WO2023198089A1 - Composition pharmaceutique comprenant un mélange d'anticorps anti-ctla4 et anti-pd1 et son utilisation thérapeutique - Google Patents
Composition pharmaceutique comprenant un mélange d'anticorps anti-ctla4 et anti-pd1 et son utilisation thérapeutique Download PDFInfo
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- WO2023198089A1 WO2023198089A1 PCT/CN2023/087714 CN2023087714W WO2023198089A1 WO 2023198089 A1 WO2023198089 A1 WO 2023198089A1 CN 2023087714 W CN2023087714 W CN 2023087714W WO 2023198089 A1 WO2023198089 A1 WO 2023198089A1
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- colorectal cancer
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- A61K39/00—Medicinal preparations containing antigens or antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
Definitions
- the present disclosure relates to the treatment of cancer, particularly colorectal cancer, including immunotherapy and combination therapy. More specifically, the present disclosure relates to the use of a pharmaceutical composition comprising a mixed antibody against CTLA4 and anti-PD1 to treat colorectal cancer.
- the 2020 version of the GLOBOCAN statistical report shows that in 2020, there will be approximately 19.3 million new cases of cancer and nearly 10 million cancer deaths around the world. Among them, the proportion of new cases of colorectal cancer (CRC) is about 10.0%, ranking third; the proportion of deaths is about 9.4%, ranking second.
- CRC colorectal cancer
- the latest cancer statistics from the National Cancer Center of China showed that the incidence rate of colorectal cancer in China ranked third, with 408,000 cases; the mortality rate ranked fourth, with 195,600 deaths.
- the incidence and mortality of colorectal cancer remain on the rise, and it is an important disease that threatens human health worldwide. Since the early symptoms of CRC are not obvious, about 20% of patients have metastasized or progressed to an advanced stage when diagnosed, and more than 50% of patients with early-stage CRC will eventually relapse or metastasize.
- CRC cancer reconstituted by dMMR (mismatch repair protein deficiency)/MSI-H (microsatellite instability high) type CRC accounts for about 12 to 15% of CRC in the entire population, and the late stage accounts for about 5%.
- KRAS and NRAS are GTPase proteins encoded by RAS family member genes. They participate in signal transduction of epidermal growth factor receptors and regulate cell growth, differentiation, proliferation, and survival. 40% to 50% of colorectal cancer patients have KRAS point mutations; 3.8% of colorectal cancer patients have NRAS gene point mutations.
- the BRAF gene is located downstream of the RAS gene and is a key member of the RAS-RAF-MEK kinase pathway.
- the BRAF mutation rate is 5.4% to 6.7%.
- patients with metastatic colorectal cancer with BRAF gene mutations 90% have BRAF V600E mutations.
- ICIs immune checkpoint inhibitors
- mCRC metastatic colorectal cancer
- pembrolizumab nivolumab Uzumab, envolizumab, tislelizumab, slutizumab, putelizumab, etc.
- pembrolizumab has been approved for dMMR/MSI- H mCRC first-line treatment.
- no anti-PD-1/PD-L1 mAb combined with anti-CTLA-4 mAb has been approved for this indication.
- ICIs for patients with MSS (microsatellite stable) CRC, ICIs, as a late-line systemic treatment option, have poor efficacy.
- Anti-PD-1 monoclonal antibodies combined with standard treatment regimens have certain efficacy in the first-line treatment of mCRC, but still need to be further improved.
- RAS/RAF gene mutations suggest that patients receiving anti-EGFR targeted therapy have a poorer prognosis compared with anti-VEGF monoclonal antibodies (such as bevacizumab). However, this prognostic indicator has not yet been confirmed in immunotherapy.
- ZPML265 is a mixed antibody pharmaceutical preparation consisting of a recombinant humanized IgG1 monoclonal antibody targeting human CTLA4 and a recombinant humanized IgG4 monoclonal antibody targeting human PD1. These two different antibodies are produced by a single host cell. . This mixed antibody can specifically bind to CTLA4 and PD1 at the same time, thereby blocking the two immune checkpoint signaling pathways of CTLA-4 and B7-1/B7-2, as well as PD-1 and PD-L1, and releasing the impact of the two pathways on T lymphocytes. The inhibitory effect of cells restores their functional activity and anti-tumor immune response, thereby enabling the body to achieve the purpose of fighting and killing tumors. Different from the combined use of nivolumab and ipilimumab, ZPML265 can achieve continuous administration of CTLA-4 monoclonal antibody during the combined treatment, thereby further improving its therapeutic effect.
- the technical problem to be solved by this disclosure is to provide an immunotherapy to fill the clinical gap that there is no dual-target immune (double-immune) therapeutic drug for colorectal cancer in the world, thereby solving such unmet clinical needs. need.
- the present disclosure provides a pharmaceutical composition for treating colorectal cancer, comprising an effective amount of a mixed antibody against CTLA4 and anti-PD1.
- the pharmaceutical composition further includes a pharmaceutically acceptable carrier.
- the pharmaceutical composition further includes additional therapeutic agents, including but not limited to chemotherapeutic agents (chemotherapeutic drugs), cytotoxic agents, radiotherapeutic agents, cancer vaccines, tumor reducing agents, targeted anti-cancer agents agents, anti-angiogenic agents, biological response modifiers, cytokines, hormones, anti-metastatic agents and immunotherapeutic agents.
- the additional therapeutic agents are chemotherapeutic agents and anti-angiogenic agents, with preferred chemotherapeutic agents being oxaliplatin and capecitabine, and the preferred anti-angiogenic agent being bevacizumab.
- the colorectal cancer of the present disclosure is unresectable or metastatic colorectal cancer.
- the unresectable or metastatic colorectal cancer is mismatch repair protein deficient (dMMR) or microsatellite unstable high (MSI-H) colorectal cancer; another preferred solution is that the unresectable or metastatic colorectal cancer Metastatic colorectal cancer is microsatellite stable (MSS) colorectal cancer.
- dMMR mismatch repair protein deficient
- MSI-H microsatellite unstable high
- MSS microsatellite stable
- the present disclosure also preferably provides a pharmaceutical composition for the treatment of unresectable or metastatic mismatch repair protein-deficient (dMMR) or microsatellite instability-high (MSI-H) colorectal cancer, which contains an effective amount Mixed anti-CTLA4 and anti-PD1 antibodies.
- dMMR unresectable or metastatic mismatch repair protein-deficient
- MSI-H microsatellite instability-high
- the present disclosure also preferably provides a pharmaceutical composition for treating unresectable or metastatic microsatellite stable (MSS) colorectal cancer, which contains an effective amount of anti-CTLA4 and anti-PD1 mixed antibodies, chemotherapy Drugs and anti-angiogenic agents.
- MSS microsatellite stable
- the unresectable or metastatic microsatellite stable (MSS) colorectal cancer is the case where the KRAS, NRAS and BRAF genes are all wild type; alternatively, the unresectable or metastatic microsatellite stable (MSS) colorectal cancer can also be This is a case where any one of the KRAS, NRAS, and BRAF genes is mutated.
- the mixed antibodies are produced from a single host cell containing nucleic acids encoding two different antibodies, anti-CTLA4 and anti-PD1, wherein the sequences of the anti-CTLA4 antibody heavy chains HCDR1, HCDR2 and HCDR3 are respectively SEQ. ID NO: 1, 2, and 3, the sequences of the anti-CTLA4 antibody light chain LCDR1, LCDR2, and LCDR3 are respectively SEQ ID NO: 4, 5, and 6, and the sequences of the anti-PD1 antibody heavy chain HCDR1, HCDR2, and HCDR3 are respectively They are shown in SEQ ID NO: 9, 10, and 11, and the sequences of the anti-PD1 antibody light chain LCDR1, LCDR2, and LCDR3 are shown in SEQ ID NO: 12, 13, and 14 respectively.
- the heavy chain variable region sequence of the anti-CTLA4 antibody is set forth in SEQ ID NO:7
- the light chain variable region sequence of the anti-CTLA4 antibody is set forth in SEQ ID NO:8
- the heavy chain sequence of the anti-PD1 antibody is set forth in SEQ ID NO:7.
- the variable region sequence is shown in SEQ ID NO: 15, and the light chain variable region sequence of the anti-PD1 antibody is shown in SEQ ID NO: 16.
- the heavy chain sequence of the anti-CTLA4 antibody is SEQ ID NO: 17
- the light chain sequence of the anti-CTLA4 antibody is SEQ ID NO: 18
- the heavy chain sequence of the anti-PD1 antibody is SEQ ID NO: As shown in 19, the light chain sequence of the anti-PD1 antibody is shown in SEQ ID NO: 20.
- the dosage of the mixed antibody is 5 mg/kg, administered once every three weeks, by intravenous infusion on the first day, and 21 days is a treatment cycle.
- the dosage of the chemotherapy drug oxaliplatin injection is 130 mg/m 2 , which is administered by intravenous infusion on the first day, with a treatment cycle of 21 days; the dosage of the chemotherapy drug capecitabine tablets is 1000 mg/m 2 , taken orally, twice a day, starting on the first day of every 3 weeks, stopping for 1 week after every 2 weeks, and every 3 weeks (21 days) is a treatment cycle; dosage of bevacizumab injection It is 7.5mg/kg, intravenous infusion, administered once on the first day of every 3 weeks, and every 3 weeks is a treatment cycle.
- oxaliplatin can be used for a maximum of 8 treatment cycles
- capecitabine tablets can be used for a maximum of 2 years.
- the present disclosure also provides a method for treating colorectal cancer, which method includes administering a pharmaceutical composition to a subject, and the pharmaceutical composition is the aforementioned mixed antibody containing an effective amount of anti-CTLA4 and anti-PD1.
- the present disclosure also preferably provides a method of treating unresectable or metastatic mismatch repair protein deficient (dMMR) or microsatellite unstable high (MSI-H) colorectal cancer, the method comprising administering to a subject a drug combination
- the pharmaceutical composition is the aforementioned mixed antibody containing an effective amount of anti-CTLA4 and anti-PD1.
- the present disclosure also preferably provides a method of treating unresectable or metastatic microsatellite stable (MSS) colorectal cancer, the method comprising administering to a subject a pharmaceutical composition, the pharmaceutical composition comprising an effective amount of A mix of anti-CTLA4 and anti-PD1 Antibodies, chemotherapeutic drugs, and anti-angiogenic agents.
- MSS microsatellite stable
- the results of a Phase I clinical study of the disclosed mixed antibody as a single agent showed that it had certain efficacy and good safety in 27 patients with advanced CRC.
- clinical studies based on the hybrid antibody of the present disclosure combined with bevacizumab have also shown that immune checkpoint inhibitors combined with anti-angiogenic drugs can exert a synergistic anti-tumor effect in advanced colorectal cancer. Therefore, the mixed antibody single drug or the combination regimen of mixed antibodies, chemotherapy drugs and bevacizumab provided by the present disclosure is expected to have controllable safety, good patient compliance, and can be used in the medical treatment of advanced colorectal cancer. To a large extent, it fills the gap where dual-immune combination therapy drugs have not yet been approved and solves the urgent unmet clinical needs.
- the term "about” is meant to include ⁇ 20%, or in some cases ⁇ 10%, or in some cases ⁇ 5%, or in some cases ⁇ 20% of the specified value. A variation of ⁇ 1% in some cases, or ⁇ 0.1% in some cases.
- an antibody typically refers to an antibody containing two heavy (H) polypeptide chains (HC) and two light (L) polypeptide chains (LC) held together by covalent disulfide bonds and non-covalent interactions. ) Y-type tetrameric protein. Natural IgG antibodies have such a structure. Each light chain consists of a variable domain (VL) and a constant domain (CL). Each heavy chain contains a variable domain (VH) and a constant region (CH).
- IgA Five major classes of antibodies are known in the art: IgA, IgD, IgE, IgG and IgM.
- the corresponding heavy chain constant domains are called ⁇ , ⁇ , ⁇ , ⁇ and ⁇ respectively.
- IgG and IgA can be further divided into different Subclasses, such as IgG can be divided into IgG1, IgG2, IgG3, IgG4 and IgA can be divided into IgA1 and IgA2.
- the light chains of antibodies from any vertebrate species can be assigned to one of two distinct types, termed kappa and lambda, based on the amino acid sequence of their constant domains.
- variable region or “variable domain” shows significant variation in the amino acid composition from one antibody to another and is primarily responsible for antigen recognition and binding.
- the variable regions of each light/heavy chain pair form the antibody binding site, such that a complete IgG antibody has two binding sites (i.e. it is bivalent).
- the variable region (VH) of the heavy chain and the variable region (VL) of the light chain each contain three regions of extreme variability known as the hypervariable region (HVR), or more commonly, as Complementarity determining region (CDR), VH and VL each have 4 framework regions FR (or framework regions), represented by FR1, FR2, FR3, and FR4 respectively.
- CDR and FR sequences typically occur in the following sequence of the heavy chain variable domain (VH) (or light chain variable domain (VL)): FR1-HCDR1(LCDR1)-FR2-HCDR2(LCDR2)-FR3 -HCDR3(LCDR3)-FR4.
- VH heavy chain variable domain
- VL light chain variable domain
- antibodies in a broad sense can include polyclonal antibodies, monoclonal antibodies, chimeric antibodies, humanized antibodies and primatized antibodies, CDR-grafted antibodies, human antibodies (including recombinantly produced human antibodies), recombinantly produced antibodies, intrabodies, multispecific antibodies, bispecific antibodies, single chain antibodies, monovalent antibodies, multivalent antibodies, single domain antibodies, Nanobodies, synthetic antibodies (including Mutated proteins and their variants), etc.
- monoclonal antibody refers to a substantially homogeneous antibody produced by a single cell clone and directed only against a specific antigenic epitope.
- Monoclonal antibodies can be prepared using a variety of techniques known in the art, including hybridoma technology, recombinant technology, phage display technology, transgenic animals, synthetic technology, or a combination of the above technologies.
- an antigen refers to a substance recognized and specifically bound by an antibody or antibody-binding fragment.
- an antigen can include any immunogenic fragment or determinant of the selected target, including single epitopes, multiple epitopes, and single structures. domain, multi-domain, or complete extracellular domain (ECD) or protein.
- polypeptide polypeptide
- peptide protein
- polymer may be linear, cyclic or branched, it may contain modified amino acids, especially conservatively modified amino acids, and it may be interrupted by non-amino acids.
- the term also includes amino acid polymers that have been modified, for example, by glycosylation, lipidation, acetylation, phosphorylation, methylation, and the like.
- the term "mixed antibodies” refers to cells containing DNA from a host that has been transfected with DNA encoding at least two different antibodies with different binding specificities, optionally full-length primate IgG antibodies A limited number of major antibody species, optionally no more than two, three, four, five, six, seven, eight, optionally produced by cells from a single host cell line) One species, nine species, or ten species.
- DNA encoding at least two different heavy chains (HC) and at least two different light chains (LC) can be introduced into the same host cell.
- the host cell can be genetically modified with DNA encoding at least two but no more than four different light chains (LC). DNA transfection of different antibodies with different binding specificities.
- the sequences of all transfected DNA encoding HC and LC can be mutated, thereby changing the amino acid sequence of the antibody to disfavor non-homologous HC/LC pairing and strongly favor homologous HC/LC pairing.
- one or both of the two different HCs can optionally be altered such that formation of heterodimers is not favored.
- only one heavy chain is altered to prevent heterodimer formation.
- DNA encoding only two different antibodies is introduced into a host cell, only one of the antibodies encoded by the DNA contains one or more partner orientation changes such that homology is favored. HC/LC pairing, whereas the other antibody did not contain such changes.
- the host cell produces only two major antibody species, where each HC primarily pairs with its cognate LC, and most antibodies are those containing two heavy chains with the same amino acid sequence and two heavy chains with the same amino acid sequence. Tetramer of light chains (see PCT/US2017/030676).
- composition refers to a preparation or a combination of preparations containing one, two or more active ingredients, which allows the active ingredients contained therein to be present in a biologically active form and which does not contain any chemicals necessary for administration. Additional components of the formulation have unacceptable toxicity to subjects.
- a “pharmaceutical composition” exists in the form of a combination of separate preparations containing two or more active ingredients, it can be administered simultaneously, sequentially, separately or at intervals. The purpose is to exert the biological activity of the multiple active ingredients and use them together. For treating diseases.
- pharmaceutically acceptable carrier refers to a diluent, adjuvant (eg, Freund's adjuvant (complete and incomplete)), excipient, or vehicle with which the therapeutic agent is administered.
- the term "effective amount" refers to that dose of a pharmaceutical formulation containing an active ingredient of the present disclosure that produces the desired effect in the patient being treated when administered to the patient in single or multiple doses.
- the effective amount can be readily determined by the attending physician, who is one of skill in the art, by considering factors such as: ethnic differences; weight, age and health status; the specific disease involved; the severity of the disease; the response of the individual patient; The specific antibody administered; the mode of administration; the bioavailability characteristics of the administered formulation; the dosing regimen selected; and the use of any concomitant therapy.
- host cell refers to cells into which exogenous nucleic acid is introduced, including the progeny of such cells.
- Host cells include “transformants” and “transformed cells,” which include the primary transformed cell and progeny derived therefrom, regardless of the number of passages.
- the progeny may not be identical in nucleic acid content to the parent cells but may contain mutations. Mutant progeny that have the same function or biological activity as screened or selected in the originally transformed cells are included herein.
- transfection refers to the introduction of exogenous nucleic acid into a eukaryotic cell. Transfection can be achieved by various means known in the art, including electroporation, microinjection, liposome fusion, etc.
- nucleic acid molecule encoding refers to the deoxyribonucleosides along the deoxyribonucleic acid strand. Acid sequence. The order of these deoxyribonucleotides determines the order of the amino acids along the polypeptide (protein) chain. Thus, a nucleic acid sequence encodes an amino acid sequence.
- Engineered antibodies of the present disclosure, or antigen-binding fragments thereof, may be prepared and purified using conventional methods.
- cDNA sequences encoding heavy and light chains can be cloned and recombined into expression vectors.
- the recombinant immunoglobulin expression vector can stably transfect CHO cells.
- Stable clones are obtained by expressing antibodies that specifically bind to human antigens. Positive clones were expanded in serum-free medium in bioreactors to produce antibodies.
- the culture medium secreting antibodies can be purified and collected using conventional techniques.
- Antibodies can be filtered and concentrated using conventional methods. Soluble mixtures and polymers can also be removed by conventional methods, such as molecular sieves and ion exchange.
- the term "individual” or “subject” refers to any animal, such as a mammal or marsupial.
- Subjects of the present disclosure include, but are not limited to, humans, non-human primates (such as cynomolgus or rhesus monkeys or other types of macaques), mice, pigs, horses, donkeys, cattle, sheep, rats and any species of poultry.
- the terms “disease” or “disorder” or “disorder” or the like refer to any change or disorder that impairs or interferes with the normal function of a cell, tissue or organ.
- the “disease” includes but is not limited to: tumors, pathogenic infections, autoimmune diseases, T cell dysfunction diseases, or immune tolerance defects (such as transplant rejection), etc.
- tumor refers to a disease characterized by pathological proliferation of cells or tissues and their subsequent migration or invasion of other tissues or organs. Tumor growth is often uncontrolled and progressive, without inducing or inhibiting normal cell proliferation. Tumor includes “cancer” and refers to all malignant tumors.
- treatment refers to clinical intervention in an attempt to modify an individual or to treat a cell-induced disease process, either prophylactically or in the clinical pathological process.
- Therapeutic effects include, but are not limited to, preventing the occurrence or recurrence of the disease, alleviating symptoms, reducing the direct or indirect pathological consequences of any disease, preventing metastasis, slowing down the progression of the disease, improving or alleviating the condition, alleviating or improving the prognosis, etc.
- the term “combination” refers to a treatment regimen that provides at least two or more different therapies to achieve a specified therapeutic effect, and the therapies may be either physical, such as radiation therapy, or chemical, such as administration of Subject drugs, the drugs also include combination drugs.
- “Combination drug” refers to a combination of two or more pharmaceutical preparations each having active ingredients, which need to be used together when administered to a subject. The active ingredients can be mixed together to form a single dosing unit, or they can be formed into separate dosing units and used separately; during administration, different pharmaceutical preparations can be administered substantially simultaneously, simultaneously or sequentially.
- OS Overall survival
- PFS Progression-free survival
- ORR Objective response rate
- DCR Disease control rate
- CR Complete response
- Partial response (PR) The sum of target lesion diameters is reduced by at least 30% from baseline.
- PD Disease progression
- Stable disease The reduction of the target lesion does not reach the PR level, and the increase does not reach the PD level. It is somewhere in between. The minimum value of the sum of diameters can be used as a reference during research.
- Duration of response was defined as the time from when the tumor was first assessed as CR or PR (whichever was recorded first) to when the tumor was first assessed as PD or death.
- Treatment-emergent adverse events refer to adverse events that occur during treatment.
- Treatment-related adverse events refer to adverse events related to the study drug that occur during treatment.
- SAE Serious adverse events
- the mixed antibody contains two active ingredients, namely a recombinant humanized IgG1 monoclonal antibody targeting human CTLA4 and an antibody targeting human PD1.
- Recombinant humanized IgG4 monoclonal antibody This mixed antibody can specifically bind to human CTLA4 and PD1 at the same time.
- the two antibodies are simultaneously expressed through a single host cell line, they are collected, purified, and combined with a pharmaceutically acceptable carrier to form a single mixed antibody drug preparation ZPML265.
- anti- The respective amino acid sequences of CTLA4 antibodies and anti-PD1 antibodies are shown in Table 1 below.
- AST Alanine aminotransferase
- ALT aspartate aminotransferase
- UPN upper limit of normal reference value
- Dosing schedule The dose of ZPML265 is 5 mg/kg, administered by intravenous infusion once every three weeks.
- ZPML265 monotherapy treated CRC Among 27 subjects, the confirmed ORR was 7.4% (95% CI: 0.910, 24.290), and the DCR was 25.9% (95% CI: 11.114, 46.285), of which 2 patients had PR. 5 cases SD. ZPML265 single agent has shown certain effectiveness in advanced CRC.
- Safety data summarized data from 609 subjects treated with ZPML265. As of May 31, 2022, 546 (89.7%) patients had experienced TEAEs, and 451 (74.1%) patients had experienced TEAEs related to ZPML265. Grade ⁇ 3 TEAEs and SAEs were reported in 187 (30.7%) and 156 (25.6%) patients, respectively, and grade ⁇ 3 TEAEs and SAEs related to ZPML265 were reported in 102 (16.7%) and 75 (12.3%) patients. SAE related to ZPML265.
- TRAEs with an incidence of ⁇ 10% include: rash (17.6%), pruritus (12.3%), hypothyroidism (11.3%), hyperthyroidism (10.3%), anemia (10%), and aspartate Acid aminotransferase was elevated (10%).
- the incidence of grade ⁇ 3 TRAEs was 16.7%, and TRAEs with an incidence ⁇ 1% included anemia (2.3%), increased aspartate aminotransferase (1.1%), and increased alanine aminotransferase (1.0% ).
- ZPML265 monotherapy shows promising therapeutic effects in the treatment of advanced CRC.
- the incidence of TRAEs is similar to that of anti-PD-(L)1 monotherapy and lower than that of Nivolumab+Ipilimumab dual-immune drug combination therapy, that is, , while ensuring the effectiveness of the drug, the safety is better than the existing clinical solutions in the existing technology.
- Example 3 An evaluation of ZPML265 alone or in combination with bevacizumab and XELOX regimen in the first-line treatment of unresectable locally advanced disease or phase II clinical studies in metastatic CRC
- AST Aspartate aminotransferase
- ALT alanine aminotransferase
- UPN upper limit of normal range
- APTT Activated partial thromboplastin time
- ILR international normalized ratio
- PT prothrombin time
- the dosage of ZPML265 is 5mg/kg, intravenous infusion, once every 3 weeks on the first day, and every 3 weeks is a treatment cycle;
- the dosage of ZPML265 is 5mg/kg, intravenous infusion, once every 3 weeks on the first day, and every 3 weeks is a treatment cycle;
- the dosage of bevacizumab injection is 7.5mg/kg, intravenous infusion, once every 3 weeks on the first day, and every 3 weeks is a treatment cycle;
- Oxaliplatin injection The dosage is 130 mg/m 2 , intravenous infusion, once every 3 weeks on the first day, and every 3 weeks is a treatment cycle; a maximum of 8 treatment cycles can be used;
- Capecitabine tablets The dosage is 1000 mg/m 2 , taken orally, twice a day, starting on the first day of every 3 weeks, stopping for 1 week after every 2 weeks, and every 3 weeks is a treatment cycle; The maximum duration of medication is 2 years.
- ZPML265 monotherapy is initially more effective than PD-(L)1 monoclonal antibody monotherapy in the first-line treatment of patients with MSI-H advanced CRC. treatment, and the safety profile is good, with no new safety signals emerging.
- ZPML265 is combined with bevacizumab and chemotherapy as a first-line treatment for patients with advanced CRC in MSS. The preliminary efficacy is good.
- the tumor size of all subjects shows a shrinking trend, and the combination of drugs does not increase safety risks.
Abstract
L'invention concerne un mélange d'anticorps anti-CTLA4 et anti-PD1, une combinaison du mélange d'anticorps, d'un médicament chimiothérapeutique et d'un agent anti-angiogénique, et son utilisation pour le traitement du cancer colorectal.
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