Use of Anti-PD-1 antibody combined with chemotherapeutic agent in treatment of tumors

Abstract

Provided is a use of an anti-PD-1 antibody combined with a chemotherapeutic agent in the treatment of tumors such as cervical cancer or endometrial cancer. In some embodiments, the chemotherapeutic agent comprises a taxane drug and / or a platinum drug. In some embodiments, the use further comprises a use of the anti-PD-1 antibody combined with bevacizumab.

Description

Use of anti-PD-1 antibodies combined with chemotherapy agents in the treatment of tumors Technical Field

[0001] The present invention belongs to the field of biomedicine, and in particular relates to the use of anti-PD-1 antibodies combined with chemotherapy agents in the treatment of tumors, such as cervical cancer or endometrial cancer. Background Art

[0002] Programmed death receptor-1 (PD-1) is an immunoinhibitory receptor expressed on activated T cells, B cells, and myeloid cells. It is a member of the CD28 immunoglobulin superfamily. PD-1 is a 55 kDa type I transmembrane glycoprotein that contains a ligand-binding Ig variable domain and a cytoplasmic tail responsible for binding signaling molecules. The PD-1 cytoplasmic tail contains two tyrosine-based signaling motifs: the ITIM (immunoreceptor tyrosine-based inhibitory motif) and the ITSM (immunoreceptor tyrosine-based switch motif).

[0003] Cervical cancer ranks first among malignant tumors of the female reproductive system. According to the World Health Organization (WHO), there are 530,000 new cases and approximately 250,000 deaths worldwide each year. Developing countries account for 80% of these deaths. This represents an unmet clinical need. Therefore, new treatments are needed to improve outcomes for these patients.

[0004] Endometrial cancer is a common gynecological malignancy with an increasing incidence rate year by year. Currently, there is still a significant clinical need for first-line treatments for endometrial cancer. Summary of the Invention

[0005] The present invention provides methods or uses of anti-PD-1 antibodies in combination with chemotherapeutic agents for treating tumors. In some embodiments, the present invention provides uses of anti-PD-1 antibodies in combination with chemotherapeutic agents in the preparation of pharmaceutical compositions for treating tumors. In some embodiments, the present invention provides uses of anti-PD-1 antibodies in the preparation of medicaments for treating tumors in combination with chemotherapeutic agents. In some embodiments, the present invention provides uses of anti-PD-1 antibodies in the treatment of tumors in combination with chemotherapeutic agents. In some embodiments, the present invention provides methods of treating patients suffering from tumors, comprising administering to the patient a therapeutically effective amount of an anti-PD-1 antibody and a chemotherapeutic agent. In some embodiments, the tumor is cervical cancer or endometrial cancer.

[0006] In some embodiments, the anti-PD-1 antibody comprises HCDR1 shown in SEQ ID NO: 1, HCDR2 shown in SEQ ID NO: 2, HCDR3 shown in SEQ ID NO: 3, LCDR1 shown in SEQ ID NO: 4, LCDR2 shown in SEQ ID NO: 5, and LCDR3 shown in SEQ ID NO: 6.

[0007] In some embodiments, the heavy chain variable region of the anti-PD-1 antibody comprises the sequence shown in SEQ ID NO: 7, a sequence having at least 80% identity to the sequence shown in SEQ ID NO: 7, or an amino acid sequence having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO: 7; and / or

[0008] The light chain variable region of the anti-PD-1 antibody comprises the sequence shown in SEQ ID NO: 8, a sequence having at least 80% identity with the sequence shown in SEQ ID NO: 8, or an amino acid sequence having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO: 8.

[0009] In some embodiments, the heavy chain variable region of the anti-PD-1 antibody comprises the sequence shown in SEQ ID NO:7, and the light chain variable region of the anti-PD-1 antibody comprises the sequence shown in SEQ ID NO:8.

[0010] In some embodiments, the heavy chain of the anti-PD-1 antibody comprises the sequence shown in SEQ ID NO: 9, a sequence having at least 80% identity to the sequence shown in SEQ ID NO: 9, or an amino acid sequence having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO: 9; and / or

[0011] The light chain of the anti-PD-1 antibody comprises the sequence shown in SEQ ID NO: 10, a sequence having at least 80% identity with the sequence shown in SEQ ID NO: 10, or an amino acid sequence having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO: 10.

[0012] In some embodiments, the anti-PD-1 antibody is antibody A, the heavy chain of antibody A comprises the sequence shown in SEQ ID NO: 9, and the light chain of antibody A comprises the sequence shown in SEQ ID NO: 10; antibody A contains two heavy chains with identical sequences and two light chains with identical sequences.

[0013] In some embodiments, the anti-PD-1 antibody is administered at about 50-600 mg per dose, or a formulation containing such a dose of the anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody is administered at about 200-400 mg per dose, or a formulation containing such a dose of the anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody is administered at about 50 mg, about 60 mg, about 80 mg, about 120 mg, about 200 mg, about 250 mg, about 290 mg, about 300 mg, about 330 mg, about 380 mg, about 400 mg, about 434 mg, about 480 mg, about 500 mg, about 567 mg, about 580 mg, about 600 mg per dose, or a range between any two of these values ​​(including the endpoints) or any value therein, or a formulation containing such a dose of the anti-PD-1 antibody.

[0014] In some embodiments, the drug is administered about once a week, or about every 2 weeks, about every 3 weeks, about every 4 weeks, about every 5 weeks, about every 6 weeks, or about every 7 weeks. In some embodiments, the drug is administered once every 2 weeks, 3 weeks, or 4 weeks. In some embodiments, the drug is administered once every 3 weeks.

[0015] In some embodiments, a treatment cycle is at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, or at least 7 weeks. In some embodiments, a treatment cycle is 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or a range (including endpoints) between any two of these values ​​or any value therein.

[0016] In some embodiments, the anti-PD-1 antibody is administered at about 200-400 mg per dose, administered once every 2-4 weeks. In some embodiments, the anti-PD-1 antibody is administered at about 100 mg, 300 mg, or 600 mg per dose, administered once every 3 weeks. In some embodiments, the anti-PD-1 antibody is administered at about 200-220 mg per dose, administered once every 2 weeks. In some embodiments, the anti-PD-1 antibody is administered at about 300 mg per dose, administered once every 3 weeks. In some embodiments, the anti-PD-1 antibody is administered at about 380-400 mg per dose, administered once every 4 weeks.

[0017] In some embodiments, the present invention provides methods or uses of an anti-PD-1 antibody in combination with a chemotherapeutic agent to treat a patient suffering from cervical cancer.

[0018] In some embodiments, the present invention discloses methods or uses of an anti-PD-1 antibody in combination with a chemotherapeutic agent for treating a patient with endometrial cancer.

[0019] In some embodiments, the chemotherapeutic agent is a taxane or a platinum drug, or a combination thereof. In some embodiments, the chemotherapeutic agent is a combination of a taxane and a platinum drug.

[0020] In some embodiments, the taxane is paclitaxel or liposomal paclitaxel.

[0021] In some embodiments, the platinum drug is cisplatin or carboplatin.

[0022] In some embodiments, the chemotherapeutic agent is selected from the group consisting of paclitaxel and cisplatin, paclitaxel and carboplatin, liposomal paclitaxel and cisplatin, and liposomal paclitaxel and carboplatin.

[0023] In some embodiments, the paclitaxel is administered at a dose of about 50-300 mg / m2 of body surface area per dose. 2 In some embodiments, the paclitaxel is administered at a dose of about 135-175 mg / m2 of body surface area. 2 In some embodiments, the paclitaxel is administered at a dose of about 100, 135, 150, 175, 200, 250, or 300 mg / m2 of body surface area. 2 In some embodiments, the paclitaxel is administered once a week, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, the paclitaxel is administered once every 3 weeks. In some embodiments, the paclitaxel is administered at a dose of about 175 mg / m2 per dose based on body surface area. 2 Administer once every 3 weeks.

[0024] In some embodiments, the cisplatin is administered at a dose of about 10-100 mg / m2 of body surface area per dose. 2 In some embodiments, the cisplatin is administered at a dose of about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 mg / m2 of body surface area. 2 In some embodiments, the cisplatin is administered once a week, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, the cisplatin is administered once every 3 weeks. In some embodiments, the cisplatin is administered at a dose of about 50 mg / m2 per dose based on body surface area. 2 Administer once every 3 weeks.

[0025] In some embodiments, the carboplatin is administered at an AUC of 4-7 mg / ml / min per dose. In some embodiments, the carboplatin is administered at an AUC of about 4, AUC 5, AUC 6, or AUC 7 mg / ml / min per dose. In some embodiments, the carboplatin is administered once a week, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, the carboplatin is administered once every 3 weeks. In some embodiments, the carboplatin is administered at an AUC of 5 mg / ml / min per dose and administered once every 3 weeks.

[0026] In some embodiments, the present invention provides a method for treating a patient with cervical cancer, comprising administering to the patient a therapeutically effective amount of an anti-PD-1 antibody (e.g., antibody A) and a chemotherapeutic agent selected from the following groups: paclitaxel and cisplatin, paclitaxel and carboplatin, paclitaxel liposomes and cisplatin, paclitaxel liposomes and carboplatin. In some embodiments, the present invention provides the use of an anti-PD-1 antibody (e.g., antibody A), paclitaxel / paclitaxel liposomes, cisplatin / carboplatin in the preparation of a pharmaceutical composition for the treatment of cervical cancer. In some embodiments, the present invention provides the use of an anti-PD-1 antibody (e.g., antibody A) in the preparation of a medicament for the combined treatment of cervical cancer with paclitaxel / paclitaxel liposomes and cisplatin / carboplatin. In some embodiments, the present invention provides the use of an anti-PD-1 antibody (e.g., antibody A) in combination with paclitaxel / paclitaxel liposomes and cisplatin / carboplatin in the treatment of cervical cancer.

[0027] In some embodiments, the present invention provides a method or use of an anti-PD-1 antibody in combination with paclitaxel / paclitaxel liposomes and cisplatin / carboplatin for treating a patient with cervical cancer, comprising administering the following drugs: (1) administering to the patient about 300 mg of an anti-PD-1 antibody (e.g., Antibody A) per dose once every 3 weeks, (2) administering paclitaxel or paclitaxel liposomes once every 3 weeks, and (3) administering cisplatin or carboplatin once every 3 weeks.

[0028] In some embodiments, the method or use comprises further administering bevacizumab. In some embodiments, the bevacizumab comprises Avastin or a biosimilar thereof, such as Probexi, Puxinting, Beianting, Hanbetai, Aritol, Boyounuo, Dayoutong, Enkeda, Alymsys, Zirabev, Mvasi, Vegzelma, Onbevzi, Oyavas, Aybintio, or Abevmy. In some embodiments, the bevacizumab is administered at a dose of about 15 mg / kg, administered once every three weeks.

[0029] In some embodiments, the method or use comprises administering to the patient a therapeutically effective amount of an anti-PD-1 antibody (e.g., Antibody A), a chemotherapeutic agent, and bevacizumab; the chemotherapeutic agent is selected from the following groups: paclitaxel and cisplatin, paclitaxel and carboplatin, liposomal paclitaxel and cisplatin, liposomal paclitaxel and carboplatin.

[0030] In some embodiments, the present invention provides a method of treating a patient having cervical cancer, comprising: (1) administering to the patient an anti-PD-1 antibody (e.g., Antibody A) at a dose of about 300 mg once every 3 weeks, (2) administering paclitaxel or liposomal paclitaxel once every 3 weeks, (3) administering cisplatin or carboplatin once every 3 weeks, and (4) administering bevacizumab at a dose of about 15 mg / kg once every 3 weeks.

[0031] In some embodiments, the paclitaxel is administered at a dose of about 175 mg / m2 of body surface area. 2 Administer once every 3 weeks.

[0032] In some embodiments, the cisplatin is administered at a dose of about 50 mg / m2 of body surface area. 2 Administer once every 3 weeks.

[0033] In some embodiments, the carboplatin is administered at an AUC of 5 mg / ml / min per dose, administered once every 3 weeks.

[0034] In some embodiments, the administration of the anti-PD-1 antibody in combination with a chemotherapeutic agent prolongs the patient's progression-free survival (PFS) and overall survival (OS) compared to patients treated with chemotherapy. In some embodiments, the administration of the anti-PD-1 antibody in combination with a chemotherapeutic agent results in at least one improvement selected from the following: objective response rate (ORR), disease control rate (DCR), duration of remission (DOR), time to disease progression (TTP), progression-free survival (PFS) and overall survival (OS) compared to patients treated with chemotherapy. In some embodiments, the solid tumor efficacy evaluation standard is RECIST 1.1. In some embodiments, the solid tumor efficacy evaluation standard is iRECIST.

[0035] In some embodiments, the present invention provides methods or uses of an anti-PD-1 antibody in combination with a chemotherapeutic agent as a first-line treatment for patients with cervical cancer.

[0036] In some embodiments, the cervical cancer includes squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, and clear cell carcinoma. In some embodiments, the cervical cancer is squamous cell carcinoma. In some embodiments, the cervical cancer is adenocarcinoma. In some embodiments, the cervical cancer is adenosquamous carcinoma. In some embodiments, the cervical cancer is clear cell carcinoma.

[0037] In some embodiments, the cervical cancer includes metastatic cervical cancer, recurrent cervical cancer, and persistent cervical cancer.

[0038] In some embodiments, the cervical cancer is PD-L1 positive (CPS ≥ 1) cervical cancer. In some embodiments, the cervical cancer is PD-L1 positive (CPS ≥ 1) metastatic cervical cancer, recurrent cervical cancer, or persistent cervical cancer.

[0039] In some embodiments, the patient with cervical cancer is not a candidate for radical surgery and / or radical radiotherapy or chemoradiotherapy.

[0040] In some embodiments, the patient with cervical cancer has not received any systemic anti-tumor treatment for recurrent or metastatic cervical cancer.

[0041] In some embodiments, the patient with cervical cancer has not previously received anti-angiogenic therapy (such as bevacizumab), immune checkpoint inhibitors (such as anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-CTLA-4 antibodies, etc.), or any treatment targeting tumor immune mechanisms such as immune co-stimulatory factors (such as antibodies targeting ICOS, CD40, CD137, GITR, OX40 targets, etc.).

[0042] In some embodiments, the patient with cervical cancer has previously received multiple cycles of paclitaxel (including paclitaxel for injection) and platinum (including cisplatin and carboplatin) treatment in the adjuvant or neoadjuvant stage or in the definitive chemoradiotherapy stage.

[0043] In some embodiments, the present invention provides a method for treating a patient with endometrial cancer, comprising administering to the patient a therapeutically effective amount of an anti-PD-1 antibody (e.g., Antibody A), paclitaxel, and carboplatin. In some embodiments, the present invention provides the use of an anti-PD-1 antibody (e.g., Antibody A), paclitaxel, and carboplatin in the preparation of a pharmaceutical composition for treating endometrial cancer. In some embodiments, the present invention provides the use of an anti-PD-1 antibody (e.g., Antibody A) in the preparation of a medicament for the combined treatment of endometrial cancer with paclitaxel and carboplatin. In some embodiments, the present invention provides the use of an anti-PD-1 antibody (e.g., Antibody A) in combination with paclitaxel and carboplatin in the treatment of endometrial cancer.

[0044] In some embodiments, the present invention provides a method or use of an anti-PD-1 antibody in combination with paclitaxel and carboplatin for treating a patient with endometrial cancer, comprising: (1) administering to the patient about 300 mg of an anti-PD-1 antibody (e.g., Antibody A) per dose once every 3 weeks, (2) administering paclitaxel once every 3 weeks, and (3) administering carboplatin once every 3 weeks.

[0045] In some embodiments, the paclitaxel is administered at a dose of about 175 mg / m2 of body surface area. 2 Administer once every 3 weeks.

[0046] In some embodiments, the carboplatin is administered at an AUC of 5 mg / ml / min per dose, administered once every 3 weeks.

[0047] In some embodiments, the present invention provides a method of treating a patient suffering from endometrial cancer comprising:

[0048] (1) administering to the patient about 300 mg of an anti-PD-1 antibody (e.g., Antibody A) per dose once every 3 weeks,

[0049] (2) Administer paclitaxel to patients in need every 3 weeks at a dose of approximately 175 mg / m2 of body surface area. 2 administration; (3) carboplatin administered once every 3 weeks, the carboplatin being administered at an AUC of 5 mg / ml / min per dose.

[0050] In some embodiments, the present invention provides methods or uses of an anti-PD-1 antibody in combination with a chemotherapeutic agent as a first-line treatment for patients with endometrial cancer.

[0051] In some embodiments, the endometrial cancer is recurrent or metastatic endometrial cancer. In some embodiments, the endometrial cancer is one of the following: a) newly diagnosed Stage III disease (measurable disease according to RECIST 1.1 after surgery or diagnostic biopsy), b) newly diagnosed Stage IV disease (with or without disease after surgery or diagnostic biopsy), c) recurrent disease (measurable or non-measurable disease according to RECIST 1.1) where there is a low likelihood of cure with surgery alone or in combination. In some embodiments, the recurrent disease has been treated with prior chemotherapy in the adjuvant setting (as part of upfront / adjuvant anticancer treatment).

[0052] In some embodiments, the endometrial cancer is mismatch repair protein-deficient (dMMR) endometrial cancer (Bonneville R, et al.; JCO Precis Oncol. 2017; 2017: PO.17.00073.). In some embodiments, the endometrial cancer is dMMR recurrent or metastatic endometrial cancer. In some embodiments, the endometrial cancer is MSI-H / dMMR.

[0053] In some embodiments, the patient with endometrial cancer has not received first-line systemic anticancer treatment.

[0054] In some embodiments, the patient with endometrial cancer has not previously received any treatment targeting tumor immune mechanisms, such as immune checkpoint inhibitors (such as anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-CTLA-4 antibodies, etc.) or immune co-stimulatory factors (such as antibodies targeting ICOS, CD40, CD137, GITR, OX40 targets, etc.).

[0055] In some embodiments, the anti-PD-1 antibody (or formulation), taxane (such as paclitaxel or liposome paclitaxel for injection), platinum drug (such as cisplatin or carboplatin), or bevacizumab is administered by intravenous infusion (iv). In some embodiments, the duration of intravenous infusion of anti-PD-1 antibody (or formulation) is about 30-90 minutes. In some embodiments, the duration of intravenous infusion of anti-PD-1 antibody (or formulation) is about 30-60 minutes. In some embodiments, bevacizumab (or its injection) is administered by intravenous infusion, and the duration of intravenous infusion is about 30-90 minutes. In some embodiments, the duration of intravenous infusion of bevacizumab (or its injection) is about 30, 60 or 90 minutes.

[0056] In some embodiments, the patient receives one treatment cycle of anti-PD-1 antibodies (e.g., antibody A) and chemotherapeutic agents. In some embodiments, the patient receives one treatment cycle of anti-PD-1 antibodies (e.g., antibody A), chemotherapeutic agents, and bevacizumab. In some embodiments, the patient receives multiple (e.g., 2-35, e.g., 5, 10, 15, 20, 25, 30, 35, or a range (including endpoints) between any two of these values ​​or any value therein, wherein chemotherapy is up to 6) treatment cycles. In some embodiments, the patient receives treatment until the condition is alleviated and no longer requires treatment.

[0057] The "combination" described herein is a mode of administration, which includes various situations in which two or more drugs are administered sequentially or simultaneously. In some embodiments, the anti-PD-1 antibody and the chemotherapeutic agent are independent administration units, and the drugs are used in combination. In some embodiments, the order of administration is: (1) anti-PD-1 antibody, (2) paclitaxel or paclitaxel liposome for injection, (3) cisplatin or carboplatin. In some embodiments, the anti-PD-1 antibody, the chemotherapeutic agent, and bevacizumab are independent administration units, and the drugs are used in combination. In some embodiments, the order of administration is: (1) anti-PD-1 antibody, (2) paclitaxel or paclitaxel liposome for injection, (3) cisplatin or carboplatin, and (4) bevacizumab.

[0058] On the other hand, the present invention also provides a kit comprising an anti-PD-1 antibody (or formulation), a chemotherapeutic agent (or formulation), and instructions for guiding patients in need to administer the anti-PD-1 antibody (or formulation) and the chemotherapeutic agent (or formulation). In some embodiments, the present invention also discloses a kit comprising a combination (or formulation) of an anti-PD-1 antibody and a chemotherapeutic agent and instructions for guiding patients in need to administer the combination (or formulation) of an anti-PD-1 antibody and a chemotherapeutic agent. In some embodiments, the kit further comprises an anti-VEGF antibody (or formulation), such as bevacizumab, and instructions for guiding patients in need to administer the anti-VEGF antibody (or formulation), such as bevacizumab.

[0059] On the other hand, the present invention also provides a pharmaceutical composition suitable for injection comprising an anti-PD-1 antibody and a chemotherapeutic agent, such as a push-in type pharmaceutical composition or an infusion (drip) type pharmaceutical composition. In some embodiments, the pharmaceutical composition further comprises an anti-VEGF antibody (or preparation) such as bevacizumab. In some embodiments, the pharmaceutical composition comprises at least 0.1% of an anti-PD-1 antibody and at least 0.1% of a chemotherapeutic agent. The percentages of antibodies and chemotherapeutic agents can vary and are between about 2% and about 90% of the weight of a given dosage form. The amount of anti-PD-1 antibody, anti-VEGF antibody, and chemotherapeutic agent in such a therapeutically useful pharmaceutical composition can be an effective amount for administration.

[0060] In another aspect, the present invention also provides a method for preparing the aforementioned pharmaceutical composition, comprising separately mixing the anti-PD-1 antibody and chemotherapeutic agent (or a combination of the anti-PD-1 antibody and chemotherapeutic agent) described herein with a pharmaceutically acceptable carrier suitable for injection (e.g., water for injection, physiological saline, etc.). Methods for mixing the aforementioned anti-PD-1 antibody and chemotherapeutic agent with a pharmaceutically acceptable carrier are generally known in the art.

[0061] In some embodiments, the administration of the anti-PD-1 antibody in combination with a chemotherapeutic agent prolongs the patient's progression-free survival (PFS) and overall survival (OS). In some embodiments, the administration of the anti-PD-1 antibody in combination with a chemotherapeutic agent results in at least one improvement selected from the group consisting of objective response rate (ORR), disease control rate (DCR), duration of response (DOR), time to disease progression (TTP), progression-free survival (PFS), and overall survival (OS).

[0062] In some embodiments, the combined drug regimen of the present invention has excellent therapeutic effects.

[0063] the term

[0064] Unless otherwise stated, each of the following terms shall have the meaning set forth below.

[0065] definition

[0066] It should be noted that the term "a" entity refers to one or more of that entity, e.g., "an antibody" should be understood as one or more antibodies, and thus, the terms "a" (or "an"), "one or more" and "at least one" can be used interchangeably herein.

[0067] As used herein, the terms "comprising" or "including" mean that compositions and methods, etc. include the recited elements, such as components or steps, but do not exclude others. "Consisting essentially of" means that compositions and methods exclude other elements that have a fundamental effect on the characteristics of the combination, but do not exclude elements that have no essential effect on the composition or method. "Consisting of" means excluding elements not specifically recited.

[0068] A "conservative amino acid substitution" is a substitution of one amino acid residue with another amino acid residue that has a side chain (R group) with similar chemical properties (e.g., charge or hydrophobicity). In general, conservative amino acid substitutions are unlikely to substantially alter the functional properties of a protein. Examples of amino acid classes with chemically similar side chains include: 1) aliphatic side chains: glycine, alanine, valine, leucine, and isoleucine; 2) aliphatic hydroxyl side chains: serine and threonine; 3) amide-containing side chains: asparagine and glutamine; 4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; 5) basic side chains: lysine, arginine, and histidine; and 6) acidic side chains: aspartic acid and glutamic acid.

[0069] The number of amino acids in a “conservative amino acid substitution of VL or VH” may be about 1, about 2, about 3, about 4, about 5, about 6, about 8, about 9, about 10, about 11, about 13, about 14, or about 15 conservative amino acid substitutions, or a range (including endpoints) between any two of these values, or any value therein. The number of amino acids in a “conservative amino acid substitution of a heavy chain or light chain” may be about 1, about 2, about 3, about 4, about 5, about 6, about 8, about 9, about 10, about 11, about 13, about 14, about 15, about 18, about 19, about 22, about 24, about 25, about 29, about 31, about 35, about 38, about 41, or about 45 conservative amino acid substitutions, or a range (including endpoints) between any two of these values, or any value therein.

[0070] "Homology" or "identity" or "similarity" refers to the sequence similarity between two peptides or two nucleic acid molecules. Homology can be determined by comparing alignable positions in each sequence. When a position in the compared sequences is occupied by the same base or amino acid, the molecules are homologous at that position. The degree of homology between the sequences is a function of the number of matching or homologous positions shared by the sequences.

[0071] "At least 80% identity" means about 80% identity, about 81% identity, about 82% identity, about 83% identity, about 85% identity, about 86% identity, about 87% identity, about 88% identity, about 90% identity, about 91% identity, about 92% identity, about 94% identity, about 95% identity, about 98% identity, about 99% identity, or a range between any two of these values ​​(including the endpoints) or any value therein.

[0072] "Antibody" and "antigen-binding fragment" refer to a polypeptide or polypeptide complex that specifically recognizes and binds to an antigen. An antibody can be a complete antibody and any antigen-binding fragment thereof or a single chain thereof. Therefore, the term "antibody" includes any protein or peptide that contains at least a portion of an immunoglobulin molecule that has the biological activity of binding to an antigen. Antibodies and antigen-binding fragments include, but are not limited to, the complementarity determining regions (CDRs) of the heavy chain or light chain or their ligand-binding portions, the heavy chain variable region (VH), the light chain variable region (VL), the heavy chain constant region (CH), the light chain constant region (CL), the framework region (FR) or any portion thereof, or at least a portion of a binding protein. The CDR region includes the CDR regions (LCDR1-3) of the light chain and the CDR regions (HCDR1-3) of the heavy chain.

[0073] The term "antibody" includes a wide variety of polypeptides that can be distinguished biochemically. It will be understood by those skilled in the art that the categories of heavy chains include gamma, mu, alpha, delta or epsilon (γ, μ, α, δ, ε), with some subclasses (e.g., γ1-γ4) also included. The nature of this chain determines the "class" of the antibody, which is IgG, IgM, IgA, IgD or IgE, respectively. Immunoglobulin subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, etc., have been fully characterized and the functional specificity conferred is also known. All immunoglobulin classes are within the scope of protection disclosed herein. In some embodiments, the immunoglobulin molecule is an IgG class. These four chains are connected in a "Y" configuration by disulfide bonds, with the light chain starting from the "Y" mouth and continuing through the variable region to surround the heavy chain.

[0074] The antibodies, antigen-binding fragments or derivatives described herein include, but are not limited to, polyclonal, monoclonal, multispecific, fully human, humanized, primatized, chimeric antibodies, single-chain antibodies (scFv), epitope-binding fragments (e.g., Fab, Fab' and F(ab')2).

[0075] Light chains can be classified as kappa (κ) or lambda (λ). Each heavy chain can be combined with a κ or λ light chain. Generally speaking, when immunoglobulins are produced by hybridomas, B cells, or genetically engineered host cells, their light chains and heavy chains are bound by covalent bonds, and the "tail" parts of the two heavy chains are bound by covalent disulfide bonds or non-covalent bonds. In the heavy chain, the amino acid sequence extends from the N-terminus of the forked end of the Y configuration to the C-terminus at the bottom of each chain. The variable region of the immunoglobulin κ light chain is Vκ; the variable region of the immunoglobulin λ light chain is V λ .

[0076] The variable regions of the light (VL) and heavy (VH) chains determine antigen recognition and specificity. The constant regions of the light (CL) and heavy (CH) chains confer important biological properties, such as secretion, transplacental movement, Fc receptor binding, and complement fixation. By convention, the numbering of the constant regions increases as they become more distal to the antibody's antigen-binding site, or amino terminus. The N-terminal portion is the variable region, and the C-terminal portion is the constant region; the CH3 and CL domains actually comprise the carboxyl termini of the heavy and light chains, respectively.

[0077] Where a term has two or more definitions used and / or accepted in the art, the definition of the term used herein includes all of these meanings unless explicitly indicated to the contrary. A specific example is the use of the term "complementarity determining region" ("CDR") to describe the non-contiguous antigen binding sites found within the variable regions of heavy and light chain polypeptides.

[0078] The CDRs defined according to Kabat and Chothia include overlapping or subsets of amino acid residues when compared to each other. Nevertheless, the application of either definition to refer to the CDRs of an antibody or its variants is within the scope of the present invention. The exact residue numbering comprising a particular CDR will vary depending on the sequence and size of the CDR. Those skilled in the art can generally determine which specific residues a CDR comprises based on the variable region amino acid sequence of an antibody.

[0079] Kabat et al. also defined a numbering system applicable to the variable region sequence of any antibody. Those skilled in the art can apply this "Kabat numbering" system to any variable region sequence independently of experimental data other than the sequence itself. "Kabat numbering" refers to the numbering system proposed by Kabat et al., U.S. Department of Health and Human Services in "Sequence of Proteins of Immunological Interest" (1983). Antibodies may also use the EU or Chothia numbering system.

[0080] "Treatment" refers to both therapeutic treatment and prophylactic or preventative measures, the purpose of which is to prevent, slow, ameliorate, and halt undesirable physiological changes or disorders, such as the progression of a disease, including but not limited to the following results, whether detectable or undetectable, relief of symptoms, reduction in the extent of the disease, stabilization of the disease state (i.e., no worsening), delay or slowing of disease progression, improvement or alleviation of the disease state, alleviation or elimination (whether partial or total), prolongation of life compared to that expected in the absence of treatment, etc. Patients in need of treatment include those already suffering from the condition or disorder, those susceptible to the condition or disorder, or those in need of prevention of the condition or disorder, and those who can or are expected to benefit from the administration of the antibodies or compositions described herein for detection, diagnostic procedures, and / or treatment.

[0081] "About" refers to the normal error range of the corresponding numerical value that is easily known to those skilled in the relevant art. In some embodiments, "about" mentioned herein refers to the described numerical value and its ±10%, ±5% or ±1% range.

[0082] An "effective amount" is an amount of an active compound or agent that elicits the biological or medical response of a tissue, system, animal, individual, or human; the effective amount is that sought by a researcher, veterinarian, medical doctor, or other clinician.

[0083] Single-dose PK parameter: C max 、T max 、T 1 / 2 , CL, Vd, Ke, MRT, AUC (0-τ) , AUC (0-∞)。

[0084] Multiple-dose PK parameters: C max,ss 、C avg,ss 、C min,ss , AUC (0-τ)ss , AUC (0-∞)ss 、T max,ss 、T 1 / 2,ss , CL, Vss , Ke, MRT, accumulation index (R ac ), volatility index DF.

[0085] The Eastern Cooperative Oncology Group (ECOG) has developed a simpler activity status scoring table, which divides the patient's activity status into 6 levels from 0 to 5. The ECOG physical condition scoring standard is 0, 1, 2, 3, 4, and 5 points.

[0086] Tumor assessment was performed according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) (Eisenhauer, EA et al., Eur J Cancer. 2009; 45(2): 228-247) and iRECIST (Seymour L, et al. Lancet Oncol. 2017; 18: e143-e152), with RECIST 1.1 as the primary evaluation criterion.

[0087] Objective response rate (ORR), duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), time to disease progression (TTP), and overall survival (OS) were defined according to RECIST 1.1.

[0088] Objective response rate (ORR) refers to the proportion of patients with a confirmed best response of CR or PR. Objective response was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). Patients must have measurable tumor lesions at baseline. Response assessment was categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) according to RECIST, version 1.1.

[0089] Duration of response (DOR): DOR is defined as the time from the first objective response of the tumor to the first PD assessment or death from any cause before PD, reflecting the duration of ORR.

[0090] Disease control rate (DCR) refers to the proportion of patients whose tumors shrink or stabilize for a certain period of time, including cases of CR, PR and SD, also known as Clinical Benefit Rate (CBR).

[0091] Progression-free survival (PFS): The time from the first dose to the occurrence of objective tumor progression or all-cause death (whichever occurs first).

[0092] Overall survival (OS) was calculated from the date of first dose until death from any cause. Patients who were still alive at the time of analysis were considered to have the last contact date as the cutoff date.

[0093] During the study period, the same imaging technique was recommended for the same area in the same patient. BRIEF DESCRIPTION OF THE DRAWINGS

[0094] Figure 1 shows the best response percentage of target lesions relative to baseline in 27 subjects. DETAILED DESCRIPTION

[0095] The following is a detailed description of the technical solution of the present invention, which does not limit the scope of protection of the present invention. Non-essential modifications and adjustments made by others based on the concept of the present invention still fall within the scope of protection of the present invention.

[0096] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

[0097] The preparation method of Antibody A can refer to the invention patent application WO2020207432A1; the amino acid sequence of Antibody A is shown in Table 1.

[0098] Table 1 Amino acid sequence of antibody A

[0099] Example 1: Phase II / III study of the safety and efficacy of Antibody A combined with chemotherapy ± bevacizumab for the first-line treatment of PD-L1-positive (CPS ≥ 1) persistent, recurrent or metastatic cervical cancer

[0100] This study is a seamless Phase II / III clinical trial. The Phase II study investigates the safety and preliminary efficacy of Antibody A in combination with chemotherapy ± bevacizumab, a single-arm, open-label, multicenter study. If the safety profile of this combination is manageable and the efficacy meets expectations (i.e., an ORR of approximately 60% at 18 weeks (W)), the study will proceed to the Phase III study, a randomized, double-blind, multicenter trial comparing Antibody A in combination with chemotherapy ± bevacizumab versus chemotherapy ± bevacizumab as first-line treatment for patients with persistent, recurrent, or metastatic PD-L1-positive cervical cancer (CPS ≥ 1). "± bevacizumab" indicates "with or without bevacizumab."

[0101] Compared with first-line chemotherapy ± bevacizumab, this study anticipates that the administration of Antibody A in combination with chemotherapy ± bevacizumab will prolong patients' PFS and OS. Compared with first-line chemotherapy ± bevacizumab, this study anticipates that the administration of Antibody A and chemotherapy ± bevacizumab will result in at least one improvement selected from the following: objective response rate (ORR), disease control rate (DCR), duration of response (DOR), time to disease progression (TTP), progression-free survival (PFS), and overall survival (OS).

[0102] 1. Patient inclusion and exclusion criteria:

[0103] Inclusion criteria:

[0104] 1. Aged ≥18 and ≤70 years old, female, voluntarily signed the informed consent form;

[0105] 2. Patients with histologically confirmed (pathology report required) persistent, recurrent, or metastatic (International Federation of Gynecology and Obstetrics [FIGO] stage IVB) cervical cancer, including squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, and clear cell carcinoma, who are not suitable for radical surgery and / or radical radiotherapy or chemoradiotherapy, and have not received any systemic anti-tumor treatment for recurrent or metastatic cervical cancer;

[0106] 3. The patient must meet the requirement of positive PD-L1 expression (CPS ≥ 1) in the central laboratory test of the tumor specimen. The patient should provide sufficient paraffin-embedded (FFPE) specimens or sections (6 slices are recommended, not less than 3 slices), and be willing to undergo tumor tissue biopsy for PD-L1 testing when necessary. The archived tissue must be a representative tumor specimen within three years, or an unstained serial section of freshly cut FFPE tumor tissue within six months, and the relevant pathology report of the above specimens must also be provided. Fresh tissue specimens can be obtained by surgical resection and biopsy; fine needle aspiration and liquid-based cytology testing (TCT) samples (i.e., lacking complete tissue structure, only providing cell suspension and / or cell smear samples) are not accepted; decalcified bone metastasis tumor tissue specimens are not accepted;

[0107] 4. According to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1), there is at least one measurable tumor lesion. Lesions that have previously received radiotherapy or other local regional treatments can only be considered non-target lesions unless the lesion has clearly progressed or biopsy confirms specific tumor activity in the lesion and the lesion is measurable.

[0108] 5. The expected survival time as assessed by the investigator is ≥12 weeks;

[0109] 6. Eastern Cooperative Oncology Group (ECOG) performance status score must be 0 or 1;

[0110] 7. Female patients of childbearing potential must have a negative serum pregnancy test within 7 days prior to the first dose and be willing to use effective birth control / contraception to prevent pregnancy during the study and for 6 months after the last dose. Postmenopausal women must have been amenorrheic for at least 12 months to be considered infertile.

[0111] Exclusion criteria:

[0112] 1. Patients with other pathological types of cervical cancer, such as small cell carcinoma, sarcoma, etc.;

[0113] 2. Pregnant and lactating women;

[0114] 3. Received radiotherapy within 14 days before the first dose. Except for palliative area radiotherapy for bone metastases that cannot be effectively controlled by systemic treatment or local analgesia (radiotherapy area < 5% of the bone marrow area); received chemotherapy drugs for radiosensitization within 14 days before the first dose; received Chinese patent medicine or treatment with anti-tumor functions clearly stated in the drug instructions approved by the NMPA within 14 days before the first dose, or received Chinese herbal medicine treatment with anti-tumor purposes clearly recorded in the medical record.

[0115] 4. Patients who have received or plan to receive live / attenuated vaccines and mRNA vaccines within 4 weeks before screening;

[0116] 5. Previous treatment with immune checkpoint inhibitors (such as anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-CTLA-4 antibodies, etc.) or any other treatment targeting tumor immune mechanisms such as immune co-stimulatory factors (such as antibodies targeting ICOS, CD40, CD137, GITR, OX40 targets, etc.).

[0117] 2. Dosage method:

[0118] The order of administration was as follows: 1) Antibody A or placebo, 2) Paclitaxel, 3) Cisplatin or Carboplatin, 4) Bevacizumab.

[0119] 1) Antibody A or placebo: Intravenous drip, recommended dose 300mg, total volume of solution after preparation is 100ml, concentration range is controlled between 1-10mg / ml. Use 5% glucose solution for dilution. The prepared Antibody A injection is administered intravenously, and it is recommended to be infused intravenously for 30 minutes to 1 hour; it is administered once every 3 weeks (21 days), on the first day of each cycle. The longest regular administration duration of the study is approximately 2 years, approximately 35 dosing cycles.

[0120] 2) Chemotherapy:

[0121] Paclitaxel for injection (or liposome paclitaxel for injection): 175 mg / m 2The drug is administered by intravenous infusion once every 3 weeks (Q3W) on the first day of each cycle for a total of 6 cycles.

[0122] Cisplatin: 50 mg / m 2 Patients were given as an intravenous infusion every 3 weeks (Q3W) immediately after the completion of the paclitaxel infusion on the first day of each cycle or on the second day of each cycle, concurrently with hydration and diuresis, for a total of 6 cycles. Patients could be switched from cisplatin to carboplatin during the trial if clinical factors (e.g., impaired renal function) required it.

[0123] Carboplatin (cisplatin intolerance): Administer AUC 5mg / ml / min via intravenous infusion once every 3 weeks (Q3W) on the first day of each cycle for a total of 6 cycles.

[0124] 3) Bevacizumab: Recommended dose is 15 mg / kg; administered once every 3 weeks (15 mg / kg / Q3W). Administered by intravenous infusion, the first intravenous infusion should last for 90 minutes. If the first infusion is well tolerated, the second infusion can be shortened to 60 minutes. If the patient also tolerates the 60-minute infusion well, all subsequent infusions can be completed in 30 minutes. It is recommended to continue bevacizumab treatment until disease progression or intolerable toxicity occurs. The first 6 cycles will be administered by infusion immediately after the administration of cisplatin or carboplatin.

[0125] 3. Phase II study endpoints:

[0126] The Phase II study is a safety and preliminary efficacy study of Antibody A combined with chemotherapy ± bevacizumab.

[0127] The primary endpoint is the safety endpoint: vital signs and physical examination, various adverse events (AEs), clinical laboratory tests, clinical auxiliary examinations (such as electrocardiogram, etc.), etc.

[0128] Secondary endpoints:

[0129] Pharmacokinetic parameters under single and multiple administration (mainly including: C max 、T max 、T 1 / 2 , CL, Vd, Ke, MRT, AUC (0-τ) , AUC (0-∞) ; Multiple doses of C max,ss 、C avg,ss 、C min, ss , AUC (0-τ)ss , AUC (0-∞)ss 、T max,ss 、T 1 / 2,ss, CL, Vss, Ke, MRT, accumulation index (Rac), fluctuation index (DF).

[0130] Immunogenicity evaluation indicators: anti-drug antibodies (ADA) / neutralizing antibodies (NAb).

[0131] Clinical efficacy indicators: Preliminary efficacy evaluated according to RECIST 1.1. The primary indicator is ORR at 18 weeks; other secondary indicators include DCR, DOR, TTP, PFS, and OS.

[0132] Biomarker: PD-L1 expression level in tumor tissue.

[0133] 4. Phase III study endpoints:

[0134] The Phase III study is a confirmatory study of the safety and efficacy of Antibody A combined with chemotherapy ± bevacizumab for the first-line treatment of PD-L1-positive (CPS ≥ 1) persistent, recurrent or metastatic cervical cancer.

[0135] The primary endpoint was to compare the PFS and OS of antibody A combined with chemotherapy ± bevacizumab versus chemotherapy ± bevacizumab as first-line treatment for patients with PD-L1-positive (CPS ≥ 1) recurrent or metastatic cervical cancer, as assessed by RECIST 1.1.

[0136] Secondary endpoints:

[0137] Safety endpoints: vital signs and physical examination, adverse events (AEs), clinical laboratory tests, and clinical auxiliary examinations (e.g., electrocardiogram).

[0138] Efficacy evaluated according to RECIST 1.1, including ORR, DCR, DOR, TTP, etc.

[0139] Immunogenicity evaluation indicators: anti-drug antibodies (ADA) / neutralizing antibodies (NAb).

[0140] Biomarkers: Correlation between PD-L1 expression levels in tumor tissue and efficacy.

[0141] Phase II study results

[0142] As of October 8, 2024, a total of 29 subjects were enrolled, all of whom had received at least one prior combination therapy. The majority of enrolled patients had relapsed after prior treatment, and more than half had previously received multiple cycles of paclitaxel (injectable paclitaxel) plus platinum (cisplatin and / or carboplatin) in the adjuvant / neoadjuvant setting or in the definitive chemoradiotherapy phase. The baseline characteristics of the enrolled subjects are shown in Table 2. Twenty-seven subjects completed at least one treatment evaluation, achieving a 100% DCR. Target lesion reduction was observed in 26 of these subjects, with reduction exceeding 30% in 20. The preliminary ORR was 74% (20 / 27), with three achieving a complete response (CR) (Figure 1).

[0143] Table 2 Baseline characteristics of enrolled subjects

[0144] Among the 27 subjects, 4 were discharged from the group due to disease progression (PD), another 6 subjects voluntarily withdrew, and 1 died (due to gastrointestinal bleeding). The remaining 16 subjects are still in the group and have been in the group for more than 18 weeks, of which 9 have been in the group for more than 27 weeks and 3 have been in the group for more than 36 weeks.

[0145] The results are shown in Table 3. In the Antibody A combined with chemotherapy and bevacizumab group, 2 patients achieved complete remission, 12 achieved partial remission, 3 had stable disease, 1 had progressive disease, 2 subjects withdrew voluntarily, and 1 patient died. In the Antibody A combined with chemotherapy group, 1 patient achieved complete remission, 3 achieved partial remission, 1 had stable disease, and 1 had progressive disease. Both groups achieved excellent preliminary efficacy. The ECOG score, disease status, histopathological type, PD-L1 expression level, and FIGO stage at initial diagnosis at enrollment did not affect the therapeutic effect of the combination therapy.

[0146] The combination therapy was safe and tolerable, with the most common anemia (82.6%), decreased white blood cell count (55.2%), alopecia (51.7%), decreased platelet count (48.3%), decreased neutrophil count (44.8%), etc., with ≥3 TRAEs accounting for 62.1%. Preliminary data showed that the overall AE and ≥3 TRAE ratios were similar to those in previous studies of the same type, and no new safety signals were found. In addition, in terms of irAEs (immune-related adverse events), the current proportion and specific events were also similar to those in similar studies. Currently, only one case of grade 3 irAE has occurred, which was grade 3 oral ulcer, and the patient continued to receive treatment in the group after improvement.

[0147] These results indicate that the combination of antibody A combined with chemotherapy and antibody A combined with chemotherapy and bevacizumab can achieve excellent preliminary efficacy with acceptable safety and tolerability, regardless of whether the same chemotherapy regimen has been used previously as adjuvant / neoadjuvant chemotherapy or definitive chemoradiotherapy.

[0148] Table 3 Specific data of efficacy of 27 subjects

[0149] Example 2: Phase II / III study of the safety and efficacy of Antibody A combined with chemotherapy for the first-line treatment of advanced or recurrent mismatch repair protein-deficient (dMMR) endometrial cancer

[0150] Phase II is a single-arm exploratory safety and efficacy study investigating the safety and preliminary efficacy of Antibody A in combination with chemotherapy. If the safety profile of this combination is manageable and the efficacy meets expectations, enrollment in Phase II will be discontinued and Phase III will be initiated. This randomized, double-blind, multicenter study will evaluate Antibody A in combination with chemotherapy versus placebo plus chemotherapy as a first-line treatment for patients with advanced or recurrent dMMR endometrial cancer.

[0151] This study anticipates that the administration of Antibody A in combination with a chemotherapeutic agent will prolong progression-free survival (PFS) in patients compared to patients who are administered chemotherapeutic agents alone. Administration of Antibody A in combination with a chemotherapeutic agent is expected to result in at least one improvement selected from the group consisting of progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), duration of response (DOR), time to disease progression (TTP), and overall survival (OS) compared to patients who are administered chemotherapeutic agents alone.

[0152] 1. Patient inclusion and exclusion criteria:

[0153] Inclusion criteria:

[0154] 1. Aged ≥18 and ≤75 years old, female; voluntarily sign the informed consent form;

[0155] 2. Patients must have one of the following types of endometrial cancer: a) newly diagnosed stage III disease (measurable disease according to RECIST 1.1 after surgery or diagnostic biopsy), b) newly diagnosed stage IV disease (with or without disease after surgery or diagnostic biopsy), c) recurrent disease (measurable or non-measurable disease according to RECIST 1.1) in which cure with surgery alone or in combination is unlikely;

[0156] 3. Not received first-line systemic anticancer treatment. For patients with recurrent disease only, previous chemotherapy is allowed if it was received in the adjuvant setting (as part of upfront / adjuvant anticancer treatment) and the last dose of chemotherapy was at least 6 months after the date of relapse;

[0157] 4. The patient must meet the requirements of the central laboratory for tumor specimen detection of mismatch repair protein deficiency (dMMR). The patient should provide sufficient paraffin-embedded (FFPE) specimens or sections (6 slices are recommended, and no less than 3 slices), and be willing to undergo tumor tissue biopsy when necessary for MMR status testing. The archived tissue must be a representative tumor specimen within three years, or an unstained serial section of freshly cut FFPE tumor tissue within six months, and the relevant pathology report of the above specimens must also be provided. Fresh tissue specimens can be obtained by surgical resection and biopsy; fine needle aspiration and liquid-based cytology (TCT) samples (i.e., lacking complete tissue structure, only providing cell suspensions and / or cell smears) are not accepted; decalcified bone metastasis tumor tissue specimens are not accepted;

[0158] 5. The Eastern Cooperative Oncology Group (ECOG) performance status score must be 0 or 1.

[0159] Exclusion criteria:

[0160] 1. Suffering from endometrial leiomyosarcoma or other high-grade sarcoma, or endometrial stromal sarcoma;

[0161] 2. Pregnant and lactating women;

[0162] 3. Received radical radiotherapy within 3 months before the first use of the study drug. Note: Palliative radiotherapy for bones or palliative radiotherapy for superficial lesions is allowed, and the course of treatment refers to local standards and has been completed 14 days before the first use of the drug. Radiotherapy covering more than 30% of the bone marrow area within 28 days before the first dose is not allowed; Received chemotherapy drugs for radiosensitization within 14 days before the first dose; Received Chinese patent medicine or treatment with anti-tumor related functions clearly stated in the NMPA-approved drug instructions within 14 days before the first dose, or received Chinese herbal medicine treatment with anti-tumor purposes clearly recorded in the medical record;

[0163] 4. Patients who are currently participating in the treatment phase of other clinical studies, or plan to start treatment in this study within 14 days of the end of the previous clinical study drug treatment;

[0164] 5. Patients who have received or plan to receive live / attenuated vaccines and mRNA vaccines within 4 weeks before screening;

[0165] 6. Previous treatment with immune checkpoint inhibitors (such as anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-CTLA-4 antibodies, etc.) or any other treatment targeting tumor immune mechanisms such as immune co-stimulatory factors (such as antibodies targeting ICOS, CD40, CD137, GITR, OX40 targets, etc.).

[0166] 2. Dosage method:

[0167] The order of administration was as follows: 1) Antibody A or placebo, 2) Paclitaxel, 3) Carboplatin.

[0168] 1) Antibody A or placebo: 300 mg intravenous infusion, once every 3 weeks (Q3W), administered on the first day of each cycle. The longest regular dosing duration of the study is approximately 2 years, approximately 35 dosing cycles. Dilute with 5% glucose solution. The prepared Antibody A injection is administered intravenously, and it is recommended that the intravenous infusion be between 30 minutes and 1 hour. It must not be administered by intravenous push or single rapid intravenous injection.

[0169] 2) Chemotherapy:

[0170] Paclitaxel: Paclitaxel 175 mg / m 2 The drug is administered by intravenous infusion every 3 weeks (Q3W) on the first day of each cycle for a total of 6 cycles. All participating patients should receive prophylaxis before infusion to prevent severe hypersensitivity reactions.

[0171] Carboplatin: Carboplatin AUC5 mg / ml / min is administered by intravenous infusion once every 3 weeks (Q3W) on the first day of each cycle for a total of 6 cycles.

[0172] 3. Phase II study endpoints:

[0173] The Phase II study is a safety and preliminary efficacy study of antibody A combined with chemotherapy.

[0174] The primary endpoint is the safety endpoint: vital signs and physical examination, various adverse events (AEs), clinical laboratory tests, clinical auxiliary examinations (such as electrocardiogram, etc.), etc.

[0175] Secondary endpoints:

[0176] Pharmacokinetic parameters under single and multiple administration (mainly including: C max 、T max 、T 1 / 2 , CL, Vd, Ke, MRT, AUC (0-τ) , AUC (0-∞) ; Multiple doses of C max,ss 、C avg,ss 、C min, ss , AUC (0-τ)ss , AUC (0-∞)ss 、T max,ss 、T 1 / 2,ss , CL, Vss, Ke, MRT, accumulation index (Rac), fluctuation index (DF)

[0177] Immunogenicity evaluation indicators: anti-drug antibodies (ADA) / neutralizing antibodies (NAb).

[0178] Clinical efficacy indicators: Preliminary efficacy evaluated according to RECIST 1.1. The primary indicator is ORR at 18 weeks; other secondary indicators include DCR, DOR, TTP, PFS, and OS.

[0179] 4. Phase III study endpoints:

[0180] The Phase III study is a confirmatory study of the safety and efficacy of antibody A combined with chemotherapy as the first-line treatment for dMMR advanced or recurrent endometrial cancer.

[0181] The primary endpoint was PFS, as assessed by RECIST 1.1, comparing antibody A plus chemotherapy versus chemotherapy as first-line treatment for advanced or recurrent dMMR endometrial cancer.

[0182] Secondary endpoints:

[0183] Safety endpoints: vital signs and physical examination, adverse events (AEs), clinical laboratory tests, and clinical auxiliary examinations (e.g., electrocardiogram).

[0184] Efficacy evaluated according to RECIST 1.1, including OS, ORR, DCR, DOR, TTP, etc.

[0185] Immunogenicity evaluation indicators: anti-drug antibodies (ADA) / neutralizing antibodies (NAb).

Claims

1. A method for treating tumors, comprising: Administering an effective amount of an anti-PD-1 antibody and a chemotherapeutic agent to a patient in need thereof; The anti-PD-1 antibody comprises HCDR1 shown in SEQ ID NO:1, HCDR2 shown in SEQ ID NO:2, HCDR3 shown in SEQ ID NO:3, LCDR1 shown in SEQ ID NO:4, LCDR2 shown in SEQ ID NO:5, and LCDR3 shown in SEQ ID NO:6; The chemotherapeutic agent is a taxane or a platinum-based drug or a combination thereof; The tumor is cervical cancer or endometrial cancer.

2. The method according to claim 1, wherein the heavy chain variable region of the anti-PD-1 antibody comprises the sequence shown in SEQ ID NO:7, a sequence having at least 80% identity with the sequence shown in SEQ ID NO:7, or an amino acid sequence having one or more conservative amino acid substitutions compared with the sequence shown in SEQ ID NO:7; and / or The light chain variable region of the anti-PD-1 antibody comprises the sequence shown in SEQ ID NO:8, a sequence having at least 80% identity with the sequence shown in SEQ ID NO:8, or an amino acid sequence having one or more conservative amino acid substitutions compared with the sequence shown in SEQ ID NO:

8.

3. The method according to claim 1, wherein the heavy chain of the anti-PD-1 antibody comprises the sequence shown in SEQ ID NO:9, a sequence having at least 80% identity with the sequence shown in SEQ ID NO:9, or an amino acid sequence having one or more conservative amino acid substitutions compared with the sequence shown in SEQ ID NO:9; and / or The light chain of the anti-PD-1 antibody comprises the sequence shown in SEQ ID NO:10, a sequence having at least 80% identity with the sequence shown in SEQ ID NO:10, or an amino acid sequence having one or more conservative amino acid substitutions compared with the sequence shown in SEQ ID NO:

10.

4. The method according to any one of claims 1-3, wherein the chemotherapeutic agent is a combination of a taxane and a platinum-based drug.

5. The method according to claim 4, wherein the chemotherapeutic agent is selected from the following groups: paclitaxel and cisplatin, paclitaxel and carboplatin, liposomal paclitaxel and cisplatin, liposomal paclitaxel and carboplatin.

6. The method according to any one of claims 1-5, wherein the tumor is cervical cancer.

7. The method according to claim 6, wherein the cervical cancer includes squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, and clear cell carcinoma.

8. The method according to claim 6 or 7, wherein the cervical cancer includes metastatic cervical cancer, recurrent cervical cancer, and persistent cervical cancer.

9. The method according to any one of claims 6-8, wherein the cervical cancer is PD-L1 positive (CPS≥1).

10. The method according to claim 6, wherein the cervical cancer is PD-L1 positive (CPS≥1) metastatic cervical cancer, recurrent cervical cancer, or persistent cervical cancer.

11. The method according to any one of claims 1-5, wherein the tumor is endometrial cancer.

12. The method according to claim 11, wherein the endometrial cancer is recurrent or metastatic endometrial cancer.

13. The method according to claim 11, wherein the endometrial cancer is dMMR recurrent or metastatic endometrial cancer.

14. The method according to any one of claims 1-13, further comprising administering bevacizumab to the patient.

15. The method according to any one of claims 1-13, further comprising administering bevacizumab at a dose of about 15 mg / kg per dose to the patient once every 3 weeks.

16. The method according to any one of claims 1-15, wherein the anti-PD-1 antibody is administered at a dose of about 50-600 mg per dose.

17. The method according to claim 16, wherein the anti-PD-1 antibody is administered at a dose of about 200-400 mg per dose.

18. The method according to claim 16, wherein the anti-PD-1 antibody is administered at a dose of about 200-220 mg per dose and administered once every 2 weeks.

19. The method according to claim 16, wherein the anti-PD-1 antibody is administered at a dose of about 300 mg per dose and administered once every 3 weeks.

20. The method according to claim 16, wherein the anti-PD-1 antibody is administered at a dose of about 380-400 mg per dose and administered once every 4 weeks.

21. The method according to any one of claims 4-20, wherein the paclitaxel is administered at about 50-300 mg / m 2 per dose based on body surface area.

22. The method according to claim 21, wherein the paclitaxel is administered at about 135-175 mg / m 2 per dose based on body surface area.

23. As described in the method of claim 21, the paclitaxel is administered at about 175 mg / m² per dose, once every three weeks. 2 ​ 24. The method according to any one of claims 4-23, wherein the cisplatin is administered at a dose of about 10-100 mg / m 2 per body surface area.

25. The method according to claim 24, wherein the cisplatin is administered at a dose of about 50 mg / m 2 per body surface area, and administered once every three weeks.

26. The method according to any one of claims 4-25, wherein the carboplatin is administered at a dose up to about AUC 4-7 mg / ml / min per dose.

27. The method according to claim 26, wherein the carboplatin is administered at a dose up to about AUC 5 mg / ml / min per dose and administered once every 3 weeks.

28. A method for treating cervical cancer, comprising: (1) Administering to the patient an anti-PD-1 antibody at a dose of about 300 mg per dose once every 3 weeks, (2) administering paclitaxel or liposomal paclitaxel once every 3 weeks, (3) administering cisplatin or carboplatin once every 3 weeks; The paclitaxel is administered at about 175 mg / m per dose based on body surface area 2 ; The cisplatin is administered at a dose of about 50 mg / m per body surface area 2 ; The carboplatin is administered at a dose of AUC 5 mg / ml / min per dose; The anti-PD-1 antibody comprises HCDR1 shown in SEQ ID NO:1, HCDR2 shown in SEQ ID NO:2, HCDR3 shown in SEQ ID NO:3, LCDR1 shown in SEQ ID NO:4, LCDR2 shown in SEQ ID NO:5, and LCDR3 shown in SEQ ID NO:

6.

29. A method for treating cervical cancer, comprising: (1) Administering to the patient an anti-PD-1 antibody at a dose of about 300 mg per dose once every 3 weeks, (2) administering paclitaxel or liposomal paclitaxel once every 3 weeks, (3) administering cisplatin or carboplatin once every 3 weeks; and (4) administering bevacizumab at a dose of about 15 mg / kg per dose once every 3 weeks; The paclitaxel is administered at about 175 mg / m per dose based on body surface area 2 ; The cisplatin is administered at a dose of approximately 50 mg / m 2 per body surface area; The carboplatin is administered at a dose of AUC 5 mg / ml / min per dose; The anti-PD-1 antibody comprises HCDR1 shown in SEQ ID NO:1, HCDR2 shown in SEQ ID NO:2, HCDR3 shown in SEQ ID NO:3, LCDR1 shown in SEQ ID NO:4, LCDR2 shown in SEQ ID NO:5, and LCDR3 shown in SEQ ID NO:

6.

30. A method for treating endometrial cancer, comprising: (1) Administer to the patient the anti-PD-1 antibody at about 300 mg per dose once every three weeks, (2) administer paclitaxel once every three weeks, and (3) administer carboplatin once every three weeks; The anti-PD-1 antibody comprises HCDR1 shown in SEQ ID NO:1, HCDR2 shown in SEQ ID NO:2, HCDR3 shown in SEQ ID NO:3, LCDR1 shown in SEQ ID NO:4, LCDR2 shown in SEQ ID NO:5, and LCDR3 shown in SEQ ID NO:6; The paclitaxel is administered at about 175 mg / m per dose based on body surface area 2 ; The carboplatin is administered at an AUC of 5 mg / ml / min per dose.

31. The method according to any one of claims 28-30, wherein the heavy chain variable region of the anti-PD-1 antibody comprises the sequence shown in SEQ ID NO:7, a sequence having at least 80% identity with the sequence shown in SEQ ID NO:7, or an amino acid sequence having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO:7; and / or the light chain variable region of the anti-PD-1 antibody comprises the sequence shown in SEQ ID NO:8, a sequence having at least 80% identity with the sequence shown in SEQ ID NO:8, or an amino acid sequence having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO:

8.

32. The method according to any one of claims 28-30, wherein the heavy chain of the anti-PD-1 antibody comprises the sequence shown in SEQ ID NO:9, a sequence having at least 80% identity with the sequence shown in SEQ ID NO:9, or an amino acid sequence having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO:9; and / or the light chain of the anti-PD-1 antibody comprises the sequence shown in SEQ ID NO:10, a sequence having at least 80% identity with the sequence shown in SEQ ID NO:10, or an amino acid sequence having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO:10.

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