Application of anti-inflammatory drug in resisting CRS caused by CART treatment

Abstract

The invention relates to an application of an anti-inflammatory drug in resisting CRS caused by CART treatment. Specifically, in CART treatment, various side effects, such as weight loss, fever and other CRS-related symptoms, of CART, TCRT, antibodies and other immunotherapy can be effectively reduced by using anti-inflammatory drugs.

Description

Application of anti-inflammatory drugs in CRS caused by resistance to CART therapy Technical Field

[0001] The present invention relates to the field of medicine, and in particular to the use of anti-inflammatory drugs in resisting CRS caused by immunotherapies such as CART. Background Art

[0002] As we all know, cytokine storm (CRS) is a very significant side effect of immunotherapy such as CART, TCRT, and antibodies.

[0003] In March 2006, serious adverse events occurred in healthy human volunteers in a trial involving the biotherapeutic agent TGN1412. These volunteers experienced cytokine release syndrome (also known as cytokine storm or CRS), which resulted in angioedema, swelling of the skin and mucous membranes.

[0004] Research shows that a cytokine storm occurs when the release of cytokines by immune (or other) cells becomes excessive and damages tissues and organs. In some patients, the reaction is so severe that it leads to death.

[0005] Currently, there is no effective treatment for CRS, which greatly limits the market promotion and application of CART.

[0006] Summary of the Invention

[0007] The purpose of the present invention is to provide the use of anti-inflammatory drugs in resisting CRS caused by immunotherapy such as CART.

[0008] The first aspect of the present invention provides a use of an anti-inflammatory drug for preparing a drug for treating autoimmune diseases.

[0009] In another preferred embodiment, the anti-inflammatory drug is selected from the following group: TLR inhibitors, mTOR inhibitors, ERK inhibitors, JAK inhibitors, NF-κB inhibitors, and NLRP3 inhibitors.

[0010] In another preferred embodiment, the TLR inhibitor is selected from the following group: TLR2 inhibitor, TLR3 inhibitor, TLR4 inhibitor, TLR antibody.

[0011] In another preferred embodiment, the TLR inhibitor is selected from the following group:

[0012] In another preferred embodiment, the mTOR inhibitor is selected from the following group:

[0013] In another preferred embodiment, the ERK inhibitor is RDEA-436.

[0014] In another preferred embodiment, the JAK inhibitor is selected from the following group:

[0015] In another preferred embodiment, the NF-κB inhibitor is selected from the following group:

[0016] In another preferred embodiment, the NLRP3 inhibitor is selected from the following group:

[0017] In another preferred embodiment, the TLR inhibitor is a TLR4 inhibitor.

[0018] In another preferred embodiment, the TLR4 inhibitor is selected from the following group:

[0019] In another preferred embodiment, the autoimmune disease is an autoimmune disease caused by CART treatment.

[0020] In another preferred embodiment, the autoimmune disease is an autoimmune disease caused by a treatment selected from the group consisting of TCR-T, monoclonal antibody, BiTE, bispecific antibody, or a combination thereof.

[0021] In another preferred embodiment, the bispecific antibody is a CD3 bispecific antibody.

[0022] In another preferred embodiment, the CD3 bispecific antibody is EpCAM-CD3+Claudin18.2-CD3. In another preferred embodiment, the autoimmune disease is CRS.

[0023] In another preferred embodiment, the symptoms of CRS are selected from the group consisting of weight loss, fever, and systemic inflammation.

[0024] In another preferred embodiment, the autoimmune disease is CRS caused by CART treatment.

[0025] In another preferred embodiment, the autoimmune disease is CRS caused by a treatment selected from the group consisting of TCR-T, monoclonal antibody, BiTE, bispecific antibody, or a combination thereof.

[0026] In another preferred embodiment, the CART treatment is carried out using a drug selected from the following group: (idecabtagenevicleucel), (lisocabtagene maraleucel), CARVYKTI™ (ciltacabtagene autoleucel), KYMRIAH™ (tisagenlecleucel), TECARTUS™ (brexucabtagene autoleucel), YESCARTA™ (axicabtagene ciloleucel). In another preferred embodiment, the cell target targeted by the CART therapy is used to treat a disease selected from the group consisting of solid tumors and hematologic malignancies.

[0027] In another preferred embodiment, the cell target targeted by the CART therapy is used to treat a disease selected from the following group: multiple myeloma (MM), acute myeloid leukemia (AML), B or T cell lymphoma, ovarian cancer, T cell malignancies, osteosarcoma, medulloblastoma, Ewing's sarcoma, pancreatic cancer, neuroblastoma, glioblastoma, testicular cancer, lung cancer, gastric cancer, melanoma, sarcoma, colon cancer, and breast cancer.

[0028] In another preferred embodiment, the cell targets targeted by the CART therapy are selected from the following group: EpCAM, Claudin 18.2, Mesothelin, CD19, CD20, GPRC5D, SLAMF7, BCMA, CD38, CD56, CD44v6, FLT3, CD33, CD123, CD37, TCRβ-chain, Annexin A2, B7-H3, CD171, Chlorotoxin, Claudin-6, EIIIB, Glypican-1, Integrinα V β3, Mucl, PD-L1, ROR1, CD22, CD30, SLAM (Signaling lymphocytic activation molecule), Mesothelin, GD2, HER2, GPC3, CEA, EGFRvIII, PSMA, EGFR.

[0029] In another preferred embodiment, the cell target targeted by the TCR-T therapy is selected from the following group: FH-MCVA2TCR T-cell, Autologous anti-NY-ESO1 T-cell receptor, Autologous anti-KRAS G12V mTCR gene-engineered cell, and MAGE-A1-specific T cell receptor-transduced autologous T-cell.

[0030] In another preferred embodiment, the monoclonal antibody used in the monoclonal antibody treatment is selected from the following group: Tocilizumab biosimilar (Livzon Group), Choriogonadotropin alfa biosimilar (Livzon Group), Belimumab, Mepolizumab, Denosumab, Abciximab, Canakinumab, Trastuzumab / Pertuzumab, Evolocumab, Ixekizumab, Brolucizumab, Pucotenlimab, Emapalumab, Panitumumab, Certolizumab Pegol, Adalimumab, Omalizumab, Nivolumab, Bevacizumab, Atezolizumab, Daclizumab, Infliximab, Tocilizumab, Eculizumab, Blinatumomab, Ranibizumab, Burosumab, Secukinumab, Spesolimab, Ramucirumab, Sacituzumab Govitecan, Emicizumab, Ustekinumab, Obinutuzumab, Cemiplimab, Tixagevimab / Cilgavimab, Vedolizumab, Mogamulizumab, Durvalumab, Sintilimab, Golimumab, Basiliximab, Dinutuximabbeta (Datuximab β), Dupilumab (Dupilizumab), Ripertamab (Ripertuzumab), Pertuzumab (Pertuzumab), Brodalumab (Brolizumab), Daclizumab biosimilar (Shanghai CP Guojian) (Daclizumab Biosimilar (Sansheng Guojian)), Ofatumumab, Necitumumab, Aducanumab, Docaravimab / Miromavimab, Satralizumab, Palivizumab, Regdanvimab, Guselkumab, Inetetamab, Camrelizumab, Trastuzumab, Daratumumab, Ipilimumab, Inebilizumab, Rituximab, Ibritumomab Ibruxetan, Idarucizumab, Brentuximab vedotin, Pembrolizumab, Adebrelimab, Retifanlimab, Margetuximab, Eptinezumab, Amubarvimab / Romlusevimab, Lanadelumab, Toripalimab, Alirocumab, Tildrakizumab, Ansuvimab, Nimotuzumab, Bevacizumab biosimilar (Biocad), Naxitamab, Tislelizumab, Itolizumab, Adalimumab biosimilar (Celltrion), Cadonilimab, Trastuzumabbiosimilar (Biocad), Casirivimab / imdevimab, Bevacizumab biosimilar (mAbixience), Inotuzumab Ozogamicin, Trastuzumab biosimilar (Synthon), Dostarlimab, Ranibizumab biosimilar (Intas Biopharmaceuticals), Ranibizumab biosimilar (Senju), Lecanemab, Penpulimab, Cetuximab, Siltuximab, Belantamab mafodotin, Trastuzumab biosimilar (Pfizer), Glofitamab, Faricimab, Trastuzumab biosimilar (AXXO), Bevacizumab biosimilar (Elea), Nirsevimab, Bevacizumab biosimilar (Samsung Bioepis), Bioepis), Sotrovimab, Rituximab biosimilar (mAbxience), Ranibizumab biosimilar (Xbrane), Disitamab Vedotin, Polatuzumab vedotin, Serplulimab, Zimberelimab, Amivantamab, Sugemalimab, Bevacizumabbevacizumab biosimilar (Celltrion), abciximab biosimilar (ISU Abxis), ormutivimab, infliximab biosimilar (Celltrion), adalimumab biosimilar (Innovent Biologics), fremanezumab, infliximab biosimilar (Pfizer), benralizumab, adalimumab biosimilar (Biocad), adalimumab biosimilar (Hisun Pharma)(adalimumab biosimilar (Hisun Pharmaceutical)), Trastuzumab biosimilar (Zydus), Ado-trastuzumab emtansine, Bevacizumab biosimilar (Pfizer), Bevacizumab biosimilar (AryoGen Biopharma), Rituximab biosimilar (Pfizer), Rituximab biosimilar (Zenotech), Ranibizumab biosimilar (Formycon / Bioeq), Bevacizumab biosimilar (Zydus) Cadila (bevacizumab biosimilar (Zydus Cadila)), Cetuximab biosimilar (CinnaGen)), Rituximab biosimilar (Biosidus)), Envafolimab, Omalizumabbiosimilar (IBC Generium), Adalimumab biosimilar (Amgen), Rituximab biosimilar (Innovent Biologics), Bevacizumab biosimilar (Boan Biopharma), Bevacizumab biosimilar (Apotex), Rituximab biosimilar (Biocad), Adalimumab biosimilar (Alvotech), Rituximab biosimilar (Intas Biopharmaceuticals), Trastuzumab biosimilar (AryoGen Pharmed), Abciximab biosimilar (Reliance Life Sciences), Hyaluronidase / Rituximab, Trastuzumab biosimilar (Celltrion), Bevacizumab biosimilar (Innovent Biologics), Trastuzumab / Hyaluronidase, Bevacizumab biosimilar (Jiangsu Hengrui Medicine), Adalimumab biosimilar (Sandoz), Rituximab biosimilar (AryoGen Pharmed), Hyaluronidase / Rituximab, Trastuzumab biosimilar (Celltrion), Bevacizumab biosimilar (Innovent Biologics), Trastuzumab / Hyaluronidase, Bevacizumab biosimilar (Jiangsu Hengrui Medicine), Adalimumab biosimilar (Sandoz), Rituximab biosimilar (AryoGen Pharmed), Biopharma) (rituximab biosimilar (AryoGen Biopharma)), Bevacizumabbiosimilar (Hetero Drugs), Bevacizumab biosimilar (CTTQ Pharma), Rituximab biosimilar (Hetero Drugs), Bevacizumab biosimilar (Biocon / Mylan), Bevacizumab biosimilar (Qilu Pharma), Bevacizumab biosimilar (Dr. Reddy's Laboratories), Ranibizumab biosimilar (Samsung Bioepis), Adalimumab biosimilar (Coherus BioSciences), Fam-trastuzumab deruxtecan, Rituximab biosimilar (Probiomed), Trastuzumab biosimilar (Intas Pharmaceuticals), Rituximab biosimilar (Reliance Life Sciences), Rituximab biosimilar (Celltrion), Adalimumab biosimilar (CTTQ Pharma), Adalimumab biosimilar (Pfizer), Adalimumab biosimilar (Zydus Cadila) (Adalimumab biosimilar (Zydus Cadila)), Adalimumabbiosimilar (Fresenius Kabi), Adalimumab biosimilar (LG Life Sciences), Adalimumab biosimilar (Samsung Bioepis), Enfortumab vedotin, Trastuzumab biosimilar (Zhejiang Hisun Pharmaceutical), Trastuzumab biosimilar (Samsung Bioepis), Bevacizumab biosimilar (Reliance Life Sciences), Denosumab biosimilar (Mabwell), Rituximab biosimilar (Center of Molecular Biology) Immunology (Rituximab biosimilar (Center of Molecular Immunology)), Adalimumab biosimilar (Bio-Thera Solutions), Adalimumab biosimilar (Reliance Life Sciences), Trastuzumab biosimilar (Reliance Life Sciences), Rituximab biosimilar (Amgen), Infliximab biosimilar (Amgen), Tocilizumab biosimilar (Bio-Thera Solutions), Bevacizumab biosimilar (Shanghai HenliusBiotech)(bevacizumab biosimilar (Shanghai Henlius Biotech)), Bevacizumab biosimilar (Bio-Thera Solutions)(bevacizumab biosimilar (Bio-Thera Solutions)), Bevacizumab biosimilar (TOT Biopharm))(bevacizumab biosimilar (TOT Biopharm)), Rituximab biosimilar (Sandoz))(rituximab biosimilar (Sandoz)), Trastuzumab biosimilar (Dr. Reddy's Laboratories))(trastuzumab biosimilar (Dr. Reddy's Laboratories)), Adalimumab biosimilar (Shanghai Henlius Biotech))(adalimumab biosimilar (Shanghai Henlius Biotech)), Bevacizumab biosimilar (Betta / Mabworks), Iodine[131I]Metuximab, Denosumab biosimilar (Reliance Life Sciences), Trastuzumab biosimilar (Shanghai Henlius Biotech), Adalimumab biosimilar (Mylan / Biocon), Bevacizumab biosimilar (Intas Pharmaceuticals), Rituximab biosimilar (Dr Reddy's Laboratories), Mouse monoclonal antibody against human interleukin-8 cream (anti-human interleukin-8 mouse monoclonal antibody cream), Trastuzumab emtansine biosimilar (Zydus Cadila), Rituximab biosimilar (Shanghai HenliusBiotech)(Rituximab biosimilar (Shanghai Henlius Biotech)), Denosumab biosimilar (Boan Biopharma / Luye), Adalimumab biosimilar (Fujifilm Kyowa Kirin Biologics / Mylan), Mouse monoclonal antibody against human CD3 antigen of T lymphocyte (Wuhan Institute of Biological Products), Adalimumab biosimilar (Jiangsu Zhonghe / Shanghai Junshi / Jiangsu T-Mab), Obiltoxaximab, Alemtuzumab, Bevacizumab biosimilar (Allergan / Amgen), Olaratumab, Raxibacumab, Natalizumab, Galcanezumab, Gemtuzumabozogamicin, Ocrelizumab, Bezlotoxumab, Romosozumab, Sarilumab, Elotuzumab, Infliximab biosimilar (Merck&Co / Samsung Bioepis), Erenumab, Trastuzumab biosimilar (Biocon / Mylan), Avelumab, Capromab pendetide, Ibalizumab, Isatuximab, Ublituximab, Dinutuximab, Infliximab biosimilar (AXXO) (infliximab biosimilar (AXXO)), Teplizumab, Infliximab biosimilar (Reliance Life Sciences) (infliximab biosimilar (Reliance Life Sciences) Sciences)), Tisotumabvedotin, Infliximab biosimilar (HisunPharma)(Infliximab biosimilar (Hisun Pharmaceutical)), Nemolizumab, Mirvetuximab soravtansine, Risankizumab, Anifrolumab, Caplacizumab, Odulimomab, Moxetumomabpasudotox, Reslizumab, Besilesomab, Tralokinumab, Iodine(131I)derlotuximab biotin, Adalimumab biosimilar (Boehringer Ingelheim), Infliximab biosimilar (Genor Biopharma), Infliximab biosimilar (Bionovis / The Instituto Vital Brazil), Infliximab biosimilar (Shanghai Biomabs)(Infliximab biosimilar (Shanghai Biomabs Pharmaceuticals)), Infliximab biosimilar (Nichiiko / Aprogen)(Infliximab biosimilar (Nichiiko / Aprogen)), Anti-CD34 mab-sirolimus (OrbusNeich), F-0530A, Prolgolimab, Tc 99m ior cea1, Tezepelumab, Evinacumab, UniGAM SD (FarmaBiagini), Teprotumumab, Racotumomab, Tremelimumab, Intragam P (CSL Ltd), Anti-rabies monoclonal antibody (Serum Institute ofIndia / MassBiologics), Atoltivimab / Maftivimab / Odesivimab, Nivolumab / Relatlimab, Tafasitamab, Bimekizumab, Crizanlizumab, Mirikizumab, Ravulizumab, Sutimlimab, Netakimab, Daratumumab / Hyaluronidase-fihj, Teclistamab, Loncastuximabtesirine, Cetuximab sarotalocan, Pabinafusp alfa, Mosunetuzumab, Ozoralizumab, Tebentafusp, Enlonstobart, Tagitanlimab, Narlumosbart, Genolizumab, Donanemab, Zuberitamab, Socazolimab, Denosumab biosimilar (Sandoz), Xeligekimab, Pozelimab, Elranatamab, Balstilimab, Crovalimab, Cosibelimab, Tafolecimab, Denosumab biosimilar (Qilu Pharma), Bevacizumab biosimilar (Oncobiologics), Zamerovimab / Mazorelvimab, Talquetamab, Narsoplimab, Bevacizumab biosimilar (Sinocelltech) (bevacizumab biosimilar (Sinocell)), Epcoritamab (Iceruituzumab), Rituximab biosimilar (Mabion) (Rituximab biosimilar (Mabion)), Rituximab biosimilar (Siam Bioscience) (Rituximab biosimilar (Siam Bioscience)Bioscience), Ranibizumab biosimilar (Qilu Pharmaceutical), Trastuzumab biosimilar (Tanvex Biopharma), Trastuzumab biosimilar (CTTQ Pharma), Adalimumab biosimilar (Sinocelltech), Trastuzumab biosimilar (Anke Biotech), Denosumab biosimilar (Alphamab), Cetuximab biosimilar (Shanghai Zhangjiang Biotechnology), Rituximab Rituximab biosimilar (Nichi-Iko / Aprogen), Tocilizumab biosimilar (Hisun Biopharma), Pertuzumab biosimilar (Qilu Pharmaceutical), Tocilizumab biosimilar (Hetero Biopharma), Tocilizumab biosimilar (Jinyu Bowo Runze Biotech), Trastuzumab biosimilar (EirGenix / Sandoz), Lenzilumab, Omburtamab I-131, TQB-2450, Rozanolixizumab, Trastuzumab duocarmazine, follicle stimulating hormonebiosimilar (Livzon), Genakumab, Ongericimab, Suciraslimab, Coprelotamab, Pembrolizumab / Quavonlimab, Fianlimab, Nofazinlimab, Freneslerbart / Mevonlerbart, Sevacizumab, Bamlanivimab, Denosumab biosimilar (AryoGen), Sibeprenlimab, Lirentelimab, Cobolimab, Erfonrilimab, Bevacizumab biosimilar (Hualan Biological Engineering), Nipocalimab, Amubarvimab, Gumokimab, Obexelimab, Imdevimab, Cendakimab, Nisevokitug, Vibostolimab, Divozilimab, Domvanalimab, Recombinant anti-VEGFR2 chimeric monoclonalyantibody (GeneScience) (Gentuximab), Zilovertamab, Vilobelimab, Glenzocimab, Relatlimab, Sasanlimab, Finotonlimab, Astegolimab, Anbenitamab, Mertuzumab, Pembrolizumab / Vibostolimab, Ba Toclimab, Meplazumab, Ziltivekimab, Birtamimab, Anselamimab, Depemokimab, Garetosmab, Ivuxolimab, Itepekimab, Latozinemab, Rulonilimab, Garadacimab, Plonmarlimab, Eculizumab biosimilar (CinnaGen), Recaticimab, Anvatabartopadotin, Magrolimab, Denosumab biosimilar (Intas Biopharmaceuticals), Ebdarokimab, Ulviprubart, Ebronucimab, Bentracimab, Tozorakimab, Upanovimab, Felzartamab, Levilimab, Tarlatamab, Ociperlimab, Eculizumab biosimilar (Biocad) (eculizumab biosimilar (Biocad)), Odronextamab (onitumumab), Tocilizumab biosimilar (Freseniuskabi) (Fresenius kabi), Adalimumab biosimilar (Incepta), Adalimumab biosimilar (CinnaGen), Otilimab, Lemzoparlimab, Trastuzumab biosimilar (Hetero), Datopotamab deruxtecan, Tebotelimab, Mavezelimab / Pembrolizumab, Adalimumab biosimilar (Hualan Biological Engineering), Pertuzumab pertuzumab biosimilar (CinnaGen), romlusecimab, omalizumab biosimilar (Synermore Biologics), adalimumab biosimilar (Oncobiologics), apitechromab, bemarituzumab, tocilizumab biosimilar (AryoGen Pharmed), zanidatamab, feladilimab, bevacizumab biosimilar (Centus Biotherapeutics), omalizumab biosimilar (Mabtech) (omalizumab biosimilar (Mabtech)), Zilovertamab vedotin (Weizelotuzumab), Rituximab biosimilar (CTTQ Pharma) (rituximab biosimilar (Zhengda Tianqing)), Rituximabbiosimilar (Hualan Biological Engineering), Imsidolimab, Trastuzumab biosimilar (Hanwha Biologics), Adalimumab biosimilar (Hetero Drugs), Becotatug, Eculizumab biosimilar (IBC GENERIUM), Enibarcimab, Simaravibart, Rocatinlimab, Bevacizumab biosimilar (Alphamab / R-Pharm), Pertuzumab biosimilar (CTTQ) (Pertuzumab Biosimilar (Zhengda Tianqing)), Cetuximab biosimilar (R-Pharm) (Cetuximab Biosimilar (R-Pharm)), Rituximab biosimilar (Boehringer Ingelheim) (Rituximab Biosimilar (Boehringer Ingelheim)), Patritumab Deruxtecan (Deruxtecan), Denosumab biosimilar (Celltrion) (Denosumab Biosimilar (Celltrion)), Eculizumab biosimilar (Samsung Bioepis) (Eculizumab Biosimilar (Samsung Bioepis)), Trastuzumab biosimilar (Alteogen) (Trastuzumab Biosimilar (Qilu Pharmaceutical)), Ustekinumab Biosimilar (Qyuns) (Ustekinumab Biosimilar (Qyuns)), Rituximab biosimilar (Samsung) (rituximab biosimilar (Samsung)), pertuzumab biosimilar (Xuanzhu / SL) (pertuzumab biosimilar (Xuanzhu / Shuanglu)), cetuximabbiosimilar (Kelun Group), Bevacizumab biosimilar (Prestige BioPharma / Hanwha Biologics), Tusamitamab Ravtansine, Ranibizumab biosimilar (Reliance Life Sciences Group), Eculizumab biosimilar (Amgen), Ipilimumab biosimilar (Innovent Biologics), Trastuzumab rezetecan, Recombinant humanized monoclonal antibody MIL62, Nimotuzumab biosimilar (IBC Generium (nimotuzumab biosimilar (IBC Generium)), QL1203 (recombinant anti-EGFR fully human monoclonal antibody (Qilu Pharmaceutical)), Bevacizumab biosimilar (Fudan-Zhangjiang), Pertuzumab biosimilar (Hisun Pharm), Adalimumab biosimilar (Tonghua Dongbao Pharmaceutical), Adalimumab biosimilar (Danhong Pharma), Cetuximab biosimilar (AlphaMab), Nimotuzumab biosimilar (El Kendi Pharmaceuticals Manufacturing), Ranibizumab biosimilar (Chong Kun Pharmaceuticals),Dang Pharmaceutical), Bevacizumab biosimilar (Genor Biopharma), Ranibizumab biosimilar (Lupin), Denosumab biosimilar (Mabxience), Denosumab biosimilar (Fresenius Kabi), Denosumab biosimilar (Alvotech Swiss), Omalizumab biosimilar (Alvotech), Recombinant human anti-RANKL momoclonal antibody (Qilu Pharmaceutical), Ustekinumab biosimilar (Formycon), recombinant humanized anti-IL-6R antibody (Hisun Pharma), bevacizumab biosimilar (Beijing Science Sun / Beijing Lvzhu), rituximab biosimilar (Hisun Pharma / Beijing Mabworks Biotech), denosumab biosimilar (Enzene Biosciences), upifimab sildurone, cetuximab biosimilar (AMPO Biotechnology), omalizumabbiosimilar (Kashiv BioSciences), Bevacizumab biosimilar (Laboratorios Sophia), Ustekinumab biosimilar (Celltrion), Omalizumab biosimilar (Celltrion), Denosumab biosimilar (Hualan Biological Engineering), Ustekinumab biosimilar (DM Bio), Girentuximab-Zr-89, Secukinumab biosimilar (Bio-Thera Solutions) (Secukinumab biosimilar (Biogen)), Omalizumab biosimilar (Reliance Life Sciences), Recombinant anti-HER2 humanized monoclonal antibody (Shanghai Institute of Biological Products), Vedolizumab biosimilar (Polpharma Biologics), Pembrolizumab biosimilar (biocad), Ustekinumab biosimilar (Bio-Thera), Pertuzumab biosimilar (Zydus Cadila), Omalizumab biosimilar (Teva) (omalizumab biosimilar (Teva Pharmaceuticals)), Rituximab biosimilar (GenorBiopharma) (recombinant anti-CD20 human-mouse chimeric monoclonal antibody (Jiahe Biopharma)), Trastuzumab biosimilar (Aprogen / Nichi-Iko)), Adalimumab biosimilar (Huabo)), Denosumab biosimilar (Shanghai Hansoh)), Denosumab biosimilar (Henlius)), Rituximab biosimilar (Shanghai Institute of Biological Products)), Pertuzumab biosimilar (Shanghai Henlius Biotech)), Pertuzumab biosimilar (Jushi Biopharmaceutical) (Pertuzumab biosimilar (Shijiazhuang Pharmaceutical Group Jushi Biopharmaceuticals)), Rituximab biosimilar (Shandong New Time Pharmaceutical) (recombinant anti-CD20 human-mouse chimeric monoclonal antibody (Shandong New Time Pharmaceutical)), Bevacizumab biosimilar (Huaota Biopharm) (recombinant humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody (Huaotai Biopharm / Junshi Biosciences)), Bevacizumab biosimilar (Jiangsu Aosaikang) (bevacizumab biosimilar (Jiangsu Aosaikang)), Bevacizumab biosimilar (Zhejiang Teruisi Pharmaceutical) (bevacizumab biosimilar (Zhejiang Teruisi Pharmaceutical)), Catumaxomab, Glutazumab (recombinant anti-human GLP-1 receptor humanized monoclonal antibody), Iodine 131tositumomab, Solanezumab, TAB-014, Ivonescimab, Tarcocimabtedromer, Sirukumab, Tanezumab, Fasinumab, Monalizumab, Emactuzumab, Golimumabbiosimilar (Bio-thera) (recombinant anti-tumor necrosis factor alpha fully human monoclonal antibody (Biogen)), Bevacizumab biosimilar (Boehringer Ingelheim), Etrolizumab, Gantenerumab, Denosumab biosimilar (Samsung Bioepis), Inclacumab, Rovalpituzumab tesirine, Oportuzumab monatox, Natalizumab biosimilar (Polpharma Biologics), Brazikumab, Dapirolizumab pegol, Inolimomab, Mavrilimumab, CMAB806 (recombinant anti-IL-6R humanized monoclonal antibody), Lebrikizumab, Roledumab, Trastuzumab monomethyl auristatin F, Onartuzumab, Ocrelizumab biosimilar (CinnaGen), Infliximab biosimilar (Biocad)(infliximab biosimilar (Biocad)), SB-17 (Samsung Bioepis), Ogalvibart / Crexavibart, Recombinant anti-IgE monoclonal antibody (CspcBaike)(recombinant anti-IgE monoclonal antibody (CSPC Baike)), Humanized IgG1κ monoclonal antibody (Viridian), Picankibart, MTX-005, MK-3475A, GR-1801, AZD5156, QL1604, REGN-5713 / REGN-5714 / REGN-5715, HL-02, Recombinant chimeric anti-CD20 antibody (Shanghai Institute of BiologicalProducts) (recombinant human-mouse chimeric anti-CD20 monoclonal antibody (Shanghai Institute of Biological Products)), Semzuvolimab, Carotuximab, Basiliximab biobetter (Mabtech / Sorrento), Porgaviximab / Larcaviximab / Cosfroviximab, Futuximab / Modotuximab, Zolbetuximab, ABP-300, JY-025 (recombinant fully human anti-VEGFR2 monoclonal antibody), Recombinant anti-TNFα monoclonal antibody (Wuhan Institute of Biological Products), CMAB807, Oleclumab, TNM-002, Tosatoxumab, Clesrovimab, Setrusumab, Cetrelimab, Ianalumab, Recombinant human anti-TNFα monoclonal antibody (Huaota Biotechnology Co., Ltd.) Biopharma) (recombinant fully human anti-TNF-alpha monoclonal antibody (Hua-O-Tai Biopharma)), SAB-185, Ontamalimab, RO-7200220, Pamrevlumab, Abelacimab, Ganitumab, Tiragolumab, Utomilumab, BDB-001, Marstacimab, Suvratoxumab, Oregovomab, ANX-005, SSGJ-608, Ligelizumab, Spartalizumab, Gotistobart, Clazakizumab, Sabatolimab, Leronlimab, Andecaliximab, Concizumab, Paridiprubart, Iparomlimab / Tuvonralimab, Vunakizumab, Litifilimab, Olokizumab, CM-310, Retlirafusp alfa (Relafulp-α), TVB-009, Varisacumab, TocilizumabBiosimilar (Celltrion), TR-009, PM-8002, Mim8, Navicixizumab, Izalontamab, Gefurulimab, Vobramitamabduocarmazine, Telisotuzumabvedotin, Bintrafusp alfa, Depatuxizumabmafodotin, SGM-101, I-131-Apamistamab, Recombinant anti-TNFα monoclonal antibody (Livzon Group), Lipustobart, Recombinant human IL-17A / F humanized antibody (Livzon Pharmaceutical Group) (recombinant anti-human IL-17A / F humanized monoclonal antibody (Livuzumab)), recombinant humanized anti-Trop2 monoclonal antibody-SN38 conjugate, Guselkumab / Golimumab, Tifcemalimab, Ametumumab, Ligufalimab, Demupitamab, Bafisontamab, Dresbuxelimab, Manfidokimab, Mezagitamab, Sudubrilimab, Zalifrelimab b (Zevolizumab), Uliledlimab, Pulocimab, Ponsegromab, MIL-86 (recombinant fully human monoclonal antibody MIL86), Volrustomig, Pradusinstobart, Quavonlimab, Tobemstomig, Rilvegostomig, Enoblituzumab, Pimurutamab, Exlinkibart, Etesevimab, Bevacizumab biosimilar (Eastern Biotech), Alemtuzumabbiosimilar (Zhangjiang Biotechnology)(alemtuzumab biosimilar (Shanghai Zhangjiang Biotechnology)), Recombinant anti-EGFR chimeric monoclonal antibody (Shanghai CP Guojian)(recombinant anti-EGFR human-mouse chimeric monoclonal antibody (Sunshine Guojian)), Recombinant anti-HER2 antibody-Tub114(recombinant humanized anti-Her2 monoclonal antibody-Tub114 conjugate), Recombinant anti-IL-17A humanized monoclonal antibody (Shanghai Junshi Biosciences) (recombinant humanized anti-IL-17A monoclonal antibody (Shanghai Junshi Pharmaceutical)), DP-303c (recombinant humanized anti-HER2 monoclonal antibody-MMAE drug conjugate (Shijiazhuang Zhongqi Pharmaceutical Group)), SHR-1703, JAB-BX102, ZS-05, SHR-1905, FAZ-053, 9MW1411, ADG-104, TQH2722, BSI-045B, CM313 (Institute of Hematology & Blood Diseases Hospital), CAN-106, CD20 monoclonal antibody (The First Affiliated Hospital of Soochow University), ASKB-589, BGB-DXP604, ZL-1211, CM-326 (Connaught Biomedical Technology), CM-338 (Connaught Biomedical Technology) Technology), KD-6001, LM-101, Afimetoran, CM-313 (Connaught Biomedical Technology), Carrizumab, Peramprizumab, KN-057, BGB-A445, SHR-1802, BAY-1158061, DXP-593, Modakafusp alfa (Mocafusp-α), CBP-201, Teprotumumab biosimilar(Innovent), Humanized anti-EGFR monoclonal antibody(Hualan Biological Engineering / Henan shengmingbiotechnology) (recombinant fully human anti-EGFR monoclonal antibody), Lesabelimab, Teropavimab, Human Respiratory Syncytial Virus Monoclonal Antibody, Iscalimab, Anti-CD3 monoclonal antibody (Jinan Tiankang Biological Products), LY-CovMab, MW-33, Recombinant human anti-PCSK9 monoclonal antibody (Salubris) (recombinant fully human anti-PCSK9 monoclonal antibody (Xinlitai)), ADG-106, LBL-007, Recombinant anti-CTLA-4 human monoclonal antibody (Hualan Biological Products Engineering)(recombinant anti-CTLA-4 fully human monoclonal antibody (Hualan Gene Engineering)), MK-4830, CS-1002, HLX-22, DS-002, VDJ-001, HLX-26, PRL3-zumab, HS-20093, Osemitamab, Getagozumab, Peresolimab, YH-001, Recombinant anti-IL-4Rα humanized monoclonal antibody (Sansheng Guojian))(recombinant anti-IL-4Rα humanized monoclonal antibody (Sansheng Guojian)), YH-003, Recombinant humanized monoclonal antibody anti-IL-1β (Cp Guojian))(recombinant anti-IL-1β humanized monoclonal antibody (Sansheng Guojian)), MG-K10, NGM-313, LBL-019, Recombinant humanized anti-PD-1 monoclonal antibody (Anhui Anke Biotechnology)(Recombinant anti-PD-1 humanized monoclonal antibody (Anhui Anke Biotechnology)), Recombinant humanized PD-L1 monoclonal antibody (Taizhou HoudeAoke Technology))(Recombinant humanized anti-PD-L1 monoclonal antibody (Taizhou HoudeAoke Technology)), Recombinant humanized anti-ST2 monoclonalantibody (recombinant humanized anti-ST2 monoclonal antibody), HH-003, LM-108, Recombinant anti-IL-5 humanized monoclonal antibody (Shanghai CP Guojian), Recombinant humanized anti-PD-1 monoclonal antibody (Shanghai CP Guojian), BIVV-020, IAP-0971, IAE-0972, GB-263, PM-8003, GB-261, HLX-301, EMB-06, Recombinant anti-PD-L1 / TGF-β bispecific antibody (recombinant anti-PD-L1 and TGF-β bispecific antibody), HX-009, PD-L1 / CTLA4 bispecific monoclonal antibody (Changhai CP Guojian), Hospital), M-701, PM-1003, EMB-02, MBS-303, IMM-2902, SI-B003, ZG-005, CN-201, MCLA-129, LBL-033, CM-336 (Connaught Biomedical Technology), 6MW-3211, CM-350, CM-355 (Beijing TiannuoJiancheng / Connaught Biomedical Technology), IMM-0306, HB-0028, PM-8001, AZD-7789, Ifinatamabderuxtecan, RC-118, BB-1701, Emfizatamab, LBL-015, HB-0025, ZGGS-18, TQB-2868, BPB-101, BL-B01D1, Anti-CD3 and anti-HER2 BiTE-expressing Tcell (MedImmune), Mupadolimab, Sirexatamab, Acapatamab, Danburstotug, Zigakibart, Porustobart, Ascrinvacumab, Tegoprubart, PE-0116, ADG-116, ADG-126, BI-1206, UB-221, PF-06823859, SAR-439459, Posdinemab, GSK3174998, UB-621, TST-003, Rozibafusp alfa, 1-A-46, HB-0036, CN-202, Anetumabravtansine, ND-021, Zenocutuzumab, Bermekimab, Zeluvalimab, Rituximab biosimilar (JHL Biotech), Crenezumab, Osocimab, Tesnatilimab, volagidemab, Amlitelimabmonoclonal antibody), CJM-112, PRV-3279, Fepixnebart, Tulisokibart, Vilamakitug, Izuralimab, Vudalimab, Ivicentamab, Nimacimab, Ieramilimab, Ordesekimab, Pacmilimab, Sotevtamab, Bexmarilimab, Lomtegovimab, Zelminemab, Murlentamab, Boserolimab, Lo Nigutamab, Bepranemab, Ulenistamab, Budigalimab, Vixarelimab, Unasnemab, Gremubamab, Sotigalimab, Mitazalimab, Quetmolimab, Olinvacimab, Praluzatamabravtansine, Perenostobart, Casdozokitug, Zagotenemab, Sonelokimab, Omalizumab Biosimilar (Glenmark) Omalizumab biosimilar (Glenmark), Plamotamab, Daxdilimab, Lorigerlimab, Cevostamab, Belrestotug, Obrindatamab, Atibuclimab, Polzastobart, Tuparstobart, Siplizumab, Devextinetug, Ragifilimab, 89Zr-Df-crefmirlimab, Acasunlimab, TrastuzumabDusigitumab, Fresolimumab, Conatumumab, Ulocuplumab, Fezakinumab, Bimagrumab, Urelumab, Ontuxizumab, Tabalumab, Ozuzumab, Seriban ab、AI011、Cixutumumab、Farletuzumab、Orticumab、Prezalumab、Naptumomabestafenatox、Glembatumumabvedotin、Bavituximab、Emibetuzumab、Dalotuzumab、Adalimub biosimilar(180Therapeutics)、Intravitreal ranibizumab(Sultan Qaboos University)、BMS-986288、BMS-986340、VGL-101、TB-006、AU-007、ABBV-916、Middle-REGN-1526 respiratory syndrome coronavirus vaccine(Organic Vaccines)、MK-0482、BA-3071、KPL-404、FPI-1434、Belantamab、STI-2099、VB-119、S-531011、NNC6019-0001、IM AB-027、AZD-8853、LY-3361237、BI-1808、Sym-015、MEDI-5884、VIR-3434、BMS-986207、NGM-120、ICT-01(Imcheck Therapeutics)、TLX-592、Anti-interleukin-6receptor monoclonal antibody(Biocad)、Lu AF-82422(Lundbeck A / S)、Telazorlimab、RG-6173、VRC-MALMAB0100-00-AB、HMBD-001、NC-762、2141-V11、ALD-1910、XTX-101、 BMS-986179、BMS-986156、BI-1607、QLS-215、BMS-986315、AZD-0171、IBIO123、BMS-986218(Bristol-MyersSquibb)、REGN-9933、DISC-0974、BMS-986249、Anti-placental growth factor monoclonal antibody、ALLO-647、VIR-2482、LY-3041658、Stromab-501(National Cancer Institute)、90Y Basiliximab、KappaMab、Frexalimab、RP-3、Visugromab、Anti-CD40 ChiLob7 / 4(BioNTech)、Flysyn、Tilavonemab、VRC-HIVMAB091-00-AB、NI-004、MAU-868、Phosphorylcholine monoclonal antibody、DR-01、BMS-936559、Elezanumab、BMS-986012、F-598、Berlimato xumab、GC-1118A、GSK-3810109、Bebtelovimab、INCAGN-02390、PGDM-1400、 Foralumab, HuMax-IL8, VRC-01, Ichorcumab, COR-101, Atinumab, SRF-114, BI-836858, CDX-1140, Fiztasovimab, Panitumumab-IRDye800 (Stanford CWC University)、PD-360324、ARGX-112、Cifurtilimab、FB-704A、Bleselumab、Atidortoxumab / Berlimatoxumab、A erubumab、Varlilumab、BMS-986178、MT-2990、Begelomab、Durvalumab / Gefitinib、BMS-986258、Zinlirvimab、 VRC-07-523、LY-3022855、Camoteskimab、Anti-MUC1 monoclonal antibody(OncoQuest)、AL-002、XOMA-358、KVA-12123、Acrixolimab、RSVA antibodies(GAMIM) Therapeutics)、CMK-389、IMT-009、PAT-SC1、OR-2805、LKA-651、MBL-HCV1、Monoclonal antibodyBR55-2、Dectrekumab / VAK-694、PGT-121、MH-1(American Biogenetic)、Gimsilumab、VIS-410、Diridavumab、MVT-5873、INCAGN-1949、AMG-820、Timolumab、Rasdegafusp alfa, Lirilumab, Namilumab, NN-9828, XAV-19, NEO-201, ATL-101, Talacotuzumab, Etigilimab, Sirpiglenastat, Bevacizumab Lyon)、P-006、Ficlatuzumab、LY-2928057、Ravagalimab、ASP-0739(Astellas Pharma Inc)、Herpevizumab、Burfiralimab、Briquilimab、Domagrozumab、Tregalizumab、GSK-2330811、GSK-1070806、NP-137、YS-110、BND-22lizumab、Luzumab pegol、LLG-783(Novartis)、COM-701、Prasinezumab、Xisomab 3G3(Oregon Health&Science University)、CM-24、Rosnilimab、NGM-621、MEDI-0680、Temelimab、CSL-346、Pidilizumab、ARGX-117、Cabiralizumab、Bevacizumab-IRDye800CW(University Hospital Groningen)、BI-655064、Neihulizumab、AO-176、ANX-007、Cusatuzumab、89Zr-DFO-huJ591、Xentuzumab、Humanized monoclonal anti-GD2 antibody(St Jude Children's ResearchHospital)、G03-52-01、ZB-131、VRC-MALMAB0114-00-AB、VRC-01-LS、LIS1、NC-318、NM- 8074、IPH-5201、EU-101、Lenvervimab、YYB-101、ASP-5094、Lacnotuzumab、BVX20-CD20 antibody(Biocon / Vaccinex)、Vopratelimab、Anti-CEmX monoclonal antibody(Fountain Biopharma)、SelK-2、OSE-279、JK-08、LMB-2、FBR-002、AOC-1020、AMG-133、GEN-3014 、LYT-200、HDP-101、SAR-445877、FR-104、SAR-443579、LMB-100、CONV-01-alpha+PSMA I&T、HPN-424、NGM-707、AGEN-1777、GEN-1047、NVG-111、HL-301、CC-1、ISB-1442、REGN -5459、IMC-I109V、AFM-24、MEDI-7352、AFM-13、REGN-5668、GNR-084、LB-101(Centessa Pharmaceuticals)、AP-203、FS118、REGN-5678、TAK-280、Fazpilodemab、Enapotamabvedotin、R EGN-5093, HMB-001, CKD-702, REGN-4336, Imvotamab, REGN-7075, Azintuxizumab, Dalutrafusp alpha、RO7515629、Tidutamab、Cinrebafusp alpha, LAVA-051, YH-32367, IMC-F106C, Indatuximabravtansine, Camidanlumabtesirine, Lorvotuzumabmertansine. Ladiratuzumabvedotin、Pivekimabsunirine、AGS-16C3F、Mecbotamabvedotin、NBE-002、Pinatuzumabvedotin、Naratuximabemtansine, HPN-536, 225Ac-J591, LAVA-1207, Romilkimab, Flotetuzumab, Linvoseltamab, Istiratumab, HPN-328, Trontinemab, Cibisatamab, lutikizumab, At 211MAb BC8-B10, Lutetium(177lu)lilotomabsatetraxetan, 89Zr-durvalumab, BI-836880, 90Y-DTPA-besilesomab, Lintuzumab Ac-225 (Actinium Pharmaceuticals), 90Y-HAT (NCI), Tc99-labeled 14F7 humanized mAb (The Center of Molecular Immunology), Anti-CD3 / anti-EGFR-activated T cells (Barbara Ann Karmanos Cancer Institute), Lutetium-177DOTA girentuximab, Radretumab.

[0031] In another preferred embodiment, the BiTE therapy is a drug selected from the group consisting of Anti-CD3 and anti-HER2 BiTE-expressing T cell (MedImmune), and Blinatumomab.

[0032] In another preferred embodiment, the dual antibody therapy is a drug selected from the group consisting of: Blinatumomab, Teclistamab, Glofitamab, Emicizumab, Amivantamab, Faricimab, Mosunetuzumab, Cadonilimab, Ozoralizumab, Tebentafusp, Elranatamab, Epcoritamab, Talquetamab, TR-009, PM-8002, Anbenitamab, Mim8, Tebotelimab, Navicixizumab, Ivonescimab, Izalontamab, Zanidatamab, Gefurulimab, Bintrafusp alfa (Bitufupu α), Catumaxomab, Odronextamab, Tarlatamab, Erfonrilimab, PD-L1 / CTLA4 bispecific monoclonal antibody (Changhai Hospital), HX-009, Lomvastomig, NGM-707, AGEN-1777, GEN-1047, NVG-111, HB-0036, EMB-06, Recombinant anti-PD-L1 / TGF-β bispecific antibody (recombinant anti-PD-L1 and TGF-β bispecific antibody), IMM-2902, MBS-303, M-701, HL-301, CC-1, GB-261, HLX-301, Bafisontamab, ISB-1442, REGN-5459, EMB-02, PM-1003, IMC-I109V, AFM-24, Petosemtamab, MEDI-7352, Acapatamab, AFM-13, SI-B003, ZG-005, REGN-5668, GNR-084, LB-101 (CentessaPharmaceuticals), CN-201, Acasunlimab, AP-203, FS118, MCLA-129, LBL-033, Tobemstomig, Volrustomig, REGN-5678, TAK-280, Tecaginlimab, CM-336 (Connaught Biomedical Technology), 6MW-3211, CM-350, Fazpilodemab, Bavunalimab, Izuralimab, REGN-4336, Imvotamab, REGN-7075, Plamotamab, Azintuxizumab, Dalutrafusp alfa, CM-355 (Beijing TiannuoJiancheng / Connaught Biomedical Technology) Technology), IMM-0306, Rilvegostomig, Cevostamab, Tidutamab, Vudalimab, RO7515629, Cinrebafusp alfa, CN-202, REGN-5093, HMB-001, CKD-702, PM-8001, Ivicentamab, IMC-F106C, HB-0028, LAVA-051, YH-32367, Lorigerlimab, AZD-7789, Ubamatamab, LBL-015, LAVA-1207, Romilkimab, Flotetuzumab, Zenocutuzumab, Linvosel tamab, Istiratumab, Gremubamab, Trontinemab, Cibisatamab, HB-0025, lutikizumab, ZGGS-18, PRV-3279, BPB-101, Obrindatamab, TQB-2868, Gontivimab, BL-B01D1, BI-836880, Tarperprumig, Anti-CD3 / anti-EGFR-activated T cells (Barbara Ann Karmanos Cancer Institute), Anti-CD3 andanti-HER2BiTE-expressing T cells (MedImmune).

[0033] In another preferred embodiment, the antigen binding domain in the chimeric antigen receptor (CAR) expressed by the CART is ScFv or VHH.

[0034] In another preferred embodiment, the ScFv has a heavy chain variable region and a light chain variable region, each comprising three heavy chain variable region HCDRs and three light chain variable region LCDRs.

[0035] In another preferred embodiment, the linker between the heavy chain variable region and the light chain variable region of the ScFv is (GGGGS)n, where n is a positive integer greater than or equal to 1, and preferably n is 3.

[0036] In another preferred embodiment, the heavy chain variable region of the VHH comprises 3 HCDRs.

[0037] In another preferred embodiment, the heavy chain variable region of the VHH comprises four FR regions R.

[0038] In another preferred embodiment, the CAR has the following structure:

[0039] LBH-TM-C-CD3ζ (I)

[0040] Where,

[0041] L is none or a signal peptide sequence;

[0042] B is the antigen binding domain;

[0043] H is none or hinge region;

[0044] TM is the transmembrane domain;

[0045] C is the costimulatory domain;

[0046] CD3ζ is a cytoplasmic signaling sequence derived from CD3ζ or a mutant / modified form thereof;

[0047] The "-" connects peptides or peptide bonds.

[0048] In another preferred embodiment, the antigen binding domain comprises ScFv or VHH.

[0049] In another preferred embodiment, the antigen binding domain targets a tumor antigen.

[0050] In another preferred embodiment, the antigen binding domain targets an antigen selected from the group consisting of EpCAM, Claudin 18.2, mesothelin, CD19, CD20, CD22, CD123, CD47, CD138, CD33, CD30, CD271, GUCY2C, CD24, CD133, CD44, CD166, ABCB5, ALDH1, EGFR, GPC3, BCMA, ErbB2, NKG2D ligands, LMP1, VEGFR-1, Lewis-Y, ROR1, CEA, or a combination thereof.

[0051] In another preferred embodiment, the L is respectively selected from the signal peptides of the following proteins: CD8, GM-CSF, CD4, CD28, CD137, or mutants / modified forms thereof, or a combination thereof.

[0052] In another preferred embodiment, the H is selected from the hinge region of the following proteins: CD8, CD28, CD137, IgG, or a combination thereof.

[0053] In another preferred embodiment, the TM is selected from the transmembrane region of the following proteins: CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154, CD278, CD152, CD279, CD233, or their mutants / modified forms, or their combinations.

[0054] In another preferred embodiment, the C is selected from the costimulatory domain of the following proteins: OX40, CD2, CD7, CD27, CD28, CD30, CD40, CD70, CD134, 4-1BB (CD137), PD1, Dap10, CDS, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278), NKG2D, GITR, OX40L, or its mutant / modified form, or a combination thereof.

[0055] In another preferred embodiment, C is a costimulatory domain derived from 4-1BB.

[0056] A method for preventing or treating CRS, comprising the steps of administering an anti-inflammatory drug to a subject in need thereof, thereby preventing or treating CRS.

[0057] In another preferred embodiment, the anti-inflammatory drug is selected from the following group: TLR inhibitors, mTOR inhibitors, ERK inhibitors, JAK inhibitors, NF-κB inhibitors, and NLRP3 inhibitors.

[0058] In another preferred embodiment, the CRS is CRS caused by a therapy selected from the group consisting of CART, TCR-T, monoclonal antibody, BiTE, bispecific antibody, or a combination thereof.

[0059] In another preferred embodiment, the subject is a human or non-human mammal, such as a mouse or a rat.

[0060] In another preferred embodiment, the subject is a subject who has received the above-mentioned treatment.

[0061] In another preferred embodiment, the subject is a cancer patient who has received the above-mentioned treatment.

[0062] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0063] Figure 1 shows that inhibiting the toll-like receptor pathway in monocytes can inhibit the occurrence of CRS without affecting the efficiency of CAR-T in vivo and in vitro. The specific CAR-T cells used are EpCAM CAR-T cells, the tumor cells are colon cancer cells HCT116 cells, and the TLR4 inhibitor is TAK-242.

[0064] A: Schematic diagram of the co-culture experiment: CAR-T cells are co-cultured with tumor cells and primary human monocytes. The supernatant is collected for cytokine analysis.

[0065] B: Histograms show the levels of representative pro-inflammatory cytokines in the co-culture system. The concentrations of IL-6, GM-CSF, and IL-1β were measured in monocytes pre-cultured with different concentrations of TLR4 inhibitors and co-cultured with tumor cells and CAR-T cells (mean ± sd). The results are representative of three independent experiments (dots of different colors represent repeated samples). Statistical analysis was performed using two-way analysis of variance.

[0066] C: In vivo mouse model of CRS toxicity: NSG mice were infused with PBMCs and HCT116 cells, followed by anti-EpCAM CAR-T cells and TAK-242. Body weight, serum levels, and body temperature were monitored regularly. Mice were euthanized on day 40. UnT, untransfected T cells.

[0067] D. Body weight changes of mice after CAR-T infusion, grouped by treatment. The line graph shows the mean body weight change ± SD of mice treated with UnT + vector, CAR-T + vector, or CAR-T + TLR4i (TAK-242) (0.5 mg / kg every two days). The dotted line indicates the threshold for the percentage change in body weight to be zero. The points of different colors represent the kinetics of body weight change from day 0 to day 14 for each group. Statistical analysis was performed using two-way analysis of variance (left).

[0068] The mean tumor volume of mice treated with CAR-T (red line), CAR-T + TLR4i (green line), and UnT (blue line) changes over time. Changes are shown in a line graph, with different colors representing different treatment groups. The standard deviation (SD) is represented by the error bars (center).

[0069] Kaplan-Meyer survival plots for tumor-bearing mice treated with CAR-T (red line), CAR-T + TLR4i (green line), and UnT (blue line). Kaplan-Meyer plots show the probability of survival over time, with different colors representing different treatment groups. Results were analyzed using the log-rank Mantel-Cox test (right).

[0070] EF: Mean serum amyloid A (SAA) concentration and body temperature changes in mice treated with UnT, CAR-T, and CAR-T + TLR4i. The dashed line represents the threshold of zero percent temperature change. The line graph shows the temporal changes in SAA concentration and body temperature from day 0 to day 12, measured every two days. Statistical analysis was performed using two-way analysis of variance with a Bonferroni correction.

[0071] GI: Mean monocyte and CAR-T cell counts per 100 μL of blood and mean concentrations of IL-6, GM-CSF, and IL-1β in mouse serum, according to UnT, CAR-T, and CAR-T + TLR4i treatment groups. Histograms show comparisons of these parameters between groups. Statistical analysis was performed using two-way analysis of variance with Bonferroni correction.

[0072] J: Hematoxylin-eosin (HE) staining of lungs and livers in vivo, with different groups representing UnT, CAR-T, and CAR-T+TLR4i.

[0073] K: Experimental design for in vivo toxicity analysis. NSG mice were injected with PBMCs and HCT116 cells, followed by CD36 + Monocytes and EpCAM-CAR T cells. Body weight, serum, and body temperature were assessed regularly. Mice were euthanized on day 40.

[0074] L: Average weight change of mice, according to UnT, CAR-T+CD36 - Monocytes and CAR-T+CD36 + Monocytes were grouped by treatment. The dashed line represents the threshold for weight change of zero percent. The line graph shows the temporal change in body weight from day 0 to day 14, with measurements taken every two days. Statistical analysis was performed using two-way analysis of variance.

[0075] M: The average concentration of serum amyloid A (SAA) in mice, according to UnT, CAR-T+CD36 - Monocytes and CAR-T+CD36 + Monocytes were grouped by treatment. The dashed line represents the threshold of zero percent temperature change. The line graph shows the temporal changes in SAA concentrations from day 0 to day 12, measured every two days. Statistical analysis was performed using two-way ANOVA with Bonferroni correction.

[0076] N: Use UnT, CAR-T+CD36 - Monocytes and CAR-T+CD36 + Kaplan-Meyer survival plots of tumor-bearing mice treated with monocytes (blue, red, and green, respectively). Statistical analysis was performed using the log-rank Mantel-Cox test.

[0077] Figure 2 shows that Toll-like receptor 4 inhibitors can suppress the occurrence of CRS without affecting the efficiency of CAR-T in vivo and in vitro.

[0078] A: Cytotoxicity of CAR-T cells against SW480 and HCT116 cells ± SD is shown as a histogram. Different groups are defined by UnT + vector, CAR-T + vector, CAR-T + TLR4i (1 μM), CAR-T + TLR4i (2 μM), and CAR-T + TLR4i (5 μM), respectively. Three levels of effector-target ratios are shown (i.e., CAR-T cell to tumor cell ratios of 3:1, 1:1, and 1:3 for SW480 (left) and HCT116 (right), respectively). Statistical analysis was performed using two-way analysis of variance.

[0079] B. Shows the fold change ± SD of CAR T cell counts in vitro, grouped by DMSO, TLR4i (1 μM), TLR4i (2 μM), and TLR4i (5 μM). The kinetic changes in each group are represented by the different colored dots on the line graph, representing the changes from day 1 to day 7 of in vitro cell culture. Statistical analysis was performed using two-way analysis of variance.

[0080] C: Cytotoxicity of CAR-T cells against SW480 and HCT116 cells ± SD is shown as a histogram, with different groups defined by UnT, CAR-T+DMSO, CAR-T+TLR4i (1 μM), CAR-T+TLR4i (2 μM), and CAR-T+TLR4i (5 μM). Three levels of effector-target ratios are shown (i.e., 3:1, 1:1, and 1:3 ratios of CAR-T cells to tumor cells for SW480 (left) and HCT116 (right), respectively). Statistical analysis was performed using two-way analysis of variance.

[0081] D: Flow cytometry of CD25 and CD69 expression, grouped by ISO, CAR-T DMSO, CAR-T+TLR4i (1 μM), CAR-T+TLR4i (2 μM), and CAR-T+TLR4i (5 μM).

[0082] E: Mean ± SD concentrations of GM-CSF, IL-1β, and IL-6 in the co-culture system are shown as histograms, with the different groups defined by UnT, UnT + Monocyte, CAR-T, CAR-T + Monocyte, Myd88i (1 μM), Myd88i (2 μM), and Myd88i (5 μM), respectively. Results are indicative of three independent experiments, with dots of different colors representing different replicates. Statistical analysis was performed using two-way ANOVA.

[0083] F: Mean concentrations of GM-CSF, IL-1β, and IL-6 (pg / ml) ± SD are shown as bar graphs, with different groups defined by mock and TLR4 knockout (KD). Statistical analysis was performed using a two-tailed unpaired two-sample t-test.

[0084] G: Mean body weight change (%) ± SD of mice after CAR T infusion is shown as a line graph, with points of different colors representing kinetic body weight change from day 0 to day 14. Groups were defined by UnT + vector, CAR-T + vector, and CAR-T + TLR4i. Body weight was measured every two days, and the threshold for body weight change is indicated by the dotted line. Statistical analysis was performed using two-way analysis of variance.

[0085] H: Average tumor volume change of mice after CAR T infusion (mm 3 ) ± SD is shown as a line graph, with points of different colors representing the kinetic changes in tumor volume from day 0 to day 21. Groups were defined by UnT + vector, CAR-T + vector, and CAR-T + TLR4i. Statistical analysis was performed using two-way analysis of variance.

[0086] I: shows the immunohistochemistry of cardiac and renal tumors in vivo, with different groups defined as UnT+vector, CAR-T+vector, and CAR-T+TLR4i.

[0087] J: The mean concentrations of IFN-γ and IL-2 in the co-culture system ± sd are shown in bar graphs, and the different groups are defined as UnT DMSO, CAR-T ISO, CD36 + Monocyte DMSO, CD36 + TLR4i in monocytes. Results are indicative of three independent experiments, with dots of different colors representing different replicates. Statistical analysis was performed using two-way ANOVA.

[0088] Figure 3 shows that Ruxolitinib phosphate (JAK inhibitor) has a significant inhibitory effect on the secretion of IL-6 associated with the occurrence of CRS;

[0089] As can be seen from Figure 4, Torin (mTOR inhibitor) and Bardoxolone methyl (NF-κB inhibitor) have a significant inhibitory effect on the secretion of IL-1β associated with the occurrence of CRS. DETAILED DESCRIPTION

[0090] After long and in-depth research, the inventors unexpectedly discovered that the use of anti-inflammatory drugs such as TLR4 inhibitors can effectively counteract the CRS side effects of immunotherapies such as CART, which is of great significance for promoting the marketization of CART and other treatments. Based on this, the inventors completed the present invention.

[0091] Cytokine storm CRS

[0092] As used herein, the term "cytokine storm" refers to the rapid and massive production of multiple cytokines (such as interleukins and chemokines) in bodily fluids caused by the infusion of CAR-T cells, TCRT, antibodies, etc. CRS typically leads to a systemic inflammatory response in the host, causing damage to multiple tissues and organs, leading to multiple organ failure and even death.

[0093] In the present invention, the autoimmune disease refers to a cytokine storm, that is, "autoimmune disease" and "cytokine storm" can be used interchangeably.

[0094] TLR4 inhibitors

[0095] Toll-like receptor 4 (TLR4), a member of the Toll-like receptor (TLR) family, participates in innate immunity and mediates inflammatory responses. Overactivation of TLR4 leads to the production of various inflammatory cytokines, which are associated with the pathogenesis of many diseases, such as sepsis, endotoxemia, and rheumatoid arthritis. The anti-inflammatory potential of TLR4 inhibitors has been demonstrated, but their effect on CRS remains unknown.

[0096] We found that the expansion of CAR-T cells and their in vitro cytotoxicity against HCT116 and SW480 cells were not affected by TLR4 inhibition (Figures 2A and 2B). In a tumor cell killing assay containing monocytes, we also found that TLR4 inhibition did not affect the cytotoxicity of CAR-T cells (Figure 2C). To test the role of TLR4 in the development of CRS, we established an in vitro cytokine release assay by co-culturing CAR-T cells with HCT116 human colon cancer cells and human primary monocytes (Figure 1A). After treatment with TLR4 and Myd88 inhibitors, systemic human IL-1β, IL-6, and GM-CSF levels were consistently reduced (Figures 1B and 2D-E). In addition, TLR4 knockout in monocytes resulted in reduced cytokine secretion in the in vitro CRS assay (Figure 2F). Together, these results indicate that TLR4 inhibition can reduce the secretion of IL-1β, IL-6, and GM-CSF in vitro.

[0097] To test the efficacy of Toll inhibitors in blocking CRS in vivo, human PBMCs and HCT116 cells were transplanted into NSG mice that are triple immunodeficient and lack functional / mature T, B, and NK cells, which are most suitable for immuno-oncology and CAR-T therapy evaluation studies. After verifying the establishment of different tumor burdens, they were injected with EpCAM CAR-T cells (Figure 1C). To determine whether the Toll signaling pathway affects CRS, we evaluated the incidence and severity of induced CRS by transplanting EpCAM-CAR T cells into NSG mice with HCT116 tumor cells. In mice with CRS, treatment with Resatorvid TLR4 inhibitor TAK-242 improved CRS symptoms, inhibited weight loss, and prolonged survival, and the increase in body temperature in mice after CAR-T cell infusion was significantly suppressed (Figures 1D and 1F). In addition, after TAK-242 treatment, the expression of SAA and most human CRS-related cytokines was reduced, indicating that the release of cytokines was suppressed after Toll inhibition, while there was no significant change in body weight (Figure 1E, Figure 1I and Figure 2G). After Toll inhibition, tissue changes caused by CRS were improved (Figure 1J and Figure 2I). In addition, after the improvement of CRS symptoms, we did not observe significant differences in tumor elimination ability between the Toll inhibitor group and the CAR-T cell expansion group (Figure 1D and Figure 2H). Moreover, Toll inhibitor treatment did not affect the number of monocytes or CAR-T cells in the peripheral blood (Figure 1G-H). In summary, TLR4 inhibitors can reduce CRS symptoms and the effects of CRS-related cytokines in vivo.

[0098] CD36 + Monocytes have been found to be the most important monocyte subset in the development of CRS, so we + Monocytes and CD36 - Monocytes were isolated and injected into mice with humanized immune systems, and CD36 + Monocytes, but not CD36, significantly increased the severity of CRS - Monocytes. The mice showed weight loss, increased SAA concentration in serum and decreased survival rate (Figure 1K-N). In addition, CD36 + Monocytes showed a significant increase in the secretion of IFN-γ and IL-2 compared with the vehicle (Figure 2J). These results indicate that CD36 + Monocytes can promote the development of CRS in vivo, which is dependent on TLR4 signaling.

[0099] Together, these results demonstrate that EpCAM CAR-T cells treated with a TLR4 inhibitor significantly reduced CRS symptoms in vivo without compromising antitumor efficacy, suggesting that TLR signaling in monocytes plays a key role in the development of CRS.

[0100] Antibody

[0101] As used herein, the term "antibody" (Ab) shall include, but is not limited to, immunoglobulins that specifically bind to an antigen and comprise at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, or antigen-binding portions thereof. Each H chain comprises a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region comprises three constant domains, CH1, CH2, and CH3. Each light chain comprises a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region comprises one constant domain, CL. The VH and VL regions can be further subdivided into hypervariable regions, called complementarity determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). Each VH and VL comprises three CDRs and four FRs, arranged in the following order from amino terminus to carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with the antigen.

[0102] Antigen binding domain

[0103] As used herein, "antigen-binding domain" and "single-chain antibody fragment" refer to ScFv, VHH, Fab fragment, Fab' fragment, F(ab')2 fragment, or single Fv fragment with antigen-binding activity. Fv antibodies contain the variable region of the antibody heavy chain and the variable region of the light chain, but no constant region, and are the smallest antibody fragments with all antigen-binding sites. Generally, Fv antibodies also contain a polypeptide linker between the VH and VL domains and are capable of forming the structure required for antigen binding. The antigen-binding domain is usually scFv (single-chain variable fragment). A single-chain antibody is preferably an amino acid chain sequence encoded by a single nucleotide chain.

[0104] As used herein, the terms "single-domain antibody (VHH)" and "nanobody" have the same meaning and refer to the variable region of the heavy chain of a monoclonal antibody. A single-domain antibody (VHH) consisting solely of a single heavy chain variable region is constructed, which is the smallest antigen-binding fragment with complete function. Typically, an antibody naturally lacking the light chain and heavy chain constant region 1 (CH1) is first obtained, and then the variable region of the antibody heavy chain is cloned to construct a single-domain antibody (VHH) consisting solely of a single heavy chain variable region.

[0105] Chimeric antigen receptor T cells (CAR-T cells)

[0106] As used herein, the terms "CAR-T cells," "CAR-T," and "CAR-T cells of the present invention" all refer to the CAR-T cells described in the first aspect of the present invention. The CAR-T cells of the present invention can be used to treat tumors that overexpress NKG2D ligands, such as colorectal cancer, ovarian cancer, and pancreatic cancer.

[0107] CAR-T cells have the following advantages over other T-cell-based treatments: (1) The action of CAR-T cells is not restricted by MHC; (2) Since many tumor cells express the same tumor antigens, once the CAR gene construction for a certain tumor antigen is completed, it can be widely used; (3) CAR can utilize both tumor protein antigens and glycolipid non-protein antigens, expanding the target range of tumor antigens; (4) The use of the patient's own cells reduces the risk of rejection; (5) CAR-T cells have immune memory function and can survive in the body for a long time.

[0108] Compared with the prior art, the present invention has the following main advantages:

[0109] (1) This invention is the first to discover that the use of anti-inflammatory drugs such as TLR4 inhibitors can effectively resist CRS caused by immunotherapy such as CART, which is of great significance for promoting the marketization of treatments such as CART and TCRT;

[0110] (2) The use of anti-inflammatory drugs such as TLR4 inhibitors will not affect the killing ability of CART cells, but can significantly resist CRS caused by CART treatment and significantly prolong the survival time of subjects;

[0111] (3) The present invention discovered for the first time that a variety of drugs for anti-inflammatory and autoimmune diseases have the effect of inhibiting the occurrence of CRS.

[0112] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0113] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0114] General experimental methods

[0115] Preparation of CAR-T cells

[0116] 1. CD3 T cells infected with EpCAM CAR virus

[0117] (I) CD3 T cell expansion MOI exploration

[0118] 1) Transfection using Hanbio virus packaging: T cells were resuspended in RPMI 1640 medium. The transfection system was as follows: 5E5 or 2E4 cells per well (divided into four groups, with the cell number increased or decreased based on the virus dose and operational requirements). The optimal MOI for the control group (HBhTLV-ZsGreen-PURO overexpression control) was determined by trial and error at 50, 25, 12.5, and 6. The final concentration of Polybrene was 6 μg / mL. The final concentration of hIL-2 was 250 IU / mL.

[0119] MOI value = virus titer (TU / mL) × virus volume (mL) / number of cells

[0120] Virus titer: HBhTLV-ZsGreen-PURO overexpression control: 2.5×108TU / ml

[0121] After adding the transfection reagent, centrifuge at 1200g for 1 hour at room temperature. Place the cells in an incubator and continue culturing. After 4 hours, add a predetermined amount of RPMI 1640 medium supplemented with 250 IU / mL hIL-2. After approximately 24 hours, carefully aspirate the virus-containing medium from the infected wells and replace with fresh complete medium. Continue culturing for another 24 hours.

[0122] The next day, transfection was continued for approximately 48 hours. The control group was monitored by flow cytometry. If the GFP-positive rate reached 50% or higher, transfection was terminated. If it was low, for example, 30%, the virus-containing medium in the infected wells was aspirated and replaced with fresh complete culture medium. The culture was continued for another 24 hours.

[0123] The next day, the total transfection time was about 72 hours. The GFP expression in the control group was monitored by flow cytometry. If the positive rate was not less than 50%, the cells were in good condition and acceptable.

[0124] II) CD3 T cell expansion

[0125] 2) Transfection using Hanbio-packaged virus: Resuspend CD3 T cells in RPMI 1640 medium at an MOI of 100, a final Polybrene concentration of 6 μg / mL, and a final hIL-2 concentration of 250 IU / mL.

[0126] MOI value = virus titer (TU / mL) × virus volume (mL) / number of cells

[0127] Virus titer: Control: HBhTLV-ZsGreen-PURO overexpression control: 2.5×108TU / ml

[0128] Experiment: HBhTLV-h-Epcam-car-Null-PURO is 3×108TU / ml

[0129] After adding the transfection reagent, centrifuge at 1200g for 1 hour at room temperature and continue culturing in an incubator. After 4 hours, add a predetermined amount of RPMI 1640 medium supplemented with 250 IU / mL hIL-2. Around 24 hours later, for the control virus group, aspirate a portion of the cells, remove the virus, resuspend in PBS, and analyze the transfection efficiency by flow cytometry. If the GFP positivity rate reaches 80%-80% or higher, terminate the transfection in the experimental group. If it is very low, for example, 30%, aspirate the virus-containing medium in the infected wells, replace with fresh complete medium, and continue culturing for another 24 hours. The next day, the total transfection time is approximately 48 hours, and the control group should continue to monitor the transfection efficiency by flow cytometry.

[0130] PS: If the MOI is very low, for example 10%, after 24 hours, the experimental group should be centrifuged and the viral supernatant discarded, and then transfected again. The second transfection should be the same as the first one.

[0131] Enzyme-linked immunosorbent assay (ELISA)

[0132] To measure cytokine expression in a 1:1:0.5 co-culture of CAR-T cells, tumor cells, and monocytes, cell-free supernatants were collected 24 hours later and analyzed using ELISA assays for human IL-6 and IL-1β, ELISA assays (R&D Systems, MA0725, human IL-1B ELISA kit; MA0728, Huan IL-6 ELISA kit) according to the manufacturer's instructions. Similarly, ELISA assays were used to measure IL-6 / IL-1β levels in animal serum. Supernatant samples were diluted 50X-100X, and each well of the ELISA plate was coated with 100 μL of 5 μg / ml goat IL-6 / IL-1β antibody in ELISA buffer and incubated overnight at 2°C. After washing with TBS-Tween and blocking with 1% BSA (diluted in PBS), 100 μL of each supernatant sample was added to the plate and incubated at 37°C for 1 hour. After washing three times with TBS-Tween, each well was incubated with 100 μL of 1:1000 anti-IL-6 / IL-1β antibody in ELISA buffer at 37°C for 1 hour. After washing, each well was incubated with 100 μL of rabbit HRP in ELISA buffer at 37°C for 30 minutes, followed by further washing. The plate was then incubated with 100 μL of TMB substrate in the dark at room temperature for 30 minutes, and the reaction was stopped by adding 100 μL of stop solution to each well. The absorbance was measured at 450 nm or 450 minus 550 nm using a microplate reader, and the results were calculated using Prism software (GraphPad). The assay was performed in triplicate and repeated at least twice.

[0133] Example 1 Co-use of CAR-T cells and TLR4 inhibitors

[0134] In vitro experiments have shown that TLR4 inhibitors of the Toll-like receptor pathway in monocytes can inhibit the occurrence of CRS without affecting the tumor killing efficiency of CAR-T in vitro.

[0135] Figure 1A: Schematic diagram of co-culture assay: CAR-T cells were co-cultured with tumor cells and primary human monocytes. Supernatants were collected for cytokine analysis.

[0136] Figure 1B: Histogram showing the levels of representative proinflammatory cytokines in the coculture system. IL-6, GM-CSF, and IL-1β concentrations (mean ± SD) were measured in monocytes pre-incubated with different concentrations of TLR4 inhibitors and co-cultured with tumor cells and CAR-T cells. Results are representative of three independent experiments (dots of different colors represent replicate samples). Statistical analysis was performed using two-way analysis of variance.

[0137] Example 2

[0138] The animal care protocol (20221215-002) was approved by the Animal Care Committee of Fudan University and followed the animal management regulations of the National Health Commission of the People's Republic of China. The in vivo CRS mouse model was developed using the methods described by Won Lee et al. (reference). Each mouse experiment included at least five mice per group. Hu-PBL NSG mice were generated by injecting 10 million human peripheral blood mononuclear cells into NSG-MHC class I / II double knockout mice. HCT116 cells were harvested at confluence, filtered through a 40 μm mesh, washed twice in PBS, and then subcutaneously injected into the right flank of hu-PBL NSG mice at a concentration of 5 million cells in 100 μl PBS. These mice were reconstituted with a humanized immune system for 1 week at 6-8 weeks of age. When tumor volume reached 100 mm3, CAR-T cells were injected through the tail vein, and different doses are indicated in the figure legends. In experiments evaluating the effect of TLR4 inhibitors on alleviating CRS, mice (n = 15) were randomly divided into three groups. TAK-242 (5 mg / kg) or Vehicle (PBS plus 0.9% DMSO) was injected intraperitoneally every two days after CAR-T infusion. Body weight and blood samples were collected for serum amylase assessment and flow cytometry. At the endpoint, organs including lungs, kidneys, heart, liver, and tumors were collected for immunohistochemical analysis. For the adoptive transfer experiment, 1 million CD36+ monocytes and CD36- monocytes were transferred into hu-PBL mice by tail vein injection 3 days before CAR-T injection. Serum samples were collected for cytokine detection and SAA measurement, and body weight was monitored every two days after CAR-T infusion. To evaluate the effects of antigen processing and expression inhibitors on the anti-tumor response of CAR-T cells, mice were randomly divided into three cohorts (n=15) and given anti-MHC-I+MHC-II antibodies (5 mg / kg) or isotype antibodies dissolved in PBS every three days (Q3D) after CAR-T infusion. Tumor volume was monitored every 4 days, and tumor growth inhibition rate (TGI%) was calculated. Tumor volume was measured every 4 days and calculated using the formula V = 0.5ab2 (where a and b are the major and minor diameters of the tumor). Tumor growth inhibition rate (TGI%) was determined using the formula: TGI% = [1-RTV(experimental) / RTV(control)] x 100%, where RTV is the relative tumor volume, calculated using the formula RTV = Vt / V0, where Vt is the tumor volume at the end of the experimental period and V0 is the tumor volume at the beginning or mid-term of the experimental period. Dosing was stopped and mice were allowed to recover their weight if they lost more than 25% of their body weight. The endpoint was reached when the tumor size exceeded 2000 mm3.

[0139] In vivo experiments have shown that TLR4 inhibitors of the Toll-like receptor pathway in monocytes can inhibit the occurrence of CRS without affecting the tumor-killing efficiency of CAR-T in vivo.

[0140] Figure 1C: In vivo CRS toxicity mouse model: NSG mice were infused with PBMCs and HCT116 cells, followed by infusion of anti-EpCAM CAR-T cells and TAK-242. Body weight, serum levels, and body temperature were monitored regularly. Mice were euthanized on day 40. UnT, untransfected T cells.

[0141] Figure 1D. Body weight changes of mice after CAR-T infusion, grouped by treatment. The broken line graph shows the mean body weight change ± SD of mice treated with UnT + vector, CAR-T + vector, or CAR-T + TLR4i (TAK-242) (0.5 mg / kg every two days). The dotted line indicates the threshold for the percentage change in weight to be zero. The points of different colors represent the kinetics of body weight change in each group from day 0 to day 14. Statistical analysis was performed using two-way analysis of variance (left).

[0142] Mean tumor volume changes over time in mice treated with CAR-T (red line), CAR-T+TLR4i (green line), and UnT (blue line). Changes are presented as a broken line graph, with different colors representing different treatment groups. Standard deviations (SD) are represented by error bars (center).

[0143] Kaplan-Meyer survival plots for tumor-bearing mice treated with CAR-T (red line), CAR-T + TLR4i (green line), and UnT (blue line). Kaplan-Meyer plots show the probability of survival over time, with different colors representing different treatment groups. The results were analyzed using the log-rank Mantel-Cox test (right).

[0144] Figure 1E-F: Mean serum amyloid A (SAA) concentration and body temperature changes in mice, grouped by UnT, CAR-T, and CAR-T + TLR4i treatment. The dashed line indicates the threshold for temperature change at 0%. The line graphs show the temporal changes in SAA concentration and body temperature from day 0 to day 12, measured every two days. Statistical analysis was performed using two-way ANOVA with Bonferroni correction.

[0145] Figure 1G-I: Mean monocyte and CAR-T cell counts per 100 μL of blood and mean concentrations of IL-6, GM-CSF, and IL-1β in mouse serum, grouped by UnT, CAR-T, and CAR-T + TLR4i treatment. Histograms show the comparison of these parameters between groups. Statistical analysis was performed using two-way ANOVA with Bonferroni correction.

[0146] Figure 1J: Hematoxylin-eosin (HE) staining of lung and liver in vivo, with different groups represented as UnT, CAR-T, and CAR-T+TLR4i.

[0147] Example 3

[0148] The animal care protocol (20221215-002) was approved by the Animal Care Committee of Fudan University and adhered to the animal management regulations of the National Health Commission of the People's Republic of China. The in vivo CRS mouse model was developed using the methods described by Won Lee et al. (reference). Each mouse experiment included at least five mice per group. Hu-PBL NSG mice were generated by injecting 10 million human peripheral blood mononuclear cells into NSG-MHC class I / II double-knockout mice. HCT116 cells were harvested at confluence, filtered through a 40-μm mesh, washed twice in PBS, and subsequently injected subcutaneously into the right flank of hu-PBL NSG mice, which had been reconstituted with a humanized immune system for 1 week at 6–8 weeks of age. CAR-T cells were injected via the tail vein when tumors reached a volume of 100 mm³; the different doses are indicated in the figure legends. To reveal the residence of CD16+ and CD36+ monocytes in tumor tissue, CD16+ and CD36+ monocytes were stained with CFSE (Biolegend) and DsRed (Invitrogen) and mixed at a ratio of 1:1. Then, 5×105 CD16+ and CD36+ monocytes were injected through the tail vein one day after CAR-T infusion. Five days later, blood samples and tumor tissues were collected to detect the ratio and cell number of CD16+ and CD36+ monocytes. Tumor volume was monitored every 4 days, and tumor growth inhibition rate (TGI%) was calculated. Tumor volume was measured every 4 days and calculated as V=0.5ab2 (where a and b are the long and short diameters of the tumor). Tumor growth inhibition (TGI%) was determined using the formula: TGI% = [1 - RTV(experimental) / RTV(control)] x 100%, where RTV is the relative tumor volume, calculated as RTV = Vt / V0, where Vt is the tumor volume at the end of the experimental period and V0 is the tumor volume at the beginning or mid-point of the experimental period. Dosing was stopped, and mice were allowed to recover if their body weight decreased by more than 25%. The endpoint was reached when tumor size exceeded 2000 mm³.

[0149] In vivo experiments showed that CD36 + Monocytes inhibit the occurrence of CRS without affecting the tumor-killing efficiency of CAR-T in vivo.

[0150] Figure 1K: Experimental design for in vivo toxicity analysis. NSG mice were infused with PBMC and HCT116 cells, followed by CD36 +Monocytes and EpCAM-CAR T cells were detected. Body weight, serum levels, and body temperature were assessed regularly. Mice were euthanized on day 40.

[0151] Figure 1L: Average body weight changes of mice, by UnT, CAR-T+CD36 - Monocytes and CAR-T+CD36 + Monocytes were grouped by treatment. The dashed line indicates the threshold for weight change of 0%. The line graph shows the temporal change in body weight from day 0 to day 14, measured every two days. Statistical analysis was performed using two-way analysis of variance.

[0152] Figure 1M: Average serum amyloid A (SAA) concentration in mice, by UnT, CAR-T+CD36 - Monocytes and CAR-T+CD36 + Monocytes were grouped by treatment. The dashed line indicates the threshold of 0% temperature change. The line graph shows the temporal changes in SAA concentrations from day 0 to day 12, measured every two days. Statistical analysis was performed using two-way ANOVA with Bonferroni correction.

[0153] Figure 1N: Using UnT, CAR-T+CD36 - Monocytes and CAR-T+CD36 + Kaplan-Meyer survival plots of monocyte-treated tumor-bearing mice, with blue, red, and green colors used for statistical analysis.

[0154] Example 4

[0155] EpCAM CAR-T cells were constructed as described above and cultured in X-vivo medium supplemented with 5% FBS, 1% P / S, and 300 IU IL-2. Monocytes and CD16+ monocytes from the same donor were sorted using magnetic beads (Miltenyi Biotec), and CD36+ monocytes were further stained with APC anti-human CD36 antibody and sorted by flow cytometry (CytoFLEX SRT, Beckman). We used the method reported by Singh et al. to perform an in vitro cytokine release syndrome (CRS) model assay. For co-culture experiments, HCT116-Luc or SW480-Luc cells were used as target cells, and 10,000 cells were seeded in 96-well plates with full growth medium. CAR-T cells with different target effect ratios and 5,000 sorted monocytes were added to the plate in a final volume of 200 μL per well and cultured in X-vivo medium with 5% FBS and 1% P / S at 37°C and 5% CO2. After 24 hours, the culture supernatant was collected for cytokine and cytotoxicity evaluation. In order to test the antigen expression ability of different subsets of monocytes, the expression of CD25 and CD69 (BioLegends) in CAR-T cells after co-culture was measured by flow cytometry. In addition, anti-human CD74 antibody (Biolegend), anti-human MHC-I antibody (Biolegend) and anti-human MHC-II antibody (Biolegend) were used to stain the CD16+ and CD36+ monocytes after co-culture. The cytotoxicity of CAR-T cells against HCT116-Luc cells was measured by the GLO luciferase assay system (Promega). For in vitro cytotoxicity of CAR-T cells against tumor cells (HCT116-Luc and SW480-Luc), 10,000 tumor cells were seeded in 96-well plates with full growth medium and CAR-T cells at different target:effect ratios (3:1, 1:1, and 1:3) were added to the plates. After 24 hours, supernatants were collected for cytotoxicity assessment.

[0156] Figure 2 shows that Toll-like receptor 4 inhibitors can suppress the occurrence of CRS without affecting the efficiency of CAR-T in vivo and in vitro.

[0157] A: Cytotoxicity of CAR-T cells against SW480 and HCT116 cells ± SD is shown as a histogram. Different groups are defined by UnT + vector, CAR-T + vector, CAR-T + TLR4i (1 μM), CAR-T + TLR4i (2 μM), and CAR-T + TLR4i (5 μM), respectively. Three levels of effector-target ratios are shown (i.e., CAR-T cell to tumor cell ratios of 3:1, 1:1, and 1:3 for SW480 (left) and HCT116 (right), respectively). Statistical analysis was performed using two-way analysis of variance.

[0158] B. Shows the fold change ± SD of CAR T cell counts in vitro, grouped by DMSO, TLR4i (1 μM), TLR4i (2 μM), and TLR4i (5 μM). The kinetic changes in each group are represented by the different colored dots on the line graph, representing the changes from day 1 to day 7 of in vitro cell culture. Statistical analysis was performed using two-way analysis of variance.

[0159] C: Cytotoxicity of CAR-T cells against SW480 and HCT116 cells ± SD is shown as a histogram, with different groups defined by UnT, CAR-T+DMSO, CAR-T+TLR4i (1 μM), CAR-T+TLR4i (2 μM), and CAR-T+TLR4i (5 μM). Three levels of effector-target ratios are shown (i.e., 3:1, 1:1, and 1:3 ratios of CAR-T cells to tumor cells for SW480 (left) and HCT116 (right), respectively). Statistical analysis was performed using two-way analysis of variance.

[0160] D: Flow cytometry of CD25 and CD69 expression, grouped by ISO, CAR-T DMSO, CAR-T+TLR4i (1 μM), CAR-T+TLR4i (2 μM), and CAR-T+TLR4i (5 μM).

[0161] E: Mean ± SD concentrations of GM-CSF, IL-1β, and IL-6 in the co-culture system are shown as histograms, with the different groups defined by UnT, UnT + Monocyte, CAR-T, CAR-T + Monocyte, Myd88i (1 μM), Myd88i (2 μM), and Myd88i (5 μM), respectively. Results are indicative of three independent experiments, with dots of different colors representing different replicates. Statistical analysis was performed using two-way ANOVA.

[0162] F: Mean concentrations of GM-CSF, IL-1β, and IL-6 (pg / ml) ± SD are shown as bar graphs, with different groups defined by mock and TLR4 knockout (KD). Statistical analysis was performed using a two-tailed unpaired two-sample t-test.

[0163] G: Mean body weight change (%) ± SD of mice after CAR T infusion is shown as a line graph, with points of different colors representing kinetic body weight change from day 0 to day 14. Groups were defined by UnT + vector, CAR-T + vector, and CAR-T + TLR4i. Body weight was measured every two days, and the threshold for body weight change is indicated by the dotted line. Statistical analysis was performed using two-way analysis of variance.

[0164] H: Average tumor volume change of mice after CAR T infusion (mm 3 ) ± SD is shown as a line graph, with points of different colors representing the kinetic changes in tumor volume from day 0 to day 21. Groups were defined by UnT + vector, CAR-T + vector, and CAR-T + TLR4i. Statistical analysis was performed using two-way analysis of variance.

[0165] I: shows the immunohistochemistry of cardiac and renal tumors in vivo, with different groups defined as UnT+vector, CAR-T+vector, and CAR-T+TLR4i.

[0166] J: The mean concentrations of IFN-γ and IL-2 in the co-culture system ± sd are shown in bar graphs, and the different groups are defined as UnT DMSO, CAR-T ISO, CD36 + Monocyte DMSO, CD36 + TLR4i in monocytes. Results are indicative of three independent experiments, with dots of different colors representing different replicates. Statistical analysis was performed using two-way ANOVA.

[0167] Example 5

[0168] 1. Co-culture

[0169] Day 1

[0170] Target HCT-116 cells were digested and counted, then seeded into 96-well plates at 10,000 cells / well and 100 μl / well.

[0171] Group settings:

[0172] G-1: T cell control

[0173] G-2 G-2: T cells + Monocytes

[0174] G-3: CAR-T cell control

[0175] G-4:CAR-T+Monocyte+Torin

[0176] G-5: CAR-T+Monocyte+Bardoxolone methyl

[0177] G-6: CAR-T+Monocyte+Ruxolitinibphosphate

[0178] There are 6 groups in total, 2 replicate wells in each group, for a total of 16 wells.

[0179] Day 2

[0180] For control T cells (CD3 T), count and resuspend in RPMI1640+10% FBS medium to the desired concentration for later use:

[0181] G-1 (T cell control): 8000 control T cells, 100 μl per well;

[0182] G-2 (T cells + Monocytes (untransfected): 10,000 control T cells + 5,000 Monocytes, 100 μl per well;

[0183] G-3 (CAR-T cell control): 8000 CAR-T cells, 100 μl per well;

[0184] G-4 (CAR-T+Monocyte (untransfected)+Torin): 8000 CAR-T cells+5000 Monocyte+Torin (final concentration 250 nM), 100 μl per well;

[0185] G-5 (CAR-T + Monocyte (untransfected) + Bardoxolone methyl): 8000 CAR-T cells + 5000 Monocytes + Bardoxolone methyl (final concentration 600 nM), 100 μl per well;

[0186] G-6 (CAR-T + Monocyte (untransfected) + Ruxolitinib phosphate): 8000 CAR-T cells + 5000 Monocytes + Ruxolitinib phosphate (final concentration 800 nM), 100 μl per well;

[0187] The final volume was 200 μl / well.

[0188] PS: 8000 CAR-T cells means that the positive cells are >50% or more, preferably >80% or more.

[0189] Day 3

[0190] After co-culture for 24 h, the cells were centrifuged and the supernatant was collected for ELISA detection.

[0191] 2. ELISA analysis of IL-6 and IL-1β

[0192] Refer to the instruction manual according to the actual situation.

[0193] 3. Experimental Results

[0194] As can be seen from Figure 3, Ruxolitinib phosphate (JAK inhibitor) has a significant inhibitory effect on the secretion of IL-6 associated with the occurrence of CRS;

[0195] As can be seen from Figure 4, Torin (mTOR inhibitor) and Bardoxolone methyl (NF-κB inhibitor) have a significant inhibitory effect on the secretion of IL-1β associated with the occurrence of CRS.

[0196] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A use of an anti-inflammatory drug, characterized in that: Used for preparing medicines for treating autoimmune diseases.

2. The use according to claim 1, characterized in that The anti-inflammatory drug is selected from the group consisting of a TLR inhibitor, an mTOR inhibitor, an ERK inhibitor, a JAK inhibitor, a NF-κB inhibitor, and a NLRP3 inhibitor.

3. The use according to claim 2, characterized in that: The TLR inhibitor is a TLR4 inhibitor.

4. The use according to claim 3, characterized in that The TLR4 inhibitor is selected from the following group:

5. The use according to claim 2, characterized in that: The mTOR inhibitor is selected from the group consisting of:

6. The use according to claim 2, characterized in that: The JAK inhibitor is selected from the following group:

7. The use according to claim 2, characterized in that: The NF-κB inhibitor is selected from the following group:

8. The use according to claim 2, characterized in that: The NLRP3 inhibitor is selected from the following group:

9. The use according to claim 1, characterized in that The autoimmune disease is an autoimmune disease caused by a treatment selected from the group consisting of CART, TCR-T, monoclonal antibody, BiTE, bispecific antibody, or a combination thereof.

10. The use according to claim 1, characterized in that The autoimmune disease is cytokine storm (CRS).

11. The use according to claim 1, characterized in that The autoimmune disease is CRS caused by a treatment selected from the group consisting of CART, TCR-T, monoclonal antibody, BiTE, bispecific antibody, or a combination thereof.

12. The use according to claim 2 or 3, characterized in that: The autoimmune disease is cytokine storm (CRS) caused by CART therapy.

13. The use according to claim 5, characterized in that the cell target targeted by the treatment is used to treat a disease selected from the following group: solid tumors and hematological tumors.

14. The use according to claim 11, characterized in that The treatment is CART treatment, and the cell target targeted by the CART treatment is used to treat a disease selected from the following group: multiple myeloma (MM), acute myeloid leukemia (AML), B or T cell lymphoma, ovarian cancer, T cell malignancies, osteosarcoma, medulloblastoma, Ewing's sarcoma, pancreatic cancer, neuroblastoma, glioblastoma, testicular cancer, lung cancer, gastric cancer, melanoma, sarcoma, colon cancer, and breast cancer.

15. The use according to claim 5, characterized in that The treatment is CART treatment, and the cell target targeted by the CART treatment is selected from the following group: EpCAM, Claudin 18.2, mesothelin, CD19, CD20, GPRC5D, SLAMF7, BCMA, CD38, CD56, CD44v6, FLT3, CD33, CD123, CD37, TCRβ-chain, Annexin A2, B7-H3, CD171, Chlorotoxin, Claudin-6, EIIIB, Glypican-1, Integrinα V β3, Mucl, PD-L1, ROR1, CD22, CD30, SLAM (Signaling lymphocytic activation molecule), Mesothelin, GD2, HER2, GPC3, CEA, EGFRvIII, PSMA, EGFR; and / or The treatment is TCR-T treatment, and the cell target targeted by the TCR-T treatment is selected from the following group: FH-MCVA2TCR T-cell, Autologous anti-NY-ESO1 T-cell receptor, Autologous anti-KRAS G12V mTCR gene-engineered cell, MAGE-A1-specific T cell receptor-transduced autologous T-cell; The treatment is monoclonal antibody treatment, and the monoclonal antibody used in the monoclonal antibody treatment is selected from the following group: Tocilizumab biosimilar (Livzon Group), Choriogonadotropin alfa biosimilar (Livzon Group), Belimumab, Mepolizumab, Denosumab, Abciximab, Canakinumab, Trastuzumab / Pertuzumab, Evolocumab, Ixekizumab, Brolucizumab, Pucotenlimab, Emapalumab, Panitumumab, Certolizumab pegol, Adalimumab, Omalizumab, Nivolumab, Bevacizumab, Atezolizumab, Daclizumab, Infliximab, Tocilizumab, Eculizumab, Blinatumomab, Ranibizumab, Burosumab, Secukinumab, Spesolimab, Ramucirumab, Sacituzumab govitecan, Emicizumab, Ustekinumab, Obinutuzumab, Cemiplimab, Tixagevimab / Cilgavimab, Vedolizumab, Mogamulizumab, Durvalumab, Sintilimab, Golimumab, Basiliximab, Dinutuximab beta, Dupilumab, Ripertamab, Pertuzumab, Brodalumab, Daclizumab biosimilar (Shanghai CPGuojian) (Daclizumab Biosimilar (Sansheng Guojian)), Ofatumumab, Necitumumab, Aducanumab, Docaravimab / Miromavimab, Satralizumab, Palivizumab, Regdanvimab, Guselkumab, Inetetamab, Camrelizumab, Trastuzumab, Daratumumab, Ipilimumab, Inebilizumab, Rituximab, Ibritumomab Tiuxetan, Idarucizumab, Brentuximab vedotin, Pembrolizumab, Adebrelimab, Retifanlimab, Margetuximab, Eptinezumab, Amubarvimab / Romlusevimab, Lanadelumab, Toripalimab, Alirocumab, Tildrakizumab, Ansuvimab, Nimotuzumab, Bevacizumab biosimilar (Biocad), Naxitamab, Tislelizumab, Itolizumab, Adalimumab biosimilar (Celltrion), Cadonilimab, Trastuzumab biosimilar (Biocad), Casirivimab / imdevimab, Bevacizumabbiosimilar (mAbixience), Inotuzumab Ozogamicin, Trastuzumab biosimilar (Synthon), Dostarlimab, Ranibizumab biosimilar (Intas Biopharmaceuticals), Ranibizumab biosimilar (Senju), Lecanemab, Penpulimab, Cetuximab, Siltuximab, Belantamab mafodotin, Trastuzumab biosimilar (Pfizer), Glofitamab, Faricimab, Trastuzumab biosimilar (AXXO), Bevacizumab biosimilar (Elea), Nirsevimab, Bevacizumab biosimilar (Samsung Bioepis), Sotrovimab, Rituximab biosimilar (mAbxience), Ranibizumab biosimilar (Xbrane), Disitamab Vedotin, Polatuzumab vedotin, Serplulimab, Zimberelimab, Amivantamab, Sugemalimab, Bevacizumab biosimilar (Celltrion), Abciximab biosimilar (ISU Abxis), Ormutivimab, Infliximab biosimilar (Celltrion), Adalimumab biosimilar (Innovent Biologics), Fremanezumab, Infliximab biosimilar (Pfizer), Benralizumab, Adalimumab biosimilar (Biocad), Adalimumab biosimilar (Hisun Pharma), Trastuzumab biosimilar (Zydus), Ado-trastuzumab emtansine, Bevacizumab biosimilar (Pfizer), Bevacizumab biosimilar (AryoGen Biopharma), Rituximab biosimilar (Pfizer), Rituximab biosimilar (Zenotech), Ranibizumabbiosimilars (Formycon / Bioeq), Bevacizumab biosimilars (Zydus Cadila), Cetuximab biosimilars (CinnaGen), Rituximab biosimilars (Biosidus), Envafolimab, Omalizumab biosimilars (IBC Generium), Adalimumab biosimilars (Amgen), Rituximab biosimilars (Innovent Biologics), Bevacizumab biosimilars (Boan Biopharma)(Bevacizumab biosimilar (Boan Bio)), Bevacizumab biosimilar (Apotex)(Bevacizumab biosimilar (Apotex)), Rituximab biosimilar (Biocad)(Rituximab biosimilar (Biocad)), Adalimumab biosimilar (Alvotech)(Adalimumab biosimilar (Alvotech)), Rituximab biosimilar (Intas Biopharmaceuticals)(Rituximab biosimilar (Intas Biopharmaceuticals)), Trastuzumab biosimilar (AryoGen Pharmed)(Trastuzumab biosimilar (AryoGen Pharmed)), Abciximab biosimilar (Reliance Life Sciences)(Abciximab biosimilar (Reliance Life Sciences)), Hyaluronidase / Rituximab(Hyaluronidase / Rituximab), Trastuzumab biosimilar (Celltrion) (trastuzumab biosimilar (Celltrion)), Bevacizumab biosimilar (InnoventBiologics)(Bevacizumab biosimilar (Innovent Biologics)), Trastuzumab / Hyaluronidase(Trastuzumab / Hyaluronidase), Bevacizumab biosimilar(Jiangsu Hengrui Medicine)(Bevacizumab biosimilar(Jiangsu Hengrui Medicine)), Adalimumab biosimilar(Sandoz)(Adalimumab biosimilar(Sandoz)), Rituximab biosimilar(AryoGen Biopharma)(Rituximab biosimilar(AryoGen Biopharma)), Bevacizumab biosimilar(Hetero Drugs)(Bevacizumab biosimilar(Hetero Drugs)), Bevacizumab biosimilar(CTTQ Pharma)(Bevacizumab biosimilar(Zhengda Tianqing)), Rituximab biosimilar(Hetero Drugs)(Rituximab biosimilar(Hetero Drugs)), Bevacizumab biosimilar (Biocon / Mylan), Bevacizumab biosimilar (Qilu Pharma), Bevacizumab biosimilar (Dr. Reddy's Laboratories), Ranibizumab biosimilar (Samsung Bioepis), Adalimumab biosimilar (Coherus BioSciences), Fam-trastuzumab deruxtecan, Rituximab biosimilar (Probiomed), Trastuzumab biosimilar (Intas Pharmaceuticals), Rituximab biosimilar (Reliance Life Sciences), Rituximab biosimilar (Celltrion), Adalimumab biosimilar (CTTQ Pharma)(Adalimumab biosimilar (Zhengda Tianqing)), Adalimumab biosimilar (Pfizer), Adalimumab biosimilar (Zydus Cadila), Adalimumab biosimilar (Fresenius Kabi), Adalimumab biosimilar (LG Life Sciences), Adalimumab biosimilar (Samsung Bioepis), Enfortumab vedotin, Trastuzumab biosimilar (Zhejiang Hisun Pharmaceutical), Trastuzumab biosimilar (Samsung Bioepis), Bioepis)(Trastuzumab biosimilar (Samsung Bioepis)), Bevacizumabbiosimilar (Reliance Life Sciences), Denosumab biosimilar (Mabwell), Rituximab biosimilar (Center of Molecular Immunology), Adalimumab biosimilar (Bio-Thera Solutions), Adalimumab biosimilar (Reliance Life Sciences), Trastuzumab biosimilar (Reliance Life Sciences), Rituximab biosimilar (Amgen), Infliximab biosimilar (Amgen), Tocilizumab biosimilar (Bio-Thera Solutions), Bevacizumab biosimilar (Shanghai Henlius Biotech), Bevacizumab biosimilar (Bio-Thera Solutions), Bevacizumab biosimilar (TOT Biopharm), Rituximab biosimilar (Sandoz), Trastuzumab biosimilar (Dr. Reddy's Laboratories), Adalimumab biosimilar (Shanghai Henlius Biotech), Biotech)(Adalimumab biosimilar (Henlius)), Bevacizumabbiosimilars (Betta / Mabworks), Iodine[131I]Metuximab, Denosumab biosimilar (Reliance Life Sciences), Trastuzumab biosimilar (Shanghai Henlius Biotech), Adalimumab biosimilar (Mylan / Biocon), Bevacizumab biosimilar (Intas Pharmaceuticals), Rituximab biosimilar (Dr Reddy's Laboratories), Mouse monoclonal antibody against human interleukin-8 cream (anti-human interleukin-8 mouse monoclonal antibody cream), Trastuzumab emtansine biosimilar (Zydus Cadila), Rituximab biosimilar (Shanghai Henlius Biotech) Biosimilars (Shanghai Henlius Biotech), Denosumab biosimilar (Boan Biopharma / Luye), Adalimumab biosimilar (Fujifilm Kyowa Kirin Biologics / Mylan), Mouse monoclonal antibody against human CD3 antigen of T lymphocyte (Wuhan Institute of Biological Products), Adalimumab biosimilar (Jiangsu Zhonghe / Shanghai Junshi / Jiangsu T-Mab), Obiltoxaximab, Alemtuzumab, Bevacizumab biosimilar(Allergan / Amgen), Olaratumab, Raxibacumab, Natalizumab, Galcanezumab, Gemtuzumabozogamicin, Ocrelizumab, Bezlotoxumab, Romosozumab, Sarilumab, Elotuzumab, Infliximab biosimilar(Merck&Co / Samsung Bioepis), Erenumab, Trastuzumab biosimilar(Biocon / Mylan), Avelumab, Capromab pendetide, Ibalizumab, Isatuximab, Ublituximab, Dinutuximab, Infliximab biosimilar(AXXO)(Infliximab biosimilar(AXXO)), Teplizumab, Infliximab biosimilar(Reliance Life Sciences)(Infliximab biosimilar(Reliance Life Sciences) Sciences)), Tisotumabvedotin, Infliximab biosimilar (HisunPharma)(Infliximab Biosimilar (Hisun Pharmaceutical)), Nemolizumab, Mirvetuximabsoravtansine, Risankizumab, Anifrolumab, Caplacizumab, Odulimomab, Moxetumomabpasudotox, Reslizumab, Besilesomab, Tralokinumab, Iodine(131I)derlotuximab biotin, Adalimumab biosimilar (Boehringer Ingelheim), Infliximab Biosimilar (Genor Biopharma), Infliximab biosimilar (Bionovis / The Instituto Vital Brazil), Infliximab biosimilar (Shanghai Biomabs)(Infliximab biosimilar (Shanghai Biomabs Pharmaceuticals)), Infliximab biosimilar (Nichiiko / Aprogen)(Infliximab biosimilar (Nichiiko / Aprogen)), Anti-CD34 mab-sirolimus (OrbusNeich), F-0530A, Prolgolimab, Tc 99m ior cea1, Tezepelumab, Evinacumab, UniGAM SD (FarmaBiagini), Teprotumumab, Racotumomab, Tremelimumab, Intragam P (CSL Ltd), Anti-rabies monoclonal antibody (Serum Institute ofIndia / MassBiologics), Atoltivimab / Maftivimab / Odesivimab, Nivolumab / Relatlimab, Tafasitamab, Bimekizumab, Crizanlizumab, Mirikizumab, Ravulizumab, Sutimlimab, Netakimab, Daratumumab / Hyaluronidase-fihj, Teclistamab, Loncastuximabtesirine, Cetuximab sarotalocan, Pabinafusp alfa, Mosunetuzumab, Ozoralizumab, Tebentafusp, Enlonstobart, Tagitanlimab, Narlumosbart, Genolizumab, Donanemab, Zuberitamab, Socazolimab, Denosumab biosimilar (Sandoz), Xeligekimab, Pozelimab, Elranatamab, Balstilimab, Crovalimab, Cosibelimab, Tafolecimab, Denosumab biosimilar (Qilu Pharma), Bevacizumab biosimilar (Oncobiologics), Zamerovimab / Mazorelvimab, Talquetamab, Narsoplimab, Bevacizumab biosimilar (Sinocelltech)(bevacizumab biosimilar (Sinocell)), Epcoritamab (Ecoruitumab), Rituximab biosimilar (Mabion)(Rituximab biosimilar (Mabion)), Rituximab biosimilar (Siam Bioscience)(Rituximab biosimilar (Siam Bioscience)), Ranibizumab biosimilar (Qilu Pharmaceutical))(Ranibizumab biosimilar (Qilu Pharmaceutical)), Trastuzumab biosimilar (Tanvex Biopharma))(Trastuzumab biosimilar (Tanvex Biopharma)), Trastuzumab biosimilar (CTTQ Pharma))(Trastuzumab biosimilar (Zhengda Tianqing)), Adalimumab biosimilar (Sinocelltech))(Adalimumab biosimilar (Shenzhou Cell Engineering)), Trastuzumab biosimilar (Anke Biotech))(Trastuzumab biosimilar (Anke Biotech)), Denosumab biosimilar (Alphamab))(Denosumab biosimilar (Alphamab)), Cetuximab biosimilar (Shanghai Zhangjiang Biotechnology))(Cetuximab biosimilar (Shanghai Zhangjiang Biotechnology)), Rituximab biosimilar (Nichi-Iko / Aprogen), Tocilizumab biosimilar (Hisun Biopharma), Pertuzumab biosimilar (Qilu Pharmaceutical), Tocilizumab biosimilar (Hetero Biopharma), Tocilizumab biosimilar (Jinyu Bowo Runze Biotech), Trastuzumab biosimilar (EirGenix / Sandoz), Lenzilumab, Omburtamab I-131, TQB-2450, Rozanolixizumab, Trastuzumab duocarmazine, follicle stimulating hormonebiosimilar (Livzon) (recombinant human follicle-stimulating hormone biosimilar (Livzon monoclonal antibody)), Genakumab, Ongericimab, Suciraslimab, Coprelotamab, Pembrolizumab / Quavonlimab, Fianlimab, Nofazinlimab, Freneslerbart / Mevonlerbart, Sevacizumab, Bamlanivimab, Denosumab biosimilar (AryoGen), Sibeprenlimab, Lirentelimab, Cobolimab, Erfonrilimab, Bevacizumab biosimilar (Hualan Biological Engineering), Nipocalimab, Amubarvimab, Gumokimab, Obexelimab, Imdevimab, Cendakimab, Nisevokitug, Vibostolimab, Divozilimab, Domvanalimab, Recombinant anti-VEGFR2 chimeric monoclonalyantibody (GeneScience) (Gentuximab), Zilovertamab, Vilobelimab, Glenzocimab, Relatlimab, Sasanlimab, Finotonlimab, Astegolimab, Anbenitamab, Mertuzumab, Pembrolizumab / Vibostolimab, Ba toclimab, meplazumab, ziltivekimab, birtimab, anselamimab, depemokimab, garetosmab, ivuxolimab, itepekimab, latozinemab, rulonilimab, garadacimab, plonmarlimab, eculizumab biosimilar (CinnaGen), Recaticimab, Anvatabartopadotin, Magrolimab, Denosumab biosimilar (Intas Biopharmaceuticals), Ebdarokimab, Ulviprubart, Ebronucimab, Bentracimab, Tozorakimab, Upanovimab, Felzartamab, Levilimab, Tarlatamab, Ociperlimab, Eculizumab biosimilar (Biocad), Odronextamab, Tocilizumab biosimilar (Fresenius kabi), Adalimumab biosimilar (Incepta), Adalimumab biosimilar (CinnaGen), otilimab, lemzoparlimab, trastuzumab biosimilar (Hetero), datopotamab deruxtecan, tebotelimab, mavezelimab / pembrolizumab, adalimumab biosimilar (Hualan Biological Engineering), pertuzumab biosimilar (CinnaGen), romlusecimab, omalizumab biosimilar (Synermore Biologics)(omalizumab biosimilar (Synermore Biologics)), Adalimumab biosimilar (Oncobiologics)), Apitegromab, Bemarituzumab, Tocilizumab biosimilar (AryoGen Pharmed)Pharmed), Zanidatamab, Feladilimab, Bevacizumab biosimilar (Centus Biotherapeutics), Omalizumab biosimilar (Mabtech), Zilovertamab vedotin, Rituximab biosimilar (CTTQ Pharma), Rituximab biosimilar (Hualan Biological Engineering), Imsidolimab, Trastuzumab biosimilar (Hanwha Biologics), Adalimumab biosimilar (Hetero Drugs)(adalimumab biosimilar (Hetero Drugs)), Becotatug, Eculizumab biosimilar (IBC GENERIUM), Enibarcimab, Simaravibart, Rocatinlimab, Bevacizumab biosimilar (Alphamab / R-Pharm), Pertuzumab biosimilar (CTTQ), Cetuximab biosimilar (R-Pharm), Rituximab biosimilar (Boehringer Ingelheim) Ingelheim), PatritumabDeruxtecan, Denosumab biosimilar (Celltrion), Eculizumab biosimilar (SamsungBioepis)(Eculizumab biosimilar (Samsung Bioepis)), Trastuzumab biosimilar (Alteogen) (Trastuzumab biosimilar (Qilu Pharmaceutical)), Ustekinumab biosimilar (Qyuns) (Ustekinumab biosimilar (Qyuns)), Rituximab biosimilar (Samsung) (Rituximab biosimilar (Samsung)), Pertuzumab biosimilar (Xuanzhu / SL) (Pertuzumab biosimilar (Xuanzhu / Shuanglu)), Cetuximab biosimilar (Kelun Group) (Cetuximab biosimilar (Kelun Group)), Bevacizumab biosimilar (Prestige BioPharma / Hanwha Biologics) (Bevacizumab biosimilar (Prestige BioPharma / Hanwha Biologics)), TusamitamabRavtansine (Ravitetuzumab), Ranibizumab biosimilar (Reliance Life Sciences Group) (Ranibiximab biosimilar (Reliance Life Sciences Group)), Eculizumab biosimilar (Amgen) (Eculizumab biosimilar (Amgen)), Ipilimumab biosimilar (Innovent Biologics) (Ipilimumab biosimilar (Innovent Biologics)), Trastuzumab rezetecan, Recombinant humanized monoclonal antibody MIL62, Nimotuzumab biosimilar (IBC Generium), QL1203, Bevacizumab biosimilar (Fudan-Zhangjiang), Pertuzumab biosimilar (Hisun Pharm), Adalimumab biosimilar (Tonghua Dongbao Pharmaceutical), Adalimumab biosimilar (Danhong Pharma), Cetuximab biosimilar (AlphaMab), Nimotuzumab biosimilar (El Kendi Pharmaceuticals Manufacturing), Ranibizumab biosimilar (Chong Kun Dang Pharmaceutical), Bevacizumab biosimilar (Genor Biopharma), Ranibizumab biosimilar (Lupin), Denosumab biosimilar (Mabxience), Denosumab biosimilar (Fresenius Kabi), Denosumab biosimilar (Alvotech Swiss), Denosumab biosimilar (Alvotech Swiss) Swiss)), Omalizumabbiosimilar (Alvotech), Recombinant human anti-RANKL momoclonal antibody (Qilu Pharmaceutical), Ustekinumab biosimilar (Formycon), Recombinant humanized anti-IL-6R antibody (Hisun Pharma), Bevacizumab biosimilar (Beijing Science Sun / Beijing Lvzhu), Rituximab biosimilar (Hisun Pharma / Beijing Mabworks Biotech), Denosumab biosimilar (Enzene Biosciences), Biosciences), Upifitamabrilsodotin, Cetuximab biosimilar (AMPO Biotechnology), Omalizumab biosimilar (Kashiv BioSciences), Bevacizumab biosimilar (Laboratorios Sophia), Ustekinumab biosimilar (Celltrion), Omalizumab biosimilar (Celltrion), Denosumab biosimilar (Hualan Biological Engineering), Ustekinumab biosimilar (DM Biotechnology), Bio)(Ustekinumab Biosimilar (DMBio), Girentuximab-Zr-89 (zirconium [89Zr] girentuximab), Secukinumab biosimilar (Bio-Thera Solutions), Omalizumab biosimilar (Reliance Life Sciences), Recombinant anti-HER2 humanized monoclonal antibody (Shanghai Institute of Biological Products), Vedolizumab biosimilar (Polpharma Biologics), Pembrolizumab biosimilar (biocad), Ustekinumab biosimilar (Bio-Thera), Pertuzumab biosimilar (Zydus Cadila) (pertuzumab biosimilar (Zydus Cadila)), Omalizumab biosimilar (Teva) (omalizumab biosimilar (Teva Pharmaceuticals)), Rituximab biosimilar (Genor Biopharma)(recombinant anti-CD20 human-mouse chimeric monoclonal antibody (Jiahe Bio)), Trastuzumab biosimilar (Aprogen / Nichi-Iko)), Adalimumab biosimilar (Huabo)), Denosumab biosimilar (Shanghai Hansoh)), Denosumab biosimilar (Henlius)), Rituximab Biosimilar (Shanghai Institute Of Biological Products)), Pertuzumab biosimilar (Shanghai Henlius Biotech)), Pertuzumab biosimilar (Jushi Biopharmaceutical)(Pertuzumab biosimilar (Shijiazhuang Pharmaceutical Group Jushi Biopharmaceutical)), Rituximab biosimilar (Shandong New Time Pharmaceutical) (recombinant anti-CD20 human-mouse chimeric monoclonal antibody (Shandong New Time Pharmaceutical)), Bevacizumab biosimilar (HuaotaBiopharm) (recombinant humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody (Huaota Biopharm / Junshi Biopharmaceuticals)), Bevacizumab biosimilar (Jiangsu Aosaikang) (bevacizumab biosimilar (Jiangsu Aosaikang)), Bevacizumab biosimilar (Zhejiang Teruisi Pharmaceutical) (bevacizumab biosimilar (Zhejiang Teruisi Pharmaceutical)), Catumaxomab, Glutazumab (recombinant anti-human GLP-1 receptor humanized monoclonal antibody), Iodine 131 tositumomab, Solanezumab, TAB-014, Ivonescimab, Tarcocimabtedromer, Sirukumab, Tanezumab, Fasinumab, Monalizumab, Emactuzumab, Golimumabbiosimilar(Bio-thera)(recombinant anti-tumor necrosis factor alpha fully human monoclonal antibody(Biotera)), Bevacizumab biosimilar(Boehringer Ingelheim), Etrolizumab, Gantenerumab, Denosumab biosimilar(Samsung Bioepis), Inclacumab, Rovalpituzumabtesirine, Oportuzumabmonatox, Natalizumab biosimilar(Polpharma Biologics), Brazikumab, Dapirolizumab pegol, Inolimomab, Mavrilimumab, CMAB806(recombinant anti-IL-6R humanized monoclonal antibody), Lebrikizumab, Roledumab, Trastuzumab monomethyl auristatin F, Onartuzumab, Ocrelizumab biosimilar(CinnaGen), Infliximab biosimilar (Biocad) (infliximab biosimilar (Biocad)), SB-17 (Samsung Bioepis), Ogalvibart / Crexavibart, Recombinant anti-IgE monoclonal antibody (CspcBaike) (recombinant anti-IgE monoclonal antibody (Shijiazhuang Pharmaceutical Group Baike)), Humanized IgG1κmonoclonal antibody (Viridian), Picankibart, MTX-005, MK-3475A, GR-1801, AZD5156, QL1604, REGN-5713 / REGN-5714 / REGN-5715, HL-02, Recombinant chimeric anti-CD20 antibody (Shanghai Institute of BiologicalProducts)(recombinant human-mouse chimeric anti-CD20 monoclonal antibody (Shanghai Institute of Biological Products)), Semzuvolimab, Carotuximab, Basiliximabbiobetter (Mabtech / Sorrento), Porgaviximab / Larcaviximab / Cosfroviximab, Futuximab / Modotuximab, Zolbetuximab, ABP-300, JY-025(recombinant anti-VEGFR2 fully human monoclonal antibody), Recombinant anti-TNFαmonoclonal antibody(Wuhan Institute of Biological Products)(recombinant fully human anti-human TNF-α monoclonal antibody (Wuhan Institute of Biological Products)), CMAB807, Oleclumab, TNM-002, Tosatoxumab, Clesrovimab, Setrusumab, Cetrelimab, Ianalumab, Recombinant human anti-TNFαmonoclonal antibody(Huaota Biopharma) (recombinant fully human anti-TNF α monoclonal antibody (Hua-O-Tai Biopharma)), SAB-185, Ontamalimab, RO-7200220, Pamrevlumab, Abelacimab, Ganitumab, Tiragolumab, Utomilumab, BDB-001, Marstacimab, Suvratoxumab, Oregovomab, ANX-005, SSGJ-608, Ligelizumab, Spartalizumab, Gotistobart, Clazakizumab, Sabatolimab, Leronlimab, Andecaliximab, Concizumab, Paridiprubart, Iparomlimab / Tuvonralimab, Vunakizumab, Litifilimab, Olokizumab, CM-310, Retlirafusp alfa, TVB-009, Varisacumab, Tocilizumab biosimilar (Celltrion), TR-009, PM-8002, Mim8, Navicixizumab, Izalontamab, Gefurulimab, Vobramitamabduocarmazine, Telisotuzumabvedotin, Bintrafusp alfa, Depatuxizumabmafodotin, SGM-101, I-131-Apamistamab, Recombinant anti-TNFα monoclonal antibody (Livzon Group), Lipustobart, Recombinant human IL-17A / F humanized antibody (Livzon Pharmaceutical Group)(Recombinant anti-human IL-17A / F humanized monoclonal antibody (Livuzumab)), recombinant humanized anti-Trop2 monoclonal antibody-SN38 conjugate, Guselkumab / Golimumab, Tifcemalimab, Ametumumab, Ligufalimab, Demupitamab, Bafisontamab, Dresbuxelimab, Manfidokimab, Mezagitamab, Sudubrilimab, Zalifrelimab b (Zevlimab), Uliledlimab, Pulocimab, Ponsegromab, MIL-86 (recombinant fully human monoclonal antibody MIL86), Volrustomig, Pradusinstobart, Quavonlimab, Tobemstomig, Rilvegostomig, Enoblituzumab, Pimurutamab, Exlinkibart, Etesevimab, Bevacizumab biosimilar (Eastern Biotech) (recombinant humanized anti-VEGF monoclonal antibody (Eastern Biotech)), Alemtuzumabbiosimilar (Zhangjiang Biotechnology)(alemtuzumab biosimilar (Shanghai Zhangjiang Biotechnology)), Recombinant anti-EGFR chimeric monoclonal antibody (Shanghai CP Guojian)(recombinant anti-EGFR human-mouse chimeric monoclonal antibody (Sansheng Guojian)), Recombinant anti-HER2 antibody-Tub114(recombinant humanized anti-Her2 monoclonal antibody-Tub114 coupling agent), Recombinant anti-IL-17A humanized monoclonal antibody (Shanghai Junshi Biosciences)(recombinant humanized anti-IL-17A monoclonal antibody(Shanghai Junshi)), DP-303c(recombinant humanized anti-HER2 monoclonal antibody-MMAE conjugate drug(Shijiazhuang Pharmaceutical Group Zhongqi Pharmaceutical)), SHR-1703, JAB-BX102, ZS-05, SHR-1905, FAZ-053, 9MW1411, ADG-104, TQH2722, BSI-045B, CM313(Institute of Hematology&Blood Diseases Hospital), CAN-106, CD20 monoclonal antibody(The First Affiliated Hospital of Soochow University), ASKB-589, BGB-DXP604, ZL-1211, CM-326(Connaught Biomedical Technology), CM-338(Connaught Biomedical Technology), KD-6001, LM-101, Afimetoran, CM-313 (Connaught Biomedical Technology), Carrizumab, Peramprizumab, KN-057, BGB-A445, SHR-1802, BAY-1158061, DXP-593, Modakafusp alfa (Mocafusp-α), CBP-201, Teprotumumab biosimilar(Innovent), Humanized anti-EGFR monoclonal antibody(Hualan Biological Engineering / Henan shengmingbiotechnology)(recombinant anti-EGFR fully human monoclonal antibody), Lesabelimab, Teropavimab, Human Respiratory Syncytial Virus Monoclonal Antibody, Iscalimab, Anti-CD3 monoclonal antibody(Jinan Tiankang Biological Products), LY-CovMab, MW-33, Recombinant human anti-PCSK9 monoclonal antibody(Salubris)(recombinant fully human anti-PCSK9 monoclonal antibody(Xinlitai)), ADG-106, LBL-007, Recombinant anti-CTLA-4 human monoclonal antibody(Hualan Biological Products Engineering)(Recombinant anti-CTLA-4 fully human monoclonal antibody (Hualan Gene Engineering)), MK-4830, CS-1002, HLX-22, DS-002, VDJ-001, HLX-26, PRL3-zumab, HS-20093, Osemitamab, Getagozumab, Peresolimab, YH-001, Recombinant anti-IL-4Rαhumanized monoclonal antibody (Sansheng Guojian)(Recombinant anti-IL-4Rαhumanized monoclonal antibody (Sansheng Guojian)), YH-003, Recombinant humanized monoclonal antibody antiIL-1β(Cp Guojian)(Recombinant Anti-IL-1β humanized monoclonal antibody (Sunshine Guojian), MG-K10, NGM-313, LBL-019, Recombinant humanized anti-PD-1 monoclonal antibody (Anhui Anke Biotechnology), Recombinant humanized PD-L1 monoclonal antibody (Taizhou HoudeAoke Technology), Recombinant humanized anti-ST2 monoclonal antibody, HH-003, LM-108, Recombinant anti-IL-5 humanized monoclonal antibody (Shanghai CP Guojian), Recombinant humanized anti-PD-1 monoclonal antibody (Shanghai CP Guojian), Guojian)(recombinant anti-PD-1 humanized monoclonal antibody(Sunshine Guojian)), BIVV-020, IAP-0971, IAE-0972, GB-263, PM-8003, GB-261, HLX-301, EMB-06, Recombinant anti-PD-L1 / TGF-β bispecific antibody(recombinant anti-PD-L1 and TGF-β bispecific antibody), HX-009, PD-L1 / CTLA4 bispecific monoclonal antibody(Changhai Hospital), M-701, PM-1003, EMB-02, MBS-303, IMM-2902, SI-B003, ZG-005, CN-201, MCLA-129, LBL-033, CM-336(Connaught Biomedical Technology), 6MW-3211, CM-350, CM-355(Beijing TiannuoJiancheng / Connaught BiomedicalTechnology), IMM-0306, HB-0028, PM-8001, AZD-7789, Ifinatamabderuxtecan, RC-118, BB-1701, Emfizatamab, LBL-015, HB-0025, ZGGS-18, TQB-2868, BPB-101, BL-B01D1, Anti-CD3 and anti-HER2 BiTE-expressing T cell(MedImmune), Mupadolimab, Sirexatamab, Acapatamab, Danburstotug, Zigakibart, Porustobart, Ascrinvacumab, Tegoprubart, PE-0116, ADG-116, ADG-126, BI-1206, UB-221, PF-06823859, SAR-439459, Posdinemab, GSK3174998, UB-621, TST-003, Rozibafusp alfa, 1-A-46, HB-0036, CN-202, Anetumabravtansine, ND-021, Zenocutuzumab, Bermekimab, Zeluvalimab, Rituximab biosimilar (JHL Biotech)Biotech), Crenezumab, Osocimab, Tesnatilimab, Volagidemab, Amlitelimab, CJM-112, PRV-3279, Fepixnebart, Tulisokibart, Vilamakitug, Izuralimab, Vudalimab, Ivicentamab, Nimacimab, Ieramilimab, Ordesekimab, Pacmilimab, Sotevtamab, Bexmarilimab, Lomtegovimab, Zelminemab Monoclonal antibody, Murlentamab, Boserolimab, Lonigutamab, Bepranemab, Ulenistamab, Budigalimab, Vixarelimab, Unasnemab, Gremubamab, Sotigalimab, Mitazalimab, Quetmolimab, Olinvacimab, Praluzutatamab, Bravtansine, Perenostobart, Casdozokitug, Zagotenemab, Sonelokimab, Omalizumab biosimilar (Glenmark) Omazumab biosimilar (Glenmark), Plamotamab, Daxdilimab, Lorigerlimab, Cevostamab, Belrestotug, Obrindatamab, Atibuclimab, Polzastobart, Tuparstobart, Siplizumab, Devextinetug, Ragifilimab, 89Zr-Df-crefmirlimab, Acasunlimab, Trastuzumabimbotolimod, trastuzumab Dusigitumab, Fresolimumab, Conatumumab, Ulocuplumab, Fezakinumab, Bimagrumab, Urelumab, Ontuxizumab, Tabalumab, Otelixizumab, Seribantumab, AI011 Cixutumumab, Farletuzumab, Orticumab, Prezalumab, Naptumomabestafenatox, Glembatumumabvedotin, Bavituximab, Emibetuzumab, Dalotuzumab, Adalimumab biosimilars (180 Therapeutics) 、Intravitreal ranibizumab (Sultan Qaboos University) 、BMS-986288、BMS-986340、VGL-101、TB-006、AU-007、ABBV-916、REGN-14256、Middle-East respiratory syndrome coronavirus vaccines MK-0482, BA-3071, KPL-404, FPI-1434, Belantamab, STI-2099, VB-119, S-531011, NNC6019-0001, IMA B-027、AZD-8853、LY-3361237、BI-1808、Sym-015、MEDI-5884、VIR-3434、BMS-986207、NGM-120、ICT-01 (Imcheck Therapeutics) 、TLX-592、Anti-interleukin-6 receptor monoclonal antibody (Biocad) 、Lu AF-82422 (Lundbeck A / S) 、Telazorlimab、RG-6173、VRC-MALMAB0100-00-AB、HMBD-001、NC-762、2141-V11、ALD-1910、XTX -101、BMS-986179、BMS-986156、BI-1607、QLS-215、BMS-986315、AZD-0171、IBIO123、BMS-986218 (Bristol-Myers Squibb)REGN-9933, DISC-0974, BMS-986249, Anti-placental growth factor monoclonal antibody, ALLO-647, VIR-2482, LY-3041658, Stromab-5, SCT (National Cancer Institute) Basiliximab、KappaMab、Frexalimab、RP-3、Visugromab、Anti-CD40 ChiLob7 / 4 (BioNTech)、Flysyn、Tilavonemab、VRC-HIVMAB091-00-AB、NI-004MAPhospholine-86 monoclonal antibody、DR-01、BMS-936559、Elezanumab、BMS-986012、F-598、Berlimatoxumab、GC-1118A、GSK-3810109、Bebtelovimab、INCAGN-02390-PGDM 1400、Foralumab、HuMax-IL8、VRC-01、Ichorcumab、COR-101、Atinumab、SRF-114、BI-836858、CDX-1140、Fiztasovimab、Panityemab 80-CRDW (Stanford University) PD-360324, ARGX-112, Cifurtilimab, FB-704A, Bleselumab, Atidortoxumab / Berlimatoxumab, Aerubumab, Varlilumab, BMS-986 178、MT-2990、Begelomab、Durvalumab / Gefitinib、BMS-986258、Zinlirvimab、VRC-07-523、LY-3022855、Camoteskimab、Anti-MUC1 monoclonal antibody (OncoQuest) 、AL-002、XOMA-358、KVA-12123、Acrixolimab、Anti-RSV G antibodies (AIMM Therapeutics) 、CMK-389、IMT-009、PAT-SC1、OR-2805、LKA-651、MBL-HCV1、Monoclonal antibodyBR55-2、Dectrekumab / VAK-694、PGT-121、MH-1 (American Biogenetic) 、Gimsilumab、VIS-410、Diridavumab、MVT-5873、INCAGN-1949、AMG-820、Timolumab、Rasdegafusp alfa、Lirilumab、Namilumab、NN-9828、XAV-19、NEO-201、ATL-101、Talacotuzumab、Etigilimab、sirpiglenastat、bevacizumab (hereditary hemorrhagic telangi, Hospitalization Lesions) 、P-006、Ficlatuzumab、LY-2928057、Ravagalimab、ASP-0739 (Astellas Pharma Inc) 、Herpevizumab, Burfiralimab, Briquilimab, Domagrozumab, Tregalizumab, GSK-2330811, GSK-1070806, NP-137, YS-110, BND-22, Lugol-78 and Lugol (Novartis) 、COM-701、Prasinezumab、Xisomab 3G3 (Oregon Health&Science University) CM-24, Rosnilimab, NGM-621, MEDI-0680, Temelimab, CSL-346, Pidilizumab, ARGX-117, Cabiralizumab, Bevacizumab-IRDye800CW (University Hospital Groningen) 、BI-655064、Neihulizumab、AO-176、ANX-007、Cusatuzumab、89Zr-DFO-huJ591、Xentuzumab、Humanized monoclonal anti-GD2 antibody (St Jude Children's Research Hospital) 、G03-52-01、ZB-131、VRC-MALMAB0114-00-AB、VRC-01-LS、LIS1、NC-318、NM-8074、IPH-5201、 EU-101、Lenvervimab、YYB-101、ASP-5094、Lacnotuzumab、BVX20-CD20 antibody(Biocon / Vaccinex)、Vopratelimab、Anti-CEmX monoclonal antibody(Fountain Biopharma)、SelK-2、OSE-279、JK-08、LMB-2、FBR-002、AOC-1020、AMG-133、GEN-3014 、LYT-200、HDP-101、SAR-445877、FR-104、SAR-443579、LMB-100、CONV-01-alpha+PSMA I&T、HPN-424、NGM-707、AGEN-1777、GEN-1047、NVG-111、HL-301、CC-1、ISB-1442、REGN -5459、IMC-I109V、AFM-24、MEDI-7352、AFM-13、REGN-5668、GNR-084、LB-101(Centessa Pharmaceuticals)、AP-203、FS 118、REGN-5678、TAK-280、Fazpilodemab、Enapotamabvedotin、REGN-5093、HMB- 001、CKD-702、REGN-4336、Imvotamab、REGN-7075、Azintuxizumab、Dalutrafusp alpha、RO7515629、Tidutamab、Cinrebafusp alpha, LAVA-051, YH-32367, IMC-F106C, Indatuximabravtansine, Camidanlumabtesirine, Lorvotuzumabmertansine. Ladiratuzumabvedotin、Pivekimabsunirine、AGS-16C3F、Mecbotamabvedotin、NBE-002、Pinatuzumabvedotin、Naratuximab emtansine、HPN-536、225Ac-J591、LAVA-1207、Romilkimab、Flotetuzumab、Linvoseltamab、Istiratumab、HPN-328、Trontinemab、Cibisatamab、Ab izumab 21BC8-B10, Lutetium(177lu)lilotomabsatetraxetan, 89Zr-durvalumab, BI-836880, 90Y-DTPA-besilesomab, Lintuzumab Ac-225 (Actinium Pharmaceuticals), 90Y-HAT (NCI), Tc99-labeled 14F7 humanized mAb (The Center of Molecular Immunology), Anti-CD3 / anti-EGFR-activated T cells (Barbara Ann Karmanos Cancer Institute), Lutetium-177 DOTA girentuximab, Radretumab; The treatment is BiTE treatment, and the BiTE treatment is a treatment with a drug selected from the group consisting of Anti-CD3 and anti-HER2 BiTE-expressing T cell (MedImmune), Blinatumomab; The treatment is a dual-antibody treatment, which is a treatment with a drug selected from the following group: Blinatumomab, Teclistamab, Glofitamab, Emicizumab, Amivantamab, Faricimab, Mosunetuzumab, Cadonilimab, Ozoralizumab, Tebentafusp, Elranatamab, Epcoritamab, Talquetamab, TR-009, PM-8002, Anbenitamab, Mim8, Tebotelimab, Navicixizumab, Ivonescimab, Izalontamab, Zanidatamab, Gefurulimab, Bintrafusp alfa (bitefupu α), Catumaxomab, Odronextamab, Tarlatamab, Erfonrilimab, PD-L1 / CTLA4 bispecific monoclonal antibody (Changhai Hospital), HX-009, Lomvastomig, NGM-707, AGEN-1777, GEN-1047, NVG-111, HB-0036, EMB-06, Recombinant anti-PD-L1 / TGF-β bispecific antibody (recombinant anti-PD-L1 and TGF-β bispecific antibody), IMM-2902, MBS-303, M-701, HL-301, CC-1, GB-261, HLX-301, Bafisontamab, ISB-1442, REGN-5459, EMB-02, PM-1003, IMC-I109V, AFM-24, Petosemtamab, MEDI-7352, Acapatamab, AFM-13, SI-B003, ZG-005, REGN-5668, GNR-084, LB-101 (Centessa Pharmaceuticals), CN-201, Acasunlimab, AP-203, FS118, MCLA-129, LBL-033, Tobemstomig, Volrustomig, REGN-5678, TAK-280, Tecaginlimab, CM-336 (Connaught Biomedical Technology), 6MW-3211, CM-350, Fazpilodemab, Bavunalimab, Izuralimab, REGN-4336, Imvotamab, REGN-7075, Plamotamab, Azintuxizumab, Dalutrafusp alfa, CM-355 (Beijing TiannuoJiancheng / Connaught Biomedical Technology), IMM-0306, Rilvegostomig, Cevostamab, Tidutamab, Vudalimab, RO7515629, Cinrebafusp alfa (Hibifupu α), CN-202, REGN-5093, HMB-001, CKD-702, PM-8001, Ivicentamab, IMC-F106C, HB-0028, LAVA-051, YH-32367, Lorigerlimab, AZD-7789, Ubamatamab, LBL-015, LAVA-1207, Romilkimab, Flotetuzumab, Zenocutuzumab, Linvosel Tamab, Istiratumab, Gremubamab, Trontinemab, Cibisatamab, HB-0025, lutikizumab, ZGGS-18, PRV-3279, BPB-101, Obrindatamab, TQB-2868, Gontivimab, BL-B01D1, BI-836880, Tarperprumig, Anti-CD3 / anti-EGFR-activated T cells(Barbara Ann Karmanos Cancer Institute), Anti-CD3 and anti-HER2 BiTE-expressing T cell(MedImmune).

16. The use according to claim 9, characterized in that The antigen binding domain in the chimeric antigen receptor (CAR) expressed by the CART is ScFv or VHH.

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