CN114099663A - Use of anti-PD-1 antibodies in the treatment of nasopharyngeal carcinoma - Google Patents
Use of anti-PD-1 antibodies in the treatment of nasopharyngeal carcinoma Download PDFInfo
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- CN114099663A CN114099663A CN202010879644.8A CN202010879644A CN114099663A CN 114099663 A CN114099663 A CN 114099663A CN 202010879644 A CN202010879644 A CN 202010879644A CN 114099663 A CN114099663 A CN 114099663A
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Abstract
The invention relates to application of an anti-PD-1 antibody or an antigen-binding fragment thereof in treating nasopharyngeal carcinoma, application of the anti-PD-1 antibody or the antigen-binding fragment thereof in preparing a medicament for treating the nasopharyngeal carcinoma, and a method for predicting curative effect of the anti-PD-1 antibody or the antigen-binding fragment thereof in treating the nasopharyngeal carcinoma by using a biomarker.
Description
Technical Field
The present invention relates to the use of an anti-PD-1 antibody or antigen-binding fragment thereof in the treatment of malignant tumors. Specifically, the invention relates to an application of an anti-PD-1 antibody or an antigen-binding fragment thereof in treating nasopharyngeal carcinoma, an application of an anti-PD-1 antibody or an antigen-binding fragment thereof in preparing a medicament for treating nasopharyngeal carcinoma, and a method for predicting the curative effect of the anti-PD-1 antibody or the antigen-binding fragment thereof in treating nasopharyngeal carcinoma by using a biomarker.
Background
Immune escape is one of the characteristics of cancer. Ahmadzadeh, m. et al, Blood,114:1537-44, disclose that tumor-specific T lymphocytes are frequently present in the tumor microenvironment, draining lymph nodes and peripheral Blood, but are often unable to control tumor progression due to the network of immunosuppressive mechanisms present in the tumor microenvironment. CD8+Tumor infiltrating T lymphocytes (TILs) typically express activation-induced inhibitory receptors, including CTLA-4 and PD-1, whereas tumor cells often express immunosuppressive ligands, including PD-1 ligand 1(PD-L1, also called B7-H1 or CD274)The ligand inhibits T cell activation and effector function. Among the inhibitory mechanisms, PD-1 and its ligands have become an important pathway for tumor cells to utilize it to inhibit activated T cells in the tumor microenvironment.
Programmed death receptor 1(PD-1) plays an important role in immune regulation and maintenance of peripheral tolerance. PD-1 is expressed primarily in activated T and B cells and functions to inhibit lymphocyte activation, a normal peripheral tissue tolerance mechanism of the immune system that prevents immune overstimulation. However, the activated T cells infiltrated in the tumor microenvironment highly express PD-1 molecules, and inflammatory factors secreted by the activated leukocytes can induce the tumor cells to highly express ligands PD-L1 and PD-L2 of PD-1, so that the PD-1 pathway of the activated T cells in the tumor microenvironment is continuously activated, the functions of the T cells are inhibited, and the tumor cells cannot be killed. The therapeutic PD-1 antibody can block the pathway, partially restore the function of T cells, and enable the activated T cells to continuously kill tumor cells.
In the last decade, blocking of the PD-1/PD-L1 pathway has proven to be an effective way to induce a durable anti-tumor response in various cancer indications. Monoclonal antibodies (mAbs) blocking the PD/PD-L1 pathway can enhance the activation and effector functions of tumor-specific T cells, reduce tumor burden, and improve survival rates. Between 2014 and 2017, the FDA has approved 2 anti-PD 1 monoclonal antibody (nivolumab) and 3 anti-PD-L1 monoclonal antibody (atezolizumab, avelumab, and durvalumab) for the treatment of human tumors.
Nasopharyngeal carcinoma (NPC) refers to a malignant tumor that occurs in the top and lateral walls of the nasopharyngeal cavity, with the incidence of the first malignancy of the ear, nose and throat. The world health organization surveys and reports that 80% of nasopharyngeal carcinoma patients are in China all over the world. Because nasopharyngeal carcinoma is insidious and has a strong tendency to metastasize, approximately 75% of patients reach advanced stages with regional lymph node and/or distant metastasis. Generally, comprehensive treatment mainly based on radiotherapy is very effective on early nasopharyngeal carcinoma, and recurrence or metastasis after treatment is extremely poor in prognosis, so that the treatment failure and the survival rate reduction of the nasopharyngeal carcinoma are main reasons. Epstein-Barr virus (EBV) infection is critical for the development of NPC. Nasopharyngeal carcinoma has 3 histopathological types according to WHO classification: keratinized (type I), non-keratinized (type II), and basal squamous cell carcinoma (type III).
However, some of the antibodies which are already marketed still have some safety problems such as adverse drug reactions and the like. Thus, there remains a high unmet clinical need for effective therapies for the treatment of malignancies (e.g., nasopharyngeal carcinoma).
Disclosure of Invention
The invention provides an application of an anti-PD-1 antibody or an antigen binding fragment thereof in preparing a medicament for preventing or treating malignant tumor patients.
In yet another aspect, the invention provides a method of preventing or treating a malignant tumor, comprising administering to an individual in need thereof an effective amount of an anti-PD-1 antibody or antigen-binding fragment thereof of the invention.
In yet another aspect, the invention provides an anti-PD-1 antibody or antigen-binding fragment thereof for use in the treatment or prevention of a malignancy.
In one or more embodiments, the malignant tumor of the invention is a nasopharyngeal carcinoma.
In one or more embodiments, the malignancy of the invention is recurrent or metastatic nasopharyngeal carcinoma.
In one or more embodiments, the malignancy described herein is a tumor tissue section immunohistochemical staining analysis for PD-L1 expression > 1%. As a preferred embodiment, the nasopharyngeal carcinoma of the invention is greater than 25% of PD-L1 analyzed by tumor tissue section.
In one or more embodiments, the malignant tumor of the invention is selected from the group consisting of a keratinizing nasopharyngeal carcinoma and a non-keratinizing nasopharyngeal carcinoma, preferably a keratinizing nasopharyngeal carcinoma.
In one or more embodiments, the nasopharyngeal carcinoma of the present invention is a nasopharyngeal carcinoma in which CCND1, FGF14, FGF3, or FGF4 is not detected in the peripheral blood circulation tumor DNA or tumor tissue, but amplified in the genome of chromosome 11q13 region; or the patient is a nasopharyngeal carcinoma patient with no CCND1, FGF14, FGF3 or FGF4 chromosome 11q13 region genome amplification detected in peripheral blood circulation tumor DNA or tumor tissues.
In one or more embodiments, the patient is a nasopharyngeal carcinoma patient who is refractory to standard systemic treatment, or whose condition has progressed 6 months after chemotherapy.
In one or more embodiments, the nasopharyngeal cancer of the invention is a nasopharyngeal cancer that has a more than two-fold decrease in peripheral blood EBV DNA copy number on day 28 relative to day 0 prior to administration.
In one or more embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof of the present invention comprises an amino acid sequence as set forth in SEQ ID NO: 1.2 and 3, and the amino acid sequence is as shown in SEQ ID NO: 4.5 and 6.
In one or more embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof of the present invention comprises a light chain variable region having an amino acid sequence as set forth in SEQ ID No. 7, and a heavy chain variable region having an amino acid sequence as set forth in SEQ ID No. 8.
In one or more embodiments, the anti-PD-1 antibody of the invention comprises a light chain having an amino acid sequence as set forth in SEQ ID NO. 9 and a heavy chain having an amino acid sequence as set forth in SEQ ID NO. 10.
In one or more embodiments, the anti-PD-1 antibody of the invention is selected from one or more of nivolumab, pembrolizumab, toreplilimuab, Sintillimuab, Camrelizumab, Tislelizumab, Cemiplimab; preferably a toriplalimab.
In one or more embodiments, the anti-PD-1 antibody of the invention is a monoclonal antibody or an antigen-binding fragment thereof.
In one or more embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof of the invention is administered at a dose of about 0.1mg/kg to about 10.0mg/kg of the individual's body weight, e.g., about 0.1mg/kg, about 0.3mg/kg, about 1mg/kg, about 2mg/kg, about 3mg/kg, about 5mg/kg, or 10mg/kg of the individual's body weight, or selected from a fixed dose of about 120mg to about 480mg, e.g., a fixed dose of 120mg, 240mg, 360mg, or 480mg, preferably a fixed dose of 3mg/kg of the individual's body weight or 240 mg.
In one or more embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof of the present invention is administered at a frequency of about once per week, once per two weeks, once per three weeks, once per four weeks, or once a month, preferably once per two weeks.
In one or more embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof of the invention is administered at a dose of 1mg/kg, 3mg/kg, 10mg/kg, or 240mg fixed dose, 480mg fixed dose once every two or three weeks.
In one or more embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof of the present invention is administered in a liquid dosage form, e.g., injection, by a parenteral route, e.g., by intravenous infusion.
In one or more embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof of the invention is administered for a period of one week, two weeks, three weeks, one month, two months, three months, four months, five months, half a year, or longer, optionally, the time for each administration period is the same or different, and the interval between each administration period is the same or different.
In a further aspect, the invention provides a use of a reagent for detecting gene mutation or amplification of CCND1, FGF14, FGF3 or FGF4 chromosome 11q13 region in peripheral blood circulation tumor DNA or tumor tissue of an individual in the preparation of a kit for predicting the effect of an anti-PD-1 antibody on treatment of nasopharyngeal carcinoma.
In yet another aspect, the invention provides a use of a reagent for detecting the EBV DNA copy number of peripheral blood of an individual in preparing a kit for predicting the effect of an anti-PD-1 antibody on treatment of nasopharyngeal carcinoma.
In yet another aspect, the present invention provides a method for predicting the effect of an anti-PD-1 antibody on the treatment of nasopharyngeal carcinoma, comprising assaying the circulating tumor DNA or tumor tissue in peripheral blood of an individual prior to treatment for a mutation or amplification of the gene in the region of CCND1, FGF14, FGF3, or FGF4 chromosome 11q13, wherein the presence of a mutation or amplification of the gene in the region of CCND1, FGF14, FGF3, or FGF4 chromosome 11q13 indicates that said patient with malignant tumor is not suitable for treatment with an anti-PD-1 antibody.
In yet another aspect, the invention provides a method for predicting the effect of an anti-PD-1 antibody on the treatment of nasopharyngeal carcinoma, comprising detecting the EBV DNA copy number in peripheral blood of an individual on day 28 of treatment, wherein a more than two-fold decrease in the EBV DNA copy number in peripheral blood indicates that said tumor patient is treated with the anti-PD-1 antibody.
In still another aspect, the present invention provides a test kit comprising reagents for detecting gene mutation or amplification in CCND1, FGF14, FGF3, or FGF4 chromosome 11q13 region in peripheral blood or tumor tissue of an individual.
In yet another aspect, the invention provides a test kit comprising reagents for detecting the copy number of EBV DNA in peripheral blood of an individual.
In still another aspect, the present invention provides a test kit comprising reagents for detecting gene mutation or amplification in CCND1, FGF14, FGF3, or FGF4 chromosome 11q13 region in peripheral blood or tumor tissue of an individual, and reagents for detecting EBV DNA copy number in peripheral blood of an individual.
Drawings
FIG. 1: results of the evaluation of clinical response according to RECIST v 1.1. 1 a: tumor phase assessed in baseline patients
Maximum change to baseline and at least one post-treatment imaging assessment (n 190); the length of the bar represents the maximum decrease or minimum increase of the target lesion; 1 b: individual tumor burden was assessed from baseline over time (n 190).
FIG. 2: 2 a: progression-free survival of nasopharyngeal carcinoma patients PFS in this study; 2 b: overall survival of nasopharyngeal carcinoma patients, OS, in this study; 2 c: duration of response time DR in patients with nasopharyngeal carcinoma in this study; 2 d: progression-free survival PFS in patients with both keratinizing and non-keratinizing nasopharyngeal carcinoma in this study; 2 e: total survival OS in patients with keratinized and non-keratinized nasopharyngeal carcinoma in this study.
FIG. 3: 3a relationship between clinical response and tumor PD-L1 expression and TMB, PD-L1 positive is defined as any intensity > 1% of membrane staining with SP142 IHC staining tumor cells or immune cells; TMB was calculated by whole exon sequencing of somatic mutations within the coding region; 3 b: progression-free survival PFS in patients with PD-L1+ and PD-L1-; 3 c: total survival number OS for patients with PD-L1+ and PD-L1-; 3 d: progression-free survival PFS in 10% of patients with the highest TMB value versus 90% of patients with the lowest TMB value; 3 e: overall survival OS for 10% of patients with the highest TMB values versus 90% of patients with the lowest TMB values.
FIG. 4: genetic variation and frequency of 174 patients by Whole Exome Sequencing (WES).
FIG. 5: 5 a: relationship between plasma EBV DNA copy number and complete remission/partial remission (CR/PR) of the disease in patients with nasopharyngeal carcinoma (n ═ 34); 5 b: relationship between plasma EBV DNA copy number and disease Stability (SD) in patients with nasopharyngeal carcinoma (n ═ 35); 5 c: correlation between plasma EBV DNA copy number and disease Progression (PD) in patients with nasopharyngeal carcinoma (n ═ 80).
Detailed Description
The present invention relates to a method for treating malignant tumors. The methods of the invention comprise administering an anti-PD-1 antibody or antigen-binding fragment thereof to a patient in need thereof. The malignant tumor is nasopharyngeal carcinoma. The invention also relates to methods of using biomarkers to predict the efficacy of anti-PD-1 antibodies in the treatment of malignant tumors, particularly nasopharyngeal carcinoma patients.
Term(s) for
In order that the invention may be more readily understood, certain technical and scientific terms are defined below. Unless otherwise defined elsewhere herein, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
By "administering," "administering," and "treating" is meant introducing a composition comprising a therapeutic agent into a subject using any of a variety of methods or delivery systems known to those skilled in the art. Routes of administration of anti-PD-1 antibodies include intravenous, intramuscular, subcutaneous, peritoneal, spinal or other parenteral routes of administration, such as injection or infusion. "parenteral administration" refers to modes of administration other than enteral or topical administration, typically by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraframe, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion, and via in vivo electroporation.
An "adverse effect" (AE) as referred to herein is any adverse and often unintentional or undesirable sign, symptom or disease associated with the use of medical treatment. For example, adverse reactions may be associated with activation of the immune system or expansion of immune system cells in response to therapy. The medical treatment may have one or more related AEs, and each AE may have the same or different severity level.
"tumor burden" refers to the total amount of tumor mass distributed throughout the body. Tumor burden refers to the total number of cancer cells or the total size of the tumor throughout the body. Tumor burden can be determined by a variety of methods known in the art, such as measuring its size using calipers after the tumor is removed from the subject, or while in vivo using imaging techniques such as ultrasound, bone scans, Computed Tomography (CT), or Magnetic Resonance Imaging (MRI) scans.
The term "tumor size" refers to the total size of a tumor, which can be measured as the length and width of the tumor. Tumor size can be determined by a variety of methods known in the art, for example, measuring its dimensions using calipers after the tumor is removed from the subject, or while in vivo using imaging techniques such as bone scans, ultrasound, CT, or MRI scans.
The terms "subject", "individual", "object" include any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, rabbit, etc.), and most preferably a human. The terms "subject" and "patient" are used interchangeably herein.
"antibody" as used herein refers to any form of antibody that achieves the desired biological or binding activity. It is therefore used in its broadest sense, but is not limited to, monoclonal, polyclonal, multispecific, humanized full-length human, chimeric and camel-derived single domain antibodies. An "antibody" specifically binds an antigen and comprises at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain comprises a heavy chain variable region (VH) and a heavy chain constant region comprising three constant domains CH1, CH2 and CH 3. Each light chain comprises a light chain variable region (VL) and a light chain constant region comprising a constant domain CL. The VH and VL regions may be further subdivided into hypervariable regions, termed Complementarity Determining Regions (CDRs), interspersed with regions that are more conserved, termed Framework Regions (FRs). Generally, from N-terminus to C-terminus, both light and heavy chain variable domains comprise FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR 4. Amino acids are typically assigned to each domain according to the following definitions: sequences of Proteins of Immunological Interest, Kabat et al; national Institutes of Health, Bethesda, Md.; 5 th edition; NIH publication No. 91-3242 (1991): kabat (1978) adv.prot.chem.32: 1-75; kabat et al, (1977) J.biol.chem.252: 6609-6616; chothia et al, (1987) J mol. biol.196: 901-883 or Chothia et al, (1989) Nature 341: 878-883.
The carboxy-terminal portion of the heavy chain may define a constant region primarily responsible for effector function. Generally, human light chains are classified into kappa chains and lambda chains. Human heavy chains are generally classified as mu, delta, gamma, alpha, or epsilon, and define the isotype of the antibody as IgM, IgD, IgG, IgA, and IgE, respectively. The IgG subclasses are well known to those skilled in the art and include, but are not limited to, IgG1, IgG2, IgG, and IgG 4.
The term "antibody" includes: naturally occurring and non-naturally occurring abs; monoclonal and polyclonal Ab; chimeric and humanized abs; human or non-human Ab; ab is fully synthesized; and a single chain Ab. Non-human abs may be humanized by recombinant methods to reduce their immunogenicity in humans.
Unless specifically indicated otherwise, "antibody fragment" or "antigen-binding fragment" as used herein refers to an antigen-binding fragment of an antibody, i.e., an antibody fragment that retains the ability of a full-length antibody to specifically bind to an antigen, e.g., a fragment that retains one or more CDR regions. Examples of antigen binding fragments include, but are not limited to, Fab ', F (ab') 2, and Fv fragments; a diabody; a linear antibody; a single chain antibody molecule; nanobodies and multispecific antibodies formed from antibody fragments.
"chimeric antibody" refers to antibodies and fragments thereof as follows: wherein a portion of the heavy and/or light chain is identical to or homologous to corresponding sequences in an antibody derived from a particular species (e.g., human) or belonging to a particular antibody class or subclass, and the remainder of the chain is identical to or homologous to corresponding sequences in an antibody derived from another species (e.g., mouse) or belonging to another antibody class or subclass, so long as it exhibits the desired biological activity.
"human antibody" refers to an antibody comprising only human immunoglobulin sequences. A human antibody may contain murine carbohydrate chains if it is produced in a mouse, mouse cells, or a hybridoma derived from a mouse cell. Similarly, "mouse antibody" or "rat antibody" refers to an antibody that comprises only mouse or rat immunoglobulin sequences, respectively.
"humanized antibody" refers to antibody forms containing sequences from non-human (e.g., murine) antibodies as well as human antibodies. Such antibodies contain a minimal sequence derived from a single side of a non-human immunoglobulin. Typically, the humanized antibody will comprise substantially all of at least one and typically two variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin. The humanized antibody optionally further comprises at least a portion of an immunoglobulin constant region (Fc), typically a human immunoglobulin constant region.
The term "nasopharyngeal carcinoma" is a malignant tumor that occurs in the nasopharyngeal cavity or upper pharyngeal portion. The common clinical symptoms are nasal obstruction, blood in nasal discharge, ear obstruction, hearing loss, double vision, headache and the like. Epstein-Barr virus (EBV) infection is critical for the development of NPC. Nasopharyngeal carcinoma has 3 histopathological types according to WHO classification: keratinized (type I), non-keratinized (type II), and basal squamous cell carcinoma (type III). Non-keratinizing nasopharyngeal carcinoma is closely related to EBV, and has higher response to radiotherapy and higher overall survival rate.
The term "immunotherapy" refers to the treatment of a subject suffering from a disease or at risk of infection or relapse from a disease by a method that includes inducing, enhancing, suppressing or otherwise modifying an immune response. By "treatment" or "therapy" of a subject is meant any type of intervention or process performed on the subject, or the administration of an agent to the subject, with the purpose of reversing, alleviating, ameliorating, slowing or preventing the onset, progression, severity, or recurrence of a symptom, complication, or condition, or biochemical indicators associated with the disease.
"programmed death receptor-1 (PD-1)" refers to an immunosuppressive receptor belonging to the CD28 family. PD-1 is expressed predominantly on previously activated T cells in vivo and binds to both ligands PD-L1 and PD-L2. The term "PD-1" as used herein includes variants, isoforms, and species homologs of human PD-1(hPD-1), hPD-1, and analogs having at least one common epitope with hPD-1.
A "therapeutically effective amount" or "therapeutically effective dose" of a drug or therapeutic agent is any amount of drug that, when used alone or in combination with another therapeutic agent, protects a subject from the onset of a disease or promotes disease regression as evidenced by a reduction in the severity of disease symptoms, an increase in the frequency and duration of asymptomatic phases of the disease, or the prevention of injury or disability resulting from the affliction of the disease. The ability of a therapeutic agent to promote disease regression can be evaluated using a variety of methods known to those skilled in the art, such as in human subjects during clinical trials, in animal model systems that predict human efficacy, or by assaying the activity of the agent in an in vitro assay.
A therapeutically effective amount of a drug includes a "prophylactically effective amount," i.e., any amount of a drug that inhibits the development or recurrence of cancer when administered to a subject at risk for developing cancer or a subject having a recurrence of cancer, alone or in combination with an anti-neoplastic agent.
"biotherapeutic agent" refers to a biological molecule, such as an antibody or fusion protein, that blocks ligand/receptor signaling in any biological pathway that supports tumor maintenance and/or growth or inhibits an anti-tumor immune response.
As used herein, unless expressly indicated otherwise, "CDR" means that the immunoglobulin variable region is a complementarity determining region defined using the Kabat numbering system.
"therapeutic anti-PD-1 monoclonal antibody" refers to an antibody that specifically binds to the mature form of a particular PD-1 expressed on the surface of certain mammalian cells. Mature PD-1 lacks a pre-secretory leader sequence, or leader peptide. The terms "PD-1" and "mature PD-1" are used interchangeably herein and, unless otherwise specifically defined or clear from context, should be understood to be the same molecule.
As described herein, a therapeutic anti-human PD-1 antibody or anti-hPD-1 antibody refers to a monoclonal antibody that specifically binds to mature human PD-1.
As used herein, "framework region" or "FR" refers to immunoglobulin variable regions that do not include CDR regions.
An "isolated antibody or antigen-binding fragment thereof" refers to a molecule that is in a purified state and in this case is designated as being substantially free of other biological molecules, such as nucleic acids, proteins, lipids, carbohydrates, or other materials (such as cell debris or growth media).
By "patient," "patient," or "subject" is meant any single subject, typically a mammal, including humans and other mammals, such as horses, cows, dogs, or cats, in need of a medical procedure or participating in a clinical trial, epidemiological study, or as a control.
The "RECIST 1.1 therapeutic criteria" as used herein refers to the definition by Eisenhauver et al, e.a. et al, eur.j Cancer45: 228-. Prior to immunotherapy, it is the most common standard for efficacy assessment of solid tumors. However, with the advent of the immune age, many problems which have not been found in the tumor evaluation before are presented, so that based on the newly appeared phenomenon caused by immunotherapy, in 2016, the RECIST working group provides a new judgment standard after correcting the existing "RECIST v.1.1", namely the "irRECIST standard" described herein, aiming at better evaluating the curative effect of immunotherapy drugs.
The term "ECOG" score is an indicator of a patient's general health and ability to tolerate treatment, as measured by their physical strength. ECOG physical performance scoring criteria score: 0 minute, 1 minute, 2 minutes, 3 minutes, 4 minutes and 5 minutes. A score of 0 means that the motility was completely normal and had no difference from the motility before onset. A score of 1 means that the person is free to walk and engage in light physical activities, including general housework or office work, but not heavy physical activities.
By "sustained response" is meant a sustained therapeutic effect following cessation of treatment with a therapeutic agent or combination therapy as described herein. In some embodiments, the sustained response has a duration that is at least the same as the duration of treatment or at least 1.5, 2.0, 2.5, or 3 times the duration of treatment.
"tissue section" refers to a single portion or piece of a tissue sample, such as a thin slice of tissue cut from a sample of normal tissue or a tumor.
As used herein, "treating" cancer refers to employing a treatment regimen described herein (e.g., administration of an anti-PD-1 antibody) to achieve at least one positive therapeutic effect (e.g., a decrease in the number of cancer cells, a decrease in tumor volume, a decrease in the rate of cancer cell infiltration into peripheral organs, or a decrease in the rate of tumor metastasis or tumor growth) in a subject having or diagnosed with cancer. Positive treatment effects in cancer can be measured in a variety of ways (see w.a. weber, j.nucl.med.,50:1S-10S (2009)). For example, for tumor growth inhibition, T/C ≦ 42% is the minimum level of anti-tumor activity according to the NCI standard. T/C (%) ═ median treated tumor volume/median control tumor volume × 100. PFS (also called "time to tumor progression") refers to the length of time during and after treatment during which cancer does not grow and includes the amount of time a patient experiences CR or PR and the amount of time a patient experiences SD. DFS refers to the length of time during and after treatment that a patient is still disease free. OS refers to an extension of life expectancy compared to an initial or untreated individual or patient. The treatment regimen for a combination of the invention effective in treating a cancer patient can vary depending on a variety of factors such as the disease state, age, weight of the patient and the ability of the therapy to elicit an anti-cancer response in the subject. Although embodiments of the invention may not achieve an effective positive therapeutic effect in each subject, a positive therapeutic effect should be effective and achieved in a statistically significant number of subjects.
The terms "mode of administration", "dosing regimen", which are used interchangeably, refer to the dosage and time of use of each therapeutic agent in the combination of the invention.
The term "Immunohistochemistry (IHC)" refers to a method of determining tissue intracellular antigens (polypeptides and proteins) by developing color-developing agents (fluorescein, enzymes, metal ions, isotopes) that label antibodies through chemical reactions using the principle that antigens are specifically bound to antibodies, and performing localized, qualitative and relatively quantitative studies thereof. In some embodiments of the invention, a tumor tissue sample from the subject is subjected to a PD-L1 assay using anti-human PD-L1 antibody SP142 from Roche (Cat No: M4422) for a staining assay prior to treatment with the anti-PD-1 antibody. In some embodiments, a tumor cell that has membrane staining intensity ≧ 1% is defined as positive for PD-L1.
Herein, the term "cancer" or "malignancy" refers to a wide variety of diseases characterized by uncontrolled growth of abnormal cells in the body. Unregulated cell division, growth division and growth lead to the formation of malignant tumors that invade adjacent tissues and may also metastasize to distal parts of the body through the lymphatic system or blood stream. Examples of cancers suitable for treatment or prevention using the methods, medicaments and kits of the invention include, but are not limited to, carcinoma, lymphoma, leukemia, blastoma and sarcoma. More specific examples of cancer include squamous cell cancer, myeloma, small-cell lung cancer, non-small cell lung cancer, glioma, hodgkin's lymphoma, non-hodgkin's lymphoma, acute myelogenous leukemia, multiple myeloma, gastrointestinal (tract) cancer, kidney cancer, ovarian cancer, liver cancer, lymphoblastic leukemia, lymphocytic leukemia, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, melanoma, chondrosarcoma, neuroblastoma, pancreatic cancer, glioblastoma multiforme, nasopharyngeal cancer, cervical cancer, brain cancer, gastric cancer, bladder cancer, hepatoma, breast cancer, colon cancer, and head and neck cancer.
As used herein, the term "Tumor Mutation Burden (TMB)" refers to the total number of somatic gene coding errors, base substitutions, gene insertion or deletion errors detected per million bases. In some embodiments of the invention, Tumor Mutational Burden (TMB) is estimated by analysis of somatic mutations, including coding base substitutions and the megabase insertions of the panel sequences studied.
In the following paragraphs, various aspects of the present invention are described in further detail.
anti-PD-1 antibodies
Herein, a "PD-1 antibody" refers to any chemical compound or biomolecule that binds to the PD-1 receptor, blocks the binding of PD-L1 expressed on cancer cells to PD-1 expressed on immune cells (T, B, NK cells), and preferably also blocks the binding of PD-L2 expressed on cancer cells to PD-1 expressed on immune cells. Alternative nouns or synonyms for PD-1 and its ligands include: for PD-1, PDCD1, PD1, CD279, and SLEB 2; for PD-L1, there are PDCD1L1, PDL1, B7-H1, B7H1, B7-4, CD274 and B7-H; and for PD-L2 there are PDCD1L2, PDL2, B7-DC and CD 273. In any of the inventive methods of treatment, medicaments and uses for treating a human subject, the PD-1 antibody blocks the binding of human PD-L1 to human PD-1, and preferably blocks the binding of both human PD-L1 and PD-L2 to human PD 1. The human PD-1 amino acid sequence can be found at NCBI locus number: NP _ 005009. Human PD-L1 and PD-L2 amino acid sequences can be found at NCBI locus numbers: NP-054862 and NP-079515.
Herein, when referring to an "anti-PD-1 antibody," unless otherwise indicated or described, the term includes antigen-binding fragments thereof.
The anti-PD-1 antibody applicable to any application, therapy, medicament and kit disclosed by the invention is combined with PD-1 with high specificity and high affinity, blocks the combination of PD-L1/2 and PD-1 and inhibits PD-1 signal transduction, thereby achieving an immunosuppressive effect. In any of the uses, therapies, medicaments and kits disclosed herein, the anti-PD-1 antibody includes the full-length antibody itself, as well as antigen-binding portions or fragments that bind to the PD-1 receptor and exhibit functional properties similar to those of an intact Ab in inhibiting ligand binding and upregulating the immune system. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is an anti-PD-1 antibody or antigen-binding fragment thereof that cross-competes for binding to human PD-1 with terieprinimab. In other embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is a chimeric, humanized, or human Ab or antigen-binding fragment thereof. In certain embodiments for treating a human subject, the Ab is a humanized Ab.
In some embodiments, the anti-PD-1 antibodies for any of the uses, therapies, medicaments and kits described herein include monoclonal antibodies (mabs) or antigen-binding fragments thereof that specifically bind to PD-1, and preferably specifically bind to human PD-1. The mAb may be a human, humanized or chimeric antibody and may include human constant regions. In some embodiments, the constant region is selected from the group consisting of human IgG1, IgG2, IgG3, and IgG4 constant regions; preferably, the anti-PD-1 antibodies or antigen-binding fragments thereof suitable for use in any of the uses, therapies, medicaments and kits described herein comprise a heavy chain constant region of human IgG1 or IgG4 isotype, more preferably a human IgG4 constant region. In some embodiments, the sequence of the IgG4 heavy chain constant region of the anti-PD-1 antibody or antigen-binding fragment thereof comprises the S228P mutation that replaces a serine residue in the hinge region with a proline residue that is typically present at the corresponding position of an IgG1 isotype antibody.
Preferably, in any one of the uses, therapies, medicaments and kits of the present invention, the PD-1 antibody is a monoclonal antibody or an antigen-binding fragment thereof, and the light chain CDRs thereof are SEQ ID NO: 1.2 and 3, and the heavy chain CDR is SEQ ID NO: 4.5 and 6.
More preferably, in any one of the embodiments of the use, therapy, medicament and kit of the invention, the PD-1 antibody specifically binds to human PD-1 and comprises: (a) comprises the amino acid sequence of SEQ ID NO:7, and (b) a light chain variable region comprising SEQ ID NO:8 in the heavy chain variable region of the antibody.
Further preferably, in any one of the uses, therapies, medicaments and kits of the present invention, the PD-1 antibody is a monoclonal antibody that specifically binds to human PD-1 and comprises: (a) comprises the amino acid sequence of SEQ ID NO:9, and (b) a light chain comprising SEQ ID NO: 10.
Table a below provides the amino acid sequence numbers of the light chain CDRs and the heavy chain CDRs of an exemplary anti-PD-1 antibody mAb for use, therapy, medicament, and kit described in the present invention:
table a: light and heavy chain CDRs of exemplary anti-human PD-1 antibodies
LCDR1 | SEQ ID NO:1 |
LCDR2 | SEQ ID NO:2 |
LCDR3 | SEQ ID NO:3 |
HCDR1 | SEQ ID NO:4 |
HCDR2 | SEQ ID NO:5 |
HCDR3 | SEQ ID NO:6 |
Examples of anti-PD-1 antibodies that bind to human PD-1 and that can be used in the uses, therapies, medicaments and kits described in the present invention are described in WO 2014206107. Human PD-1 mabs that may be used as anti-PD-1 antibodies in the uses, therapies, medicaments and kits described in this invention include any of the anti-PD-1 antibodies described in WO2014206107, including: teraprimab (Toripalimab), a humanized IgG4 mAb having the structure described in WHO Drug Information (Vol.32, phase 2, p.372-373 (2018)), and comprising the light and heavy chain amino acid sequences shown in sequences SEQ ID NO. 9 and 10 in a preferred embodiment, the anti-PD-1 antibody useful in any of the uses, therapies, drugs, and kits described herein is selected from the humanized antibodies 38, 39, 41, and 48 described in WO 206107. in a particularly preferred embodiment, the anti-PD-1 antibody useful in any of the uses, therapies, drugs, and kits described herein is Teraprimab.
anti-PD-1 antibodies useful in any of the uses, therapies, medicaments and kits described herein also include Nivolumab and Pembrolizumab, which have been approved by the FDA.
In certain embodiments, anti-PD-1 antibodies useful in any of the uses, therapies, medicaments and kits described herein also include anti-PD-L1 monoclonal antibodies that specifically bind to PD-L1 to block the binding of PD-L1 to PD-1, such as nivolumab, pembrolizumab, toriplalimab, sinilimab, Camrelizumab, tislellizumab, cemipimab.
"PD-L1" expression or "PD-L2" expression as described herein refers to any detectable expression level of a particular PD-L protein on the surface of a cell or a particular PD-L mRNA within a cell or tissue. PD-L protein expression can be detected in IHC analysis of tumor tissue sections or by flow cytometry using diagnostic PD-L antibodies. Alternatively, PD-L protein expression of tumor cells can be detected by PET imaging using a binding agent that specifically binds to a desired PD-L target (such as PD-L1 or PD-L2).
Methods for quantifying PD-L1 protein expression in IHC analysis of tumor tissue sections, see but not limited to Thompson, r.h. et al, PNAS 101 (49): 17174 and 17179 (2004); taube, j.m. et al, Sci trans Med 4, 127ra37 (2012); and Toplian, S.L. et al, New Eng.J.Med.366(26):2443-2454(2012), etc.
One method employs a simple binary endpoint of positive or negative PD-L1 expression, where positive results are defined as the percentage of tumor cells showing histological evidence of cell surface membrane staining. Counting tumor tissue sections to greater than 1% of total tumor cells is defined as positive for PD-L1 expression.
In another method, PD-L1 expression in tumor tissue sections was quantified in tumor cells as well as in infiltrating immune cells. The percentages of tumor cells and infiltrating immune cells that exhibit membrane staining were quantified individually at ≦ 1%, 1% to 50%, and then 50% up to 100%. For tumor cells, PD-L1 expression was counted as negative if the score was < 1%, and positive if > 1%.
In some embodiments, the expression level of PD-L1 by malignant cells and/or by infiltrating immune cells within the tumor is determined to be "overexpressed" or "elevated" based on comparison to the expression level of PD-L1 by an appropriate control. For example, the protein or mRNA expression level of control PD-L1 can be a level quantified in non-malignant cells of the same type or in sections from matched normal tissue.
Methods of treatment and uses
The invention provides the use of an anti-PD-1 antibody or antigen-binding fragment thereof of the invention as described above in the preparation of a medicament for the prevention or treatment of a malignant tumor.
The present invention provides a method of preventing or treating a malignant tumor, comprising administering to an individual in need thereof an effective amount of an anti-PD-1 antibody or antigen-binding fragment thereof of the invention. The effective amount includes a prophylactically effective amount and a therapeutically effective amount.
The present invention provides the aforementioned anti-PD-1 antibody or antigen-binding fragment thereof of the present invention for use in the prevention or treatment of malignant tumor.
The malignant tumor of the invention may be as described in any of the embodiments above; preferably, the malignant tumor of the present invention is nasopharyngeal carcinoma, and preferably, the malignant tumor of the present invention is recurrent or metastatic nasopharyngeal carcinoma.
Preferably, the method, use or anti-PD-1 antibody according to any one of the embodiments of the present invention is particularly suitable for keratinized and non-keratinized nasopharyngeal carcinomas, preferably keratinized nasopharyngeal carcinomas.
Preferably, the method, use or anti-PD-1 antibody according to any embodiment of the present invention is particularly suitable for use in a malignant tumor that is positive for PD-L1 expression in an immunohistochemical staining assay of tumor tissue sections; preferably, the tumor tissue section is a malignant tumor with PD-L1> 25% in immunohistochemical staining analysis.
Preferably, the method, use or anti-PD-1 antibody according to any one of the embodiments of the present invention is particularly suitable for a malignant tumor in which gene amplification of CCND1, FGF14, FGF3 or FGF4 in chromosome 11q13 region is not detected in peripheral blood circulation tumor DNA or tumor tissue.
Preferably, the method, use or anti-PD-1 antibody according to any embodiment of the invention is particularly suitable for malignancies in which the DNA copy number of peripheral blood EBV (treatment day 28) is reduced by more than two times.
Preferred anti-PD-1 antibodies for use in malignancies may be as described in any of the embodiments herein, more preferably the light chain CDRs are SEQ ID NO: 1.2 and 3, and the heavy chain CDR is SEQ ID NO: 4.5 and 6, more preferably an antibody comprising the amino acids shown in SEQ ID NOs: 7 and the variable region of the light chain shown in SEQ ID NO:8, more preferably a monoclonal antibody comprising the heavy chain variable region of SEQ ID NO:9 and SEQ ID NO:10, more preferably the humanized antibodies 38, 39, 41 and 48 described in WO2014206107, most preferably terepril mab.
In a particularly preferred embodiment, the present invention provides a method of preventing or treating nasopharyngeal cancer, said method comprising administering to a nasopharyngeal cancer patient a therapeutically effective amount of tereprinimab; preferably, the patient is positive for PD-L1 expression. In certain embodiments, preferred nasopharyngeal carcinomas are keratotic nasopharyngeal carcinomas; in certain embodiments, preferred nasopharyngeal carcinoma patients are patients in which gene amplification of CCND1, FGF14, FGF3, or FGF4 chromosome 11q13 region is not detected in peripheral blood circulating tumor DNA or tumor tissue; in certain embodiments, the patient is preferably a nasopharyngeal carcinoma patient who has more than a two-fold decrease in the DNA copy number of peripheral blood EBV after 28 days of treatment.
In a particularly preferred embodiment, the present invention provides the use of an anti-PD-1 antibody or antigen-binding fragment thereof in the manufacture of a medicament for the prevention or treatment of nasopharyngeal carcinoma. Preferably, said nasopharyngeal carcinoma has positive expression of PD-L1 in a tumor tissue section immunohistochemical staining assay. In certain embodiments, preferred nasopharyngeal carcinoma is a peripheral blood circulating tumor DNA or no detectable gene amplification of CCND1, FGF14, FGF3, or FGF4 chromosome 11q13 region in tumor tissue. In certain embodiments, nasopharyngeal carcinoma in which the DNA copy number of EBV in peripheral blood decreases more than two-fold after 28 days of treatment is preferred.
The therapeutic agents of the present invention may constitute pharmaceutical compositions, such as pharmaceutical compositions containing the anti-PD-1 antibodies described herein or/and other anti-cancer agents other than the anti-PD-1 antibodies, and other pharmaceutically acceptable carriers. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, which are physiologically compatible. Preferably, the carriers suitable for use in the composition comprising the anti-PD-1 antibody are suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration, such as by injection or infusion, while the carriers for the composition comprising the other anti-cancer agent are suitable for parenteral administration, such as oral administration. The pharmaceutical compositions of the present invention may contain one or more pharmaceutically acceptable salts, antioxidants, water, non-aqueous carriers, and/or adjuvants such as preserving, wetting, emulsifying, and dispersing agents.
The dosage regimen is adjusted to provide the optimum desired response, such as the maximum therapeutic response and/or the minimum adverse effect. For anti-PD-1 antibodies, including administration in combination with another anti-cancer agent, the dose range may be from about 0.01 to about 20mg/kg, from about 0.1 to about 10mg/kg of the individual's body weight, or a fixed dose of 120mg, 240mg, 360mg, 480 mg. For example, the dosage may be about 0.1, about 0.3, about 1, about 2, about 3, about 5, or about 10mg/kg of the individual's body weight. Dosing regimens are generally designed to achieve such exposure, which results in sustained Receptor Occupancy (RO) based on the typical pharmacokinetic properties of abs. A representative dosing regimen may be about once per week, about once every two weeks, about once every three weeks, about once every four weeks, about once a month, or longer. In some embodiments, the anti-PD-1 antibody is administered to the individual about once every two weeks.
Method for predicting effect of anti-PD-1 antibody on treatment of malignant tumor
As used herein, the term "gene amplification" refers to a process in which the copy number of a gene encoding a specific protein is selectively increased while other genes are not increased proportionally. Under natural conditions, gene amplification is achieved by excision of repeated sequences of the gene from the chromosome and extrachromosomal replication in a plasmid or by transcribing the entire repeated sequences of ribosomal RNA to give RNA transcripts to give additional copies of the original DNA molecule. In some embodiments of the invention, gene sequencing analysis is disclosed.
In some embodiments of the invention, the subject of the invention has some unique gene amplification, e.g., some subjects have CCND1, FGF14, FGF3, or FGF4 chromosome 11q13 region gene amplification. In some embodiments of the invention, gene amplification of the region having CCND1, FGF14, FGF3, or FGF4 chromosome 11q13 is predictive of an undesirable therapeutic effect in the patient using the anti-PD-1 antibody of the invention alone.
In some embodiments of the invention, the DNA copy number of EBV in peripheral blood of some subjects decreases on day 28 of treatment in the subject of the invention. In some embodiments of the invention, a more than two-fold decrease in the DNA copy number of peripheral blood EBV is indicative of a better therapeutic outcome of the patient treated with the anti-PD-1 antibody of the invention.
Accordingly, the present invention provides a method for predicting the effect of using an anti-PD-1 antibody of the present invention, particularly tereprimab, for treating a malignancy in an individual, comprising detecting a biomarker in peripheral blood of the patient prior to treatment, said biomarker being selected from, but not limited to, a mutation in CCND1, FGF14, FGF3, or FGF4 chromosome 11q13 region, or detecting the DNA copy number of EBV in peripheral blood of the patient on day 28 of treatment.
The invention also includes a method of predicting the effect of anti-PD-1 antibody treatment in a patient with a tumor by detecting the presence or absence of CCND1, FGF14, FGF3, or FGF4 gene amplification in the 11q13 region of chromosome. Preferably, the presence of gene amplification of CCND1, FGF14, FGF3 or FGF4 in the 11q13 region of chromosome indicates that the tumor patient is not suitable for treatment with anti-PD-1 antibody alone. Preferably, the tumor patient is selected from patients with nasopharyngeal carcinoma.
The invention also includes a method of predicting the efficacy of anti-PD-1 antibody treatment in a tumor patient by measuring the DNA copy number of EBV in the peripheral blood of the tumor patient on day 28 of administration. Preferably, a more than two-fold decrease in the DNA copy number of the peripheral blood EBV (DNA copy number of the peripheral blood EBV before treatment on day 0/DNA copy number of the peripheral blood EBV on day 28. gtoreq.2) indicates that the tumor patient is suitable for treatment with the anti-PD-1 antibody. Preferably, the tumor patient is selected from patients with nasopharyngeal carcinoma.
The invention also comprises application of the reagent for detecting gene mutation of the CCND1, FGF14, FGF3 or FGF4 chromosome 11q13 region in preparing a kit for predicting the effect of the anti-PD-1 antibody on treating malignant tumors. Such reagents include, but are not limited to, reagents conventionally used in assays, including, but not limited to, primers, probes, reagents required for PCR, and the like.
The invention also comprises the application of the reagent for detecting the DNA copy number of the EBV in the peripheral blood in preparing a kit for predicting the effect of the anti-PD-1 antibody on treating malignant tumors. Such reagents include, but are not limited to, reagents conventionally used in assays, including, but not limited to, primers, probes, reagents required for PCR, and the like.
Abbreviations
Throughout the description and examples of the present invention, the following abbreviations are used:
BID one dose, 2 times daily
CDR complementarity determining region
Disease-free survival of DFS
FR framework regions
IgG immunoglobulin G
IHC immunohistochemistry
OR Overall response
Objective rate of remission of ORR
OS Total survival
Progression of PD disease
Progression free survival of PFS
PR partial response
CR complete response
Stabilization of SD disease
Dose limiting toxicity of DLT
Maximum tolerated dose of MTD
AE adverse events
Q2W one dose every two weeks
One daily dose of QD
Long-term exposure to CSD
non-CSD non-long-term sun exposure type
IRC independent review Committee
Adverse effects of TRAE associated with therapy
SAE Severe adverse reaction
RO receptor occupancy rate
UC urothelial carcinoma
RCC renal cell carcinoma
MM metastatic melanoma
Therapeutic effect evaluation standard of RECIST solid tumor
Therapeutic efficacy evaluation criteria for irRECIST immune-related solid tumors
DOR mitigation duration
MSI microsatellite instability
The invention is further illustrated by the following examples, which should not be construed as limiting the invention. The contents of all references cited throughout this application are expressly incorporated herein by reference.
Examples
Example 1: clinical study of anti-PD-1 antibody for treating nasopharyngeal carcinoma
Grouping standard: eligible subjects must (1) be over 18 years of age, (2) have recurrent or metastatic nasopharyngeal carcinoma, (3) be refractory to standard systemic treatment or develop disease after 6 months of chemotherapy, (4) have an ECOG score of 0 or 1, (5) have normal organ function within 10 days after initiation of treatment, (6) have no history of autoimmune disease or other malignancy, and (7) have not previously received any anti-PD-1/or anti-PD-L1 immunotherapy.
The subject must have an evaluable lesion according to RECIST v1.1 standard, not receive anti-tumor monoclonal antibody drug therapy within 4 weeks before treatment, not receive any anti-tumor drug therapy within 2 weeks before treatment, and not receive systemic steroid drug therapy within 7 days before treatment begins.
From 22/2016 in 2016 to 19/2/2019, a total of 17 centers from continental china screened 279 patients with recurrent or metastatic NPC, and 190 patients were enrolled in the study. The average age was 46.4 years, with the majority of patients being males (n 158, 83.2%). Of the two histological subtypes, 182 (95.8%) were non-keratinized NPCs and 8 (4.2%) were keratinized NPCs. There were 116 patients (61.1%) who received at least two systemic treatments. Demographic data for the enrolled subjects are shown in table 1.
Table 1: demographic data of the subjects in the cohort
Note: PD-L1 positive was defined as > 1% expression of PD-L1 staining tumor cells with SP142 IHC.
The tested drugs are: anti-PD-1 antibody terlipril mab (WO 2014206107).
Subjects in the cohort received 3mg/kg of Terapril mab (tropipalimab) intravenously every two weeks (Q2W) until disease progression was confirmed, intolerable toxicity, individual consent was given for withdrawal, investigator decided to discontinue treatment, or treatment was completed by 24 months.
The evaluation was performed every 8 weeks for the first year, and every 12 weeks thereafter according to RECIST v1.1 and the solid tumor immune-related response evaluation criteria (irRECIST). Evaluation was performed every 3 months after drug withdrawal.
And (3) clinical design:
this is a one-armed, phase II, non-blind clinical trial. This study was conducted to evaluate the safety and anti-tumor activity of anti-PD-1 antibodies for the treatment of recurrent or metastatic nasopharyngeal carcinoma patients.
1.1 safety study:
by 2 months and 19 days of 2020, i.e. 12 months after the last patient was admitted, the average number of patients receiving Tereprinimab was 8 doses (range: 1 to 69 doses). 181 (95.3%) patients experienced adverse reactions (TEAE) occurring during treatment, of which 141 (74.2%) experienced treatment-related adverse events (TRAE). Common (> 5%) TRAEs are shown in table 2. 63 (33.2%) patients experienced a TEAE grade 3 and above, while 27 (14.2%) patients experienced a TRAE grade 3 and above in relation to treatment. 4 (2.1%) patients were discontinued due to TRAE and 7 (3.7%) patients were discontinued due to TRAE dose. Immune-related adverse reactions (AEs) included 45 cases (23.7%) hypothyroidism, 5 cases (2.6%) hyperthyroidism, 3 cases (1.6%) liver dysfunction, 3 cases (1.6%) interstitial lung disease, 1 case (0.5%) dermatomyositis, and 1 case (0.5%) autoimmune myocarditis.
Table 2: common (> 5%) adverse events associated with tropimalimab treatment (n 190)
N(%) | All of | |
|
|
4 | Grade | 5 |
All adverse reactions | 141(74.2) | 55(28.9) | 59(31.1) | 17(8.9) | 4(2.1) | 6(3.2) | |
Hypothyroidism | 45(23.7) | 19(10.0) | 26(13.7) | 0 | 0 | 0 | |
Anemia (anemia) | 29(15.3) | 15(7.9) | 12(6.3) | 2(1.1) | 0 | 0 | |
AST elevation | 29(15.3) | 26(13.7) | 3(1.6) | 0 | 0 | 0 | |
ALT elevation | 26(13.7) | 21(11.1) | 5(2.6) | 0 | 0 | 0 | |
Fatigue | 25(13.2) | 18(9.5) | 5(2.6) | 2(1.1) | 0 | 0 | |
Proteinuria | 24(12.6) | 24(12.6) | 0 | 0 | 0 | 0 | |
Leukopenia | 19(10.0) | 8(4.2) | 11(5.8) | 0 | 0 | 0 | |
Generate heat | 18(9.5) | 13(6.8) | 5(2.6) | 0 | 0 | 0 | |
Itching (pruritus) | 16(8.4) | 14(7.4) | 2(1.1) | 0 | 0 | 0 | |
Rash | 12(6.3) | 8(4.2) | 4(2.1) | 0 | 0 | 0 | |
Neutropenia | 10(5.3) | 6(3.2) | 3(1.6) | 1(0.5) | 0 | 0 |
1.2 antitumor Activity Studies:
by 19 months 2 of 2020, 94 (49.5%) of all 190 patients died, 78 (41.1%) stopped taking the drug, and 18 (9.5%) were still under study. Median treatment time was 3.7 months (0.2 to 34.8 months). The Objective Remission Rate (ORR) was 20.5% (95% CI: 15.0-27.0) in 190 patients evaluated by IRCIST/RECIST v1.1, with 5 CR, 34 PR and 37 SD and a Disease Control Rate (DCR) of 40.0% (95% CI: 33.0-47.3). ORR was 20.5% (95% CI: 15.0-27.0) and DCR was 47.9% (95% CI: 40.6-55.2) as assessed by IRC/irRECIST (Table 3).
Table 3: assessment of clinical efficacy according to RECIST v1.1 or irRECIST criteria
Note:
ORR ═ CR + PR)/total × 100%;
DCR ═ CR + PR + SD)/total × 100%;
CR: a full response; PR: a partial response; SD: stabilization of the disease; PD: disease progression; NE: not evaluated; ORR: an objective response rate; DCR: the rate of disease control; CI: a confidence interval.
Target lesions were reduced from baseline in 73 (38.4%) subjects, with target lesions reduced by more than 30% from baseline in 48 (25.3%) subjects (fig. 1a and 1 b). Median response time was 1.8 months (95% CI: 1.8-2.1). The median progression-free survival (mPFS) was 1.9 months (95% CI: 1.8-3.5) (FIG. 2 a). The median overall survival (mOS) was 17.4 months (95% CI: 11.7-22.9) (FIG. 2 b). Since the median DOR was 12.8 months (95% CI: 9.4-NE), the response persisted (FIG. 2 c). For patients who received at least two prior treatments (n ═ 116), ORR was 21.6% (95% CI from 14.5 to 30.1), DOR median 21.5 months, mPFS 2.0 months, and mOS 15.1 months.
Since only 7 PR/CR subjects and 11 SD subjects died, median OS was not achieved in subjects experiencing objective response (n-39) or stable disease (n-38). The median OS of subjects with disease progression (n 113) was 8.4 months.
1.3 immunogenicity
Anti-drug antibody (ADA) assays were performed on 190 patients. ADA positive 7 cases (3.7%). 4 of these were consecutive positive samples. The incidence rate, the withdrawal or the dose delay and the clinical curative effect of AE of grade 3 and above of the ADA positive and negative patients have no obvious difference.
1.4 histological subtype
The ORR of the keratinized NPC (n ═ 8) was significantly better than the non-keratinized NPC (n ═ 182), as assessed by IRC, at 62.5% and 18.7%, respectively, and p ═ 0.01. The PFS of the keratinized NPC was also significantly better than the non-keratinized NPC at 16.6 months and 1.9 months, HR 0.46 (95% CI: 0.25-0.85), and p 0.013. OS was not achieved and 15.1 months, respectively, with no statistical difference, HR 0.51 (95% CI: 0.21-1.24), p 0.14 (fig. 2d and 2 e).
Example 2: correlation study of biomarker and clinical curative effect
2.1 expression of PD-L1 in tumors
PD-L1 expression status in tumor biopsies was determined by SP142 IHC staining, with Tumor Proportion Score (TPS) > 1%, determined as positive. Of the 190 patients, 48 (25.3%) were positive for PD-L1 and 134 (70.5%) were negative for PD-L1 (FIG. 3 a). The PD-L1 expression status was unknown in 8 (4.2%) patients. Of the PD-L1+ patients, 21 (11.1%) were determined to be highly expressed (> 25%) PD-L1. According to histological subtype, the percentage PD-L1+ was significantly higher in keratinized NPC (75.0%) than in non-keratinized NPC (24.1%), p 0.0047. The ORR values were higher in PD-L1+ patients than in PD-L1-patients, with 27.1% and 19.4% ORR, respectively, but the difference was not statistically significant (p ═ 0.31). The difference in ORR was more pronounced in PD-L1> 25% of patients (38.1% versus 19.3%, p-value 0.08) (fig. 3 a). PFS and OS were also better in > 25% of PD-L1 than in 25% of PD-L1 ≤ 25%, mPFS was 7.2 months and 1.9 months, HR ═ 0.64 (95% CI: 0.40-1.02), p ═ 0.059; mOS was not achieved and 15.1 months, HR 0.57 (95% CI: 0.31-1.05), p 0.071 (fig. 3b and 3c), respectively, but the differences were not statistically significant.
2.2 Tumor Mutation Burden (TMB) analysis
Tumor biopsies and paired peripheral blood samples from subjects were subjected to Whole Exome Sequencing (WES) to identify tumor-specific mutations. Effective WES results were 174 patients. In this NPC patient, TMB is very low, with a median of 0.95 mutations per million base pairs (Muts/Mb). Only 1 patient with high MSI, 4 patients had TMB over 10 mutations/Mb, and the remaining patients had TMB of no more than 5.8 mutations/Mb. The cut-off values of the first 10% or 20% of the TMB values (2.9 and 2.0Muts/Mb, respectively) were selected for the assessment of clinical response in this study. The ORRs were 17.6% and 14.3% in the first 10% and 20% of patients, respectively (fig. 3 a). 4 patients with TMB over 10Muts/Mb, including 1 patient with MSI-high, progressed to the best response. Furthermore, at 1.9 months, the 10% of patients with the highest TMB values had similar PFS to the 90% of patients with the lowest TMB values (fig. 3 d). In contrast, the high TMB patients had lower OS values than the low TMB patients, 9.2 months and 17.4 months, respectively, but the differences were not statistically significant (fig. 3 e). In summary, in this study, TMB was not associated with clinical response in patients with advanced NPC who received terepril mab monotherapy.
2.3 genomic mutation analysis
Genes that changed most frequently (> 10%) were identified by WES, including CDKN2A (20%), TP53 (13%), NFKB1A (13%), CDKN2B (11%), ETV6 (11%) and MCL1 (10%) (fig. 4). Genomic alterations were analyzed for correlation with clinical efficacy. It was found that 11 patients with CCND1(n ═ 11) and/or genomic amplification of the FGF14, FGF3, FGF4 chromosome 11q13 region received 0% ORR of terlipril mab treatment. 19 patients had a mutation in ETV6 with an ORR of only 5.3%.
2.4 plasma EBV DNA copy number
Patient plasma was collected before dosing and analyzed for EBV DNA copy number by the qRT-PCR method every 4 weeks. Patients with baseline EBV titers <10000IU/mL had higher ORRs than patients with EBV titers > 10000IU/mL, 26.7% and 15.4%, respectively, with p ═ 0.088. Dynamic plasma EBV DNA copy number over the course of treatment was collected from 149 patients (fig. 5). Studies found that in patients with objective responses (n ═ 34), the median plasma EBV DNA copy number decreased 31-fold from baseline to the lowest copy number, whereas in patients with stable disease (n ═ 35) it decreased 3-fold, and in patients with disease progression no change (n ═ 80) (fig. 5). Furthermore, on day 28, i.e., two weeks prior to the first radiologic assessment of clinical activity, patients with a 2-fold or greater decrease in plasma EBV DNA copy number (n-60) had significantly better clinical response rates than patients with a 2-fold or less decrease (n-88), ORR of 48.3% and 5.7%, respectively, and p-0.0001. In contrast, the median 3 months prior to imaging disease progression increased plasma EBV DNA copy number by at least 2-fold in 14 patients undergoing disease progression (fig. 5).
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<211> 17
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 5
Val Ile Glu Ser Glu Thr Gly Gly Thr Ala Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 6
<211> 16
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 6
Glu Gly Ile Thr Thr Val Ala Thr Thr Tyr Tyr Trp Tyr Phe Asp Val
1 5 10 15
<210> 7
<211> 112
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 7
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 8
<211> 125
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 8
Gln Gly Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Glu Met His Trp Val Arg Gln Ala Pro Ile His Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Glu Ser Glu Thr Gly Gly Thr Ala Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ile Thr Thr Val Ala Thr Thr Tyr Tyr Trp Tyr Phe
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 9
<211> 219
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 9
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 10
<211> 452
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 10
Gln Gly Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Glu Met His Trp Val Arg Gln Ala Pro Ile His Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Glu Ser Glu Thr Gly Gly Thr Ala Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ile Thr Thr Val Ala Thr Thr Tyr Tyr Trp Tyr Phe
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr
115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser
130 135 140
Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
165 170 175
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys
195 200 205
Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
210 215 220
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu
225 230 235 240
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
245 250 255
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
260 265 270
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
275 280 285
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
290 295 300
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
305 310 315 320
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
325 330 335
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
340 345 350
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
355 360 365
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
370 375 380
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
385 390 395 400
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
405 410 415
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
420 425 430
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
435 440 445
Ser Leu Gly Lys
450
Claims (21)
1. Use of an anti-PD-1 antibody or antigen-binding fragment thereof in the manufacture of a medicament for the prevention or treatment of a malignant tumor.
2. The use of claim 1, wherein the malignant tumor is nasopharyngeal carcinoma.
3. The use of claim 2, wherein the malignancy is recurrent or metastatic nasopharyngeal carcinoma.
4. The use of claim 1 or 2, wherein the malignancy is a malignancy in which PD-L1 expresses > 1% in an immunohistochemical staining assay of a tumor tissue section; preferably, the tumor tissue section is a malignant tumor with PD-L1> 25% in immunohistochemical staining analysis.
5. Use according to claim 2, wherein the malignant tumor is selected from the group consisting of a keratinizing nasopharyngeal carcinoma and a non-keratinizing nasopharyngeal carcinoma, preferably a keratinizing nasopharyngeal carcinoma.
6. The use of claim 2, wherein said nasopharyngeal carcinoma is a nasopharyngeal carcinoma wherein no amplification of the genome of CCND1, FGF14, FGF3, or FGF4 region at chromosome 11q13 is detected in peripheral blood circulating tumor DNA or tumor tissue.
7. The use of claim 2, wherein the nasopharyngeal cancer is a nasopharyngeal cancer that has a more than two-fold decrease in peripheral blood EBV DNA copy number on day 28 relative to day 0 prior to administration.
8. The use of any one of claims 1 to 7, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises an amino acid sequence as set forth in SEQ ID NO: 1.2 and 3, and the amino acid sequence is as shown in SEQ ID NO: 4.5 and 6.
9. The use of claim 8, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain variable region having an amino acid sequence as set forth in SEQ ID NO. 7 and a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO. 8.
10. The use of claim 8, wherein the anti-PD-1 antibody comprises a light chain having the amino acid sequence shown in SEQ ID NO. 9 and a heavy chain having the amino acid sequence shown in SEQ ID NO. 10.
11. The use according to any one of claims 1 to 7, wherein the anti-PD-1 antibody is selected from one or more of nivolumab, pembrolizumab, toreplalimumab, Sintilizumab, Camrelizumab, Tislelizumab, Cemipilimab; preferably a toriplalimab.
12. The use of any one of claims 1 to 11, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of about 0.1mg/kg to about 10.0mg/kg of the individual's body weight, such as about 0.1mg/kg, about 0.3mg/kg, about 1mg/kg, about 2mg/kg, about 3mg/kg, about 5mg/kg, or 10mg/kg of the individual's body weight, or is selected from about 120mg to about 480mg fixed dose, such as 120mg, 240mg, 360mg or 480mg fixed dose, preferably 3mg/kg of the individual's body weight or 240mg fixed dose.
13. The use of claim 12, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a frequency of about once every week, once every two weeks, once every three weeks, once every four weeks, or once a month, preferably once every two weeks.
14. The use of claim 12, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 1mg/kg, 3mg/kg, 10mg/kg, or 240mg fixed dose, 480mg fixed dose once every two or three weeks.
15. The use of claim 12, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered parenterally, such as by intravenous infusion, in a liquid dosage form, such as an injection.
16. The use of claim 12, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered for a period of one week, two weeks, three weeks, one month, two months, three months, four months, five months, half a year, or longer, optionally, the time for each administration period is the same or different, and the interval between each administration period is the same or different.
17. A method of preventing or treating a malignant tumor, the method comprising administering to an individual in need thereof an effective amount of the anti-PD-1 antibody or antigen-binding fragment thereof of any one of claims 8-11.
18. Use of a reagent for detecting gene mutation or amplification of CCND1, FGF14, FGF3 or FGF4 chromosome 11q13 region in peripheral blood circulation tumor DNA or tumor tissue of an individual in preparation of a kit for predicting the effect of an anti-PD-1 antibody on treatment of nasopharyngeal carcinoma.
19. Use of a reagent for detecting the copy number of EBV DNA in peripheral blood of an individual in preparing a kit for predicting the effect of an anti-PD-1 antibody on treating nasopharyngeal carcinoma.
20. A detection kit comprises a reagent for detecting gene mutation or amplification of CCND1, FGF14, FGF3 or FGF4 chromosome 11q13 region in peripheral blood circulation tumor DNA or tumor tissue of an individual.
21. A test kit comprising reagents for detecting the EBV DNA copy number of peripheral blood of an individual.
Priority Applications (11)
Application Number | Priority Date | Filing Date | Title |
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CN202010879644.8A CN114099663A (en) | 2020-08-27 | 2020-08-27 | Use of anti-PD-1 antibodies in the treatment of nasopharyngeal carcinoma |
PCT/CN2021/114668 WO2022042626A1 (en) | 2020-08-27 | 2021-08-26 | Use of anti-pd-1 antibody in treatment of nasopharyngeal carcinoma |
AU2021330872A AU2021330872A1 (en) | 2020-08-27 | 2021-08-26 | Use of anti-pd-1 antibody in treatment of nasopharyngeal carcinoma |
BR112023002912A BR112023002912A2 (en) | 2020-08-27 | 2021-08-26 | USE OF ANTI-PD-1 ANTIBODY IN THE TREATMENT OF NASOPHARYNGEAL CARCINOMA |
JP2023513229A JP2023538683A (en) | 2020-08-27 | 2021-08-26 | Use of anti-PD-1 antibodies in the treatment of nasopharyngeal carcinoma |
EP21860461.9A EP4205763A1 (en) | 2020-08-27 | 2021-08-26 | Use of anti-pd-1 antibody in treatment of nasopharyngeal carcinoma |
MX2023002279A MX2023002279A (en) | 2020-08-27 | 2021-08-26 | Use of anti-pd-1 antibody in treatment of nasopharyngeal carcinoma. |
US18/043,204 US20230365691A1 (en) | 2020-08-27 | 2021-08-26 | Use of anti-pd-1 antibody in treatment of nasopharyngeal carcinoma |
CA3190934A CA3190934A1 (en) | 2020-08-27 | 2021-08-26 | Use of anti-pd-1 antibody in treatment of nasopharyngeal carcinoma |
CN202180053354.0A CN116209466A (en) | 2020-08-27 | 2021-08-26 | Use of anti-PD-1 antibodies in the treatment of nasopharyngeal carcinoma |
CL2023000551A CL2023000551A1 (en) | 2020-08-27 | 2023-02-24 | Use of an anti-pd-1 antibody in the treatment of nasopharyngeal carcinoma |
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CN202010879644.8A CN114099663A (en) | 2020-08-27 | 2020-08-27 | Use of anti-PD-1 antibodies in the treatment of nasopharyngeal carcinoma |
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Cited By (1)
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CN116549633A (en) * | 2022-12-28 | 2023-08-08 | 广州誉衡生物科技有限公司 | anti-PD-1 antibodies and their use in the preparation of a medicament for the treatment of patients with nasopharyngeal carcinoma |
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Publication number | Priority date | Publication date | Assignee | Title |
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CN116549633A (en) * | 2022-12-28 | 2023-08-08 | 广州誉衡生物科技有限公司 | anti-PD-1 antibodies and their use in the preparation of a medicament for the treatment of patients with nasopharyngeal carcinoma |
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