WO2020177627A1 - Anticorps bispécifique - Google Patents

Anticorps bispécifique Download PDF

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WO2020177627A1
WO2020177627A1 PCT/CN2020/077181 CN2020077181W WO2020177627A1 WO 2020177627 A1 WO2020177627 A1 WO 2020177627A1 CN 2020077181 W CN2020077181 W CN 2020077181W WO 2020177627 A1 WO2020177627 A1 WO 2020177627A1
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bispecific antibody
msh
binding domain
antibody
receptor
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PCT/CN2020/077181
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Chinese (zh)
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王峰
郑花鸯
张雨菡
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上海一宸医药科技有限公司
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Priority to CN202080006179.5A priority Critical patent/CN113272330A/zh
Publication of WO2020177627A1 publication Critical patent/WO2020177627A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells

Definitions

  • the present invention relates to a bispecific antibody, especially a bifunctional antibody directed against tumor cell surface antigen and immune checkpoint protein at the same time, and a pharmaceutical composition and application thereof.
  • immune checkpoint inhibitors represented by programmed death receptor 1 (PD-1) and its ligands (PD-L1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a milestone in tumor treatment
  • FDA U.S. Food and Drug Administration
  • NSCLC non-small cell lung cancer
  • RRC Renal cell carcinoma
  • urothelial carcinoma urothelial carcinoma
  • non-Hodgkin’s lymphoma have demonstrated exciting therapeutic effects, effectively prolonging the survival period of patients (Li Hanzhong et al. Peking Union Medical College 2018; 9(4): 289- 294).
  • immune checkpoint inhibitors Although the successful clinical application of immune checkpoint inhibitors has changed the treatment mode of many cancers, due to the high heterogeneity of human tumors, in addition to classic Hodgkin’s lymphoma, fibroproliferative melanoma, and Merkel Cell carcinoma and cancers with highly unstable microsatellites show a higher response rate (40%-80%).
  • the objective response rate of a single immune checkpoint inhibitor is in NSCLC, RCC, head and neck cancer, liver cancer, and urinary tract.
  • Skin cancer and other solid tumors usually do not exceed 20-30% (Borghaei H, et al. NEJM 2015, 373(17): 1627-1639; Motzer RJ, et al. NEJM 2015 373(19): 1803-1813), At the same time, there will be an inevitable problem of drug resistance, and there are still few patients who can obtain a lasting effect.
  • immune checkpoint inhibitors have been combined with other drugs to play a complementary role in tumor killing and overcome the insufficient response rate of immune checkpoint inhibitors, which has become one of the research hotspots in the field of tumor immunity.
  • the combination medication greatly improves the objective response rate of immune checkpoint inhibitors, its side effects also increase.
  • Larkini J et al. combined the immune checkpoint inhibitors Nivolumab and Ipilimumb, and the objective remission in the treatment of melanoma was 58%, which was much higher than the objective remission rates of Nivolumab and Ipilimumab alone (43.7% and 19%, respectively).
  • grade 3-4 adverse reactions related to combination medication was 55.0%, and the rate of drug withdrawal due to medication toxicity was as high as 36.4%, which was much higher than the ratio when Nivolumab or Ipilimumab were used alone: with Nivolumab and Ipilimumab alone
  • the incidence of treatment-related grade 3-4 adverse reactions was 16.3% and 27.3%, respectively, while the rates of treatment termination due to the toxicity of Nivolumab and Ipilimumab were 7.7% and 14.8%, respectively (Larkini J et al. NJEM 2015; 373: 23-34). Hammers HJ et al.
  • PD-1 inhibitor nivolumab and CTAL-4 inhibitor ipilimumab in the treatment of advanced renal cell carcinoma with an objective response rate of 42.1% to 36.8%, and a 2-year survival rate of 69.6% to 67.3%, suggesting that the combined treatment effect may be superior In monotherapy, but the side effects of combined therapy are more serious than monotherapy (Hammers HJ et al. J Clin Oncol 2017; 35(34):3851-3858).
  • the study of PD-1 inhibitor combined with vascular endothelial growth factor inhibitor targeted drugs in the treatment of renal cancer has also shown the superiority of combined therapy.
  • the objective response rate of nivolumab combined with sunitinib in the treatment of metastatic clear cell renal cell carcinoma is 52%.
  • the present invention uses the first binding domain (e.g., polypeptide) that specifically targets the tumor surface antigen as a delivery vehicle, and aggregates the immune checkpoint inhibitor (e.g., anti-PD-L1 antibody) connected to it on tumor cells, or
  • the attachment and the tumor microenvironment greatly reduce the extensive immune activation caused by the use of conventional immune checkpoint inhibitors in the body.
  • the present invention relates to a bispecific antibody, which comprises: a first binding domain targeting an immune checkpoint protein and a second binding domain targeting a tumor cell surface antigen.
  • the first binding domain of the bispecific antibody of the present invention targets the immune checkpoint protein PD-L1, and the second binding fragment targets the tumor cell surface antigen MC1R.
  • the first binding domain of the bispecific antibody of the present invention is an antibody targeting PD-L1
  • the second binding domain is a polypeptide ⁇ -MSH, ⁇ MSH or (NDP)MSH targeting MC1R.
  • the C-terminus of the second binding domain of the bispecific antibody of the present invention is connected to the N-terminus of the heavy chain or light chain variable region of the first binding domain through a connecting peptide.
  • the N-terminus of the second binding domain of the bispecific antibody of the present invention is connected to the C-terminus of the heavy chain or light chain variable region of the first binding domain through a connecting peptide.
  • the N-terminus and or C-terminus of the second binding domain of the bispecific antibody of the present invention is inserted into the CDR1-H, CDR2-H, CDR3-H, Within CDR1-L, CDR2-L or CDR3-L.
  • the second binding domain of the bispecific antibody of the present invention is coupled to the first binding domain through a chemical linker.
  • the present invention also relates to a nucleic acid, which encodes the bispecific antibody of the present invention.
  • the present invention also relates to an expression vector comprising the nucleic acid of the present invention.
  • the present invention also relates to a host cell comprising the expression vector of the present invention.
  • the present invention also relates to a pharmaceutical composition comprising the bispecific antibody of the present invention.
  • the present invention also relates to the use of bispecific antibodies in the preparation of medicines for the treatment of autoimmune diseases or cancer.
  • the present invention fuses tumor surface antigen-specific polypeptides such as ⁇ -MSH or ⁇ MSH with antibodies against immune checkpoint proteins, such as heavy or light chains of anti-PD-L1, or combines (NDP) MSH with antibodies against immune checkpoint proteins
  • immune checkpoint proteins such as heavy or light chains of anti-PD-L1
  • NDP combines
  • the resulting bifunctional antibody can simultaneously target the MC1R antigen and PD-L1 antigen on tumor cells, antagonize the function of MC1R, and block the relationship between PD-L1 and PD-1
  • the inter-signal pathway specifically promotes the immune cells surrounding tumor cells, such as T cells from an incompetent state to an activated state, and exerts the specific killing effect of immune cells on tumor cells.
  • the anti-tumor cell surface antigen polypeptide ⁇ -MSH, ⁇ MSH or (NDP) MSH is used as a delivery carrier, and it is connected to the binding domain of the targeted immune checkpoint protein (such as anti-PD-L1) through a connecting peptide or chemical linker.
  • Antibody connection, by targeting specific targets on the surface of tumor cells with high affinity, and gathering functional molecules for immune checkpoints on tumor cells, or its vicinity and within the tumor microenvironment, the immune checkpoints can be regulated (inhibited Or enhance) the specific killing effect of effector cells on tumor cells is limited to the tumor or tumor microenvironment, which greatly reduces the extensive immune activation caused by the use of conventional immune checkpoint modulators in the body; at the same time, with the help of delivery vectors
  • the high affinity of tumor-specific antigens can adjust the affinity or functional activity of effector molecules to immune checkpoints within a certain range, and has a wide range of clinical applications.
  • Figure 1 is a bispecific antibody SDS-PAGE, where M is the protein marker, Ave is the Avelumab antibody, A is the MSH-SynL fusion antibody (MSH-SynL fusion), and B is the MSH-Ate antibody light chain fusion.
  • Antibody MSH-AteL fusion
  • C is the fusion of MSH and Ate antibody heavy chain (MSH-AteH fusion)
  • + represents adding reducing agent DTT when loading
  • Figure 2 shows the results of antibody gel exclusion chromatography
  • Figure 3 shows the comparison of the binding ability of different antibody conjugates or different fusion forms to the antigen PD-L1
  • Figure 4 shows the binding of different antibody conjugates or different fusion forms to MC1R on the surface of HER293-MC1R cells ( Figures 4A and 4C), and free MSH inhibitory antibody conjugates or fusion double antibodies to HER293-MC1R cells Surface bonding ( Figure 4B and 4D)
  • Figure 5 shows the binding of different antibody conjugates or different fusion forms of double antibodies to B16.SIY cells
  • Figure 6 shows that different antibody conjugates or different fusion forms of double antibodies stimulate signal transduction in HER293-MC1R cells
  • FIG. 7 shows the serum stability of different antibody conjugates
  • Figure 8 shows the effect of 5mg/kg (NDP) MSH-Ave conjugate on the size of tumor mass in B16-SIY tumor-bearing mice, where the arrow indicates the time point of administration
  • Figure 9 shows the proportion of tumor-infiltrating lymphocytes (TILs) in B16-SIY tumor-bearing mice after receiving different doses of double antibodies.
  • Group a normal saline group; group b: 5 mg/kg Ave injection group; group c: 1 mg/kg Ave injection group; group d: 5 mg/kg NR-Ave conjugate injection group; group e: 1 mg/kg NR-Ave conjugate Injection group; group f: 5mg/kg (NDP) MSH-Ave conjugate injection group; group g: 1mg/kg (NDP) MSH-Ave conjugate injection group.
  • NDP tumor-infiltrating lymphocytes
  • the "bispecific antibody” of the present invention is an antibody with two different antigen binding specificities. Where the antibody has more than one specificity, the recognized epitope can bind a single antigen or bind more than one antigen.
  • Antibody specificity refers to the selective recognition of specific epitopes of an antigen by antibodies. Natural antibodies are, for example, monospecific.
  • the antibody of the present invention is directed against two different antigens, one of which is tumor cell surface antigen and the other is immune checkpoint protein.
  • the first antigen-binding fragment and the second antigen-binding fragment are chemically coupled.
  • the first antigen-binding fragment and the second antigen-binding fragment of the bispecific antibody of the present invention are connected by a connecting peptide.
  • tumor surface antigen includes proteins or polypeptides that are preferentially expressed on the surface of tumor cells.
  • preferentially expressed means that the antigen is expressed on tumor cells at least 10% higher than the expression level of the antigen on non-tumor cells (e.g., 10%, 20%, 30%, 40%, 50%). %, 60%, 70%, 80%, 90%, 100%, 110%, 150%, 200%, 400% or higher).
  • the target molecule is an antigen that is preferentially expressed on the surface of selected tumor cells (such as solid tumors or hematological tumor cells): non-limiting examples of specific tumor-associated antigens include, for example, EGFR, HER2, HER3, HER4, MUC1, MUC2, MUC3A, MUC3B, MUC4, MUC5AC, MUC5B, MUC6, MUC7, MUC8, MUC12, MUC13, MUC15, MUC16, MUC17, MUC19, MUC20, VEGFR-1 (FLT1), VEGFR-2 (KDR/FIK-1 ), VEGFR-3, PDGF-RA, PDGF-RB, IGF-1R, IGF2B3, K-RAS, N-RAS, Bly-S (BAFF), BAFF-R, EpCAM, SAGE, XAGE-1b, BAGE, MAGE Protein (such as MAGE-1, MAGE-2, MAGE-3, MAGE-4, MAGE-6, MAGE-9,
  • CASP-8 cdc27, CDK4, CDKN2A, CLPP, COA-1, CPSF, Cw6, RANKL, DEK-CAN, DKK1, EFTUD2, elongation factor 2, ENAH (hMena), ETV6-AML1, EZH2, FLT3- ITD, FN1, G250, MN, CAIX, GnTVf, GPNMB, HERV-K-MEL, hsp70-2, IDO1, IL13Ra2, intestinal carboxyl esterase, kallikrein 4, KIF20A, KK-LC-1, KM- HN-1, LAGE-1, LDLR-Salcosyltransferase AS fusion protein, Lengsin, M-CSF, lactoglobulin-A, MART-1, Melan-A/MART-1, MART2, MCSP, mdm-2 , ME-1, Meloe, MMP-2, MMP-7, Mucin, MUM-1, MUM-2, M
  • Immune examination is a type of signal that regulates T cell receptor (TCR) antigen recognition during the immune response. Including costimulatory immune signals that stimulate immunity and co-suppressive immune signals that suppress immunity. Immune examination can prevent autoimmune damage caused by excessive activation of immune cells (for example, T cells). Tumor cells use the protective mechanism of the human immune system to overexpress immune checkpoint proteins, thereby inhibiting the anti-tumor response of the human immune system and forming an immune escape. Immune checkpoint therapy uses costimulatory signal agonists or co-inhibitory signal antagonists to allow the immune system to function normally.
  • TCR T cell receptor
  • Common immune checkpoint proteins include CD27, CD28, CD40, CD122, CD137, OX40, GITR, ICOS, A2AR, B7-H3, B7-H4, BTLA, CD40, CTLA-4, IDO, KIR, LAG3, PD-1 , PD-L1, PD-L2, TIM-3, VISTA, GARP, PS, CSF1R, CD94/NKG2A, TDO, GITR, TNFR and FasR/DcR.
  • Immune checkpoint proteins are mainly expressed on the surface of immune cells. Immune checkpoint proteins are also expressed on the surface of tumor cells.
  • PD-L1 is highly expressed on the surface of many tumor cells, such as lung cancer, breast cancer, malignant melanoma, esophageal cancer, gastric cancer, and pancreatic cancer.
  • the pharmaceutical composition as described herein is prepared by mixing the bifunctional antibody of the present invention with the desired purity and one or more optional pharmaceutically acceptable carriers, which is in the form of a lyophilized preparation or an aqueous solution.
  • the pharmaceutically acceptable carrier is generally non-toxic to the recipient at the dose and concentration used.
  • the bifunctional antibody of the present invention can be used as a single active ingredient or administered in combination with, for example, adjuvants or with other drugs such as immunosuppressive or immunomodulatory agents or other anti-inflammatory agents, for example for the treatment or prevention of acute lymphoblastic leukemia ( ALL), acute medullary leukemia (AML), adrenal cortical cancer, anal cancer, appendix cancer, astrocytoma, basal cell carcinoma, brain tumor, cholangiocarcinoma, bladder cancer, bone cancer, breast cancer, bronchial tumor, primordial cancer Special lymphoma, cancer of unknown primary origin, heart tumor, cervical cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, colon cancer, colorectal cancer, Craniopharyngioma, skin T-cell lymphoma, ductal carcinoma, embryonal tumor, endometrial cancer, ependymom
  • Atezolizumab (hereinafter referred to as "Ate") antibody Fab (Ate FabH), the light chain of Ate antibody Fab (Ate FabL), and avelumab antibody ( Hereinafter referred to as "Ave") Fab heavy chain (Ave FabH), Ave antibody Fab light chain (Ave FabL), palivizumab antibody (hereinafter referred to as "Syn”) Fab heavy chain (Syn FabH), Syn antibody Fab light chain (Syn FabL) (synthesized by IDT).
  • MSH Synthesize ⁇ -MSH polypeptide (hereinafter referred to as "MSH") (SEQ ID NO. 2) or ⁇ MSH polypeptide (SEQ ID NO. 4), and clone them into the above-constructed Ate HC, Ate LC, Ave HC through the connecting peptide, respectively , Ave LC, HC, Syn LC N-terminal or C-terminal. All constructed vectors are verified by sequencing.
  • the heavy chain and light chain of the antibody expression vector constructed in Example 1 were transiently transfected into FreeStyle HEK293 cells (ThermoFisher)) and co-transfected separately.
  • the amount of plasmid for the heavy chain and the plasmid for the light chain during transfection was 1:1 by molar ratio) :Inoculate 28ml FreeStyle HEK 293 (3 ⁇ 10 7 cells/ml) into a 125ml cell culture flask, and the plasmid is diluted with 1ml Opti-MEM (Invitrogen) and added to 1ml Opti-MEM containing 60 ⁇ l 293Fectin (Invitrogen), statically at room temperature Leave it for 30 minutes, add the plasmid-293Fectin mixture to the cell culture medium at 125 rpm, 37°C, and 5% CO2.
  • the cell culture supernatant was collected at 48h and 96h after transfection, purified by Protein A Resin (Thermo Fisher
  • BCN-NHS Sigma, Cat#744867
  • the reaction product obtained above and the fusion double antibodies MSH-AteL fusion and MSH-AteH fusion of Example 2 were subjected to gel exclusion chromatography using GE's AKTA chromatography.
  • the chromatography column used is Superdex 200 Increase10/300 GL gel exclusion chromatography column, and the solution used for gel exclusion chromatography is PBS buffer (0.010M phosphate buffer, 0.0027M KCl, 0.14M NaCl, pH 7.4 ), the flow rate used in gel exclusion chromatography is 0.4 ml/min.
  • the fusion bi-antibody obtained in Example 2 and the chemically coupled bi-specific antibody obtained in Example 3 were incubated with PNGase F (NEB) at 37°C for 8 hours, and then treated with 10 mM dithiothreitol and passed through ESI-qTOF -MS (Agilent, USA) analysis.
  • the drug/antibody ratio (DAR) of chemically coupled bispecific antibodies is calculated by molecular weight.
  • the results are shown in Table 2 and Table 3.
  • the number of (NDP) MSH conjugated in 90% (NDP) MSH-Ave conjugate is between 1-6, and the average number of (NDP) MSH conjugated per Ave antibody is DAR
  • the number of (NDP) MSH conjugated in 90%-98% (NDP) MSH-Ate conjugates is between 1-7, and the average number of (NDP) MSH conjugated per Ate antibody DAR is 2.2.
  • hPD-L1-hIGg1Fc (SinoBiological) (100ng/well) (DPBS buffer, pH 7.4) in a 96-well plate, incubated overnight at 4°C; blocked in DPBST containing 2% skimmed milk powder for 1 hour at room temperature, containing 0.05% Tween- After washing 3 times with 20 DPBS, add gradient dilution MSH- ⁇ PD-L1 or NR- ⁇ PD-L1/ ⁇ PD-L1 and incubate for 2h at room temperature.
  • HEK293-MC1R Cultivate HEK293 cells (HEK293-MC1R) overexpressing MC1R (DMEM medium containing 10% FBS, 1% double antibody). After trypsinization, 2x104/well HEK293-MC1R cells were placed on a 96-well flat-bottomed blackboard at 37°C, 5% CO2 culture overnight to make it adherent. After washing 3 times with PBS, centrifuge to discard the supernatant, add 8% formalin solution and incubate at room temperature for 15 min.
  • B16-SIY cells Cultivate B16-SIY cells (DMEM medium containing 10% FBS, 1% double antibody), take 2x105 cells and wash 3 times with pre-chilled PBS, block with 2% FBS (dissolved in PBS) and incubate with samples of different concentrations at 4°C 2h, 2% FBS (dissolved in PBS) to wash away unbound antibodies, incubate with APCanti-human IgG Fc (KPL, Inc., MD) at 4°C for 1 h, 2% FBS (dissolved in PBS) and then use LSR II Flow cytometry (Becton Dickinson, NJ) detection, and FlowJo software (TreeStar, OR) for analysis.
  • Prizm Graphpad uses log(agonist) vs.response model to perform nonlinear regression on data. The result is shown in Figure 5.
  • Cultivate HER293 cells overexpressing MC1R and CRE-Luc (DMEM medium, 10% FBS), inoculate the cells into 384-well plates at 5000 cells/well, use different concentrations of bifunctional antibodies or controls at 37°C, 5% CO2 After 24 hours, the fluorescence intensity was detected by One-Glo (Promega, WI) according to the instructions provided by the manufacturer, and the Prizm Graphpad software used log (agonist) vs. response model to perform nonlinear regression on the data.
  • the Tm value of (NDP) MSH-Ave conjugate is 64°C, similar to Ave; the melting curve of (NDP) MSH-Ate conjugate is similar to Ate, but its Tm value is slightly lower than that of Ate; MSH-AteL fusion and MSH- The thermal stability of AteH fusion is also similar to that of Ate.
  • the bispecific antibody or control was added to a tube containing 100ul of freshly isolated mouse serum (final concentration 1uM), and incubated at 37°C for 0h, 6h, 24h, 48h and 72h. The incubated samples were quickly frozen with liquid nitrogen and placed at -80°C for later use. The content of antibody in each tube was detected by PD-L1 combined with sandwich ELISA, and the detection and result analysis process was as described in Example 5.1.
  • the conjugate of (NDP) MSH and antibody is very stable in mouse serum. After incubating at 37°C for 72 hours, no (NDP) MSH-Ate conjugate or (NDP) MSH-Ate conjugate is degraded.
  • the samples were intraperitoneally injected (I.P.) C57BL/6 mice (3 mice per group, 4 mg/kg). Heparin anticoagulant blood was collected from the tail vein or saphenous vein, and the blood collection time was as follows: 30min, 1h, 2h, 4h, 6h, 4h, 48h, 3d, 4d, 6d, 8d, 10d, 12d and 14d. After centrifugation, plasma was collected and stored at -80°C for later use. Sandwich ELISA detects the content of the sample in the plasma bound to PD-L1. The ELISA detection process is as described in Example 5.1. According to the standard curve (the abscissa is the sample concentration, the ordinate is the fluorescence signal value), the content of the sample in the plasma is calculated. The pharmacokinetic parameters are estimated using modeling program WinNonlin (Pharsight).
  • NDP 5mg/kg MSH-Ave conjugate significantly reduced the volume of tumors in tumor-bearing mice, showing stronger tumor suppressor activity.
  • TIL tumor infiltrating lymphocytes
  • the tumor cell suspension is obtained by enzymatically hydrolyzing the tumor block.
  • the specific steps place the tumor block in HBSS (Life) containing 1mg/ml collagenase, 0.1mg/ml DNAse I, 2.5U/ml hyaluronidase (Sigma-Aldrich) Technologies), stirring at room temperature for 2h.
  • 5mg/kg (NDP) MSH-Ave conjugate treatment has significantly increased CD3-positive infiltrating T lymphocytes in mouse tumors. The tumor suppressor activity shown is consistent.
  • the 1mg/kg (NDP) MSH-Ave conjugate treatment did not show a significant increase in CD3-positive infiltrating T lymphocytes in mouse tumors.
  • the weaker tumor suppressor activity was consistent.

Abstract

La présente invention concerne un anticorps bispécifique, en particulier, un anticorps bispécifique ciblant simultanément des antigènes de surface de cellules tumorales et des protéines de point de contrôle immunitaire. L'anticorps comprend un premier domaine de liaison ciblant des protéines de point de contrôle immunitaire d'une première cellule cible et un second domaine de liaison se liant à des antigènes de surface de cellules tumorales d'une seconde surface de cellule cible. L'anticorps se lie avec une affinité élevée à des antigènes de surface de cellules tumorales au moyen de polypeptides, par agrégation de fragments (par exemple, des anticorps PD-L1) ciblant des points de contrôle immunitaires fusionnés sur les cellules tumorales, ou à proximité de celles-ci et dans le microenvironnement tumoral, exerçant un effet destructeur spécifique des cellules effectrices sur des cellules tumorales.
PCT/CN2020/077181 2019-03-02 2020-02-28 Anticorps bispécifique WO2020177627A1 (fr)

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CN114195900A (zh) * 2020-09-17 2022-03-18 普米斯生物技术(珠海)有限公司 一种抗4-1bb/pd-l1双特异性抗体及其用途
WO2022078277A1 (fr) * 2020-10-16 2022-04-21 Lanova Medicines Limited Company Anticorps monoclonaux anti-ccr8 et leurs utilisations
CN114539416A (zh) * 2020-11-26 2022-05-27 盛禾(中国)生物制药有限公司 一种双特异性抗体的层析纯化工艺
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