, the pH of the aqueous solution is about 5.4. In some embodiments, the pH of the aqueous solution is about 5.5. In some embodiments, the pH of the aqueous solution is about 5.6. In some embodiments, the pH of the aqueous solution is about 5.8. In some embodiments, the pH of the aqueous solution is about 6.0.
In some embodiments of the present application, the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody at a mass volume concentration of about 20mg/mL, (b) sucrose at a mass volume concentration of about 70mg/mL, (c) polysorbate 80 at a mass volume concentration of about 0.1mg/mL, (d) histidine at a molar concentration of about 20mM, (e) optionally, a suitable amount of hydrochloric acid to adjust the pH of the composition to about 5.0. In a specific embodiment of the present invention, the pharmaceutical composition comprises: (a) anti-PD-L1 mab at a mass-volume concentration of about 20mg/mL, (b) sucrose at a mass-volume concentration of about 70mg/mL, (c) polysorbate 80 at a mass-volume concentration of about 0.1mg/mL, (d) histidine at a molar concentration of about 20mM, (e) optionally, a suitable amount of hydrochloric acid to adjust the pH of the composition to about 5.0.
In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody at a mass volume concentration of about 10mg/mL, (b) sucrose at a mass volume concentration of about 80mg/mL, (c) polysorbate 80 at a mass volume concentration of about 0.2mg/mL, (d) histidine at a molar concentration of about 10mM, (e) optionally, a suitable amount of hydrochloric acid to adjust the pH of the composition to about 5.5.
In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody at a mass volume concentration of about 50mg/mL, (b) sucrose at a mass volume concentration of about 80mg/mL, (c) polysorbate 80 at a mass volume concentration of about 0.3mg/mL, (d) histidine at a molar concentration of about 10mM, (e) optionally, a suitable amount of hydrochloric acid to adjust the pH of the composition to about 5.5.
In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody at a mass volume concentration of about 100mg/mL, (b) sucrose at a mass volume concentration of about 80mg/mL, (c) polysorbate 80 at a mass volume concentration of about 0.5mg/mL, (d) histidine at a molar concentration of about 10mM, (e) optionally, a suitable amount of hydrochloric acid to adjust the pH of the composition to about 5.5.
In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody at a mass volume concentration of about 30mg/mL, (b) sucrose at a mass volume concentration of about 80mg/mL, (c) polysorbate 80 at a mass volume concentration of about 0.2mg/mL, (d) histidine at a molar concentration of about 10mM, (e) optionally, a suitable amount of hydrochloric acid to adjust the pH of the composition to about 5.5.
In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody at a mass volume concentration of about 60mg/mL, (b) sucrose at a mass volume concentration of about 80mg/mL, (c) polysorbate 80 at a mass volume concentration of about 0.2mg/mL, (d) histidine at a molar concentration of about 10mM, (e) optionally, a suitable amount of hydrochloric acid to adjust the pH of the composition to about 5.5.
In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody at a mass volume concentration of about 10mg/mL, (b) sucrose at a mass volume concentration of about 70mg/mL, (c) polysorbate 80 at a mass volume concentration of about 0.4mg/mL, (d) histidine at a molarity of about 20mM, (e) optionally, a suitable amount of acetic acid to adjust the pH of the composition to about 6.5.
In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) anti-PD-L1 mab at a mass-volume concentration of about 10mg/mL, (b) sucrose at a mass-volume concentration of about 80mg/mL, (c) polysorbate 80 at a mass-volume concentration of about 0.2mg/mL, (d) histidine at a molar concentration of about 20mM, (e) optionally, a suitable amount of hydrochloric acid to adjust the pH of the composition to about 5.5.
In another specific embodiment of the present application, the pharmaceutical composition is an aqueous injection solution, including but not limited to an aqueous formulation that is not lyophilized or an aqueous formulation that is reconstituted from a lyophilized powder. In some embodiments, the pharmaceutical composition is an aqueous solution. 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, which is a stabilization process in which a substance is first frozen, then the amount of solvent is reduced by sublimation (primary drying process) and then by desorption (secondary drying process) until the amount of solvent is a value that no longer supports biological activity or chemical reaction. The lyophilized formulation of the present invention may also be dried by other methods known in the art, such as spray drying and bubble drying.
Arotinib pharmaceutical composition
In some embodiments of the present application, the single dose or single dose form of the pharmaceutical composition of anitinib comprises 6mg, 8mg, 10mg, or 12mg of anitinib.
In some embodiments of the present application, the total dose of the aritinib pharmaceutical composition administered per cycle comprises 84-168 mg, as a treatment cycle of 2 weeks to 1 week of administration. In some embodiments, the total dose of the anitinib pharmaceutical composition comprises 84mg, 112mg, 140mg, 168mg, or a range formed by any of the foregoing values. In some embodiments, the total dose of the anitinib pharmaceutical composition preferably comprises 112mg to 168 mg.
anti-PD-L1 antibody
In some embodiments of the present application, the anti-PD-L1 antibody is an antibody in WO2016022630 or CN 107001463A.
In some embodiments of the present application, the anti-PD-L1 antibody comprises the 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 set forth 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 set forth 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 set forth 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 of the present application, 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.
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 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 set forth in SEQ ID NO 13 or SEQ ID NO 14; a light chain variable region that is 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%) homologous to the amino acid sequence set forth in SEQ ID NO 15 or SEQ ID NO 16.
In some embodiments of the present application, the anti-PD-L1 antibody comprises the amino acid sequence: the heavy chain variable region as set forth in SEQ ID NO 13; the light chain variable region shown as SEQ ID NO. 15.
In some embodiments of the present application, the anti-PD-L1 antibody comprises the amino acid sequence: the heavy chain variable region as set forth in SEQ ID NO. 14; the variable region of the light chain as shown in SEQ ID NO 16.
In some embodiments of the present application, the anti-PD-L1 antibody comprises the amino acid sequence: the heavy chain amino acid sequence shown as SEQ ID NO. 17; the light chain amino acid sequence shown as SEQ ID NO. 18.
In some embodiments of the present application, the anti-PD-L1 antibody comprises the amino acid sequence: the heavy chain amino acid sequence shown as SEQ ID NO. 19; the light chain amino acid sequence shown as SEQ ID NO. 20.
In some embodiments of the present application, the anti-PD-L1 antibody comprises the amino acid sequence: the heavy chain amino acid sequence shown as SEQ ID NO. 21; the light chain amino acid sequence shown as SEQ ID NO. 18.
In a specific embodiment, the anti-PD-L1 humanized monoclonal antibodies provided herein comprise conservative substitution variants selected from one or more 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. An anti-PD-L1 humanized mab comprising the conservative substitution variants retains the ability to specifically recognize and bind to PD-L1.
In some embodiments of the present application, the anti-PD-L1 antibody can 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 heavy chain Complementarity Determining Regions (CDRs) selected from the group consisting of the 13C5 or 5G11 antibodies, and light chain complementarity determining regions selected from the group consisting of the 13C5 or 5G11 antibodies. In one embodiment, an anti-PD-L1 antibody according to the invention comprises a variable heavy chain selected from a ch5G11-hIgG1, ch5G11-hIgG4, ch13C5-hIgG1, ch13C5-hIgG4 chimeric antibody, and a variable light chain selected from a ch5G11-hIgG1, ch5G11-hIgG4, ch13C5-hIgG1, ch13C5-hIgG4 chimeric antibody. In one embodiment, an anti-PD-L1 antibody according to the invention comprises a variable heavy chain selected from a humanized antibody of hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG4, and a variable light chain selected from a humanized antibody of hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG 4. Reference may be made to the description of patent documents WO2016022630 or CN 107001463A: 13C5, ch13C5-hIgG1, ch13C5-hIgG4, hu13C5-hIgG1, or hu13C5-hIgG4 has the HCDR1 sequence SYGMS (SEQ ID NO:4), the HCDR2 sequence SISSGGSTYYPDSVKG (SEQ ID NO:5), the HCDR3 sequence GYDSGFAY (SEQ ID NO:6), the LCDR1 sequence ASQSVSTSSSSFMH (SEQ ID NO:10), the LCDR2 sequence YASNLES (SEQ ID NO:11), and the LCDR3 sequence QHSWEIPYT (SEQ ID NO: 12); the sequence of HCDR1 of 5G11, ch5G11-hIgG1, ch5G11-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG4 is TYGVH (SEQ ID NO:1), the sequence of HCDR2 is VIWRGVTTDYNAAFMS (SEQ ID NO:2), the sequence of HCDR3 is LGFYAMDY (SEQ ID NO:3), the sequence of LCDR1 is KASQSVSNDVA (SEQ ID NO:7), the sequence of LCDR2 is YAANRYT (SEQ ID NO:8), and the sequence of LCDR3 is QQDYTSPYT (SEQ ID NO: 9).
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, e.g., 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 a heavy chain variable region as set forth in SEQ ID NO. 13 and a light chain variable region as set forth in SEQ ID NO. 15, or from the group consisting of a heavy chain variable region as set forth in SEQ ID NO. 14 and a light chain variable region as set forth in SEQ ID NO. 16, or from a combination thereof. As another example, the anti-PD-L1 antibody is selected from 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, or from the heavy chain amino acid sequence shown in SEQ ID NO.19 and the light chain amino acid sequence shown in SEQ ID NO.20, or from the heavy chain amino acid sequence shown in SEQ ID NO.21 and the light chain amino acid sequence shown in SEQ ID NO.18, or from a combination of any of the foregoing.
Arotinib
As used herein, the arotinib chemical name is 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine, having the following structural formula:
as used herein, the nilotinib includes its non-salt forms (e.g., the free base), as well as its pharmaceutically acceptable salts, which are all included within the scope of the present application. For example, the pharmaceutically acceptable salt of the nilotinib can be the hydrochloride salt or the dihydrochloride salt. The dosage of the nilotinib or salt thereof referred to herein is based on the molecular weight of the free base of the nilotinib, unless otherwise indicated.
Colorectal cancer
In some embodiments of the present application, the colorectal cancer is selected from colon cancer or rectal cancer.
Mode of administration
The following is not intended to limit the mode of administration of the pharmaceutical combinations of the present application.
The components of the pharmaceutical compositions of the present application may be administered independently of each other, or some or all of them together in a variety of routes as appropriate, including, but not limited to, oral or parenteral (by intravenous, intramuscular, topical or subcutaneous routes). In some embodiments, the components of the pharmaceutical combination of the present application may be administered orally or parenterally, each independently, or some or all of them together, for example intravenously or intraperitoneally.
The components of the pharmaceutical compositions 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 capsules, soft capsules, enteric capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and dosage forms for sustained release formulations for oral or non-oral administration.
The components of the pharmaceutical combination of the present application may each independently, or some or all of them together contain a pharmaceutically acceptable carrier and/or excipient.
The pharmaceutical combination of the present application may also comprise additional therapeutic agents. In one embodiment, the additional therapeutic agent may be a small cell cancer therapeutic agent known in the art.
Technical effects
The use of the combination pharmaceutical composition of the present application described above facilitates:
(1) better efficacy in reducing tumor growth or even eliminating tumors than either drug of the combination administered alone;
(2) provides for administration of a lower amount than either drug of the combination alone;
(3) providing a treatment that is well tolerated in a patient with fewer adverse effects and/or complications than either drug administered alone;
(4) provide better disease control rates among treated patients;
(5) providing longer survival (e.g., median survival, progression-free survival, or overall survival) in the treated patient;
(6) providing a longer survival (e.g., median survival, progression-free survival, or overall survival) for the treated patient compared to standard chemotherapy;
(7) provide a longer duration of disease remission (DOR); and/or
(8) Compared with the single administration of any one of the medicines in the combination, the composition has good colorectal cancer inhibition activity and shows more excellent antitumor synergistic effect.
Definitions and explanations
The following terms used in the present application have the following meanings, unless otherwise specified. A particular term should not be considered as ambiguous or unclear without special definition, but rather construed according to ordinary meaning in the art. When a trade name appears in this application, it is intended to refer to its corresponding commodity or its active ingredient.
As used herein, the term "combination pharmaceutical composition" refers to a combination of two or more active ingredients (administered as the respective active ingredients themselves, or as their respective pharmaceutically acceptable salts or esters, derivatives, prodrugs or compositions) that are administered simultaneously or sequentially. Herein, the terms "combination pharmaceutical composition" and "pharmaceutical combination" are used interchangeably.
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 invention may be whole antibodies or any fragment thereof. Thus, the antibodies and fragments of the invention 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)' fragments, Fv fragments, isolated CDR regions, single chain Fv molecules (scFv), and other antibody fragments known in the art. Antibodies and fragments thereof can also include recombinant polypeptides, fusion proteins, and bispecific antibodies. The anti-PD-L1 antibodies and fragments thereof disclosed herein may be of the IgG1, IgG2, IgG3, or IgG4 isotype. The term "isotype" refers to the class of antibodies encoded by the heavy chain constant region gene. In one embodiment, the anti-PD-L1 antibodies and fragments thereof disclosed herein are of the IgG1 or IgG4 isotype. The PD-L1 antibodies and fragments thereof of the present invention may be derived from any species, including but not limited to mouse, rat, rabbit, primate, llama, and human. The PD-L1 antibody and fragments thereof can be chimeric, humanized or fully human. 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 antibody comprises Complementarity Determining Regions (CDRs) derived from a non-human antibody; and framework regions and constant regions derived from human antibodies. For example, an anti-PD-L1 antibody provided herein can comprise CDRs derived from one or more murine antibodies as well as human framework and constant regions. Thus, in one embodiment, a humanized antibody provided herein binds to the same epitope on PD-L1 as a murine antibody from which the CDRs of the antibody are derived. Provided herein are exemplary humanized antibodies. Additional anti-PD-L1 antibodies or variants thereof comprising the heavy and light chain CDRs provided herein can be produced using any human framework sequence and are also included in the invention. In one embodiment, suitable for use in the invention of the framework sequences include the structure and the provision of framework sequences similar to those of the framework sequences. 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 the VH and/or VL of the humanized antibodies provided herein are back mutated to the corresponding amino acids in the parent murine antibody. For example, for the VH and VL of humanized 5G11 and humanized 13C5, several sites of the framework amino acids of the template human antibody described above 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 acid at position 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 is back mutated to the corresponding amino acid found at said position in the mouse 5G11 or 13C5 heavy chain variable region. In one embodiment, the humanized 5G11 antibody comprises a light chain variable region wherein 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 wherein the amino acid at position 53 is mutated from tyr (y) to lys (k); and a heavy chain variable region wherein the amino acid at position 28 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 can be made in the framework regions of the humanized antibodies provided herein to improve the properties of the antibody. The invention 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 antibody properties.
The present invention provides an isolated antibody or fragment thereof that binds PD-L1, wherein the antibody is produced by a hybridoma selected from the group consisting of the hybridomas designated herein as 13C5, 5G 11. Accordingly, the invention also includes hybridomas 13C5, 5G11, and any hybridoma that produces an antibody disclosed herein. The invention also provides isolated polynucleotides encoding the antibodies and fragments thereof provided herein. The invention also includes expression vectors comprising the isolated polynucleotides, and host cells comprising the expression vectors.
The term "isolated antibody" refers to an antibody that: it 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). Furthermore, the isolated antibody 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 base sequences are substantially identical and which exhibit a single binding specificity and affinity for a particular epitope). mabs are an example of an isolated antibody. Mabs can be produced by hybridoma techniques, recombinant techniques, transgenic techniques, or other techniques known to those of skill in the art.
The antibodies and antigen binding fragments thereof disclosed herein are specific for PD-L1. In one embodiment, the antibody or fragment thereof is specific for PD-L1. In one embodiment, the antibodies and fragments provided herein bind to human or primate PD-L1, but not PD-L1 from any other mammal. In another embodiment, the antibody or and fragments 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 variants or isoforms of human PD-L1 and human PD-L1. By "specific to" is meant that the antibody and fragments thereof bind PD-L1 with greater affinity than any other target.
The term "treating" generally refers to obtaining a desired pharmacological and/or physiological effect. The effect partially or completely stabilizes or cures the disease and/or side effects due to the disease, which may be therapeutic. 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 or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of active substance (e.g., an antibody or compound of the present application) that constitutes 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 skill in the art based on his own knowledge and this disclosure.
The term "administering" means physically introducing a composition comprising a therapeutic agent to a subject using any of a variety of methods and delivery systems known to those skilled in the art. Routes of administration of the immune checkpoint inhibitor (e.g., anti-PD-1 antibody or anti-PD-L1 antibody) include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral routes of administration, e.g., by injection or infusion. The phrase "parenteral administration" as used herein refers to modes of administration other than enteral and topical administration, typically by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, 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, and in certain embodiments, orally. Other non-parenteral routes include topical, epidermal or mucosal routes of administration, e.g., intranasally, vaginally, rectally, sublingually or topically. Administration may also be performed, for example, once, multiple times, and/or over one or more extended periods of time.
Unless otherwise indicated, use of the term "dose" refers to a dose administered to a patient without regard to the weight or Body Surface Area (BSA) of the patient. For example, a 60kg human and a 100kg human will receive the same dose of antibody (e.g., 240mg anti-PD-1 antibody).
The term "weight-based dose" as referred to herein refers to a dose administered to a patient that is calculated based on the weight of the patient. For example, when a patient having a body weight of 60kg requires 3mg/kg of the anti-PD-1 antibody, one can extract an appropriate amount of the anti-PD-1 antibody (i.e., 180mg) at a time from a fixed dose preparation of the anti-PD-1 antibody.
Arotinib can be administered by a variety of routes including, but not limited to, oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intralipid, intraarticular, intraperitoneal, and intrathecal. In some particular embodiments, administration is by oral administration. The amount of nilotinib administered can be determined by the severity of the disease, the response to the disease, any treatment-related toxicity, the age and health of the patient. For example, the daily dose of erlotinib administered may be from 2mg to 20mg, and in some embodiments, the daily dose of a compound of formula I or a pharmaceutically acceptable salt thereof administered may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16 mg. The erlotinib can be administered one or more times daily. In some embodiments, the anitinib is administered once daily in an oral solid formulation.
The dosage scheme of the anitinib can be comprehensively determined according to the activity and toxicity of the drug, the tolerance of a patient and the like. Preferably, the administration of the nilotinib is in a staggered dosing regimen. The interval administration comprises an administration period and a drug withdrawal period, and the administration period can be one or more times per day by administration of the nilotinib. For example, the ratio of the administration period to the withdrawal period in days is 2:0.5 to 5, preferably 2:0.5 to 3, more preferably 2:0.5 to 2, and still more preferably 2:0.5 to 1. In some embodiments, the administration is discontinued for 2 weeks. In some embodiments, the administration is discontinued for 1 week for 2 weeks. In some embodiments, the administration is continued for 5 days and discontinued for 2 days. For example, the administration of erlotinib can be carried out orally at a dose of 6mg, 8mg, 10mg or 12mg once daily for 2 weeks followed by 1 week rest.
The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salt" includes salts of the base ion with the free acid or salts of the acid ion with the free base, including, for example, hydrochloride, hydrobromide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, fumarate, oxalate, maleate, citrate, succinate, methanesulfonate, benzenesulfonate or p-methylbenzenesulfonate, preferably hydrochloride, hydrobromide, sulfate, formate, acetate, trifluoroacetate, fumarate, maleate, methanesulfonate, p-methylbenzenesulfonate, sodium salt, potassium salt, ammonium salt, amino acid salt and the like. In the present application, when forming a pharmaceutically acceptable salt, the molar amount of free acid to base ion is about 1:0.5 to 1:5, preferably 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, or 1: 8. In the present application, when forming a pharmaceutically acceptable salt, the molar ratio of the free base to the acid ion is about 1:0.5 to 1:5, preferably 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7 or 1: 8.
The term "subject" is a mammal. In some embodiments, the subject is a mouse. In some embodiments, the subject is a human.
The term "about" should be understood to include within three standard deviations of the mean or within a standard tolerance in the particular art. In certain embodiments, about is understood to mean a variation of no more than 0.5. "about" modifies all values recited thereafter. For example, "about 1, 2, 3" means "about 1", "about 2", "about 3".
As used herein, "in combination" or "in combination" means that two or more active substances may be administered to an individual in need thereof each simultaneously as a single formulation, or each sequentially in any order as a single formulation.
The term "single dose" refers to the smallest unit of packaging containing a quantity of pharmaceutical product, for example a box of seven capsules, each capsule then being a single dose; or each bottle of injection is single dose.
The term "multiple dose" consists of multiple single doses.
The term "pharmaceutical composition" refers to a mixture of one or more of the active ingredients of the present application or a pharmaceutical combination thereof with pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present application or pharmaceutical combinations thereof to an individual in need thereof.
The term "mM" is millimole/liter.
In this document, unless otherwise indicated, the terms "comprises, comprising and including" or equivalents thereof, are open-ended and mean that elements, components and steps other than those listed may be included.
All patents, patent applications, and other established publications are herein expressly incorporated 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 of these documents or representation as to the contents of these documents is based on the information available to the applicant and does not constitute any admission as to the correctness of the dates of these documents or the contents of these documents. Moreover, any reference to such publications in this specification does not constitute an admission that the publications form part of the common general knowledge in the art in any country.
Detailed Description
For clarity, the invention is further illustrated by examples, which do not limit the scope of the application. All reagents used herein were commercially available and used without further purification. Examples anti-PD-L1 antibody was prepared as described in example 2 of WO2016022630 and after affinity chromatography an eluate containing the antibody was obtained according to conventional antibody purification methods.
Example 1 antitumor experiment on MC-38/PD-L1 mouse model
anti-PD-L1 humanized monoclonal antibody injection hu5G11-hIgG 1: the anti-PD-L1 humanized monoclonal antibody comprises a heavy chain variable region sequence shown as SEQ ID NO. 13 and a light chain variable region sequence shown as SEQ ID NO. 15. The heavy chain amino acid sequence of the anti-PD-L1 humanized monoclonal antibody in example 1 is shown in SEQ ID NO.17, and the light chain amino acid sequence is shown in SEQ ID NO. 18. The nilotinib is selected from the group consisting of nilotinib dihydrochloride.
MC-38/PD-L1 mouse colon cancer subcutaneous transplantation tumor with concentration of 2X 1060.2 mL/mouse, inoculated under sterile conditions in the right axilla of C57BL/6 mice (the site of inoculation was shaved at the time of inoculation), and passaged by the insert method. The C57BL/6 mice, weighing 16-18g, female, rearing environment: SPF grade. Animals were randomized into 4 groups the following day after subcutaneous transplantation tumor inserts:
i. a control group;
a single drug group: 4, Arotinib;
a single drug group: an anti-PD-L1 humanized monoclonal antibody;
combination group: anti-PD-L1 humanized monoclonal antibody + antrotinib;
of these, 12 were used as a control group and 6 were used for each of the other groups.
The dosing regimen is shown in table 1:
TABLE 1 dosing regimen
i.p. intraperitoneal injection;
i.g. intragastric administration;
qd: once daily administration;
and qod: the administration is once every other day.
The control group and the single drug group are administered with a vehicle (physiological saline) or a drug (physiological saline dissolved) in a volume of 10mL/kg, and when 2 drugs are administered simultaneously in the combined group, the administration volume of each drug is 10mL/kg respectively. Body weight and tumor size were measured every three days starting on day 6 of dosing and animal performance was observed daily.
Mice were grouped on day 0 with 12 controls and 6 in each of the other groups. Dosing was administered on day 1, intragastrically (i.g.) and intraperitoneally (i.p.). Dosing was stopped on day 22. During the experiment, tumor volumes were measured on days 6, 9, 12, 15, 18, 21, 24, and 27, respectively, and the experiment was terminated on day 28.
Tumor volume and tumor inhibition rate were calculated using the following formulas:
tumor Volume (TV) ═ gamma (gamma long wide)2)/2。
Tumor inhibition rate (TGI) ═ 1-treatment group tumor weight/control group tumor weight × 100%.
The results are shown in Table 2, which shows that the combination of anti-PD-L1 humanized monoclonal antibody and Arotinib can inhibit the growth of colorectal cancer.
TABLE 2 test results for murine MC-38/PD-L1 subcutaneous transplantable tumors of colon carcinoma
P <0.05vs. control, P <0.01vs. control.
The results show that the tumor inhibition rate of the combined group reaches 78.2%, which is obviously higher than that of the solitinib single drug group and the anti-PD-L1 humanized monoclonal antibody single drug group, and the combination of the solitinib and the anti-PD-L1 humanized monoclonal antibody has a good inhibition effect on colorectal cancer.
Sequence listing
<110> Nanjing Shunxin pharmaceutical Co., Ltd, Ningdanqing pharmaceutical industry group
CHIA TAI TIANQING PHARMACEUTICAL GROUP Co.,Ltd.
<120> pharmaceutical composition for combined use for the treatment of colorectal cancer
<130> 2020
<160> 21
<170> SIPOSequenceListing 1.0
<210> 1
<211> 5
<212> PRT
<213> Mus sp.
<400> 1
Thr Tyr Gly Val His
1 5
<210> 2
<211> 16
<212> PRT
<213> Mus sp.
<400> 2
Val Ile Trp Arg Gly Val Thr Thr Asp Tyr Asn Ala Ala Phe Met Ser
1 5 10 15
<210> 3
<211> 8
<212> PRT
<213> Mus sp.
<400> 3
Leu Gly Phe Tyr Ala Met Asp Tyr
1 5
<210> 4
<211> 5
<212> PRT
<213> Mus sp.
<400> 4
Ser Tyr Gly Met Ser
1 5
<210> 5
<211> 16
<212> PRT
<213> Mus sp.
<400> 5
Ser Ile Ser Ser Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val Lys Gly
1 5 10 15
<210> 6
<211> 8
<212> PRT
<213> Mus sp.
<400> 6
Gly Tyr Asp Ser Gly Phe Ala Tyr
1 5
<210> 7
<211> 11
<212> PRT
<213> Mus sp.
<400> 7
Lys Ala Ser Gln Ser Val Ser Asn Asp Val Ala
1 5 10
<210> 8
<211> 7
<212> PRT
<213> Mus sp.
<400> 8
Tyr Ala Ala Asn Arg Tyr Thr
1 5
<210> 9
<211> 9
<212> PRT
<213> Mus sp.
<400> 9
Gln Gln Asp Tyr Thr Ser Pro Tyr Thr
1 5
<210> 10
<211> 14
<212> PRT
<213> Mus sp.
<400> 10
Ala Ser Gln Ser Val Ser Thr Ser Ser Ser Ser Phe Met His
1 5 10
<210> 11
<211> 7
<212> PRT
<213> Mus sp.
<400> 11
Tyr Ala Ser Asn Leu Glu Ser
1 5
<210> 12
<211> 9
<212> PRT
<213> Mus sp.
<400> 12
Gln His Ser Trp Glu Ile Pro Tyr Thr
1 5
<210> 13
<211> 116
<212> PRT
<213> Artificial Sequence
<400> 13
Gln Ile Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Thr Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Arg Gly Val Thr Thr Asp Tyr Asn Ala Ala Phe Met
50 55 60
Ser Arg Leu Thr Ile Thr Lys Asp Asn Ser Lys Asn Gln Val Val Leu
65 70 75 80
Thr Met Asn Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala
85 90 95
Arg Leu Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 14
<211> 116
<212> PRT
<213> Artificial Sequence
<400> 14
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Phe Arg Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Asp Cys Ala
85 90 95
Arg Gly Tyr Asp Ser Gly Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 15
<211> 107
<212> PRT
<213> Artificial Sequence
<400> 15
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Ser Asn Asp
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Ala Ala Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Asp Tyr Thr Ser Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 16
<211> 111
<212> PRT
<213> Artificial Sequence
<400> 16
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly
1 5 10 15
Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Thr Ser
20 25 30
Ser Ser Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Lys Tyr Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asn Asp Thr Ala Asn Tyr Tyr Cys Gln His Ser Trp
85 90 95
Glu Ile Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 17
<211> 446
<212> PRT
<213> Artificial Sequence
<400> 17
Gln Ile Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Thr Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Arg Gly Val Thr Thr Asp Tyr Asn Ala Ala Phe Met
50 55 60
Ser Arg Leu Thr Ile Thr Lys Asp Asn Ser Lys Asn Gln Val Val Leu
65 70 75 80
Thr Met Asn Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala
85 90 95
Arg Leu Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Ala Val Ser His Glu Asp Pro Glu Val
260 265 270
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 18
<211> 214
<212> PRT
<213> Artificial Sequence
<400> 18
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Ser Asn Asp
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Ala Ala Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Asp Tyr Thr Ser Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 19
<211> 446
<212> PRT
<213> Artificial Sequence
<400> 19
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Phe Arg Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Asp Cys Ala
85 90 95
Arg Gly Tyr Asp Ser Gly Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Ala Val Ser His Glu Asp Pro Glu Val
260 265 270
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 20
<211> 218
<212> PRT
<213> Artificial Sequence
<400> 20
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly
1 5 10 15
Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Thr Ser
20 25 30
Ser Ser Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Lys Tyr Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asn Asp Thr Ala Asn Tyr Tyr Cys Gln His Ser Trp
85 90 95
Glu Ile Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 21
<211> 442
<212> PRT
<213> Artificial Sequence
<400> 21
Gln Ile Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Thr Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Arg Gly Val Thr Thr Asp Tyr Asn Ala Ala Phe Met
50 55 60
Ser Arg Leu Thr Ile Thr Lys Asp Asn Ser Lys Asn Gln Val Val Leu
65 70 75 80
Thr Met Asn Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala
85 90 95
Arg Leu Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro
210 215 220
Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
290 295 300
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
340 345 350
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
435 440
Claims (10)
1. A combination pharmaceutical composition for the treatment of colorectal cancer comprising an anti-PD-L1 antibody and nilotinib.
2. Combination pharmaceutical composition according to claim 1 or 2, characterized in that it comprises an anti-PD-L1 antibody pharmaceutical composition and an aniotinib pharmaceutical composition.
3. Combination pharmaceutical composition according to claim 1 or 2, wherein said combination pharmaceutical composition is packaged in the same kit, said kit further comprising instructions for the combined use of the PD-L1 antibody and the nilotinib for the treatment of colorectal cancer.
4. The pharmaceutical combination composition according to claim 1 or 2, wherein the pharmaceutical combination composition comprises a pharmaceutical composition comprising 600-2400 mg of the anti-PD-L1 antibody and a pharmaceutical composition with a single dose of 6mg, 8mg, 10mg and/or 12mg of aniotinib.
5. Use of a pharmaceutical composition in combination according to any one of claims 1 to 4 for the preparation of a medicament for the treatment of colorectal cancer.
6. Use of an anti-PD-L1 antibody and nilotinib for the manufacture of a medicament for the treatment of colorectal cancer.
7. The use according to claim 5 or 6, wherein the anti-PD-L1 antibody and the aniotinib are each in a pharmaceutical composition, which can be administered simultaneously, sequentially or at intervals; or the anti-PD-L1 antibody may be administered once per week, every 2 weeks, every 3 weeks, or every 4 weeks; alternatively, the aritinib may be administered at a dose of 6mg, 8mg, 10mg or 12mg once daily for 2 weeks followed by a 1-week rest schedule.
8. The pharmaceutical combination composition of any one of claims 1 to 4, or the use of any one of claims 5 to 7, 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 set forth 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 set forth 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 set forth 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 set forth 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 set forth in SEQ ID NO. 8 or SEQ ID NO. 11; a light chain CDR3 region having at least 80% homology to the amino acid sequence set forth in SEQ ID NO. 9 or SEQ ID NO. 12.
9. The pharmaceutical combination composition of any one of claims 1 to 4, or the use of any one of claims 5 to 7, 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.
10. Pharmaceutical composition for combination use according to any one of claims 1 to 4, or use according to any one of claims 5 to 7, said colorectal cancer being selected from colon cancer or rectal cancer.
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| WO2023030532A1 (en) * | 2021-09-06 | 2023-03-09 | 正大天晴药业集团股份有限公司 | Drug combination for treating esophageal cancer |
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