CN105531288A - 抗pd1抗体及其作为治疗剂与诊断剂的用途 - Google Patents

抗pd1抗体及其作为治疗剂与诊断剂的用途 Download PDF

Info

Publication number
CN105531288A
CN105531288A CN201380079581.6A CN201380079581A CN105531288A CN 105531288 A CN105531288 A CN 105531288A CN 201380079581 A CN201380079581 A CN 201380079581A CN 105531288 A CN105531288 A CN 105531288A
Authority
CN
China
Prior art keywords
cell
sequence numbering
antibody
territory
cdr
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201380079581.6A
Other languages
English (en)
Other versions
CN105531288B (zh
Inventor
宋兢
李康
张彤
徐兰兰
刘琦
彭浩
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guangzhou Baiji Shenzhou biopharmaceutical Co.,Ltd.
Original Assignee
Beigene Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Beigene Ltd filed Critical Beigene Ltd
Priority to CN201710208535.1A priority Critical patent/CN107090041B/zh
Priority to CN202011322092.7A priority patent/CN112552401B/zh
Priority to CN201710207300.0A priority patent/CN107011441B/zh
Priority to CN201810552595.XA priority patent/CN108715615B/zh
Priority to CN202011322081.9A priority patent/CN112457403B/zh
Publication of CN105531288A publication Critical patent/CN105531288A/zh
Application granted granted Critical
Publication of CN105531288B publication Critical patent/CN105531288B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/395Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39591Stabilisation, fragmentation
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/505Medicinal preparations containing antigens or antibodies comprising antibodies
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/20Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/30Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/33Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/30Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52Constant or Fc region; Isotype
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52Constant or Fc region; Isotype
    • C07K2317/53Hinge
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/55Fab or Fab'
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565Complementarity determining region [CDR]
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/567Framework region [FR]
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/569Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/70Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/70Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/71Decreased effector function due to an Fc-modification
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/70Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/70Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/90Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/90Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/94Stability, e.g. half-life, pH, temperature or enzyme-resistance

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Mycology (AREA)
  • Epidemiology (AREA)
  • Microbiology (AREA)
  • Communicable Diseases (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Virology (AREA)
  • Biomedical Technology (AREA)
  • Oncology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

本发明提供特异性结合程序性死亡-1(PD1、Pdcd-1或CD279)、抑制免疫细胞中PD1介导的细胞信号传导及活性,并结合PD1的配体所需要的一套氨基酸残基的抗体,及这些抗体治疗或诊断由PD1介导的功能所调控的癌症、传染性疾病或其他病理病症的用途。

Description

抗PD1抗体及其作为治疗剂与诊断剂的用途
发明背景
程序性死亡-1(ProgrammedDeath-1;PD-1,也称为CD279)是一种与CD28/CTLA4共同刺激/抑制受体家族相关的55KD受体蛋白质(Blank等人,2005CancerImmunolImmunother54:307-314)。在小鼠及人类中克隆及表征了编码PD-1的基因及cDNA(Ishida等人,1992EMBOJ11:3887-3395;Shinohara等人,1994Genomics23:704-706)。全长PD-1含有288个氨基酸残基(NCBI登录号:NP_005009)。它的胞外域由氨基酸残基1-167组成,而胞质C末端尾部包含残基191-288,该尾部具有两个假设性免疫调节基序,一个是基于免疫受体酪氨酸的抑制基序(ITIM;Vivier等人,1997ImmunolToday18:286-291),一个是免疫受体酪氨酸转换基序(ITSM;Chemnitz等人,2004JImmunol173:945-954)。
迄今为止,两个序列相关配体PD-L1(B7-H1)与PD-L2(B7-DC)已被鉴定为与PD-1特异性相互作用,诱导细胞内信号转导,该细胞内信号转导抑制CD3及CD28介导的T细胞激活(Riley,2009ImmunolRev229:114-125),继而削弱T细胞活性(例如,减少细胞增殖、IL-2与IFN-γ分泌,以及其他生长因子及细胞因子分泌)。
经常在诸如T细胞、B细胞、单核细胞及天然杀伤(NK)细胞等免疫细胞中发现PD-1的表达。PD-1很少在诸如肌肉、上皮、神经元组织等其他人类组织中表达。此外,高水平的PD-1表达常常与免疫细胞的激活关联。举例而言,当藉由植物血球凝集素(PHA)或佛波醇酯(12-O-十四酰基佛波醇-13-乙酸酯或TPA)激活人类T细胞系Jurkat时,在Western印迹中可见PD-1的表达上调(Vibharka等人,1997ExpCellRes232:25-28)。在被抗CD3抗体刺激后,在受刺激鼠类T淋巴细胞及B淋巴细胞中及在原代人类CD4+T细胞中观察到相同现象(Agata等人,1996IntImmunol8:765-772;Bennett等人,2003JImmunol170:711-118)。T效应细胞刺激后的PD-1表达增强使得朝耗竭及减少免疫活性方向再导向激活的T效应细胞。因此,PD-1介导的抑制信号在免疫耐受方面起到重要作用(Bour-Jordan等人,2011ImmunolRev241:180-205)。
在各种涉及不同类型组织及器官的癌症方面,报告了肿瘤浸润淋巴细胞(TIL)中的PD-1表达及肿瘤细胞中的PD-1配体表达的增强,所述组织及器官诸如肺(Konishi等人,2004ClinCancerRes10:5094-5100)、肝(Shi等人,2008IntJCancer128:887-896;Gao等人,2009ClinCancerRes15:971-979)、胃(Wu等人,2006ActaHistochem108:19-24)、肾(Thompson等人,2004ProcNatlAcadSci101:17174-17179;Thompson等人,2007ClinCancerRes13:1757-1761)、乳腺(Ghebeh等人,2006Neoplasia8:190-198)、卵巢(Hamanishi等人,2007ProcNatlAcadSci104:3360-3365)、胰腺(Nomi等人,2007ClinCancerRes13:2151-2157)、黑素细胞(Hino等人,2010Cancer116:1757-1766)及食道(Ohigashi等人,2005ClinCancerRes11:2947-2953)。更经常地,那些癌症中的PD-1及PD-L1增强表达与患者生存结果的不良预后关联。具有抑制异体移植癌细胞生长的PD-1基因敲除的转基因小鼠进一步阐明在癌症根治或耐受的免疫系统调控中PD-1信号传导的重要性(Zhang等人,2009Blood114:1545-1552)。
PD-1信号传导上调不仅导致对癌生长的免疫耐受,而且导致人类中的病毒感染及扩充。流行性肝感染病毒HBV及HCV诱导肝细胞中的PD-1配体的过度表达及激活T效应细胞中的PD-1信号传导,从而引起T细胞耗竭及对病毒感染的耐受(Boni等人,2007JVirol81:4215-4225;Golden-Mason等人,2008JImmunol180:3637-3641)。同样地,HIV感染常常藉由类似机制避开人类免疫系统。拮抗剂分子对PD-1信号传导的治疗性调控可从耐受中反转免疫细胞,并经再激活以根治癌症及慢性病毒感染(Blank等人,2005CancerImmunolImmunother54:307-314;Okazaki等人,2007IntImmunol19:813-824)。
发明概述
本发明提供PD-1的免疫抑制的方法及组合物。在一个方面中,本发明提供一种抗体抗原结合域,该抗体抗原结合域特异性结合人类PD-1,且包含具有选自序列编号11-22、31-42及59-63的序列的互补决定区(CDR)。
CDR可经历重组成为重链可变区(Vh)及轻链可变区(Vκ),所述区分别包含(CDR-H1、CDR-H2及CDR-H3)及(CDR-L1、CDR-L2及CDR-L3)序列,且保持特异于PD-1的结合及/或功能性。
在特定实施方案中,域包含重链可变区(Vh)或轻链可变区(Vκ),所述可变区包含:
在特定实施方案中,域包含重链可变区(Vh)及/或轻链可变区(Vκ),所述可变区包含:
a)mu317CDR-H1、CDR-H2及CDR-H3(序列编号11-13);
CDR-L1、CDR-L2及CDR-L3(序列编号14-16);
b)mu326CDR-H1、CDR-H2及CDR-H3(序列编号17-19);
CDR-L1、CDR-L2及CDR-L3(序列编号20-22);
c)317-4B6CDR-H1、CDR-H2及CDR-H3(序列编号31-33);
CDR-L1、CDR-L2及CDR-L3(序列编号34-36);
d)326-4A3CDR-H1、CDR-H2及CDR-H3(序列编号37-39);
CDR-L1、CDR-L2及CDR-L3(序列编号40-42);
e)317-1CDR-H1、CDR-H2及CDR-H3(序列编号11、59、13);
CDR-L1、CDR-L2及CDR-L3(序列编号14-16);
f)317-4B2CDR-H1、CDR-H2及CDR-H3(序列编号11、60、13);
CDR-L1、CDR-L2及CDR-L3(序列编号61、15、16);
g)317-4B5CDR-H1、CDR-H2及CDR-H3(序列编号11、60、13);
CDR-L1、CDR-L2及CDR-L3(序列编号61、15、16);
h)317-4B6CDR-H1、CDR-H2及CDR-H3(序列编号11、32、13);
CDR-L1、CDR-L2及CDR-L3(序列编号61、15、16);
i)326-1CDR-H1、CDR-H2及CDR-H3(序列编号17、62、19);
CDR-L1、CDR-L2及CDR-L3(序列编号20-22);
j)326-3B1CDR-H1、CDR-H2及CDR-H3(序列编号17、62、19);
CDR-L1、CDR-L2及CDR-L3(序列编号20-22);
k)326-3G1CDR-H1、CDR-H2及CDR-H3(序列编号17、62、19);及
CDR-L1、CDR-L2及CDR-L3(序列编号20-22)。
在特定实施方案中,域包含重链可变区(Vh)及轻链可变区(Vκ),所述可变区包含:
(a)CDR-H1(序列编号31)、CDR-H2(序列编号12、32、59或60)及CDR-H3(序列编号33),
CDR-L1(序列编号14、34或61)、CDR-L2(序列编号35)及CDR-L3(序列编号36);或
(b)CDR-H1(序列编号37)、CDR-H2(序列编号18、38或62)及CDR-H3(序列编号39),
CDR-L1(序列编号40)、CDR-L2(序列编号41)及CDR-L3(序列编号42)。
在特定实施方案中,域包含重链可变区(Vh)或轻链可变区(Vκ),所述可变区包含:
在特定实施方案中,域特异性结合PD1残基:(a)K45及I93(基于2008PNAS,105:10483进行AA编号;相当于序列编号2中的K58及I106);或(b)I93、L95及P97(基于2008PNAS,105:10483进行AA编号;相当于序列编号2中的I106、L108及P110)。
在特定实施方案中,域诱导与HEK293/OS8/PD-L1细胞或与HEK293/OS8/PD-L2细胞共同培养的HuT78/PD-1细胞中的IL-2释放,及/或抑制与HEK293/PD-L1细胞或与HEK293/PD-L2细胞共同培养的HuT78/P3Z细胞中的IL-2分泌。
本发明还提供一种抗体IgG4重链效应器或恒定域,该效应器或恒定域包含序列编号83-88中的任一者,尤其是序列编号87或88。
本发明还提供包含专属PD-1结合域的抗体、F(ab)或F(ab)2。
本发明还提供抗体,所述抗体包含专属PD-1结合域及IgG4重链效应器或恒定域,该效应器或恒定域包含序列编号83-88中的任一者,尤其是序列编号87或88。
本发明还提供一种编码专属PD-1结合域的多核苷酸,尤其是cDNA序列。
本发明提供使用该专属域的方法,该方法藉由向确定患有癌症或病毒感染或确定另外需要PD-1拮抗作用的个人施用该域。
本发明还提供融合蛋白,所述融合蛋白包含:(a)融合至小鼠CD8α的C末端域(113-220)的抗人类CD3单抗OKT3的单链可变片段(scFv)(序列编号89);或(b)融合至人类CD3ζ链的胞质域的人类PD-1的胞外域及跨膜域(序列编号90)。
本发明还提供使用该专属融合蛋白的方法,该方法包含用表达融合蛋白的细胞系检定、筛选或选择抗PD-1抗体。
附图简述
图1:PD-1/Fc(上图)及PD-1/His(下图)的示意性呈现。ECD:胞外域。L:接头。H:His标签。Fc:人类IgG4中的γ4Fc片段。N:N末端。C:C末端。
图2:在ELISA中结合至人类PD-1的鼠类单抗的剂量依赖型反应曲线。各图的左上角指示鼠类单抗。单抗317及517共享重链及轻链的可变区的高度同源性。藉由直接OD450读数指示结合信号强度。抗原PD-1/His以50微升的体积中增加浓度,至高达每孔70纳克来包被。在实施例1中描述该方法。
图3:藉由FACS分析产生的结合至活细胞上所表达的人类PD-1的鼠类单抗的剂量依赖型反应曲线。在各个小图上指示鼠类抗体代码及EC50。MFI代表荧光强度均值。使HuT78/PD-1细胞以每孔5x104个细胞悬浮于96孔板中用于FACS。如实施例1中所描述执行PD-1单抗结合至细胞表面靶点及FACS检测。
图4:用于检定抗PD-1单抗的功能活性的细胞共同培养系统的示意性表示。T细胞(CD4+或CD8+)表示HuT78/PD-1或PBMC中的原代T细胞。TCR:T细胞受体。N:细胞核。C:细胞质。
图5:与HEK293/OS8/PD-L1细胞共同培养的HuT78/PD-1细胞中鼠类单抗诱导的IL-2分泌的剂量依赖型反应曲线。基线:在所有受测试浓度下由mIgG所诱导的平均IL-2释放。顶线:基于PrizmSoftware回归计算所得的最高IL-2释放。
图6:(A)图示与细胞系HEK293/OS8/PD-L1共同培养的PBMC(供体19)中抗PD-1单抗所诱导的IFN-γ分泌的直方图。(B)图示与细胞系HEK293/OS8/PD-L1共同培养的PBMC(供体20)中抗PD-1单抗所诱导的IFN-γ分泌的直方图。
图7:(A)与(B)藉由共同培养效应细胞(NK92MI/PD-1)及靶细胞(HuT78/PD-1)所得的抗PD-1单抗的ADCC活性。由代表性实验的两个数据点计算均值。将单抗添加到10μg/ml的浓度。如实施例9中所描述执行实验。
图8:藉由ELISA(上图)及Western印迹(下图)定位抗PD-1单抗的结合表位。使用含有WT或MtPD-1的条件培养基藉由ELISA及Western印迹评估结合活性。**指示单抗结合活性降低至WTPD-1的25-50%的AA残基。***指示单抗结合活性降低至WTPD-1的25%以下的AA残基。
图9:来自不同健康供体的原代人类PBMC中由人源化抗PD-1单抗所诱导的IFN-γ释放,原代人类PBMC与HEK293/OS8/PD-L1细胞共同培养。
图10:由人源化抗PD-1单抗hu317(A)及hu326(B)增强的NK92MI/PD-1细胞的细胞毒性。靶肺癌细胞SK-MES-1/PD-L1与效应细胞以1:2的(T比E)比率共同培养,以及如实施例12所述进行检定。
图11:三个治疗群组:媒剂(PBS)、人类IgG(huIgG)及抗PD-1单抗(hu317-1/IgG4mt2)中的个体肿瘤生长曲线。各个曲线表示肿瘤生长路径,藉由各小图右侧指示数字对负有肿瘤小鼠编代码。在第1天时接种Hep3B/OS8/PD-L1细胞(自肝细胞癌系Hep3B建立),在第15天时植入PBMC,及在第18天、第28天及第38天时分别注射三剂hu317-1/IgG4mt2。在实施例12中描述方法。
发明详述
当被PD-1的配体PD-L1或PD-L2接合时,PD-1启动免疫细胞中的抑制性信号传导。在癌长出及病毒感染的情况下,PD-1信号传导的激活促进了免疫耐受,导致癌症或病毒感染细胞逃避免疫监视及癌症转移或病毒负荷增长。藉由治疗剂抑制PD-1介导的细胞信号传导可激活包括T细胞、B细胞及NK细胞在内的免疫细胞,并因此增强抑制癌细胞生长或病毒感染的免疫细胞功能,及恢复免疫监视及免疫记忆功能以治疗此类人类疾病。
本发明提供抗体,这些抗体的功能拮抗免疫细胞中配体诱导及PD-1介导的细胞信号传导。鼠类抗PD-1抗体经人源化为在框架区中高度类似于人类抗体。以经修饰的人类IgG4变体形式产生的全抗体在效应器功能及物理化学特性的方面中具有独特的特征集合。所揭露抗PD-1抗体适合于癌症治疗、控制病毒感染及机制上涉及加剧免疫耐受的其他人类疾病中的治疗用途。
定义
除非上下文另有指示,否则术语“抗体”是用于广义上,且具体覆盖抗体(包括全长单克隆抗体)及抗体片段,只要它们识别PD-1即可。抗体分子通常为单特异性,但也可描述为独特特异性、异种特异性或多特异性。抗体分子经由特异性结合位点结合至抗原上的特定抗原决定簇或表位。“抗体片段”包含全长抗体的一部分,大体而言为全长抗体的抗原结合或可变区。抗体片段的实例包括Fab、Fab′、F(ab′)2及Fv片段;双抗体;线性抗体;单链抗体分子;及由抗体片段形成的多特异性抗体。
可藉由熟悉此项技术者已知的方法获得单克隆抗体(单抗)。请参看例如,Kohler等人(1975);美国专利第4,376,110号;Ausubel等人(1987-1999);Harlow等人(1988);及Colligan等人(1993)。本发明的单抗可以是任何免疫球蛋白类别,包括IgG、IgM、IgE、IgA及上述的任何亚类。可在体外或体内培养产生单抗的杂交瘤。在体内产生中可获得高滴度的单抗,其中将来自个别杂交瘤中的细胞经腹膜内注射至小鼠(诸如原始致敏Balb/c小鼠)体内以产生含有高浓度所欲单抗的腹水液。可使用熟习此项技术者所熟知的柱层析法自此类腹水液或自培养物上清液中纯化同种型IgM或IgG的单抗。
“经分离多核苷酸”是指已与天然产生状态下位于侧翼的序列分开的多核苷酸区段或片段,例如已自正常邻接于片段的序列移除的DNA片段,例如在天然产生片段的基因组中邻接于片段的序列。因此,该术语包括(例如)并入载体中、并入自主复制质粒或病毒中或并入原核生物或真核生物的基因组DNA中的重组DNA,或作为独立于其他序列的单独分子存在(例如,作为cDNA或由PCR或限制酶消化产生的基因组或cDNA片段)的重组DNA。还包括如下重组DNA,该重组DNA为杂合基因中编码额外多肽序列的一部分。
“构建体”意谓任何重组多核苷酸分子(诸如质粒、粘粒、病毒、自主复制多核苷酸分子、噬菌体或线性或环状单链或双链DNA或RNA多核苷酸分子),衍生自任何来源,能够基因组整合或自主复制,构成如下多核苷酸分子,其中已经以功能操作的方式连接(即,可操作地连接)一或多个多核苷酸分子。重组构建体通常会包含可操作地连接至转录起始调节序列的本发明的多核苷酸,这些序列会导引多核苷酸在所欲宿主细胞中的转录。可使用异源及非异源(即,内源)启动子两者导引本发明的核酸的表达。
“载体”是指任何重组多核苷酸构建体,该构建体可用于转化的目的(即,将异源DNA引入到宿主细胞中)。一种类型的载体为“质粒”,是指环状双链DNA环,可将额外DNA区段连接至该环中。另一类型的载体为病毒载体,其中可将额外DNA区段连接至病毒基因组中。某些载体能够在被引入到的宿主细胞中自主复制(例如,具有细菌复制起点的细菌载体及游离型哺乳动物载体)。在引入到宿主细胞中后,其他载体(例如,非游离型哺乳动物载体)整合至宿主细胞的基因组中,且因此与宿主基因组一起复制。此外,某些载体能够导引被操作性连接的基因的表达。本文将此类载体称为“表达载体”。
本文所使用的“表达载体”是指能够在转化、转染或转导至宿主细胞中时复制及表达感兴趣基因的核酸分子。表达载体包含一或多个表型选择标记及复制起点,以确保维护载体及以在需要的情况下于宿主内提供扩增。表达载体进一步包含启动子,以驱动多肽在细胞内的表达。适宜表达载体可为衍生自pBR322的质粒或各种pUC质粒,这些质粒为市售。其他表达载体可衍生自噬菌体、噬菌粒或粘粒表达载体。
本发明的额外实施方案
在特定实施方案中,本发明提供自筛选本文所揭露的鼠类杂交瘤克隆所鉴定的小鼠单克隆抗体。
在其他实施方案中,本发明提供以下多核苷酸及蛋白质序列的组合物:
a)编码鼠类单抗317的重链可变区的cDNA序列,序列编号3;
b)mu317_Vh或鼠类单抗317的重链可变区的蛋白质序列(序列编号4);
c)编码鼠类单抗317的轻链可变区的cDNA序列,序列编号5;
d)mu317_Vκ或鼠类单抗317的轻链可变区的蛋白质序列(序列编号6);
e)编码鼠类单抗326的重链可变区的cDNA序列,序列编号7;
f)mu326_Vh或鼠类单抗326的重链可变区的蛋白质序列(序列编号8);
g)编码鼠类单抗326的轻链可变区的cDNA序列,序列编号9;
h)mu326_Vκ或鼠类单抗326的轻链可变区的蛋白质序列(序列编号10)。
在一个方面中,本发明提供包含互补决定区(CDR)序列的组合物,这些序列介导结合至靶抗原PD-1,包括mu317及mu326的CDR序列:
a)mu317重链的CDR1(mu317H-CDR1)含有氨基酸序列GFSLTSYGVH(序列编号11);
b)mu317H-CDR2含有氨基酸序列VIWAGGSTNYNSALMS(序列编号12);
c)mu317H-CDR3含有氨基酸序列ARAYGNYWYIDV(序列编号13);
d)mu317轻链的CDR1(mu317L-CDR1)含有氨基酸序列KASQSVSNDVA(序列编号14);
e)mu317L-CDR2含有氨基酸序列YAFHRFT(序列编号15);
f)mu317L-CDR3含有氨基酸序列HQAYSSPYT(序列编号16);
g)mu326H-CDR1含有氨基酸序列GYTFTNYGMN(序列编号17);
h)mu326H-CDR2含有氨基酸序列WINNNNGEPTYAEEFKG(序列编号18);
i)mu326H-CDR3含有氨基酸序列ARDVMDY(序列编号19);
j)mu326L-CDR1含有氨基酸序列RASESVDNYGYSFMH(序列编号20);
k)mu326L-CDR2含有氨基酸序列RASNLES(序列编号21);
l)mu326L-CDR3含有氨基酸序列QQSKEYPT(序列编号22)。
在另一实施方案中,本发明提供包含源自鼠类单抗mu317及mu326的人源化单克隆抗体的序列的组合物,包括:
a)人源化单抗hu317-4B6包含作为序列编号24的重链可变区(Vh)的蛋白质序列,该重链可变区由以下编码:
b)hu317-4B6_Vh的cDNA(序列编号23);
c)人源化单抗hu317-4B6还包含作为序列编号26的轻链可变区(Vκ)的蛋白质序列,该轻链可变区由以下编码:
d)hu317-4B6的cDNA(序列编号25);
e)人源化单抗hu326-4A3包含作为序列编号28的Vh的蛋白质序列,该Vh由以下编码:
f)hu326-4A3-Vh的cDNA(序列编号27);
g)人源化单抗hu326-4A3还包含作为序列编号30的Vκ的蛋白质序列,该Vκ由以下编码:
h)hu326-4A3_Vκ的cDNA(序列编号29);
i)hu317-4B2_Vh的蛋白质序列(序列编号43)与hu317-4B2_Vκ的蛋白质序列(序列编号44);
j)hu317-4B5_Vh的蛋白质序列(序列编号45)与hu317-4B5_Vκ的蛋白质序列(序列编号46);
k)hu317-1_Vh的蛋白质序列(序列编号48)与编码hu317-1_Vh的cDNA(序列编号47);
l)hu317-1_Vκ的蛋白质序列(序列编号50)与编码hu317-1_Vκ的cDNA(序列编号49);
m)hu326-3B1_Vh的蛋白质序列(序列编号51)与hu326-3B1_Vκ的蛋白质序列(序列编号52);
n)hu326-3G1_Vh的蛋白质序列(序列编号53)与hu326-3G1_Vκ的蛋白质序列(序列编号54);
o)hu326-1_Vh的蛋白质序列(序列编号56)与编码hu326-1_Vh的cDNA(序列编号55);
p)hu326-1_Vκ的蛋白质序列(序列编号58)与编码hu326-1_Vκ的cDNA(序列编号57);
q)源自mu317的其他人源化单抗的蛋白质序列(序列编号63-74);
r)源自mu326的其他人源化单抗的蛋白质序列(序列编号75-82)。
在一个方面中,本发明提供包含人源化单克隆抗体的CDR序列的组合物。在相同系列的人源化单抗(诸如hu317或hu326)中可共享CDRs(参看表15-16)。以下列出非冗余CDRs:
a)H-CDR1序列GFSLTSYGVH(序列编号31),为所有人源化单抗hu317及mu317重链所共享;
b)H-CDR3序列ARAYGNYWYIDV(序列编号33),为所有人源化单抗hu317及mu317重链所共享;
c)L-CDR1序列KSSESVSNDVA(序列编号34),为所有人源化单抗hu317-4B2、hu317-4B5及hu317-4B6轻链所共享;
d)L-CDR2序列YAFHRFT(序列编号35),为所有人源化单抗hu317及mu317轻链所共享;
e)L-CDR3序列HQAYSSPYT(序列编号36),为所有人源化单抗hu317及mu317轻链所共享;
f)hu317-4B6_Vh中的H-CDR2序列VIYADGSTNYNPSLKS(序列编号32);
g)hu317-4B2_Vh与hu317-4B5_Vh中的H-CDR2序列VIYAGGSTNYNPSLKS(序列编号60);
h)hu317-1_Vh中的H-CDR2序列VIWAGGSTNYNPSLKS(序列编号59);
i)hu317-1_Vk中的L-CDR1序列KASQSVSNDVA(序列编号11);
j)H-CDR1序列GYTFTNYGMN(序列编号37),为所有人源化单抗hu326及mu326重链所共享;
k)H-CDR3序列ARDVMDY(序列编号39),为所有人源化单抗hu326及mu326重链所共享;
l)L-CDR1序列RASESVDNYGYSFMH(序列编号40),为所有人源化单抗hu326及mu326轻链所共享;
m)L-CDR2序列RASNLES(序列编号41),为所有人源化单抗hu326及mu326轻链所共享;
n)L-CDR3序列QQSKEYPT(序列编号42),在为所有人源化单抗hu326及mu326轻链所共享;
o)hu326_4A3_Vh中的H-CDR2序列WINNNNAEPTYAQDFRG(序列编号38);
p)hu326_1及其他hu317单抗的Vh中的H-CDR2序列WINNNNGEPTYAQGFRG(序列编号62)。
在另一方面中,本发明提供抗原上人源化抗PD-1单抗的特定结合表位及其功能用途。使PD-1中配体结合所需要的六个关键氨基酸(AA)残基个别突变,及使用突变体与野生型PD-1蛋白质评估结合表位。将突变使抗体结合明显削弱的残基视为关键或明显结合表位。单抗hu317-4B5及hu317-4B6的明显结合表位为K45及I93(基于2008PNAS,105:10483进行AA编号;相当于序列编号2中的K58及I106);及单抗hu326-3B1及hu317-4A3的明显结合表位为I93、L95及P97(基于2008PNAS,105:10483进行AA编号;相当于序列编号2中的I106、L108及P110)。
在又一方面中,本发明提供包含重组人类IgG4变体的恒定区序列的组合物,该恒定区序列可连接至特定抗体(包括人源化抗PD-1单抗)的可变区,这些恒定区序列展示出优选的效应器功能及物理化学特性。序列如下:
IgG4mt10的恒定区序列(序列编号88);
a)IgG4mt1的参考序列(序列编号83);
b)IgG4mt2的参考序列(序列编号84);
c)IgG4mt6的参考序列(序列编号85);
d)IgG4mt8的参考序列(序列编号86);
e)IgG4mt9的参考序列(序列编号87)。
在另一实施方案中,本发明提供检定抗PD-1抗体功能的方法,该方法使用表达重组融合蛋白OS8的质粒产生稳定细胞系HEK293/OS8/PD-L1或HEK293/OS8/PD-L2,该稳定细胞系共同表达OS8(一种T细胞激活分子)及PD-1配体。使用细胞系藉由共同培养接合T细胞及PBMCs,以评估抗PD-1单抗的功能性(参看实施例3及实施例4)。或者,使用表达重组融合蛋白P3Z的另一质粒产生稳定细胞系HuT78/P3Z,其中P3Z用作分子传感器及信号转导介体。当由PD-1配体接合P3Z时,P3Z会传导细胞内信号以激活HuT78细胞中的IL-2释放。这些系统可用于评估抗PD-1单抗的抑制效果(参看实施例3)。
在一个方面中,本发明提供包含重组融合蛋白的氨基酸序列的组合物,这些序列如下:
a)OS8的蛋白质序列(序列编号89);
b)P3Z的蛋白质序列(序列编号90)。
在另一方面中,本发明提供产生表达本文所描述的重组融合蛋白的稳定细胞系的方法,及使用该系统定量检定抗PD-1单抗的功能活性的方法。
在另一实施方案中,本发明提供编码主题蛋白质的多核苷酸。可将多核苷酸可操作地连接至异源转录调节序列用于表达及可并入载体、细胞等中。
在另一实施方案中,本发明提供鼠类抗PD-1抗体及人源化型式的抗PD-1抗体,这些人源化型式的抗PD-1抗体包括hu317-4B6、hu317-4B5、hu317-4B2等及hu326-4A3、hu326-3B1、hu326-3G1等,这些抗体具有抑制PD-1介导的信号转导及激活免疫细胞的功能,这些功能触发包括细胞因子分泌及对靶细胞(诸如癌细胞)的细胞毒性的级联免疫反应,及提供这些抗体的此类功能用途。
在一个方面中,本发明提供激活表达PD-1的若干类型免疫细胞的人源化抗PD-1抗体,这些免疫细胞包括人类T细胞、NK细胞及PBMCs,这些免疫细胞的功能为放大免疫应答信号,调动免疫系统,及充当免疫效应细胞以便清除癌细胞及病毒感染,及提供这些抗体的此类功能用途。
在另一方面中,将人源化抗PD-1单抗用作治疗剂来治疗涉及由PD-1介导的细胞内信号传导抑制免疫细胞而导致病情恶化的人类疾病,尤其是癌症及病毒感染。
本发明的组合物对于治疗癌症、神经退化性疾病及传染性疾病(尤其是病毒性疾病)及人类PD-1的不适宜或不利表达是其病因学或病理学的组份的其他疾患是有用的。因此,本发明提供用专属抗PD-1蛋白质在有需要的受试者中治疗癌症或抑制肿瘤发展的方法。本发明进一步提供专属多核苷酸制造在受试者中治疗癌症或抑制肿瘤发展的药剂中的用途。
本发明包括所叙述特定实施方案的所有组合。本发明的进一步实施方案及可应用性的完整范畴将自下文所提供的详细描述变得显而易见。然而,应理解,尽管详细描述及特定实施例指示本发明的优选实施方案,但仅以说明的方式提供这些描述及实施例,因为本发明的精神及范畴内的各种改变及修改将自此详细描述对熟悉此项技术者变得显而易见。出于所有目的,包括引文在内的本文所引用的所有公开物、专利及专利申请将以引用的方式全部并入本文。
实施例
实施例1:抗PD-1单克隆抗体的产生
基于常规杂交瘤融合技术(Kohler与Milstein1976EurJImmunol6:511-519;deStGroth与Sheidegger1980,JImmunolMethods35:1-21;Mechetner2007MethodsMolBiol378:1-13)并略作修改产生抗PD-1单克隆抗体(单抗)。选择在酶联免疫吸附检定(ELISA)及荧光激活细胞分选(FACS)检定中具有高结合活性的单抗以便进一步作表征。
用于免疫及结合检定的PD-1重组蛋白质
含有全长人类PD-1cDNA的表达质粒购自Origene(产品编号SC117011,NCBI登录号:NM_005018.1,中国,北京)。PCR扩增由PD-1的氨基酸(AA)1-168(序列编号1、序列编号2)组成的胞外域,在基于pcDNA3.1的表达载体(Invitrogen,Carlsbad,CA,USA)中亚克隆,其中C末端融合至His6标签或者融合至人类IgG4重链的γFc域,从而产生两个重组融合蛋白表达质粒PD-1-EC/His与PD-1-EC/Fc(缩写为PD-1/His与PD-1/Fc)。图1图示免疫原/抗原蛋白质的示意性呈现。针对重组融合蛋白产生,在1-3升培养基(Invitrogen)中将PD-1/His与PD-1/Fc质粒瞬时转染入293-F细胞,及在配备有旋转振动器的CO2培育箱中培养5-7天。收集含有重组蛋白质的上清液及在15000g下离心处理30分钟使该上清液透明。经由使用Ni-SepharoseFastFlow(产品编号17531801,GELifesciences,中国,上海)的固定化金属亲和层析法,然后使用HiLoad16/60Superdex200柱(产品编号17106901,GELifesciences,中国,上海)执行大小排阻层析法纯化PD-1/His。使用蛋白GSepharoseFastFlow柱(产品编号17061805,GELifesciences)纯化PD-1/Fc。用磷酸盐缓冲盐水(PBS)透析PD-1/His与PD-1/Fc蛋白质两者,并以小等分试样储存于-80℃冷冻箱中。
基于已公开序列(NCBI登录号:NM_014143),藉由Genescript(中国,南京)化学合成编码人类PD-L1的cDNA。PD-L2表达质粒购自Origene(产品编号SC108873,NCBI登录号:NM_025239.2,中国,北京)。在pcDNA3.1/潮霉素(产品编号V870-20,Invitrogen)及pcDNA3.1/V5-His(产品编号V810-20,Invitrogen)中分别克隆两个cDNA。
稳定表达细胞系
藉由分别将含有PD-1、PD-L1及PD-L2的pcDNA3.1质粒转染至HuT78(ATCC,Manassas,VA,USA)及HEK293(ATCC),及然后用含有每毫升200微克潮霉素(产品编号10687-010,Invitrogen)或1mgG418(Sigma)的培养基选择来建立表达人类PD-1、PD-L1或PD-L2的稳定细胞系。藉由常规方法分离单个克隆,该方法为有限稀释或从培养皿表面采集单个群落。分别使用抗PD-1、PD-L1及PD-L2抗体(产品编号12-9969、17-5983、12-5888,eBioscience,SanDiego,USA)藉由Western印迹及FACS分析筛选所有克隆,及选择顶级表达克隆用于FACS结合检定以筛选杂交瘤单克隆抗体,或在功能性检定中使用。
免疫、杂交瘤融合及克隆
用含有5微克PD-1/Fc的100μl佐剂(产品编号KX0210041,康碧泉公司,中国,北京)皮下注射使八至十二周大Balb/c小鼠(购自北京华阜康生物科技股份有限公司,中国,北京)免疫。间隔三周注射上述免疫原两次来实施免疫。在第二次免疫后两周,藉由FACS(下文中)评估小鼠血清的PD-1结合。选择血清中具有高抗PD-1抗体滴度的小鼠及在腹膜内注射无任何佐剂的50微克PD-1/Fc进行强化。在强化后三天,使用标准技术(Gefter,M.L.等人,1977SomatCellGenet,3:231-236)使脾细胞分离及与鼠类骨髓瘤细胞系SP2/0细胞(ATCC)融合。
藉由ELISA及FACS评估抗体的PD-1结合活性
如在“Flanagan,M.L.等人,2007MethodsinMolecularBiology378:33-52”中所描述的并略作修改,最初藉由酶联免疫吸附检定(ELISA)筛选杂交瘤克隆的上清液。简而言之,在96孔板(深圳市金灿华实业有限公司,中国,深圳)中的每个孔基底上包被50微升磷酸盐缓冲盐水(PBS)中50-200纳克PD-1/His或PD-1/Fc蛋白质。使用HRP偶联抗小鼠IgG抗体(产品编号7076S,CellSignalingTechnology,USA与中国上海)及化学发光试剂(产品编号PA107-01,TIANGEN,中国)检测及显现ELISA信号,该信号在450nm的波长处由读板仪(PHREAstarFS,BMGLABTECH,Germany)读取。使用常规方法藉由荧光激活细胞分选(FACS)进一步验证ELISA阳性抗体产生者克隆。在V形底96孔板(产品编号3897,Corning,USA与中国上海)中用来自抗PD-1杂交瘤的上清液染色上文所描述的PD-1稳定表达细胞系HuT78/PD-1(105个细胞/孔)。为了封闭人类Fc受体,用人类IgG(20μg/ml)(产品编号H11296,LifeHolder,USA与中国上海)预温育细胞。用DylightTM649标记山羊抗小鼠IgG抗体(产品编号405312,Biolegend,SandyDiego,USA)检测PD-1抗体及使用流式细胞仪(GuavaeasyCyte8HT,Merck-Millipore,USA与中国上海)检测细胞荧光。
在ELISA与FACS检定两者中展示阳性信号的杂交瘤细胞的条件培养基经受功能性检定以鉴定在基于人类免疫细胞的检定中(在本文中)具有良好功能活性的抗体。进一步亚克隆及表征具有阳性功能活性的抗体。
亚克隆及对无血清或低血清培养基的适应
藉由受限稀释的常规方法亚克隆来自经由ELISA、FACS及功能性检定的初级筛选的阳性杂交瘤克隆。在96孔板中放入各个阳性克隆,在CO2培育箱中,在具有10%胎牛血清(FBS,产品编号SH30084.03,Hyclone,中国,北京)的RPMI1640培养基(产品编号SH30809.01B,Hyclone,中国,上海)中培养。选择各个有限稀释板中的三个亚克隆及藉由FACS及功能性检定表征这些亚克隆。将经由功能性检定所选择的亚克隆定义为单克隆抗体。顶级亚克隆经适应在具有1-3%FBS的CDM4MAb培养基(产品编号SH30801.02,Hyclone)中生长。
单克隆抗体的表达及纯化
在37℃的CO2培育箱中,在CDM4MAb培养基(产品编号SH30801.02,Hyclone)或Freestyle293表达培养基(产品编号12338018,Invitrogen)内分别培养产生鼠类单克隆抗体的杂交瘤细胞或重组抗体质粒转染的293-F细胞(产品编号R79007,Invitrogen)5至7天。经由在10,000g下离心处理30分钟移除所有细胞及细胞碎片收集条件培养基,并在纯化前经由0.22μm薄膜过滤。遵循制造商规则,将鼠类或重组抗体加入及结合至蛋白A柱(产品编号17127901,GELifeSciences),用PBS清洗,在含有20mM柠檬酸盐、150mMNaCl的缓冲液(pH3.5)中洗脱。用1MTrispH8.0中和所洗脱物质,这些物质通常含有90%以上纯度的抗体。用PBS透析或使用HiLoad16/60Superdex200柱(产品编号17531801,GELifeSciences)进一步纯化经蛋白A亲和纯化的抗体以移除聚集体。藉由在280nm处测量吸收率或藉由Bradford检定(产品编号1856210,ThermoScientific,Rockford,IL,USA)测定蛋白质浓度,使用所界定浓度的牛IgG(产品编号23212,ThermoScientific)作为标准品。在-80℃的冷冻箱中以等分试样储存纯化抗体。
实施例2:抗PD-1抗体中的结合活性的比较
经由筛选数千种杂交瘤克隆,发明人鉴定出一些顶级单克隆抗体(单抗),这些单克隆抗体以高特异性及强度结合人类PD-1。如ELISA检定(图2)所示,顶级抗体中的三者引发此结合强度及特异性。FACS分析结果表明,选定单克隆抗体结合至表达于细胞表面上的天然PD-1蛋白质。鼠类单抗317(mu317)、mu326及mu150展示出浓度依赖型结合活性,且其结合EC50(50%活性处的有效浓度)明显比对照mu55更低(图3)。
藉由表面等离子共振(SPR)评定单抗结合亲和力
对在ELISA及FACS中具有高结合活性以及在基于细胞的检定中(在本文中)具有有力功能活性的单抗在实时结合反应中检查结合动力学常数。使用蛋白AFlow柱(产品编号17531801,GELifeSciences),然后使用HiLoad16/60Superdex200柱(产品编号17106901,GELifeSciences)执行排阻层析法从杂交瘤上清液中纯化鼠类抗PD-1单抗。将纯化抗PD-1抗体浓缩至PBS中0.5-1mg/mL及以等份试样储存于-80℃冷冻箱中。
为了测定PD-1单抗的结合亲和力,使用BIAcoreTMT-200仪器(GELifeSciences)在HBS-N缓冲液(10mMHEPESpH7.4,0.15MNaCl,3mMEDTA,0.005%v/v表面活性剂P20,GEHealthcare)中执行SPR测量。使用标准伯胺偶联规程产生抗小鼠FcCM5生物传感器芯片(GEHealthcare)。以10μl/分钟在抗小鼠Fc表面上捕捉0.3μg/ml的PD-1单抗达1分钟。以30μl/分钟在抗体结合表面上注射自3.3nM连续稀释至120nM的PD-1/Fc达3分钟,然后经历10分钟解离阶段。使用一对一朗谬(Langmuir)结合模型(BIAEvaluationSoftware,GELifeSciences)计算结合速率(Ka或kon)及解离速率(Kd或koff)。以比率koff/kon来计算平衡解离常数(KD)。
如表1所示,与mu317相关的关联序列家族成员mu326及mu517两者具有分别等于0.324nM及0.289nM的亚纳摩尔KD,此情况明显比mu134更佳。表1中所列出的三个单抗的kon速率相似,但koff速率明显不同,mu134中所观察到的解离速率快得多。
表1:某些顶级抗体的结合常数
藉由SPR测定抗PD-1Fab的亲和力
藉由PCR将抗PD-1单抗转换成Fab形式以使重链及轻链的可变区分别融合至人类IgG2-CH1及κ链恒定区的N末端,及在pcDNA3.1载体(Invitrogen)中亚克隆。使用与整个抗体的瞬时表达类似的瞬时转染方法在293-F细胞中共同表达两个表达载体。简而言之,PCR扩增Fabκ链及在基于pcDNA3.1的表达载体(Invitrogen,Carlsbad,CA,USA)中亚克隆。在另一质粒中,藉由交叠PCR将重链可变区(VH)以及来自人类IgG2中的CH1编码序列与C末端c-Myc-His8标签融合,及随后在表达载体中亚克隆。在IgG2重链中引入C232S及C233S(Kabat残基编号,Kabat等人,Sequenceofproteinsofimmunologicinterest,第5版,Bethesda,MD,NIH1991)突变以防止二硫键交换及稳定人类IgG2处于IgG2-A构象(Lightle等人,2010ProteinSci19(4):753-762)。两个构建体含有Fab成熟序列上游的信号肽。藉由上述2个质粒共同转染入293-F细胞实现Fab的分泌表达及在转染后6-7天收获细胞培养物上清液。使用Ni-SepharoseFastFlow柱(产品编号17531801,GELifeSciences),然后使用HiLoad16/60Superdex200柱(产品编号17106901,GELifeSciences)执行大小排阻层析法从细胞培养物上清液中纯化带有His8标签的Fab。将纯化Fab浓缩至PBS中0.5-5mg/mL及以等份试样储存于-80℃冷冻箱中。
针对抗PD-1Fab的亲和力测定,使用BIAcoreTMT-200仪器(GELifeSciences)进行SPR检定。简而言之,将人类PD-1/His或食蟹猴PD-1/His偶联至已活化的CM5生物传感器芯片(产品编号BR100530,GELifeSciences)以实现大约100-200个响应单位(RU),然后用1M乙醇胺封闭未反应基团。以30μL/分钟在SPR运行缓冲液(10mMHEPES,150mMNaCl,0.05%Tween20,pH7.4)中注射自0.12nM至90nM递增浓度的Fab样品,且藉由减去来自空白流动室的RU来计算人类PD-1/His或猴PD-1/His上的结合响应。使用一对一朗谬结合模型(BIAEvaluationSoftware,GELifeSciences)计算结合速率(kon)及解离速率(koff)。以比率koff/kon来计算平衡解离常数(KD)。
表18中列出SPR测定的抗PD-1Fab的结合亲和力。各个抗PD-1Fab以高亲和力(KD=0.15-1nM)结合至人类PD-1。除326-3G1外的所有Fab以略微较低但相当(KD的5倍内)亲和力结合至食蟹猴PD-1。
实施例3:抗PD-1抗体在人类T细胞中的功能活性
稳定细胞系的产生
逆转录病毒封装细胞系PT67、人类T细胞系HuT78及HEK293购自美国典型培养物保藏中心(ATCC,Rockville,MD)。根据前述操作程序(Zhang等人,2005Blood106:1544-1551),使用含有PD-1基因的pFB-neo载体(Strategene/AgilentTech,SantaClara,CA)藉由逆转录病毒转导产生表达PD-1的HuT78亚株HuT78/PD-1。藉由将抗人类CD3单抗OKT3的单链可变片段(scFv)(Kipriyanov等人,1997,PEDS10:445-453)融合至小鼠CD8α的C末端域(113-220)(NCBI登录号:NP_001074579.1)建构T细胞接合物,膜锚定嵌合抗体(OS8),该小鼠CD8α的C末端域包括铰链、跨膜及胞质域。藉由此举,将抗CD3scFv锚定至细胞表面作为T细胞激活物。将人类PD-L1、PD-L2及OS8cDNA亚克隆入pcDNA3.1载体。藉由用成对质粒共同转染HEK293及Hep3B细胞(ATCC),然后用潮霉素或G418选择10-14天来产生共同表达OS8与PD-L1或PD-L2cDNA两者的稳定细胞系HEK293/OS8/PD-L1、Hep3B/OS8/PD-L1及HEK293/OS8/PD-L2。随后藉由如先前所描述的有限稀释法克隆细胞系(FullerSA等人,CurrProtocMolBiol.,第11章:第11.8.单元,2001)。藉由将人类PD-1的胞外域及跨膜域融合至人类CD3ζ链的胞质域(NCBI登录号:NP_932170.1)构建称为P3Z的嵌合PD-1受体。将P3Z编码cDNA序列克隆入pFB-neo,并经由逆转录病毒转导输送入HuT78细胞中以产生HuT78/P3Z细胞。
藉由HuT78/PD-1细胞中的IL-2释放测定PD-1抗体功能
为了测定抗PD-1抗体是否能阻断PD-L1诱导的PD-1信号传导的相互作用,用杂交瘤上清液或PD-1抗体预温育HuT78/PD-1细胞(在96孔板中每孔1.5x104个细胞)15分钟,之后在37℃下于平底板中与HEK293/OS8/PD-L1或HEK293/OS8/PD-L2细胞(每孔4x104)共同培养,每孔以200μlRPMI1640生长培养基供给营养。在16-18小时后,收集共同培养物上清液。藉由ELISA使用人类IL-2Ready-Set-Go!ELISA试剂盒(产品编号88-7025,eBiosciences,SanDiego,CA)检定IL-2。在此检定中,用抗PD-1抗体阻断PD-1信号传导引发增强的TCR信号传导及IL-2产生(图4)。
如图5及表2所示,鼠类抗PD-1单抗mu317及mu326引发比mu30明显更高的功能活性,抑制PD-L1诱导的PD-1信号传导,从而导致IL-2分泌增加。两者比mu30抗体皆具有较高IL-2分泌(顶线,表2),分别为675及634pg/ml,且两者皆具有更低的EC50(在IL-2分泌诱导的50%水平上的单抗的有效浓度)。
表2:与HEK293/OS8/PD-L1细胞共同培养的HuT78/PD-1细胞中藉由抗PD-1单抗所诱导的IL-2释放
由抗PD-1单抗结合HuT78/PD-1细胞不仅阻断了PD-L1诱导的T细胞激活,而且阻断了PD-L2诱导的IL-2释放。表3呈现数据,这些数据展示,mu317及mu326在激活T细胞中具有比mu476高得多的效能,如IL-2分泌的参数(EC50)所指示。
表3:与HEK293/OS8/PD-L2细胞共同培养的HuT78/PD-1细胞中藉由抗PD-1单抗所诱导的IL-2释放
藉由HuT78/P3Z细胞中的IL-2释放的反向信号传导测定PD-1抗体功能
在嵌合受体P3Z中,用CD3ζ的胞质域替换PD-1信号传导域。因此,P3Z在与PD-L1结合后介导激活,而非像原始PD-1受体那样产生抑制。在此检定中,用杂交瘤上清液或PD-1抗体预温育HuT78/P3Z细胞(3x104/孔)15分钟,之后在37℃于96孔平底板(总体积200μl/孔)中与HEK293/PD-L1或HEK293/PD-L2细胞(5x104/孔)共同培养。在16-18小时后,收集上清液及藉由如上所述的ELISA检定IL-2产生。
藉由在上文所描述的反向信号传导检定中直接读出T细胞激活进一步证实鼠类抗PD-1单抗的功能活性。与上文所描述的结果一致,mu317及mu326在发明人所筛选的单抗中具有最佳功能活性。如表4及表5所示,就IC50及最大抑制两方面而言,mu317及mu326比低活性单抗之一的mu37有力得多。
表4:在与HEK293/PD-L1细胞共同培养的HuT78/P3Z细胞中藉由抗PD-1单抗抑制IL-2分泌
表5:在与HEK293/PD-L2细胞共同培养的HuT78/P3Z细胞中藉由抗PD-1单抗抑制IL-2分泌
实施例4:与HEK293/OS8/PD-L1细胞共同培养的原代人类PBMC中藉由抗PD-1单抗激活IFN-γ分泌
为了验证针对PD-1选定的顶级单抗是否也对原代人类免疫细胞施加功能性效果,发明人藉由使用新鲜分离的外周血单个核细胞(PBMC)检定抗体功能,这些PBMC主要由T细胞(50-70%)、B细胞及NK细胞(15-30%)及单核细胞(2-10%)组成。根据制造商说明书,藉由使用Ficoll淋巴细胞分离介质(Histopaque-1077;Sigma-Aldrich,MO)的密度梯度离心处理而从健康供体中分离人类PBMC。所有人类血液采集遵循Beigene的内部程序。随后用抗CD3单抗(40ng/mL)OKT3(产品编号16-0037,eBioscience,CA)刺激PBMCs达3天,之后进行检定。FACS分析(实施例1)显示,激活的PBMC(原代T细胞)上的PD-1表达均有不同程度的增加,取决于不同供体(表6)。为了测定在结合TCR/CD3复合物后预激活T细胞对PD-1配体阳性肿瘤细胞的反应,在96孔平底板中将PBMCs(1x104)与HEK293/OS8/PD-L1或HEK293/OS8/PD-L2细胞(3x104)共同培养15-18小时。藉由ELISA使用Ready-Set-Go!ELISA试剂盒(产品编号88-7316,eBiosciences)对无细胞上清液检定IFN-γ水平,此IFN-γ水平为T细胞激活以及其他免疫细胞激活的最突出指标(ThakurA.等人,2012Vaccine,30:4907-4920)。
图6表明预激活PBMCs与HEK293/OS8/PD-L1细胞的共同培养液中存在单抗mu317及mu326导致以剂量依赖型方式增加IFN-γ累积。尽管用对照鼠类IgG处理的IFN-γ的基础水平在不同供体间各异,但由mu317或mu326处理的PBMC,在0.1至10μg/ml抗体处理范围内,IFN-γ分泌的增加在统计学上是明显的。与mIgG处理的PBMCs的对应水平相比,由介于0.1至10μg/ml浓度水平之间的mu317及mu326所诱导的IFN-γ分泌分别在供体-19的PBMCs中增加2.5至3.2倍及在供体-20的PBMCs中增加1.4至2.3倍。
实施例5:藉由抗PD1单抗激活人类NK细胞
用于NK细胞中的功能性检定的稳定细胞系
先前报告了原代人类NK细胞响应IL-2处理表达PD-1蛋白质及抑制PD-1介导的信号传导,增强了NK细胞的细胞毒性(2010Blood,116:2286)。为了定量检定NK细胞中由抗PD-1单抗所施加的功能效果,人类NK细胞系NK92MI(ATCC)及肺癌细胞系SK-Mes-1(ATCC)经工程设计以根据先前所描述的操作程序,藉由逆转录病毒转导分别稳定表达人类PD-1及PD-L1(Zhang等人,2005,Blood106:1544-1551;Zhang等人,2006,CancerRes,66:5927)。两个稳定细胞系被命名为NK92MI/PD-1及SK-Mes-1/PD-L1。
抗PD-1抗体促进NK92MI/PD-1细胞中的IFN-γ产生及分泌
藉由定量测量NK92MI/PD-1细胞中的IFN-γ产生及分泌检定抗PD-1单抗对NK细胞的功能活性,在96孔平底板中将这些NK92MI/PD-1细胞与肺癌细胞系SK-MES-1/PD-L1以1:2的比率共同培养,每孔总计6x104个细胞。在共同培养开始前15分钟,将抗PD-1单抗添加至NK92MI/PD-1细胞,随后在CO2培育箱中将这些细胞共同培养过夜。藉由实施例4中所描述的ELISA对无细胞上清液检定IFN-γ水平。
所有抗PD-1单抗触发IFN-γ产生,自具有低浓度抗体处理的基线明显增加至具有高浓度抗体处理的顶线。两个顶级抗体mu317及mu326具有比参照抗体5C更低的EC50,显示这些抗体具有对NK细胞有力得多的激活效果(表7)。
表7:在抗PD-1单抗及SK-MES-1/PD-L1细胞存在下,NK92MI/PD-1细胞在培养基中分泌的IFN-γ(pg/ml)
抗PD-1抗体增强由NK92MI/PD-1细胞所介导的癌细胞杀死
藉由使用CytoTox96非放射性细胞毒性检定试剂盒(Promega,Madison,WI)的乳酸脱氢酶(LDH)释放检定测定NK92MI/PD-1细胞针对SK-MES-1/PD-L1细胞的细胞毒性。简言之,用抗PD-1单抗以最终浓度为0.004-10μg/ml的范围将NK92MI/PD-1细胞(105)预温育15分钟,并以效应细胞与肿瘤细胞(E:T)成5:1的比率将SK-MES-1/PD-L1细胞(2x104)添加至96孔V形底板中的免疫细胞培养物中,随后共同培养5小时。将完全肿瘤细胞裂解设定为最大细胞杀死,将各个样品的LDH释放检定读值计算为最大细胞杀死的百分比。使用基线的10%作为共同标准,跨板标准化所有样品的细胞杀死(%)。
在上文所设定的特异性细胞毒性检定中,所选定抗PD-1单抗以高浓度的单抗输入引发净肿瘤细胞杀死(=顶线-基线),范围自19%至20.2%。Mu317及mu326具有比mu336更低的EC50,显示触发NK92MI/PD-1细胞介导的肿瘤细胞杀死的较佳效力(表8)。
表8:由抗PD-1单抗诱导的NK92MI/PD-1细胞对肿瘤细胞的细胞毒性
实施例6:PD-1单抗的克隆及序列分析
在100mm组织培养皿中将分泌特定单抗的鼠类杂交瘤克隆培养至3x106至10x106个细胞的密度,经由在摇摆桶旋转器中以1500rpm离心处理来收获细胞。遵循制造商操作程序,使用UltrapureRNA试剂盒(产品编号CW0581,CWBIOTECH,中国,北京)分离总细胞RNA。在二次去离子水中再悬浮RNA,藉由NanoDrop(ThermoFisher,中国,上海)测量浓度。
基于先前所报告的序列(Brocks等人,2001MolMed7:461-469),藉由Invitrogen(中国,北京)合成用于单抗cDNA克隆的PCR引物。使用逆转录酶(产品编号AH301-02,TransgenBiotech,中国,北京)合成第一链cDNA。使用PCR试剂盒(产品编号Ap221-12,TransgenBiotech,中国,北京)且遵循制造商操作程序进行特定单抗cDNA的PCR扩增。由服务提供商对PCR产物直接测序(GeneWiz,中国,北京)或将PCR产物亚克隆入pCR载体(Invitrogen),随后测序(GeneWiz)。
藉由序列同源性比对分析鼠类单抗的蛋白质序列。基于序列同源性及表位定位结果(实施例13)将单抗分组。基于Kabat(Wu,T.T.及Kabat,E.A.,1970J.Exp.Med.132:211-250)及IMGT系统(LefrancM.-P.等人,1999NucleicAcidsResearch,27,209-212),藉由序列批注及藉由基于因特网的序列分析(http://www.imgt.org/IMGT_vquest/share/textes/index.html与http://www.ncbi.nlm.nih.gov/igblast/)鉴定互补决定区(CDR)。如表9所示,mu317及mu326的CDR在序列长度及同源性上极为不同。
表9:mu317及mu326的CDR
实施例7:鼠类单抗的人源化
抗体3D结构的模拟
针对mu317及mu326的可变域模拟三维结构,以便鉴定对于支持CDR环结构可能重要的框架残基。在第一轮抗体人源化中将潜在重要的框架残基保持为原始鼠类残基。采用先前建立的针对抗体的结构建模方法(Morea等人,Methods200020:267-279)基于抗体的已知规范结构模拟抗PD-1单抗的3D结构(Al-Lazikani等人,1997JournalofMolecularBiology273:927-948)。简而言之,在PDB数据库(ProteinDataBank,http://blast.ncbi.nlm.nih.gov/)中检索(blast)鼠类抗体的各个可变域(Vk及Vh)的序列以鉴定具有已知高分辨率结构(分辨率小于2.5埃)的最同源抗体序列。针对mu317及mu326建模选定的结构模板(表10中列出)在L-CDR1、L-CDR2、L-CDR3、H-CDR1及H-CDR2中具有与待建模的靶抗体相同类别的规范环结构。若Vκ及Vh的模板来自不同的免疫球蛋白,则藉由主链原子的最小平方拟合将这些模板堆叠(pack)在一起,以形成Vκ-Vh界面残基的杂合结构,该结构被Swiss模型程序用作结构同源性建模的模板(Kiefer等人,2009NucleicAcidsResearch37,D387-D392)。在保持主链构象的同时,调整某些侧链构象。在亲本结构与建模结构具有相同残基的位点处,保持侧链构象。在残基为不同的位点处,在模板结构、旋转异构体库及堆叠考虑的基础上对侧链构象建模。在同源性建模后,使用PLOP程序(Jacobson等人,2002JournalofPhysicalChemistry106:11673-11680)细化同源性模型以最小化所有原子能量及优化Vκ及Vh界面。执行此步骤以改良立体化学,尤其是在来自不同抗体的结构的区段已被结合在一起的那些区域中。
表10:用于抗体结构模拟的结构模板
也针对CDR嫁接317-1及326-1模拟结构,以便导引更多轮抗体工程设计以增强人源化的程度及/或增强抗体稳定性。表10也列出选定结构模板。以与上文程序类似的方式实行结构模拟,所不同的是分别从针对317-1的PDB模板1AY1及针对326-1的模板3CXD中取得H-CDR3的可能构象,这些模板含有相似大小及躯干(torso)区域的H-CDR3。使用PLOP实行嫁接H-CDR3残基的能量最小化。
人源化
对于抗PD-1单抗的人源化,发明人藉由检索IMGT(http://www.imgt.org/IMGT_vquest/share/textes/index.html)及NCBI(http://www.ncbi.nlm.nih.gov/igblast/)网站中的人类免疫球蛋白基因数据库搜寻与mu317及mu326可变区的cDNA序列同源的人类种系IgG基因。将与PD-1单抗具有高同源性的人类IGVH及IGVκ选为人源化模板。
原则上藉由CDR嫁接实施人源化。在第一轮人源化中,如上文所描述的,藉由模拟3D结构导引可变区的框架序列中鼠类至人类氨基酸残基的突变,且仅使得其变化保持了总体抗体及CDR环结构的鼠类氨基酸残基突变至人类序列。人源化单抗的初始型式为hu317-1(序列编号47-50)及hu326-1(序列编号55-58),它们包含:重链,其中人源化可变重链(Vh)融合至人类IgG2恒定区(NCBI登录号:P01859);及轻链,其中人源化可变轻链κ(Vκ)融合至人类IgκC区(NCBI登录号:P01834)。同样地,发明人从mu317及mu326中产生嵌合抗体,这些嵌合抗体由融合至人类IgG2恒定区的鼠类VH及融合至人类IgκC区的鼠类Vκ组成。将全嵌合抗体分别命名为ch317及ch326。如实施例1所描述表达及纯化所有重组单抗。
FACS及功能性检定表明,单抗hu317-1几乎保持了与mu317及ch317相同的结合及功能活性。可藉由在FACS中使用两个不同检测抗体(山羊抗小鼠IgG及山羊抗人类IgG)的事实解读mu317对比ch317与hu317-1之间在FACS分析中的EC50差异。在两个功能性检定中,更同等地处理317的所有三个型式,且结果也接近于彼此(表11)。
作为针对mu326的初轮人源化的结果,单抗hu326-1保持了与亲本ch326及mu326相似的功能特征,尽管FACS结合检定及基于HuT78/PD-1细胞的IL-2释放检定中的功能活性可比ch326略微更弱(表12)。
表11:藉由FACS及功能性检定比较mu317、ch317及hu317-1
表12:藉由FACS及功能性检定比较mu326、ch326及hu326-1
基于第一轮人源化,发明人进一步使hu317-1_Vh及_Vκ的框架(FR)中的其他鼠类氨基酸(AA)残基个别突变,以评估对抗体功能的影响。如表13所示,hu317-1的Vh中的七个个体突变及Vκ中的一个突变皆具有相似功能活性。在一些Vh突变中仅观察到较小变化,诸如hu317-2_K71V在突变中具有略微较弱的抑制功能。然而,当所有鼠类氨基酸残基一起突变成人类时(hu317-3A),在FACS及IL-2释放检定中功能比其余突变明显更弱。
在上文所描述的初期试验中,除留下少数鼠类AA残基外,hu326-1在FR中达到明显的人源化水平。然而,hu326-1具有比mu326更弱的功能。因此,发明人实行更个别的突变,这些突变返回到鼠类残基或者朝向人类残基,以探索各个个体AA对单抗326功能的贡献。表14呈现基于hu326-1_Vh模板(序列编号56、序列编号57)产生的所有单个AA突变及其功能性检定结果。大多数突变展示出比hu326-1更好的功能活性,匹配原始mu326单抗。一对突变(E46K及F95Y)展示出EC50或IC50上略微较少的效力,表明那些残基在抗体结构及功能中的作用。
表13:hu317-1框架中具有人源化突变的Fab的功能活性的比较
表14:hu326-1框架中具有突变的单抗的功能活性的比较
为了探索可在人类中用作治疗剂的单抗317及326的最佳可能Vh及Vκ序列组成,发明人考虑到抗体特征实行各种组合突变(包括在CDR序列中的一些突变),这些抗体特征诸如FR中的人源化水平、功能活性、物理化学特性、抗体依赖性细胞介导的细胞毒性(ADCC)及补体依赖性细胞毒性(CDC)。认为突变中的大多数未通过合格标准。经由工程设计过程,出于它们的潜在治疗效用选择人源化重组单抗中的六个:hu317-4B2(序列编号43-44)、hu317-4B5(序列编号45-46)、hu317-4B6(序列编号23-26)、hu326-3B1(序列编号51-52)、hu326-3G1(序列编号53-54)及hu326-4A3(序列编号27-30)。将单抗的CDRs与原始鼠类抗体相比较,展示于表15及表16中。
在六个单抗中,hu317-4B2、hu317-4B5及hu317-4B6在序列上彼此密切相关且在功能活性及强度上极为相似。另一方面,hu326-3B1、hu326-3G1及hu326-4A3在序列及功能性上彼此相当接近(表17-18)。在两组单抗的各者内,尽管存在一些较小差异,但它们也共享在序列及功能以外的许多其他特征,诸如物理化学特性及结合表位(实施例10及11中所描述)。
表15:单抗317的不同型式间的CDR比较
表16:单抗326的不同型式间的CDR比较
表17:藉由ELISA及FACS检定的人源化单抗的结合活性
表18:藉由SPR检定的Fab的结合亲和力
Fab kon(M-1,s-1) koff(s) KD(M)
hu317-4B5 3.89x 105 9.07x 10-5 2.33x 10-10
hu317-4B6 5.71x 105 8.37x 10-5 1.47x 10-10
hu326-3B1 2.18x 105 1.90x 10-4 8.70x 10-10
hu326-3G1 2.00x 105 2.01x 10-4 1.00x 10-9
藉由SPR的人源化抗PD-1Fab的亲和力测定
藉由PCR将抗PD-1单抗转换成Fab型式以使重链及轻链的可变区分别融合至人类IgG2-CH1及κ链恒定区的N末端,及在pcDNA3.1载体(Invitrogen)中亚克隆。使用与整个抗体的瞬时表达类似的瞬时转染方法在293-F细胞中共同表达两个表达载体。简而言之,PCR扩增Fabκ链及在基于pcDNA3.1的表达载体(Invitrogen,Carlsbad,CA,USA)中亚克隆。在另一质粒中,藉由交叠PCR将重链可变区(VH)以及来自人类IgG2中的CH1编码序列与C末端c-Myc-His8标签融合,及随后在表达载体中次克隆。在IgG2重链中引入C232S及C233S(Kabat残基编号,Kabat等人,Sequenceofproteinsofimmunologicinterest,第5版,Bethesda,MD,NIH1991)突变以防止二硫键交换及稳定人类IgG2处于IgG2-A构象(Lightle等人,2010ProteinSci19(4):753-762)。两个构建体含有Fab成熟序列上游的信号肽。藉由上述2个质粒共同转染入293-F细胞实现Fab的分泌表达及在转染后6-7天收获细胞培养物上清液。使用Ni-SepharoseFastFlow柱(产品编号17531801,GELifeSciences),然后使用HiLoad16/60Superdex200柱(产品编号17106901,GELifeSciences)执行大小排阻层析法从细胞培养物上清液中纯化带His8标签的Fab。将纯化Fab浓缩至PBS中0.5-5mg/mL及以等份试样储存于-80℃冷冻箱中。
为了抗PD-1Fab的亲和力测定,使用BIAcoreTMT-200仪器(GELifeSciences)进行SPR检定。简而言之,将人类PD-1/His或食蟹猴PD-1/His偶联至已活化的CM5生物传感器芯片(产品编号BR100530,GELifeSciences)以实现大约100-200个响应单位(RU),然后用1M乙醇胺封闭未反应基团。以30μL/分钟在SPR运行缓冲液(10mMHEPES,150mMNaCl,0.05%Tween20,pH7.4)中注射自0.12nM至90nM递增浓度的Fab样品,且藉由减去来自空白流动室的RU来计算在人类PD-1/His或猴PD-1/His上的结合响应。使用一对一朗谬结合模型(BIAEvaluationSoftware,GELifeSciences)计算结合速率(kon)及解离速率(koff)。以比率koff/kon来计算平衡解离常数(KD)。
表18中列出SPR测定的抗PD-1Fab的结合亲和力。各个抗PD-1Fab以高亲和力(KD=0.15-1nM)结合至人类PD-1。除326-3G1外的所有Fab以略微较低但相当(KD的5倍内)亲和力结合至食蟹猴PD-1。
实施例8:具有经修饰人类IgG4恒定区的重组抗PD-1单抗的产生及表达
由于PD-1主要表达于激活T细胞中,连接至天然产生类型IgG-Fc模块的PD-1阻断性抗体预期取决于IgG亚类会以不同程度诱导Fc介导的效应器功能(诸如ADCC及CDC),从而导致消除激活T细胞(NatsumeA等人,2009DrugDesDevelTher.3:7-16)。在许多先前报告中已展示人类抗体亚类IgG4,IgG4具有适度ADCC且几乎没有CDC效应器功能(MooreGL等人,2010MAbs,2:181-189)。另一方面,已发现天然IgG4在压力条件下(诸如在酸性缓冲液中或在上升的温度下)不太稳定(Angal,S.1993MolImmunol,30:105-108;Dall′Acqua,W.等人,1998Biochemistry,37:9266-9273;Aalberse等人,2002Immunol,105:9-19)。为了使PD-1+T细胞免遭杀死及改良抗PD-1抗体的物理化学特性,将人源化单抗连接至由突变组合所设计的IgG4以具有减小的或零FcγR结合或C1q结合活性,因此减弱或消除ADCC及CDC效应器功能。考虑到抗体作为生物学药物的物理化学特性,IgG4的不太理想的固有特性之一为其在溶液中动态分离两个重链而形成半抗体,此举导致经由称为“Fab臂交换”的过程在体内产生双特异性抗体(VanderNeutKolfschotenM等人,2007Science,317:1554-157)。在位置228(EU编号系统)处的丝氨酸至脯氨酸的突变呈现对IgG4重链分离的抑制(Angal,S.1993MolImmunol,30:105-108;Aalberse等人,2002Immunol,105:9-19)。已报告铰链及γFc区中的一些氨基酸残基对抗体与Fcγ受体的相互作用具有影响(ChappelSM等人,1991Proc.Natl.Acad.Sci.USA,88:9036-9040;Mukherjee,J.等人,1995FASEBJ,9:115-119;Armour,K.L.等人,1999EurJImmunol,29:2613-2624;Clynes,R.A.等人,2000NatureMedicine,6:443-446;ArnoldJ.N.,2007AnnuRevImmunol,25:21-50)。此外,人类群体中一些罕见发生的IgG4同等型也可引发不同的物理化学特性(Brusco,A.等人,1998EurJImmunogenet,25:349-55;Aalberse等人,2002Immunol,105:9-19)。然而,将先前发现的所有突变及同等型集中成特定抗体并不保证理想抗体分子共享诸如上文所描述的用作治疗剂的所有特征,原因可为组合突变的矛盾效果及可变区对抗体的效应器功能及物理化学特性的影响(IgawaT.等人,2010ProtEngDesignSelect,23:385-392;PerchiaccaJ.M.与TessierP.M.,2012AnnRevBiomolEng3:263-286)。
为了产生具有最小ADCC、CDC及不稳定性的抗PD-1单抗,发明人藉由引入一定数目突变组合来修饰人类IgG4的铰链及γFc区,创建IgG4mt1至IgG4mt12。如发明人的检定结果所示,一些经修饰的IgG4变体显然不太理想,表19中列出若干相关IgG4变体及修饰后序列。本文描述这些抗体的评估。
表19:IgG4变体的序列修饰
实施例9:IgG4mt10没有FcγR结合、具有最低的ADCC及CDC效应器功能
当抗体结合至细胞表面靶蛋白质,然后连接至效应细胞上所表达的Fcγ受体(FcγR)时,启动ADCC。很清楚地记载了人类IgG1对FcγR具有比IgG2及IgG4明显更高的结合亲和力,尤其是结合FcγR-I及FcγR-IIIA,该亲和力与IgG1激活ADCC的强度相关联。联想到ADCC,当抗体交联细胞表面靶点及C1q蛋白质,继之以补体复合物形成及靶细胞裂解的级联反应时,激活CDC。作为ADCC及CDC的代理,抗体结合至FcγR及C1q的检定可充当ADCC及CDC的基本指标。因此,发明人系统地评估单抗对所有主要FcγR的结合。
FcγR结合
藉由流式细胞术测定各种IgG4突变体对FcγR的结合。简言之,建立表达人类FcγR的一系列HEK293转染子。这些转染子表达FcγRI、FcγRIIA、FcγRIIB或FcγRIIIA。与FcRγ共同表达多亚基FcγR(即,FcγRI及FcγRIIIA)。还包括多态性变体(即,FcγRIIAH131与R131、FcγRIIIAF158与V158)。使用二体(山羊抗人类IgGF(ab)′2-AlexaFluor488,JacksonImmunoResearch,WestGrove,PA,USA)检测抗PD-1单抗与经修饰IgG4变体(表19)对FcγR+HEK293细胞的结合。如预期,IgG1型式的抗PD-1单抗(hu317-1/IgG1及hu317-4B6/IgG1)强有力地结合所有FcγR,包括FcγRI、FcγRIIA(H131及R131等位基因)、FcγRIIB及FcγRIIIA(V158及F158等位基因)(表20)。有趣的是,当以相同IgG4变体型式(诸如IgG4mt1或者IgG4mt6型式)产生两个不同型式的人源化单抗,即hu317-1及hu317-4B6(在Vh及Vκ两者中具有差异)时,它们的结合强度(MFI)自2倍至接近于100倍的范围变化(例如,455.2/115.7=3.9倍;13.6/1.0=13.6倍;434.6/4.9=88.7倍;等等,参看表20)。与其他人的先前发现一致的是,抗体的可变区对与FcR的结合具有明显影响,因此,对诸如ADCC的效应器功能施加影响(IgawaT.等人,2010ProtEngDesignSelect,23:385-392;PerchiaccaJ.M.与TessierP.M.,2012AnnRevBiomolEng3:263-286)。
如表20中所表明,当以IgG4mt10型式产生hu317-4B6及hu326-4A3时,它们在表中所列出的PD-1单抗及IgG变体型式中以及研究中已测试的许多其他人源化单抗及IgG型式中具有对FcγR的最低结合活性。IgG4mt10型式的hu317-4B6及hu326-4A3在这个方面的独特性不可延伸至具有某些远序列同源性的人源化单抗的相同家族(诸如hu317-1),如上文所描述。
表20:由FACS所测定的抗PD-1单抗对FcγR的结合强度(MFI*)
ADCC
经典ADCC涉及藉由抗体结合至FcγRIIIA或CD16而激活NK细胞。为了验证人源化抗PD-1单抗是否诱导ADCC,将NK92MI/CD16V细胞用作效应细胞,该细胞藉由共同转导含有CD16(V158等位基因)与FcRγ基因的表达质粒自NK92MI细胞(ATCC)产生,及将表达PD-1的T细胞系HuT78/PD-1用作靶细胞。在96孔V形底板中将NK92MI/CD16V细胞(4x104)与相等数目的HuT78/PD-1细胞共同培养5小时。由前文中所描述的LDH释放检定测定细胞毒性。结果确认,与阳性对照相比较,hu317-4B2/IgG4mt6、hu317-4B6/IgG4mt6、hu317-4B6/IgG4mt10及hu326-4A3/IgG4mt10全部具有ADCC的基础水平(图7)。那4个单抗之间ADCC的较小差异可归因于实验误差(参看图7中的误差棒)。
CDC
大体而言,人类IgG4抗体并不经由经典路径诱导任何CDC。使用PD-1表达T细胞系HuT78/PD-1及来自健康供体的新鲜人类血清评估IgG4mt10型式的抗PD-1单抗是否会触发CDC。藉由Celltiterglo检定试剂盒(Promega,中国,北京)测定CDC的细胞裂解。简言之,在96孔平底板中,在37℃在具有抗PD-1抗体(10μg/ml)的无血清RPMI1640(Invitrogen)中温育HuT78/PD-1细胞(2x104)15分钟,随后添加正常人类血清(NHS),终浓度为15%或50%,总体积为120μl。在37℃过夜温育后,细胞裂解并检定ATP浓度。为了测试IgG4mt10的人源化抗PD-1单抗是否能经由CDC杀死PD-1+原代T细胞,用抗CD3抗体OKT3(40ng/ml)预激活自健康供体分离的PBMCs达3天,随后与抗PD-1抗体加NHS共同培养。ATP量与培养液中存在的细胞数目成正比。使用96孔荧光计(PHERAStarFS,BMGLABTECH)读取荧光。以与活细胞数目成比例的相对荧光单位(RFU)表述这些结果。百分比CDC活性计算如下:%CDC活性=[(RFU测试-RFU背景)/(完全细胞裂解下的RFU-背景下的RFU)]x100。大体而言,发明人未能检测由结合至激活PBMCs的IgG4mt10型式的抗PD-1单抗所介导的任何ADCC。在高度敏感性实验条件下,诸如使用PD-1高表达细胞系、高血清与抗体浓度,发明人在一些场合中检测到极低水平的CDC,且不同型式与抗PD-1单抗之间不存在太多差异,此指示IgG4变体型式的抗PD-1单抗保持与常见形式的IgG4相同的低CDC活性或无CDC活性的特征。
实施例10:IgG4mt10型式的人源化抗PD-1单抗在压力条件下具有增强的稳定性
抗PD-1抗体在高温及酸性条件中的稳定性
用于稳定性研究的抗PD-1抗体全部由前文中所描述的蛋白A柱及随后的大小排阻层析法(SEC)纯化。在纯化后,在分析性大小排阻层析法-高效液体层析法(SEC-HPLC)中监测纯化抗体样品的聚集体含量,这些含量处于0%-0.5%的范围内。
对于SEC-HPLC分析,在等度洗脱条件下(洗脱缓冲液0.2M磷酸钠,pH7.2),使用TSKgelG3000SWXL柱(7.8x300mm,产品编号08541,TosohBioscience,中国,上海)分析抗体样品,随后在UV-215nm处检测。在各次执行中,将10微升抗体样品加载到柱上并以1mL/分钟的流速洗脱。将抗体的二聚体或较大聚集体种类与单体种类分开,并基于UV线的积分峰面积测定二聚体及聚集体的百分比。
对于速度增强的贮存稳定性研究,将抗PD-1抗体(PBS中10-40mg/mL)保存于40-50℃的培育箱中长达4-7天,以便测试抗体在高温条件中的稳定性。随后在SEC-HPLC中针对热诱导形成二聚体及聚集体分析抗体样品。对于所分析的各个抗PD-1抗体,2%以下变成较高分子量种类(二聚体及聚集体),说明抗PD-1抗体在高温条件下具有良好稳定性。
在下游制造过程中,酸性条件中的抗体稳定性已成为关键性挑战(Liu等人,2010mAbs2:480-499)。自蛋白A的抗体洗脱及病毒的灭活通常需要在低pH(2.5-4)条件中温育抗体。然而,此类酸性条件可潜在引发抗体变性及聚集。已知人类IgG4比IgG1及IgG2稳定性低(2002Immunology105:9)。因此,发明人检定用各种IgG4突变体型式所产生的人源化单抗。简而言之,藉由1:1体积的各个抗体样品(PBS中10mg/mL)与低pH缓冲液混合研究低pH条件中的抗体稳定性,这些缓冲液含有50mM柠檬酸钠,100mMNaCl,pH分别为3.6、3.3、3.0或2.7。在室温下温育1小时后,藉由1:5稀释入含有0.2M磷酸钠(pH7.2)的SEC-HPLC洗脱缓冲液中和低pH条件中的抗体样品。如上文所描述进行SEC-HPLC分析及量化由低pH条件所诱导的二聚体及聚集体的百分比。IgG1型式的抗PD-1单抗317-4B6在生物工艺相关的酸性条件中最稳定,即使当pH值低到2.7时亦如此。在若干IgG4变体中产生的抗PD-1单抗之中,hu317-4B6/IgG4mt10与hu326-4A3/IgG4mt10在酸性缓冲液条件下最稳定(表21),因为酸诱导的聚集体明显减少到与IgG1型式的抗PD-1单抗317-4B6及326-4A3相当的水平(即,可溶性聚集体小于2%(表21))。
表21:在酸性缓冲液中形成及藉由SEC-HPLC检定的二聚体及可溶性聚集体
实施例11:定位抗PD-1单抗的结合表位
关于PD-1/PD-L1及PD-1/PD-L2复合物的晶体结构的先前报告已经阐明而理解PD-1上配体结合所需要的关键氨基酸(AA)残基(Zhang等人,2004Immunity,20:337-347;LinD.Y.等人,2008PNAS105:3011-3016;Lazar-MolnarE.等人,2008PNAS,105:10483-10488)。事实上,在受体上经由点突变分析鉴定此类AA残基中的六个是PD-L1结合所需要的。六个AA残基中的五个也是PD-L2结合所需要的(LinD.Y.等人,2008PNAS105:3011-3016)。基于结构导引突变分析中的信息,发明人假设,功能性单抗阻断PD-1介导的信号传导的最有效方式为藉由结合至六个关键AA残基,从而占据配体结合所需要的结合表位而与PD-1配体竞争。为了探索该假设及理解功能性PD-1抗体的作用机制,发明人已藉由将六个关键AA的每一个个别地替换成Ala,产生PD-1的六个突变体,即K45A、I93A、L95A、P97A、I101A及E103A(基于LinD.Y.等人,2008PNAS105:3011-3016进行的AA残基编号)。将突变型PD-1/Fc及PD-1/His(图1)作为模板,用于使用快速诱变系统(产品编号FM111,TransgenBiotech,中国,北京)的PCR导引诱变或滚环诱变。在发明人基于pcDNA的表达载体中亚克隆所有突变体,并藉由测序验证。藉由瞬时转染(实施例1中所描述)表达突变型及野生型PD-1蛋白质,并在培养4-6天后制备这些蛋白质。藉由Western印迹分析条件培养基(CM),以就质量与数量而言验证PD-1蛋白质表达。在清除细胞碎片后,在ELISA分析或Western印迹中直接使用上清液(CM)以进行表位定位。
为了研究人源化抗PD-1单抗的结合表位,执行使用野生型(WT)及突变型(Mt)PD-1的ELISA检定以评估hu317-4B5、hu317-4B6、hu326-3B1及hu326-4A3的结合活性。为了进行比较以检查抗体结合签名的独特性,在研究中包括两个参考抗体(分别来自US8008449B2及US8168757B2的参考抗体-1与参考抗体-2)。在相同ELISA检定中,在用于所有单抗的96孔板中包被相等体积的含有WT或MtPD-1的CM。使用WTPD-1结合信号的平均ELISA读数作为标准,标准化所有ELISA结果。针对对某特定MtPD-1的最高抗体结合读数(设定为100%)进一步标准化针对该特定MtPD-1的ELISA结合信号。为了便于数据分析,当单抗针对特定突变体的ELISA结合信号相对于WTPD-1下降到50%以下时,将该氨基酸残基定义为明显结合表位,因为其突变明显消除了抗体结合。同样地,若单抗针对特定突变体的ELISA结合信号下降到25%以下,则定义为极其明显。如图8所示,PD-1中关键AA残基中的两者K45及I93为单抗hu317-4B5及hu317-4B6结合的明显或极其明显表位,且三个AA残基I93、L95及P97为hu326-3B1及hu326-4A3的明显或极其明显表位。另一方面,两个参考抗体具有可区别的结合表位,P97对于参考抗体-1明显,而L95及P97对于参考抗体-2明显。
有趣的是,当PD-1蛋白质在Western印迹中变性后,单抗hu317-4B5及hu317-4B6仍然能够结合至WTPD-1,虽然关键结合表位(K45及I93)彼此并不接近(非线性)。此表明,在Western印迹过程的SDS-PAGE中变性后,PD-1蛋白质在某种程度上复性,从而允许抗PD-1单抗识别及结合它。利用此观察结果,发明人针对上文ELISA研究中所使用的所有六个抗体执行Western印迹分析。Western印迹的总体结果很好地印证了ELISA结果,即,,其突变在ELISA中引发弱结合信号的明显或极其明显表位也提供与其他突变型PD-1的结合相比最弱的Western印迹带(图8)。还观察到ELISA与Western印迹之间的一些较小差异,例如,由参考抗体-2在I93A及E103A上的ELISA结合信号比Western印迹中的信号相对更强。这可能指示,那些AA残基还可帮助结合,因为那些AA残基突变影响结合,但仅在压力条件下(即,变性或丧失天然构象)。如表22中所归纳的,本发明中的抗PD-1单抗具有与其他抗PD-1抗体不同的可鉴定结合表位。
表22:抗PD-1单抗的关键表位的归纳*
实施例12:抗PD-1单抗在异种移植物小鼠模型中激活原代人类PBMC及抑制肿瘤生长
人源化抗PD-1单抗激活人类PBMC
贯穿人源化过程,人源化抗PD-1单抗在各种阶段处保持相似功能活性,由ELISA、FACS及基于免疫细胞的细胞因子释放检定评估该功能活性。为了确认人源化单抗的最终型式的功能,发明人使用原代人类PBMCs检定了hu317-4B5、hu317-4B6、hu326-3B1及hu326-4A3的激活功能。结果表明,尽管因个体遗传背景不同造成四个供体之间的激活程度不同,但贯穿人源化的那些单抗维持了原始鼠类单抗激活原代PBMC的功能(图9)。
人源化抗PD-1单抗增强基于NK细胞的对癌细胞的细胞毒性
联想到原始鼠类单抗,人源化抗PD-1单抗hu317-4B5、hu317-4B6、hu326-3B1及hu326-3G1以剂量依赖型方式增强针对靶肺癌细胞SK-MES-1/PD-L1的NK92MI/PD-1细胞介导的细胞毒性(图10,表23)。很明显,原理上人源化抗PD-1单抗可发挥破坏由PD-1信号传导所介导的免疫细胞耐受的功能,从而增强免疫细胞(例如,NK细胞及细胞毒性T淋巴细胞)的杀癌活性。
人源化抗PD-1单抗在小鼠异种移植物癌症模型中体内激活人类PBMCs及抑制肿瘤生长
所有上述实验证据显示,抗PD-1单抗可在小鼠癌症模型中起作用,这些模型利用异种移植有人类癌细胞的免疫受损小鼠,随后植入人类PBMCs及应用单抗处理,以抑制体内癌细胞生长。实验设计如下。在七至八周大SCID雄性小鼠(VitalRiverLaboratories,中国)右体侧处皮下接种50%Matrigel(BDBiosciences,NewJesey,USA)中的3x106个Hep3B/OS8-PD-L1细胞。在肿瘤接种后15天,使带肿瘤大小100-250mm3的小鼠随机分为三个处理组。瘤内注射来自2个健康供体的100微升汇集PBMCs(5x105)。在PBMCs植入后3天,经由皮下注射以10mg/kg的剂量分别施用抗PD-1抗体(Hu317-IgG4mt2)及人类IgG。抗体处理每10天重复一次,共计3次。在平行组中注射PBS作为阴性对照。在第7天开始,使用测径规每周两次测量肿瘤。使用以下公式计算肿瘤体积:[Dx(d2)]/2,其中D表示肿瘤的大直径,及d表示小直径。所有动物研究皆遵循Beigene动物护理及使用程序执行。
在体内研究中,尽管对照组中的60%肿瘤为自动消退,但体内实验的剩余部分仍相当具有教益,此呈现于图11中。在对照组中,媒剂处理组或人类IgG(huIgG)处理组各具有40%的肿瘤(5只小鼠中的2只)比在起始点处的基线长出更大。PBS处理组中的两个肿瘤生长大得多(2000mm3以上,由于超过规程的肿瘤大小限制,提前终止一只带肿瘤小鼠)。huIgG处理组中的两个肿瘤生长到800及1370mm3的大小,明显超过164mm3的平均基线,但比PBS处理的肿瘤小。另一方面,在抗PD-1单抗(hu317-1/IgG4mt2)处理组中,肿瘤完全消退或者接近于基线大小(一个肿瘤=200mm3,该肿瘤在自PBMC植入起两周时消退到基线的50%后缓慢重新生长)。结果显示,上文所描述的抗PD-1单抗能在小鼠体内癌症模型中激活抑制肿瘤细胞生长的人类免疫细胞,该结果与上文所描述的体外实验结果一致。

Claims (17)

1.一种抗体抗原结合域,该抗体抗原结合域特异性结合人类PD-1,且该抗体抗原结合域包含具有选自序列编号11-22、31-42及59-63的序列的互补决定区(CDR)。
2.如权利要求1所述的域,该域包含重链可变区(Vh)或轻链可变区(Vκ),所述可变区包含:
3.如权利要求1所述的域,该域包含重链可变区(Vh)或轻链可变区(Vκ),所述可变区包含:
4.如权利要求1所述的域,该域包含重链可变区(Vh)及轻链可变区(Vκ),所述可变区包含:
5.如权利要求1所述的域,该域包含重链可变区(Vh)及轻链可变区(Vκ),所述可变区包含:
(a)CDR-H1(序列编号31)、CDR-H2(序列编号12、32、59或60)及CDR-H3(序列编号33),
CDR-L1(序列编号14、34或61)、CDR-L2(序列编号35)及CDR-L3(序列编号36);或
(b)CDR-H1(序列编号37)、CDR-H2(序列编号18、38或62)及CDR-H3(序列编号39),
CDR-L1(序列编号40)、CDR-L2(序列编号41)及CDR-L3(序列编号42)。
6.如权利要求1所述的域,该域包含重链可变区(Vh)或轻链可变区(Vκ),所述可变区包含:
7.如权利要求1所述的域,该域包含重链可变区(Vh)及轻链可变区(Vκ),所述可变区包含:
8.如权利要求1所述的域,该域特异性结合PD1残基:
(a)K45及I93(基于2008PNAS,105:10483进行AA编号;相当于序列编号2中的K58及I106);或
(b)I93、L95及P97(基于2008PNAS,105:10483进行AA编号;相当于序列编号2中的I106、L108及P110)。
9.如权利要求1所述的域,该域诱导与HEK293/OS8/PD-L1细胞或与HEK293/OS8/PD-L2细胞共同培养的HuT78/PD-1细胞中的IL-2释放,及/或该域抑制与HEK293/PD-L1细胞或与HEK293/PD-L2细胞共同培养的HuT78/P3Z细胞中的IL-2分泌。
10.一种抗体IgG4重链效应器或恒定域,该效应器或恒定域包含序列编号83-88中的任一者。
11.一种抗体、F(ab)或F(ab)2,其包含如权利要求1-8中任一项所述的域。
12.一种抗体,该抗体包含如权利要求7所述的域及包含序列编号87或88的IgG4重链效应器或恒定域。
13.一种多核苷酸,该多核苷酸编码如权利要求1所述的域。
14.一种多核苷酸,该多核苷酸包含编码如权利要求1所述的域的cDNA序列。
15.一种使用如权利要求1所述的域的方法,该方法包含向确定患有癌症或病毒感染或确定另外需要PD-1拮抗作用的人施用该域的步骤。
16.一种融合蛋白,该融合蛋白包含:
(a)融合至小鼠CD8α的C末端域(113-220)的抗人类CD3单抗OKT3的单链可变片段(scFv)(序列编号89);或
(b)融合至人类CD3ζ链的胞质域的人类PD-1的胞外域及跨膜域(序列编号90)。
17.一种使用如权利要求16所述的融合蛋白的方法,该方法包含用表达该融合蛋白的细胞系检定、筛选或选择抗PD-1抗体。
CN201380079581.6A 2013-09-13 2013-09-13 抗pd1抗体及其作为治疗剂与诊断剂的用途 Active CN105531288B (zh)

Priority Applications (5)

Application Number Priority Date Filing Date Title
CN201710208535.1A CN107090041B (zh) 2013-09-13 2013-09-13 抗pd1抗体及其作为治疗剂与诊断剂的用途
CN202011322092.7A CN112552401B (zh) 2013-09-13 2013-09-13 抗pd1抗体及其作为治疗剂与诊断剂的用途
CN201710207300.0A CN107011441B (zh) 2013-09-13 2013-09-13 抗pd1抗体及其作为治疗剂与诊断剂的用途
CN201810552595.XA CN108715615B (zh) 2013-09-13 2013-09-13 抗pd1抗体及其作为治疗剂与诊断剂的用途
CN202011322081.9A CN112457403B (zh) 2013-09-13 2013-09-13 抗pd1抗体及其作为治疗剂与诊断剂的用途

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2013/083467 WO2015035606A1 (en) 2013-09-13 2013-09-13 Anti-pd1 antibodies and their use as therapeutics and diagnostics

Related Child Applications (5)

Application Number Title Priority Date Filing Date
CN202011322081.9A Division CN112457403B (zh) 2013-09-13 2013-09-13 抗pd1抗体及其作为治疗剂与诊断剂的用途
CN201710208535.1A Division CN107090041B (zh) 2013-09-13 2013-09-13 抗pd1抗体及其作为治疗剂与诊断剂的用途
CN201810552595.XA Division CN108715615B (zh) 2013-09-13 2013-09-13 抗pd1抗体及其作为治疗剂与诊断剂的用途
CN202011322092.7A Division CN112552401B (zh) 2013-09-13 2013-09-13 抗pd1抗体及其作为治疗剂与诊断剂的用途
CN201710207300.0A Division CN107011441B (zh) 2013-09-13 2013-09-13 抗pd1抗体及其作为治疗剂与诊断剂的用途

Publications (2)

Publication Number Publication Date
CN105531288A true CN105531288A (zh) 2016-04-27
CN105531288B CN105531288B (zh) 2020-12-11

Family

ID=50736425

Family Applications (6)

Application Number Title Priority Date Filing Date
CN202011322081.9A Active CN112457403B (zh) 2013-09-13 2013-09-13 抗pd1抗体及其作为治疗剂与诊断剂的用途
CN201710208535.1A Active CN107090041B (zh) 2013-09-13 2013-09-13 抗pd1抗体及其作为治疗剂与诊断剂的用途
CN201710207300.0A Active CN107011441B (zh) 2013-09-13 2013-09-13 抗pd1抗体及其作为治疗剂与诊断剂的用途
CN202011322092.7A Active CN112552401B (zh) 2013-09-13 2013-09-13 抗pd1抗体及其作为治疗剂与诊断剂的用途
CN201380079581.6A Active CN105531288B (zh) 2013-09-13 2013-09-13 抗pd1抗体及其作为治疗剂与诊断剂的用途
CN201810552595.XA Active CN108715615B (zh) 2013-09-13 2013-09-13 抗pd1抗体及其作为治疗剂与诊断剂的用途

Family Applications Before (4)

Application Number Title Priority Date Filing Date
CN202011322081.9A Active CN112457403B (zh) 2013-09-13 2013-09-13 抗pd1抗体及其作为治疗剂与诊断剂的用途
CN201710208535.1A Active CN107090041B (zh) 2013-09-13 2013-09-13 抗pd1抗体及其作为治疗剂与诊断剂的用途
CN201710207300.0A Active CN107011441B (zh) 2013-09-13 2013-09-13 抗pd1抗体及其作为治疗剂与诊断剂的用途
CN202011322092.7A Active CN112552401B (zh) 2013-09-13 2013-09-13 抗pd1抗体及其作为治疗剂与诊断剂的用途

Family Applications After (1)

Application Number Title Priority Date Filing Date
CN201810552595.XA Active CN108715615B (zh) 2013-09-13 2013-09-13 抗pd1抗体及其作为治疗剂与诊断剂的用途

Country Status (30)

Country Link
US (9) US8735553B1 (zh)
EP (3) EP3044234B9 (zh)
JP (1) JP6623353B2 (zh)
KR (1) KR102100419B1 (zh)
CN (6) CN112457403B (zh)
AU (3) AU2013400609B9 (zh)
BR (1) BR112016005408B1 (zh)
CA (3) CA3078121A1 (zh)
CY (2) CY1125652T1 (zh)
DK (2) DK3044234T3 (zh)
EA (1) EA034666B1 (zh)
ES (2) ES2927567T3 (zh)
FR (1) FR24C1001I1 (zh)
HK (1) HK1217501A1 (zh)
HR (1) HRP20221262T1 (zh)
HU (3) HUE049281T2 (zh)
IL (5) IL296026B2 (zh)
LT (1) LT3702373T (zh)
MX (1) MX2016003292A (zh)
NL (1) NL301252I2 (zh)
NO (1) NO2023045I1 (zh)
NZ (1) NZ718643A (zh)
PL (2) PL3044234T3 (zh)
PT (2) PT3044234T (zh)
RS (1) RS63571B9 (zh)
SG (1) SG11201601844TA (zh)
SI (1) SI3702373T1 (zh)
TW (1) TWI636995B (zh)
WO (1) WO2015035606A1 (zh)
ZA (1) ZA201601953B (zh)

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107840887A (zh) * 2016-09-21 2018-03-27 基石药业(苏州)有限公司 一种新的pd‑1单克隆抗体
WO2018113258A1 (zh) * 2016-12-22 2018-06-28 安源医药科技(上海)有限公司 抗pd-1抗体及其用途
WO2018176505A1 (zh) * 2017-03-29 2018-10-04 上海科医联创生物科技有限公司 一种恢复衰竭性免疫细胞功能的融合蛋白及其应用
WO2018192089A1 (zh) 2017-04-20 2018-10-25 苏州思坦维生物技术股份有限公司 拮抗抑制人pd-1抗原与其配体结合的单克隆抗体及其制备方法与应用
WO2019001417A1 (en) * 2017-06-26 2019-01-03 Beigene, Ltd. IMMUNOTHERAPY FOR HEPATOCELLULAR CARCINOMA
CN109452229A (zh) * 2018-11-19 2019-03-12 北京百奥赛图基因生物技术有限公司 狗源化pd-1基因改造动物模型的制备方法及应用
CN109475536A (zh) * 2016-07-05 2019-03-15 百济神州有限公司 用于治疗癌症的PD-l拮抗剂和RAF抑制剂的组合
WO2019101062A1 (zh) * 2017-11-24 2019-05-31 长春百克生物科技股份公司 重组疫苗及其应用
CN110087730A (zh) * 2016-09-27 2019-08-02 百济神州有限公司 使用包含parp抑制剂的组合产品治疗癌症
CN110214153A (zh) * 2016-11-18 2019-09-06 西福根有限公司 抗pd-1抗体及组合物
WO2020143749A1 (zh) 2019-01-10 2020-07-16 迈威(上海)生物科技有限公司 重组抗人pd-1抗体及其应用
CN112351794A (zh) * 2018-02-09 2021-02-09 百济神州有限公司 用于尿路上皮癌的免疫治疗方法
WO2021047623A1 (en) * 2019-09-11 2021-03-18 Beigene, Ltd. Treatment of cancer using a combination comprising multi-tyrosine kinase inhibitor and immune checkpoint inhibitor
US11186637B2 (en) 2013-09-13 2021-11-30 Beigene Switzerland Gmbh Anti-PD1 antibodies and their use as therapeutics and diagnostics
US11512132B2 (en) 2014-07-03 2022-11-29 Beigene, Ltd. Anti-PD-L1 antibodies and their use as therapeutics and diagnostics
US11555038B2 (en) 2017-01-25 2023-01-17 Beigene, Ltd. Crystalline forms of (S)-7-(1-(but-2-ynoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide, preparation, and uses thereof
US11701357B2 (en) 2016-08-19 2023-07-18 Beigene Switzerland Gmbh Treatment of B cell cancers using a combination comprising Btk inhibitors
US11786529B2 (en) 2017-11-29 2023-10-17 Beigene Switzerland Gmbh Treatment of indolent or aggressive B-cell lymphomas using a combination comprising BTK inhibitors
WO2024012584A1 (en) * 2022-07-15 2024-01-18 Beigene Switzerland Gmbh Methods of cancer treatment using anti-tigit antibodies
WO2024012364A1 (en) * 2022-07-12 2024-01-18 Beigene Switzerland Gmbh Preparation methods for a highly concentrated pd1 antibody solution by ultrafiltration/diafiltration (uf/df)
WO2024165043A1 (en) * 2023-02-08 2024-08-15 Beigene Switzerland Gmbh Preparation methods for a highly concentrated pd1 antibody solution by applying single-pass tangential flow filtration (sptff)

Families Citing this family (593)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010062960A2 (en) 2008-11-26 2010-06-03 Cedars-Sinai Medical Center METHODS OF DETERMINING RESPONSIVENESS TO ANTI-TNFα THERAPY IN INFLAMMATORY BOWEL DISEASE
EP2663579B1 (en) 2011-01-14 2017-04-26 The Regents of the University of California Therapeutic antibodies against ror-1 protein and methods for use of same
WO2013013188A1 (en) 2011-07-21 2013-01-24 Tolero Pharmaceuticals, Inc. Heterocyclic protein kinase inhibitors
DK2797921T3 (en) 2011-12-31 2017-10-02 Beigene Ltd FUSED TETRA- OR PENTA-CYCLIC DIHYDRODIAZEPINOCARBAZOLONES AS PARB INHIBITORS
KR102343212B1 (ko) 2013-03-27 2021-12-23 세다르스-신나이 메디칼 센터 Tl1a 기능 및 관련된 신호전달 경로의 저해에 의한 섬유증 및 염증의 완화 및 반전
MX367918B (es) 2013-04-25 2019-09-11 Beigene Ltd Compuestos heterociclicos fusionados como inhibidores de proteina quinasa.
US10316083B2 (en) 2013-07-19 2019-06-11 Cedars-Sinai Medical Center Signature of TL1A (TNFSF15) signaling pathway
HUE038169T2 (hu) 2013-09-06 2018-09-28 Aurigene Discovery Tech Ltd 1,2,4-Oxadiazol származékok mint immunomodulátorok
KR20160081898A (ko) 2013-09-06 2016-07-08 오리진 디스커버리 테크놀로지스 리미티드 면역조절제로서 1,3,4-옥사디아졸 및 1,3,4-티아디아졸 유도체
PT3041468T (pt) 2013-09-06 2018-09-28 Aurigene Discovery Tech Ltd Compostos peptidomiméticos cíclicos como imunomoduladores
EP3757130A1 (en) 2013-09-26 2020-12-30 Costim Pharmaceuticals Inc. Methods for treating hematologic cancers
HUE046249T2 (hu) 2013-12-12 2020-02-28 Shanghai hengrui pharmaceutical co ltd PD-1 antitest, antigén-kötõ fragmense, és gyógyászati alkalmazása
US10023636B2 (en) 2013-12-20 2018-07-17 Intervet Inc. Caninized murine antibodies to human PD-1
JOP20200094A1 (ar) 2014-01-24 2017-06-16 Dana Farber Cancer Inst Inc جزيئات جسم مضاد لـ pd-1 واستخداماتها
JOP20200096A1 (ar) 2014-01-31 2017-06-16 Children’S Medical Center Corp جزيئات جسم مضاد لـ tim-3 واستخداماتها
US10519237B2 (en) 2014-03-12 2019-12-31 Yeda Research And Development Co. Ltd Reducing systemic regulatory T cell levels or activity for treatment of disease and injury of the CNS
US9394365B1 (en) 2014-03-12 2016-07-19 Yeda Research And Development Co., Ltd Reducing systemic regulatory T cell levels or activity for treatment of alzheimer's disease
CN114081946A (zh) 2014-03-12 2022-02-25 耶达研究与开发有限公司 降低系统性调节性t细胞水平或活性来治疗cns疾病和损伤
US10618963B2 (en) 2014-03-12 2020-04-14 Yeda Research And Development Co. Ltd Reducing systemic regulatory T cell levels or activity for treatment of disease and injury of the CNS
TWI693232B (zh) 2014-06-26 2020-05-11 美商宏觀基因股份有限公司 與pd-1和lag-3具有免疫反應性的共價結合的雙抗體和其使用方法
RU2711141C2 (ru) * 2014-07-22 2020-01-15 СиБи ТЕРЕПЬЮТИКС, ИНК. Антитела против pd-1
SG10201901057UA (en) 2014-08-05 2019-03-28 Cb Therapeutics Inc Anti-pd-l1 antibodies
KR102357893B1 (ko) * 2014-08-05 2022-02-04 맵퀘스트 에스아 Pd-1 에 결합하는 면역학적 시약
US9982052B2 (en) 2014-08-05 2018-05-29 MabQuest, SA Immunological reagents
TW201618775A (zh) 2014-08-11 2016-06-01 艾森塔製藥公司 Btk抑制劑、pi3k抑制劑、jak-2抑制劑、pd-1抑制劑及/或pd-l1抑制劑之治療組合物
ES2727137T3 (es) 2014-08-28 2019-10-14 Halozyme Inc Terapia combinada con una enzima de degradación de hialuronano y un inhibidor de puntos de control inmunitario
TW201617368A (zh) 2014-09-05 2016-05-16 史坦森特瑞斯公司 新穎抗mfi2抗體及使用方法
JP6681905B2 (ja) 2014-09-13 2020-04-15 ノバルティス アーゲー Alk阻害剤の併用療法
CA3203273A1 (en) 2014-10-14 2016-04-21 Halozyme, Inc. Compositions of adenosine deaminase-2 (ada2), variants thereof and methods of using same
EP3215182B1 (en) 2014-11-05 2023-01-04 The Regents of The University of California Combination immunotherapy
US10822414B2 (en) 2014-11-11 2020-11-03 Sutro Biopharma, Inc. Anti-PD-1 antibodies, compositions comprising anti-PD-1 antibodies and methods of using anti-PD-1 antibodies
ME03806B (me) 2014-11-21 2021-04-20 Bristol Myers Squibb Co Antitela protiv cd73 i njihova upotreba
CN107250157B (zh) 2014-11-21 2021-06-29 百时美施贵宝公司 包含修饰的重链恒定区的抗体
US11639385B2 (en) 2014-12-22 2023-05-02 Pd-1 Acquisition Group, Llc Anti-PD-1 antibodies
DK3237446T3 (en) * 2014-12-22 2021-07-26 Pd 1 Acquisition Group Llc Anti-PD-1-antistoffer
US10509033B2 (en) * 2015-01-20 2019-12-17 Kyushu University, National University Corporation Method, kit and biomarker for diagnosing chronic inflammatory demyelinating polyneuropathy
MY196130A (en) 2015-03-10 2023-03-16 Aurigene Discovery Tech Ltd 1,2,4-Oxadiazole and Thiadiazole Compounds as Immunomodulators
MY194225A (en) 2015-03-13 2022-11-22 Cytomx Therapeutics Inc Anti-pdl1 antibodies, activatable anti-pdl1 antibodies, and methods of use thereof
WO2016150899A2 (en) 2015-03-23 2016-09-29 Bayer Pharma Aktiengesellschaft Anti-ceacam6 antibodies and uses thereof
CN106146667B (zh) * 2015-03-27 2020-06-19 四川大学华西医院 一种Exendin-4融合蛋白及其制备方法与用途
US10836827B2 (en) 2015-03-30 2020-11-17 Stcube, Inc. Antibodies specific to glycosylated PD-L1 and methods of use thereof
US11933786B2 (en) 2015-03-30 2024-03-19 Stcube, Inc. Antibodies specific to glycosylated PD-L1 and methods of use thereof
WO2016161410A2 (en) 2015-04-03 2016-10-06 Xoma Technology Ltd. Treatment of cancer using inhibitors of tgf-beta and pd-1
GB201506411D0 (en) 2015-04-15 2015-05-27 Bergenbio As Humanized anti-axl antibodies
AU2016249395B2 (en) 2015-04-17 2022-04-07 Bristol-Myers Squibb Company Compositions comprising a combination of an anti-PD-1 antibody and another antibody
US20160362489A1 (en) 2015-04-28 2016-12-15 Bristol-Myers Squibb Company Treatment of PD-L1-Positive Melanoma Using an Anti-PD-1 Antibody
JP2018514550A (ja) 2015-04-28 2018-06-07 ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company 抗pd−1抗体および抗ctla−4抗体を使用するpd−l1陰性黒色腫の処置
SG11201708706YA (en) 2015-05-06 2017-11-29 Snipr Tech Ltd Altering microbial populations & modifying microbiota
WO2016179472A2 (en) * 2015-05-07 2016-11-10 University Of Maryland, Baltimore Modulation of natural killer cell tolerance
EP3297672B1 (en) 2015-05-21 2021-09-01 Harpoon Therapeutics, Inc. Trispecific binding proteins and methods of use
US20180155429A1 (en) 2015-05-28 2018-06-07 Bristol-Myers Squibb Company Treatment of pd-l1 positive lung cancer using an anti-pd-1 antibody
MA53355A (fr) 2015-05-29 2022-03-16 Agenus Inc Anticorps anti-ctla-4 et leurs procédés d'utilisation
US11078278B2 (en) 2015-05-29 2021-08-03 Bristol-Myers Squibb Company Treatment of renal cell carcinoma
TWI773646B (zh) 2015-06-08 2022-08-11 美商宏觀基因股份有限公司 結合lag-3的分子和其使用方法
CN105061597B (zh) * 2015-06-09 2016-04-27 北京东方百泰生物科技有限公司 一种抗pd-1的单克隆抗体及其获得方法
SG10201913303XA (en) * 2015-07-13 2020-03-30 Cytomx Therapeutics Inc Anti-pd-1 antibodies, activatable anti-pd-1 antibodies, and methods of use thereof
EP3858859A1 (en) 2015-07-14 2021-08-04 Bristol-Myers Squibb Company Method of treating cancer using immune checkpoint inhibitor; antibody that binds to programmed death-1 receptor (pd-1) or programmed death ligand 1 (pd-l1)
CN108136025B (zh) 2015-07-16 2022-09-06 比奥克斯塞尔医疗股份有限公司 一种使用免疫调节治疗癌症的新颖方法
PL3328419T3 (pl) 2015-07-30 2021-12-27 Macrogenics, Inc. Cząsteczki wiążące pd-1 i sposoby ich zastosowania
EP3331901A1 (en) 2015-08-07 2018-06-13 Pieris Pharmaceuticals GmbH Novel fusion polypeptide specific for lag-3 and pd-1
WO2017024465A1 (en) 2015-08-10 2017-02-16 Innovent Biologics (Suzhou) Co., Ltd. Pd-1 antibodies
US10457680B2 (en) 2015-08-25 2019-10-29 Beigene, Ltd. Process for preparing a PARP inhibitor, crystalline forms, and uses thereof
CN114605548A (zh) 2015-09-01 2022-06-10 艾吉纳斯公司 抗-pd-1抗体及其使用方法
MA44909A (fr) 2015-09-15 2018-07-25 Acerta Pharma Bv Association thérapeutique d'un inhibiteur du cd19 et d'un inhibiteur de la btk
KR20180054824A (ko) * 2015-09-29 2018-05-24 셀진 코포레이션 Pd-1 결합 단백질 및 이의 사용 방법
US10947598B2 (en) 2015-09-29 2021-03-16 Inserm (Institut National De La Sante Et De La Recherche Medicale) Methods for determining the metabolic status of lymphomas
JP6952028B2 (ja) * 2015-09-29 2021-10-20 シャンハイ チャンジアン バイオテクノロジー カンパニー リミテッド Pd−1抗体およびその使用
EP4183451A1 (en) * 2015-10-01 2023-05-24 Heat Biologics, Inc. Compositions and methods for adjoining type i and type ii extracellular domains as heterologous chimeric proteins
US12030942B2 (en) 2015-10-02 2024-07-09 Les Laboratoires Servier Anti-PD-1 antibodies and compositions
CN106632674B (zh) * 2015-10-30 2018-11-16 泽达生物医药有限公司 一种抗pd-1单克隆抗体、其药物组合物及其用途
LT3370733T (lt) 2015-11-02 2021-10-25 Board Of Regents, The University Of Texas System Cd40 aktyvinimo ir imuninės kontrolės taškų blokados būdai
SG11201803520PA (en) 2015-11-03 2018-05-30 Janssen Biotech Inc Antibodies specifically binding pd-1 and their uses
US20190038713A1 (en) 2015-11-07 2019-02-07 Multivir Inc. Compositions comprising tumor suppressor gene therapy and immune checkpoint blockade for the treatment of cancer
CN106699889A (zh) 2015-11-18 2017-05-24 礼进生物医药科技(上海)有限公司 抗pd-1抗体及其治疗用途
TWI795347B (zh) 2015-11-18 2023-03-11 美商必治妥施貴寶公司 使用抗pd-1抗體與抗ctla-4抗體之組合以治療肺癌
JP7003036B2 (ja) 2015-12-02 2022-02-04 エスティーキューブ,インコーポレイテッド グリコシル化pd-1に対して特異的な抗体およびその使用方法
KR102424513B1 (ko) 2015-12-14 2022-07-25 마크로제닉스, 인크. Pd-1 및 ctla-4과의 면역반응성을 가진 이중특이적 분자, 및 이것의 사용 방법
US10392442B2 (en) 2015-12-17 2019-08-27 Bristol-Myers Squibb Company Use of anti-PD-1 antibody in combination with anti-CD27 antibody in cancer treatment
US11091556B2 (en) 2015-12-18 2021-08-17 Intervet Inc. Caninized human antibodies to human IL-4R alpha
RS63135B1 (sr) 2015-12-23 2022-05-31 Modernatx Inc Postupci upotrebe polinukleotida koji kodiraju ox40 ligand
ES2837155T3 (es) 2016-01-04 2021-06-29 Inst Nat Sante Rech Med Uso de PD-1 y Tim-3 como medida de células CD8+ para predecir y tratar el carcinoma de células renales
EP3402503B1 (en) 2016-01-13 2020-10-21 Acerta Pharma B.V. Therapeutic combinations of an antifolate and a btk inhibitor
US10759859B2 (en) * 2016-01-14 2020-09-01 Bps Bioscience, Inc. Anti-PD-1 antibodies and uses thereof
US11214617B2 (en) 2016-01-22 2022-01-04 MabQuest SA Immunological reagents
EP3964529A1 (en) 2016-01-22 2022-03-09 Mabquest SA Non-blocking pd1 specific antibodies
EP3195878A1 (en) 2016-01-22 2017-07-26 Werner Lubitz Bacterial ghosts for the treatment of cancer
RU2018131123A (ru) 2016-02-17 2020-03-17 Новартис Аг Антитела к tgf-бета2
JP7082945B2 (ja) 2016-03-17 2022-06-09 シーダーズ―シナイ メディカル センター Rnaset2により炎症性腸疾患を診断する方法
WO2017165742A1 (en) 2016-03-24 2017-09-28 Millennium Pharmaceuticals, Inc. Methods of treating gastrointestinal immune-related adverse events in anti-ctla4 anti-pd-1 combination treatments
US11760803B2 (en) 2016-03-24 2023-09-19 Takeda Pharmaceutical Company Limited Methods of treating gastrointestinal immune-related adverse events in immune oncology treatments
CN109195991B (zh) 2016-03-29 2023-10-31 斯特库比股份有限公司 对糖基化pd-l1特异的双重功能抗体及其使用方法
KR20230031373A (ko) 2016-03-29 2023-03-07 주식회사 에스티큐브앤컴퍼니 글리코실화된 면역체크포인트 단백질에 특이적으로 결합하는 항체를 선택하는 방법
WO2017173091A1 (en) 2016-03-30 2017-10-05 Musc Foundation For Research Development Methods for treatment and diagnosis of cancer by targeting glycoprotein a repetitions predominant (garp) and for providing effective immunotherapy alone or in combination
WO2017176925A1 (en) 2016-04-05 2017-10-12 Bristol-Myers Squibb Company Cytokine profiling analysis for predicting prognosis of a patient in need of an anti-cancer treatment
BR112018072286A2 (pt) 2016-04-29 2019-02-12 Yale University medida direcionada de atividade transcricional relacionada a receptores de hormônios
US11352413B2 (en) 2016-05-17 2022-06-07 Albert Einstein College Of Medicine Engineered PD-1 variants
PT3458083T (pt) 2016-05-18 2023-03-06 Modernatx Inc Polinucleotídeos que codificam interleucina-12 (il12) e seus usos
JP2019519516A (ja) 2016-05-18 2019-07-11 モデルナティーエックス, インコーポレイテッド がんの治療のためのmRNA併用療法
KR102482867B1 (ko) 2016-05-18 2023-01-02 모더나티엑스, 인크. 면역 조정 폴리펩타이드를 암호화하는 mRNA의 조합물 및 이의 용도
US11623958B2 (en) 2016-05-20 2023-04-11 Harpoon Therapeutics, Inc. Single chain variable fragment CD3 binding proteins
CN105968200B (zh) 2016-05-20 2019-03-15 瑞阳(苏州)生物科技有限公司 抗人pd-l1人源化单克隆抗体及其应用
CN106008714B (zh) * 2016-05-24 2019-03-15 瑞阳(苏州)生物科技有限公司 抗人pd-1人源化单克隆抗体及其应用
CN109476751B (zh) 2016-05-27 2024-04-19 艾吉纳斯公司 抗tim-3抗体及其使用方法
HUE063911T2 (hu) 2016-06-02 2024-02-28 Bristol Myers Squibb Co Anti-PD-1 antitest felhasználása anti-CD30 atnitesttel kombinációban limfóma kezelésben
WO2017210453A1 (en) 2016-06-02 2017-12-07 Bristol-Myers Squibb Company Pd-1 blockade with nivolumab in refractory hodgkin's lymphoma
CN109476753A (zh) 2016-06-03 2019-03-15 百时美施贵宝公司 用于治疗肿瘤的方法的抗-pd-1抗体
KR102515509B1 (ko) 2016-06-03 2023-03-28 브리스톨-마이어스 스큅 컴퍼니 결장직장암을 갖는 환자의 치료에서의 항-pd-1 항체의 용도
WO2017210631A1 (en) 2016-06-03 2017-12-07 Bristol-Myers Squibb Company Anti-pd-1 antibody for use in a method of treatment of recurrent small cell lung cancer
GB201609811D0 (en) 2016-06-05 2016-07-20 Snipr Technologies Ltd Methods, cells, systems, arrays, RNA and kits
WO2017214182A1 (en) * 2016-06-07 2017-12-14 The United States Of America. As Represented By The Secretary, Department Of Health & Human Services Fully human antibody targeting pdi for cancer immunotherapy
JP7185530B2 (ja) 2016-06-13 2022-12-07 トルク セラピューティクス, インコーポレイテッド 免疫細胞機能を促進するための方法および組成物
ES2966973T3 (es) * 2016-06-17 2024-04-25 Univ Pennsylvania Compuestos, composiciones y métodos para la prevención y/o el tratamiento del cáncer
EP3471753A1 (en) 2016-06-20 2019-04-24 Kymab Limited Anti-pd-l1 and il-2 cytokines
EP3476865B1 (en) 2016-06-28 2023-09-13 Biocytogen Pharmaceuticals (Beijing) Co., Ltd. Method for constructing pd-1 gene-modified humanized animal model and use thereof
RU2656181C1 (ru) * 2016-07-13 2018-05-31 Закрытое Акционерное Общество "Биокад" Анти-pd-1-антитела, способ их получения и способ применения
EP3487883B1 (en) 2016-07-20 2023-01-04 Stcube, Inc. Methods of cancer treatment and therapy using a combination of antibodies that bind glycosylated pd-l1
KR20230162137A (ko) 2016-08-16 2023-11-28 베이진 스위찰랜드 게엠베하 (s)-7-(1-아크릴로일피페리딘-4-일)-2-(4-페녹시페닐)-4,5,6,7-테트라-하이드로피라졸로 [1,5-a] 피리미딘-3-카르복스아미드의 제조 및 그 용도
AU2017317227B2 (en) 2016-08-26 2024-08-01 Beigene, Ltd. Anti-Tim-3 antibodies and use thereof
CN110121352B (zh) 2016-09-01 2020-12-11 嵌合体生物工程公司 Gold优化的car t-细胞
EP3510378A4 (en) 2016-09-06 2020-07-08 IncellDx, Inc. METHOD FOR DETECTION OF PD-L1 EXPRESSION BY CELL AND USES THEREOF
US11726089B2 (en) 2016-09-06 2023-08-15 Incelldx, Inc. Methods of assaying neoplastic and neoplasia-related cells and uses thereof
CN109923211A (zh) 2016-09-08 2019-06-21 蓝鸟生物公司 Pd-1归巢核酸内切酶变体、组合物及使用方法
KR102266788B1 (ko) 2016-09-14 2021-06-22 베이징 한미 파마슈티컬 컴퍼니 리미티드 Pd-1에 특이적으로 결합하는 항체 및 그의 기능성 단편
BR112019004733A2 (pt) 2016-09-19 2019-05-28 Celgene Corp métodos de tratamento de distúrbios imunes usando proteínas de ligação a pd-1
US10766958B2 (en) 2016-09-19 2020-09-08 Celgene Corporation Methods of treating vitiligo using PD-1 binding antibodies
CN110267651B (zh) 2016-09-27 2023-09-01 得克萨斯系统大学评议会 通过调节微生物组来增强免疫检查点阻断疗法的方法
AU2017343621B2 (en) 2016-10-11 2021-12-02 Agenus Inc. Anti-LAG-3 antibodies and methods of use thereof
CN110072540B (zh) 2016-10-12 2023-06-02 得克萨斯州大学系统董事会 用于tusc2免疫治疗的方法和组合物
MY191324A (en) 2016-10-26 2022-06-15 Cedars Sinai Medical Center Neutralizing anti-tl1a monoclonal antibodies
EP3532504A1 (en) 2016-10-28 2019-09-04 Bristol-Myers Squibb Company Methods of treating urothelial carcinoma using an anti-pd-1 antibody
TWI788307B (zh) 2016-10-31 2023-01-01 美商艾歐凡斯生物治療公司 用於擴增腫瘤浸潤性淋巴細胞之工程化人造抗原呈現細胞
CA3039992A1 (en) 2016-11-02 2018-05-11 Jounce Therapeutics, Inc. Antibodies to pd-1 and uses thereof
WO2018085555A1 (en) 2016-11-03 2018-05-11 Bristol-Myers Squibb Company Activatable anti-ctla-4 antibodies and uses thereof
CA3043356A1 (en) 2016-11-09 2018-05-17 Musc Foundation For Research Development Cd38-nad+ regulated metabolic axis in anti-tumor immunotherapy
WO2018094275A1 (en) 2016-11-18 2018-05-24 Tolero Pharmaceuticals, Inc. Alvocidib prodrugs and their use as protein kinase inhibitors
WO2018098352A2 (en) 2016-11-22 2018-05-31 Jun Oishi Targeting kras induced immune checkpoint expression
PT3551660T (pt) 2016-12-07 2023-11-30 Ludwig Inst For Cancer Res Ltd Anticorpos anti-ctla-4 e métodos de uso dos mesmos
MA50948A (fr) 2016-12-07 2020-10-14 Agenus Inc Anticorps et procédés d'utilisation de ceux-ci
AU2017375958A1 (en) 2016-12-12 2019-07-04 Multivir Inc. Methods and compositions comprising viral gene therapy and an immune checkpoint inhibitor for treatment and prevention of cancer and infectious diseases
CN108239083B (zh) 2016-12-26 2021-08-17 阿里根公司 芳香烃受体调节剂
US11584733B2 (en) 2017-01-09 2023-02-21 Shuttle Pharmaceuticals, Inc. Selective histone deacetylase inhibitors for the treatment of human disease
US11034667B2 (en) 2017-01-09 2021-06-15 Shuttle Pharmaceuticals, Inc. Selective histone deacetylase inhibitors for the treatment of human disease
MX2019008346A (es) 2017-01-13 2019-09-09 Agenus Inc Receptores de celulas t que se unen a ny-eso-1 y metodos de uso de estos.
WO2018134279A1 (en) 2017-01-18 2018-07-26 Pieris Pharmaceuticals Gmbh Novel fusion polypeptides specific for lag-3 and pd-1
WO2018133837A1 (en) 2017-01-20 2018-07-26 Tayu Huaxia Biotech Medical Group Co., Ltd. Anti-pd-1 antibodies and uses thereof
EP3571227A1 (en) 2017-01-20 2019-11-27 Sanofi Anti-tgf-beta antibodies and their use
AR110755A1 (es) 2017-01-20 2019-05-02 Genzyme Corp Anticuerpos dirigidos a hueso
TWI787230B (zh) 2017-01-20 2022-12-21 法商賽諾菲公司 抗TGF-β抗體及其用途
WO2018134784A1 (en) 2017-01-20 2018-07-26 Novartis Ag Combination therapy for the treatment of cancer
CN108341871A (zh) 2017-01-24 2018-07-31 三生国健药业(上海)股份有限公司 抗pd-1单克隆抗体及其制备方法和应用
PL3579874T3 (pl) 2017-02-10 2022-02-28 Novartis Ag 1-(4-amino-5-bromo-6-(1 h-pirazol-1-ilo)pirymidyn-2-ylo)-1 h-pirazol-4-ol i jego zastosowanie w leczeniu nowotworu złośliwego
TWI674261B (zh) 2017-02-17 2019-10-11 美商英能腫瘤免疫股份有限公司 Nlrp3 調節劑
US11693007B2 (en) 2017-02-24 2023-07-04 Board Of Regents, The University Of Texas System Assay for detection of early stage pancreatic cancer
AU2018223821B2 (en) 2017-02-27 2022-05-19 Shattuck Labs, Inc. TIGIT- and LIGHT-based chimeric proteins
CR20190444A (es) 2017-02-28 2019-12-17 Sanofi Sa Arn terapéutico
US10899763B2 (en) 2017-02-28 2021-01-26 Beigene, Ltd. Crystalline forms of salts of fused penta-cyclic dihydrodiazepinocarbazolones, and uses thereof
WO2018162944A1 (en) 2017-03-04 2018-09-13 Shenzhen Runshin Bioscience Recombinant antibodies to programmed death 1 (pd-1) and uses therefor
US20200095323A1 (en) * 2017-03-20 2020-03-26 The General Hospital Corporation MITIGATING Fc-Fc RECEPTOR INTERACTIONS IN CANCER IMMUNOTHERAPY
US20210186982A1 (en) 2017-03-24 2021-06-24 Universite Nice Sophia Antipolis Methods and compositions for treating melanoma
IL269026B1 (en) 2017-03-31 2024-08-01 Bristol Myers Squibb Co Anti-PD-1 antibodies for the treatment of tumors in patients with a high tumor mutational burden (TMB)
CA3058960C (en) 2017-04-05 2023-08-29 Symphogen A/S Combination therapies targeting pd-1, tim-3, and lag-3
TWI788340B (zh) 2017-04-07 2023-01-01 美商必治妥美雅史谷比公司 抗icos促效劑抗體及其用途
MX2019012223A (es) 2017-04-13 2019-12-09 Agenus Inc Anticuerpos anti-cd137 y metodos de uso de los mismos.
CA3057748A1 (en) 2017-04-20 2018-10-25 Adc Therapeutics Sa Combination therapy with an anti-axl antibody-drug conjugate
WO2018231339A2 (en) * 2017-04-20 2018-12-20 Dana-Farber Cancer Institute, Inc. Anti-phosphotyrosinylated pd-1 antibodies and uses thereof
AU2018253950A1 (en) 2017-04-20 2019-09-19 Adc Therapeutics Sa Combination therapy with an anti-CD25 antibody-drug conjugate
AR111651A1 (es) 2017-04-28 2019-08-07 Novartis Ag Conjugados de anticuerpos que comprenden agonistas del receptor de tipo toll y terapias de combinación
CN110809582B (zh) * 2017-05-01 2023-12-22 儿童医疗中心有限公司 涉及抗pd1抗体试剂的方法以及组合物
TWI805582B (zh) 2017-05-01 2023-06-21 美商艾吉納斯公司 抗tigit抗體類和使用彼等之方法
CA3063359A1 (en) 2017-05-12 2018-11-15 Harpoon Therapeutics, Inc. Mesothelin binding proteins
JP7285220B2 (ja) 2017-05-18 2023-06-01 モデルナティエックス インコーポレイテッド 連結したインターロイキン-12(il12)ポリペプチドをコードするポリヌクレオチドを含む脂質ナノ粒子
AR111760A1 (es) 2017-05-19 2019-08-14 Novartis Ag Compuestos y composiciones para el tratamiento de tumores sólidos mediante administración intratumoral
MX2019012076A (es) 2017-05-30 2019-12-09 Bristol Myers Squibb Co Composiciones que comprenden un anticuerpo anti gen-3 de activacion del linfocito (lag-3) o un anticuerpo anti-lag-3 y un anticuerpo anti muerte celular programada 1 (pd-1) o anti ligando 1 de muerte celular programada (pd-l1).
MX2019012032A (es) 2017-05-30 2019-10-30 Bristol Myers Squibb Co Tratamiento de tumores positivos a gen 3 de activacion de linfocitos (lag-3).
CA3060989A1 (en) 2017-05-30 2018-12-06 Bristol-Myers Squibb Company Compositions comprising a combination of an anti-lag-3 antibody, a pd-1 pathway inhibitor, and an immunotherapeutic agent
JOP20190279A1 (ar) 2017-05-31 2019-11-28 Novartis Ag الصور البلورية من 5-برومو -2، 6-داي (1h-بيرازول -1-يل) بيريميدين -4- أمين وأملاح جديدة
NZ759442A (en) 2017-06-01 2024-07-05 Cytomx Therapeutics Inc Activatable anti-pdl1 antibodies, and methods of use thereof
EP3630180A1 (en) 2017-06-01 2020-04-08 Compugen Ltd. Triple combination antibody therapies
EP3630840A1 (en) 2017-06-01 2020-04-08 Bristol-Myers Squibb Company Methods of treating a tumor using an anti-pd-1 antibody
US11318211B2 (en) 2017-06-14 2022-05-03 Adc Therapeutics Sa Dosage regimes for the administration of an anti-CD19 ADC
WO2018229715A1 (en) 2017-06-16 2018-12-20 Novartis Ag Compositions comprising anti-cd32b antibodies and methods of use thereof
US20190048072A1 (en) 2017-06-22 2019-02-14 Novartis Ag USE OF IL-1beta BINDING ANTIBODIES
WO2018237173A1 (en) 2017-06-22 2018-12-27 Novartis Ag ANTIBODY MOLECULES DIRECTED AGAINST CD73 AND CORRESPONDING USES
WO2018235056A1 (en) 2017-06-22 2018-12-27 Novartis Ag IL-1BETA BINDING ANTIBODIES FOR USE IN THE TREATMENT OF CANCER
SG11201912473PA (en) 2017-06-22 2020-01-30 Novartis Ag Antibody molecules to cd73 and uses thereof
WO2019006007A1 (en) 2017-06-27 2019-01-03 Novartis Ag POSOLOGICAL REGIMES FOR ANTI-TIM3 ANTIBODIES AND USES THEREOF
EP3421494A1 (en) 2017-06-29 2019-01-02 Sanofi Use of isatuximab in combination with an anti-pd-1 antibody
AU2018301681B2 (en) 2017-07-14 2022-07-14 Innate Tumor Immunity, Inc. NLRP3 modulators
US20200172617A1 (en) 2017-07-20 2020-06-04 Novartis Ag Dosage regimens of anti-lag-3 antibodies and uses thereof
EP3658565B1 (en) 2017-07-28 2022-11-09 Bristol-Myers Squibb Company Cyclic dinucleotides as anticancer agents
US11899017B2 (en) 2017-07-28 2024-02-13 Bristol-Myers Squibb Company Predictive peripheral blood biomarker for checkpoint inhibitors
WO2019034009A1 (en) 2017-08-12 2019-02-21 Beigene, Ltd. BTK INHIBITOR WITH ENHANCED DOUBLE SELECTIVITY
MX2020001980A (es) 2017-08-28 2020-03-24 Bristol Myers Squibb Co Antagonistas de celulas t con dominios de inmunoglobulina y mucina 3 (tim-3) para el tratamiento y diagnostico de canceres.
JP7316263B2 (ja) 2017-08-31 2023-07-27 ブリストル-マイヤーズ スクイブ カンパニー 抗癌剤としての環状ジヌクレオチド
CN111051327B (zh) 2017-08-31 2023-11-03 百时美施贵宝公司 作为抗癌剂的环二核苷酸
US10953032B2 (en) 2017-08-31 2021-03-23 Bristol-Myers Squibb Company Cyclic dinucleotides as anticancer agents
CA3073055A1 (en) 2017-09-04 2019-03-07 Agenus Inc. T cell receptors that bind to mixed lineage leukemia (mll)-specific phosphopeptides and methods of use thereof
US11497756B2 (en) 2017-09-12 2022-11-15 Sumitomo Pharma Oncology, Inc. Treatment regimen for cancers that are insensitive to BCL-2 inhibitors using the MCL-1 inhibitor alvocidib
WO2019061324A1 (en) 2017-09-29 2019-04-04 Curis Inc. CRYSTALLINE FORMS OF IMMUNOMODULATORS
US11660311B2 (en) 2017-10-10 2023-05-30 Bristol-Myers Squibb Company Cyclic dinucleotides as anticancer agents
CA3078872A1 (en) 2017-10-11 2019-04-18 Aurigene Discovery Technologies Limited Crystalline forms of 3-substituted 1,2,4-oxadiazole
WO2019072241A1 (en) 2017-10-13 2019-04-18 Beijing Biocytogen Co., Ltd NON-HUMAN ANIMAL GENETICALLY MODIFIED WITH PD-1 HUMAN OR CHIMERIC
JP7066837B2 (ja) 2017-10-13 2022-05-13 ハープーン セラピューティクス,インク. B細胞成熟抗原結合タンパク質
KR101982001B1 (ko) * 2017-10-13 2019-05-27 한국과학기술원 동종 또는 이종 거부반응을 이용한 항 pd-1 또는 항 pd-l1 항체 선별 방법
WO2019075468A1 (en) 2017-10-15 2019-04-18 Bristol-Myers Squibb Company TUMOR TREATMENT METHODS
JP7254821B2 (ja) 2017-10-16 2023-04-10 ブリストル-マイヤーズ スクイブ カンパニー 抗がん剤としての環状ジヌクレオチド
US20210040205A1 (en) 2017-10-25 2021-02-11 Novartis Ag Antibodies targeting cd32b and methods of use thereof
SG11202003625VA (en) 2017-11-03 2020-05-28 Aurigene Discovery Tech Ltd Dual inhibitors of tim-3 and pd-1 pathways
WO2019090263A1 (en) 2017-11-06 2019-05-09 Genentech, Inc. Diagnostic and therapeutic methods for cancer
EP3706778A1 (en) 2017-11-06 2020-09-16 Bristol-Myers Squibb Company Methods of treating a tumor
JP7378395B2 (ja) 2017-11-06 2023-11-13 オーリジーン オンコロジー リミテッド 免疫調節のためのコンジョイントセラピー
JP7339944B2 (ja) 2017-11-07 2023-09-06 ザ ボード オブ リージェンツ オブ ザ ユニバーシティー オブ テキサス システム がんの処置におけるcar-t細胞またはcar-nk細胞を用いるlilrb4のターゲティング法
WO2019094265A1 (en) * 2017-11-10 2019-05-16 Armo Biosciences, Inc. Pd1 polypeptide binding molecules
KR20200088386A (ko) 2017-11-14 2020-07-22 화이자 인코포레이티드 Ezh2 억제제 병용 요법
CN111655288A (zh) 2017-11-16 2020-09-11 诺华股份有限公司 组合疗法
TW201925194A (zh) 2017-11-20 2019-07-01 美商雅里俊公司 吲哚化合物及其用途
WO2019108900A1 (en) 2017-11-30 2019-06-06 Novartis Ag Bcma-targeting chimeric antigen receptor, and uses thereof
JP7314146B2 (ja) * 2017-12-28 2023-07-25 中外製薬株式会社 細胞傷害誘導治療剤
EP3735590A1 (en) 2018-01-04 2020-11-11 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma resistant
US20200368268A1 (en) 2018-01-08 2020-11-26 Novartis Ag Immune-enhancing rnas for combination with chimeric antigen receptor therapy
CN112004537A (zh) 2018-01-09 2020-11-27 穿梭药业公司 用于治疗人疾病的选择性组蛋白去乙酰化酶抑制剂
EP3740507A4 (en) 2018-01-15 2022-08-24 Nanjing Legend Biotech Co., Ltd. SINGLE DOMAIN ANTIBODIES AND VARIANTS THEREOF AGAINST PD-1
KR20200109339A (ko) 2018-01-16 2020-09-22 브리스톨-마이어스 스큅 컴퍼니 Tim3에 대한 항체를 사용하여 암을 치료하는 방법
CA3096287A1 (en) 2018-01-22 2019-07-25 Pascal Biosciences Inc. Cannabinoids and derivatives for promoting immunogenicity of tumor and infected cells
CA3088542A1 (en) 2018-01-22 2019-07-25 Bristol-Myers Squibb Company Compositions and methods of treating cancer
AU2019215031A1 (en) 2018-01-31 2020-08-20 Novartis Ag Combination therapy using a chimeric antigen receptor
WO2019157124A1 (en) 2018-02-08 2019-08-15 Bristol-Myers Squibb Company Combination of a tetanus toxoid, anti-ox40 antibody and/or anti-pd-1 antibody to treat tumors
US20200399383A1 (en) 2018-02-13 2020-12-24 Novartis Ag Chimeric antigen receptor therapy in combination with il-15r and il15
US10519187B2 (en) 2018-02-13 2019-12-31 Bristol-Myers Squibb Company Cyclic dinucleotides as anticancer agents
EP3756012A1 (en) 2018-02-21 2020-12-30 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of sk1 as biomarker for predicting response to immunecheckpoint inhibitors
JP7110369B2 (ja) 2018-02-23 2022-08-01 ユーキュア・(ベイジン)・バイオファーマ・カンパニー・リミテッド 抗pd-1抗体及びその用途
GB201803746D0 (en) 2018-03-08 2018-04-25 Ultrahuman Eight Ltd PD1 binding agents
GB201803745D0 (en) * 2018-03-08 2018-04-25 Ultrahuman Eight Ltd PD1 binding agents
US11945834B2 (en) 2018-03-08 2024-04-02 Bristol-Myers Squibb Company Cyclic dinucleotides as anticancer agents
AU2019322487B2 (en) 2018-03-19 2024-04-18 Multivir Inc. Methods and compositions comprising tumor suppressor gene therapy and CD122/CD132 agonists for the treatment of cancer
TW202003565A (zh) 2018-03-23 2020-01-16 美商必治妥美雅史谷比公司 抗mica及/或micb抗體及其用途
EP3773685A1 (en) 2018-03-25 2021-02-17 SNIPR Biome ApS. Treating & preventing microbial infections
US10760075B2 (en) 2018-04-30 2020-09-01 Snipr Biome Aps Treating and preventing microbial infections
WO2019191279A2 (en) 2018-03-27 2019-10-03 Board Of Regents, The University Of Texas System Compounds with anti-tumor activity against cancer cells bearing her2 exon 19 mutations
KR20200139724A (ko) 2018-03-30 2020-12-14 브리스톨-마이어스 스큅 컴퍼니 종양을 치료하는 방법
US12110337B2 (en) 2018-04-04 2024-10-08 Bristol-Myers Squibb Company Anti-CD27 antibodies and uses thereof
US20210147547A1 (en) 2018-04-13 2021-05-20 Novartis Ag Dosage Regimens For Anti-Pd-L1 Antibodies And Uses Thereof
PE20210160A1 (es) 2018-04-25 2021-01-26 Innate Tumor Immunity Inc Moduladores de nlrp3
EP3784699A4 (en) 2018-04-25 2022-04-13 Prometheus Biosciences, Inc. OPTIMIZED ANTI-TL1A ANTIBODIES
JP2021522239A (ja) 2018-04-26 2021-08-30 アジェナス インコーポレイテッド 熱ショックタンパク質結合ペプチド組成物およびその使用方法
US11957695B2 (en) 2018-04-26 2024-04-16 The Broad Institute, Inc. Methods and compositions targeting glucocorticoid signaling for modulating immune responses
WO2019213660A2 (en) 2018-05-04 2019-11-07 The Broad Institute, Inc. Compositions and methods for modulating cgrp signaling to regulate innate lymphoid cell inflammatory responses
JP7519907B2 (ja) 2018-05-07 2024-07-22 ジェンマブ エー/エス 抗pd-1抗体と抗組織因子抗体-薬物コンジュゲートとの組み合わせを用いるがんの治療方法
JP7535503B2 (ja) 2018-05-17 2024-08-16 ナンジン リーズ バイオラブズ カンパニー リミテッド Pd-1に結合する抗体及びその使用
EP3796942A1 (en) 2018-05-23 2021-03-31 ADC Therapeutics SA Molecular adjuvant
BR112020023746A2 (pt) 2018-05-23 2021-02-17 Beigene, Ltd. anticorpo, composição farmacêutica, método para tratar câncer, ácido nucleico isolado, vetor, célula hospedeira, processo para a produção de um anticorpo e reagente de diagnóstico
AR126019A1 (es) 2018-05-30 2023-09-06 Novartis Ag Anticuerpos frente a entpd2, terapias de combinación y métodos de uso de los anticuerpos y las terapias de combinación
TW202017569A (zh) 2018-05-31 2020-05-16 美商佩樂敦治療公司 用於抑制cd73之組合物及方法
US20210214459A1 (en) 2018-05-31 2021-07-15 Novartis Ag Antibody molecules to cd73 and uses thereof
US11492409B2 (en) 2018-06-01 2022-11-08 Novartis Ag Binding molecules against BCMA and uses thereof
CN114181296B (zh) * 2018-06-07 2023-06-30 江苏东抗生物医药科技有限公司 一种高亲和力的pd-1膜外区突变体的融合蛋白及其药物组合物和用途
TWI819011B (zh) 2018-06-23 2023-10-21 美商建南德克公司 以pd-1 軸結合拮抗劑、鉑劑及拓撲異構酶ii 抑制劑治療肺癌之方法
AR116109A1 (es) 2018-07-10 2021-03-31 Novartis Ag Derivados de 3-(5-amino-1-oxoisoindolin-2-il)piperidina-2,6-diona y usos de los mismos
TW202428612A (zh) 2018-07-10 2024-07-16 美商雷傑納榮製藥公司 修飾結合分子以最小化已存在的交互作用
JOP20210001A1 (ar) 2018-07-10 2021-01-05 Novartis Ag مشتقات 3-(5- هيدروكسي -1- أوكسو أيزو إندولين -2- يل) بيبريدين -2، 6- دايون واستخدامها لمعالجة أمراض مرتبطة ببروتين ذات أصبع الزنك من عائلة (ikaros 2 (ikzf2
WO2020014543A2 (en) 2018-07-11 2020-01-16 Actym Therapeutics, Inc. Engineered immunostimulatory bacterial strains and uses thereof
WO2020014583A1 (en) 2018-07-13 2020-01-16 Bristol-Myers Squibb Company Ox-40 agonist, pd-1 pathway inhibitor and ctla-4 inhibitor combination for use in a mehtod of treating a cancer or a solid tumor
KR20210034622A (ko) 2018-07-18 2021-03-30 제넨테크, 인크. Pd-1 축 결합 길항제, 항 대사제, 및 백금 제제를 이용한 폐암 치료 방법
EP3823991A4 (en) * 2018-07-19 2022-08-03 Tayu Huaxia Biotech Medical Group Co., Ltd. ANTI-PD-1 ANTIBODIES, DOSAGES AND USES THEREOF
WO2020021465A1 (en) 2018-07-25 2020-01-30 Advanced Accelerator Applications (Italy) S.R.L. Method of treatment of neuroendocrine tumors
EP3826660A1 (en) 2018-07-26 2021-06-02 Bristol-Myers Squibb Company Lag-3 combination therapy for the treatment of cancer
WO2020021061A1 (en) 2018-07-26 2020-01-30 Pieris Pharmaceuticals Gmbh Humanized anti-pd-1 antibodies and uses thereof
KR20210045430A (ko) 2018-08-16 2021-04-26 인네이트 튜머 이뮤니티, 인코포레이티드 이미다조[4,5-c]퀴놀린 유래 NLRP3-조정제
US20210308123A1 (en) 2018-08-16 2021-10-07 Innate Tumor Immunity, Inc. Nlrp3 modulators
CN112888677A (zh) 2018-08-16 2021-06-01 先天肿瘤免疫公司 被取代的4-氨基-1H-咪唑并[4,5-c]喹啉化合物及其改进的制备方法
WO2020041655A1 (en) 2018-08-24 2020-02-27 Sanofi Therapeutic rna for solid tumor cancers
JP7459058B2 (ja) 2018-08-27 2024-04-01 ピエリス ファーマシューティカルズ ゲーエムベーハー Cd137/her2二重特異性物質とpd-1系阻害物質とを含む併用療法およびその使用法
US10780121B2 (en) 2018-08-29 2020-09-22 Shattuck Labs, Inc. FLT3L-based chimeric proteins
WO2020044252A1 (en) 2018-08-31 2020-03-05 Novartis Ag Dosage regimes for anti-m-csf antibodies and uses thereof
TW202031273A (zh) 2018-08-31 2020-09-01 美商艾歐凡斯生物治療公司 抗pd-1抗體難治療性之非小細胞肺癌(nsclc)病患的治療
TW202024023A (zh) 2018-09-03 2020-07-01 瑞士商赫孚孟拉羅股份公司 治療性化合物及其使用方法
WO2020049534A1 (en) 2018-09-07 2020-03-12 Novartis Ag Sting agonist and combination therapy thereof for the treatment of cancer
AU2019345151A1 (en) 2018-09-19 2021-04-29 Alpine Immune Sciences, Inc. Methods and uses of variant CD80 fusion proteins and related constructs
WO2020061429A1 (en) 2018-09-20 2020-03-26 Iovance Biotherapeutics, Inc. Expansion of tils from cryopreserved tumor samples
WO2020069028A1 (en) 2018-09-25 2020-04-02 Harpoon Therapeutics, Inc. Dll3 binding proteins and methods of use
JP2022512642A (ja) 2018-10-09 2022-02-07 ブリストル-マイヤーズ スクイブ カンパニー がんを治療するための抗MerTK抗体
JP2022504905A (ja) 2018-10-16 2022-01-13 ノバルティス アーゲー 標的化療法に対する応答を予測するためのバイオマーカーとしての単独の又は免疫マーカーと組み合わせた腫瘍突然変異負荷
CN109470806A (zh) * 2018-10-19 2019-03-15 张骐 通过二维液相对单抗类产品细胞株进行高通量筛选的方法
US20210338813A1 (en) 2018-10-19 2021-11-04 Bristol-Myers Squibb Company Combination Therapy for Melanoma
WO2020086724A1 (en) 2018-10-23 2020-04-30 Bristol-Myers Squibb Company Methods of treating tumor
EP3873532A1 (en) 2018-10-31 2021-09-08 Novartis AG Dc-sign antibody drug conjugates
US20220001026A1 (en) 2018-11-08 2022-01-06 Modernatx, Inc. Use of mrna encoding ox40l to treat cancer in human patients
CA3119563A1 (en) 2018-11-14 2020-05-22 Bayer Aktiengesellschaft Pharmaceutical combination of anti-ceacam6 and either anti-pd-1 or anti-pd-l1 antibodies for the treatment of cancer
US20220008515A1 (en) 2018-11-16 2022-01-13 Neoimmunetech, Inc. Method of treating a tumor with a combination of il-7 protein and an immune checkpoint inhibitor
WO2020102501A1 (en) 2018-11-16 2020-05-22 Bristol-Myers Squibb Company Anti-nkg2a antibodies and uses thereof
EP3883969A4 (en) 2018-11-19 2022-11-16 Biocytogen Pharmaceuticals (Beijing) Co., Ltd. ANTI-PD-1 ANTIBODIES AND THEIR USES
EP3883605A1 (en) 2018-11-19 2021-09-29 Ariagen, Inc. Methods of treating cancer
US20220033848A1 (en) 2018-11-19 2022-02-03 Board Of Regents, The University Of Texas System A modular, polycistronic vector for car and tcr transduction
WO2020104479A1 (en) 2018-11-20 2020-05-28 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating cancers and resistant cancers with anti transferrin receptor 1 antibodies
US20230183379A1 (en) 2018-11-20 2023-06-15 INSERM (Institut National de la Santé et de la Recherche Médicale) Bispecific antibody targeting transferrin receptor 1 and soluble antigen
US20220031749A1 (en) 2018-11-28 2022-02-03 Board Of Regents, The University Of Texas System Multiplex genome editing of immune cells to enhance functionality and resistance to suppressive environment
KR20210096648A (ko) 2018-11-29 2021-08-05 보드 오브 리전츠, 더 유니버시티 오브 텍사스 시스템 자연 살해 세포의 생체외 확장을 위한 방법 및 이의 용도
US11034710B2 (en) 2018-12-04 2021-06-15 Sumitomo Dainippon Pharma Oncology, Inc. CDK9 inhibitors and polymorphs thereof for use as agents for treatment of cancer
US20220099637A1 (en) 2018-12-04 2022-03-31 Bristol-Myers Squibb Company Methods of analysis using in-sample calibration curve by multiple isotopologue reaction monitoring
WO2020115261A1 (en) 2018-12-07 2020-06-11 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma
KR102195135B1 (ko) * 2018-12-07 2020-12-24 한국과학기술원 면역조절제의 스크리닝 방법
CA3122094A1 (en) * 2018-12-10 2020-06-18 Bluebird Bio, Inc. Pdcd-1 homing endonuclease variants
EP3666905A1 (en) 2018-12-11 2020-06-17 Sanofi E. coli positive for pks island as marker of positive response to anti-pd1 therapy in colorectal cancer
MA54448A (fr) 2018-12-11 2021-10-20 Theravance Biopharma R&D Ip Llc Dérivés naphthyridine et quinoléine en tant qu'inhibiteurs de alk5
WO2020120592A1 (en) 2018-12-12 2020-06-18 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for predicting and treating melanoma
WO2020127411A1 (en) 2018-12-19 2020-06-25 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating cancers by immuno-modulation using antibodies against cathespin-d
KR20210106437A (ko) 2018-12-20 2021-08-30 노파르티스 아게 3-(1-옥소이소인돌린-2-일)피페리딘-2,6-디온 유도체를 포함하는 투약 요법 및 약학적 조합물
WO2020128613A1 (en) 2018-12-21 2020-06-25 Novartis Ag Use of il-1beta binding antibodies
AU2019408408A1 (en) 2018-12-21 2021-06-03 Valerio Therapeutics New conjugated nucleic acid molecules and their uses
EP3897854A2 (en) 2018-12-21 2021-10-27 Aim Immunotech Inc. Compositions and methods for cancer therapy
WO2020127885A1 (en) 2018-12-21 2020-06-25 INSERM (Institut National de la Santé et de la Recherche Médicale) Compositions for treating cancers and resistant cancers
US20220056123A1 (en) 2018-12-21 2022-02-24 Novartis Ag Use of il-1beta binding antibodies
WO2020128637A1 (en) 2018-12-21 2020-06-25 Novartis Ag Use of il-1 binding antibodies in the treatment of a msi-h cancer
KR20210107730A (ko) 2018-12-21 2021-09-01 노파르티스 아게 골수 형성이상 증후군의 치료 또는 예방에서의 il-1 베타 항체의 용도
US11739156B2 (en) 2019-01-06 2023-08-29 The Broad Institute, Inc. Massachusetts Institute of Technology Methods and compositions for overcoming immunosuppression
WO2020150113A1 (en) 2019-01-14 2020-07-23 Innate Tumor Immunity, Inc. Substituted quinazolines as nlrp3 modulators, for use in the treatment of cancer
KR20210116525A (ko) 2019-01-14 2021-09-27 제넨테크, 인크. Pd-1 축 결합 길항제 및 rna 백신으로 암을 치료하는 방법
US20220089572A1 (en) 2019-01-14 2022-03-24 Innate Tumor Immunity, Inc. Nlrp3 modulators
WO2020150116A1 (en) 2019-01-14 2020-07-23 Innate Tumor Immunity, Inc. Nlrp3 modulators
EP3911417B1 (en) 2019-01-14 2022-10-26 Innate Tumor Immunity, Inc. Heterocyclic nlrp3 modulators , for use in the treatment of cancer
JP2022518236A (ja) 2019-01-21 2022-03-14 サノフイ 進行期固形腫瘍がんに対する治療用rnaおよび抗pd1抗体
CN113366316A (zh) 2019-01-30 2021-09-07 国家医疗保健研究所 用于鉴定患有癌症的受试者是否将获得对免疫检查点抑制剂的应答的方法和组合物
US20220117911A1 (en) 2019-02-04 2022-04-21 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for modulating blood-brain barrier
MX2021009371A (es) 2019-02-12 2021-09-10 Sumitomo Pharma Oncology Inc Formulaciones que comprenden inhibidores de proteina cinasa heterociclicos.
CA3129031A1 (en) 2019-02-12 2020-08-20 Novartis Ag Pharmaceutical combination comprising tno155 and a pd-1 inhibitor
EP3924520A1 (en) 2019-02-13 2021-12-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for selecting a cancer treatment in a subject suffering from cancer
EP3924055B1 (en) 2019-02-15 2024-04-03 Novartis AG Substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
CN113490528A (zh) 2019-02-15 2021-10-08 诺华股份有限公司 3-(1-氧代-5-(哌啶-4-基)异吲哚啉-2-基)哌啶-2,6-二酮衍生物及其用途
EP3924521A4 (en) 2019-02-15 2023-03-29 IncellDx, Inc. BLADDER-ASSOCIATED SPECIMEN ASSAY, IDENTIFICATION AND TREATMENT OF BLADDER-ASSOCIATED NEOPLASIA, AND KITS FOR USE THEREOF
CN110297093B (zh) * 2019-03-18 2022-04-22 山西瑞豪生物科技有限公司 一种检测人免疫球蛋白g4的方法和试剂盒
US20220142948A1 (en) 2019-03-18 2022-05-12 The Broad Institute, Inc. Compositions and methods for modulating metabolic regulators of t cell pathogenicity
US11793802B2 (en) 2019-03-20 2023-10-24 Sumitomo Pharma Oncology, Inc. Treatment of acute myeloid leukemia (AML) with venetoclax failure
MX2021011289A (es) 2019-03-22 2021-11-03 Sumitomo Pharma Oncology Inc Composiciones que comprenden moduladores de isoenzima m2 muscular de piruvato cinasa pkm2 y metodos de tratamiento que usan las mismas.
EP3946625A1 (en) 2019-03-28 2022-02-09 Bristol-Myers Squibb Company Methods of treating tumor
KR20210146349A (ko) 2019-03-28 2021-12-03 브리스톨-마이어스 스큅 컴퍼니 종양을 치료하는 방법
WO2020201442A1 (en) 2019-04-03 2020-10-08 Orega Biotech Combination therapies based on pd1 and il-17b inhibitors
EP3956327A1 (en) 2019-04-15 2022-02-23 Ariagen, Inc. Chiral indole compounds and their use
EP3725370A1 (en) 2019-04-19 2020-10-21 ImmunoBrain Checkpoint, Inc. Modified anti-pd-l1 antibodies and methods and uses for treating a neurodegenerative disease
KR20220002967A (ko) 2019-04-19 2022-01-07 제넨테크, 인크. 항 mertk 항체 및 이의 사용 방법
WO2020221796A1 (en) 2019-04-30 2020-11-05 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma
US20220220440A1 (en) 2019-05-09 2022-07-14 FUJIFILM Cellular Dynamics, Inc. Methods for the production of hepatocytes
US20230295087A1 (en) 2019-05-13 2023-09-21 Bristol-Myers Squibb Company AGONISTS OF ROR GAMMAt
US12012374B2 (en) 2019-05-13 2024-06-18 Bristol-Myers Squibb Company Agonists of ROR GAMMAt
KR20230031981A (ko) 2019-05-14 2023-03-07 프로벤션 바이오, 인코포레이티드 제1형 당뇨병을 예방하기 위한 방법 및 조성물
TW202110431A (zh) 2019-05-17 2021-03-16 美商癌症預防製藥股份有限公司 治療家族性腺瘤性瘜肉症之方法
JP2022534889A (ja) 2019-05-24 2022-08-04 ファイザー・インコーポレイテッド Cdk阻害剤を使用した組合せ療法
EP3976832A1 (en) 2019-05-30 2022-04-06 Bristol-Myers Squibb Company Methods of identifying a subject suitable for an immuno-oncology (i-o) therapy
WO2020243570A1 (en) 2019-05-30 2020-12-03 Bristol-Myers Squibb Company Cell localization signature and combination therapy
WO2020243563A1 (en) 2019-05-30 2020-12-03 Bristol-Myers Squibb Company Multi-tumor gene signatures for suitability to immuno-oncology therapy
CN114206355A (zh) 2019-06-03 2022-03-18 芝加哥大学 用靶向癌症的佐剂治疗癌症的方法和组合物
CA3144535A1 (en) 2019-06-03 2020-12-10 The University Of Chicago Methods and compositions for treating cancer with collagen binding drug carriers
US20210038684A1 (en) 2019-06-11 2021-02-11 Alkermes Pharma Ireland Limited Compositions and Methods for Cancer Immunotherapy
MA56523A (fr) 2019-06-18 2022-04-27 Janssen Sciences Ireland Unlimited Co Combinaison de vaccins contre le virus de l'hépatite b (vhb) et d'anticorps anti-pd-1 ou anti-pd-l1
CA3143634A1 (en) 2019-06-18 2020-12-24 Janssen Sciences Ireland Unlimited Company Combination of hepatitis b virus (hbv) vaccines and anti-pd-1 antibody
CN117447596A (zh) * 2019-06-30 2024-01-26 福州创方医药科技有限公司 一种靶向pd-1的单克隆抗体及其应用
CN112225809B (zh) * 2019-06-30 2023-09-05 福州创方医药科技有限公司 一种靶向pd-1的单克隆抗体及其应用
CA3145864A1 (en) 2019-07-03 2021-01-07 Sumitomo Dainippon Pharma Oncology, Inc. Tyrosine kinase non-receptor 1 (tnk1) inhibitors and uses thereof
KR20220030956A (ko) 2019-07-05 2022-03-11 오노 야꾸힝 고교 가부시키가이샤 Pd-1/cd3 이중 특이성 단백질에 의한 혈액암 치료
WO2021024020A1 (en) 2019-08-06 2021-02-11 Astellas Pharma Inc. Combination therapy involving antibodies against claudin 18.2 and immune checkpoint inhibitors for treatment of cancer
WO2021026179A1 (en) 2019-08-06 2021-02-11 Bristol-Myers Squibb Company AGONISTS OF ROR GAMMAt
TW202120550A (zh) 2019-08-08 2021-06-01 日商小野藥品工業股份有限公司 雙特異性蛋白質
US20220282333A1 (en) 2019-08-13 2022-09-08 The General Hospital Corporation Methods for predicting outcomes of checkpoint inhibition and treatment thereof
GB201912107D0 (en) 2019-08-22 2019-10-09 Amazentis Sa Combination
CA3152027A1 (en) 2019-08-30 2021-03-04 Agenus Inc. Anti-cd96 antibodies and methods of use thereof
WO2021048292A1 (en) 2019-09-11 2021-03-18 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma
BR112022004791A2 (pt) 2019-09-17 2022-06-21 Bial R&D Invest S A Carboxamidas de imidazol substituídas e seu uso no tratamento de distúrbios médicos
KR20220100859A (ko) 2019-09-17 2022-07-18 비알 - 알&디 인베스트먼츠, 에스.에이. 산성 세라미다아제 저해제로서의 치환된 n-헤테로시클릭 카르복사미드, 및 약제로서의 이의 용도
US20220380314A1 (en) 2019-09-17 2022-12-01 Bial - R&D Investments, S.A. Substituted, saturated and unsaturated n-heterocyclic carboxamides and related compounds for their use in the treatment of medical disorders
TW202124446A (zh) 2019-09-18 2021-07-01 瑞士商諾華公司 與entpd2抗體之組合療法
EP4031578A1 (en) 2019-09-18 2022-07-27 Novartis AG Entpd2 antibodies, combination therapies, and methods of using the antibodies and combination therapies
WO2021055994A1 (en) 2019-09-22 2021-03-25 Bristol-Myers Squibb Company Quantitative spatial profiling for lag-3 antagonist therapy
CA3152263A1 (en) 2019-09-25 2021-04-01 Julia SANTUCCI PEREIRA DEL BUONO Composite biomarker for cancer therapy
KR20220069964A (ko) 2019-09-25 2022-05-27 씨젠 인크. 조혈암의 치료를 위한 항-cd30 adc, 항-pd-1 및 화학치료제 조합
US11981922B2 (en) 2019-10-03 2024-05-14 Dana-Farber Cancer Institute, Inc. Methods and compositions for the modulation of cell interactions and signaling in the tumor microenvironment
WO2021064180A1 (en) 2019-10-03 2021-04-08 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for modulating macrophages polarization
US11793787B2 (en) 2019-10-07 2023-10-24 The Broad Institute, Inc. Methods and compositions for enhancing anti-tumor immunity by targeting steroidogenesis
WO2021074391A1 (en) 2019-10-17 2021-04-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for diagnosing nasal intestinal type adenocarcinomas
AU2020370832A1 (en) 2019-10-21 2022-05-19 Novartis Ag TIM-3 inhibitors and uses thereof
KR20220103947A (ko) 2019-10-21 2022-07-25 노파르티스 아게 베네토클락스 및 tim-3 억제제를 사용한 조합 요법
KR20220103721A (ko) 2019-10-24 2022-07-22 프로메테우스 바이오사이언시즈, 인크. Tnf 유사 리간드 1a(tl1a)에 대한 인간화 항체 및 그의 용도
TW202137984A (zh) 2019-10-29 2021-10-16 日商衛材R&D企管股份有限公司 用於治療癌症之PD-1拮抗劑、VEGFR/FGFR/RET酪胺酸激酶抑制劑及CBP/β-連環蛋白抑制劑之組合
US20240122938A1 (en) 2019-10-29 2024-04-18 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating uveal melanoma
WO2021087458A2 (en) 2019-11-02 2021-05-06 Board Of Regents, The University Of Texas System Targeting nonsense-mediated decay to activate p53 pathway for the treatment of cancer
WO2021091964A1 (en) 2019-11-04 2021-05-14 Duke University Treatment for primary and metastatic cancer
EP4055392A1 (en) 2019-11-05 2022-09-14 Bristol-Myers Squibb Company M-protein assays and uses thereof
WO2021092220A1 (en) 2019-11-06 2021-05-14 Bristol-Myers Squibb Company Methods of identifying a subject with a tumor suitable for a checkpoint inhibitor therapy
WO2021092221A1 (en) 2019-11-06 2021-05-14 Bristol-Myers Squibb Company Methods of identifying a subject with a tumor suitable for a checkpoint inhibitor therapy
AU2020380384A1 (en) 2019-11-08 2022-05-26 Bristol-Myers Squibb Company LAG-3 antagonist therapy for melanoma
CN112794906B (zh) * 2019-11-13 2022-04-05 合肥瀚科迈博生物技术有限公司 抗4-1bb的单链抗体及其应用
WO2021097110A1 (en) 2019-11-13 2021-05-20 Genentech, Inc. Therapeutic compounds and methods of use
WO2021097256A1 (en) 2019-11-14 2021-05-20 Cohbar, Inc. Cxcr4 antagonist peptides
KR20220103708A (ko) * 2019-11-21 2022-07-22 베이진 엘티디 항-pd1 또는 항-pdl1 항체와의 병용물 형태로 항-ox40 항체를 사용하는 암 치료의 방법
US20230000864A1 (en) 2019-11-22 2023-01-05 Sumitomo Pharma Oncology, Inc. Solid dose pharmaceutical composition
CN114728941A (zh) 2019-11-22 2022-07-08 施万生物制药研发Ip有限责任公司 作为alk5抑制剂的经取代的1,5-萘啶或喹啉
GB201917254D0 (en) 2019-11-27 2020-01-08 Adc Therapeutics Sa Combination therapy
WO2021113644A1 (en) 2019-12-05 2021-06-10 Multivir Inc. Combinations comprising a cd8+ t cell enhancer, an immune checkpoint inhibitor and radiotherapy for targeted and abscopal effects for the treatment of cancer
WO2021119105A1 (en) 2019-12-09 2021-06-17 Seagen Inc. Combination therapy with liv1-adc and pd-1 antagonist
US20230346901A1 (en) 2019-12-19 2023-11-02 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and vaccine compositions to treat cancers
WO2021127554A1 (en) 2019-12-19 2021-06-24 Bristol-Myers Squibb Company Combinations of dgk inhibitors and checkpoint antagonists
MX2022007759A (es) 2019-12-20 2022-07-19 Novartis Ag Combinacion del anticuerpo anti tim-3 mbg453 y anticuerpo anti tgf-beta nis793, con o sin decitabina o el anticuerpo anti pd-1 spartalizumab, para el tratamiento de mielofibrosis y sindrome mielodisplasico.
US20230044381A1 (en) * 2019-12-20 2023-02-09 Guangdong Feipeng Pharmaceutical Co., Ltd Anti-human programmed death-1 monoclonal antibody
IL294557A (en) 2020-01-07 2022-09-01 Univ Texas Enhanced human methylthioadenosine/adenosine-depleting enzyme variants for cancer therapy
EP4087842A1 (en) 2020-01-10 2022-11-16 Innate Tumor Immunity, Inc. Nlrp3 modulators
KR20220128389A (ko) 2020-01-17 2022-09-20 노파르티스 아게 골수이형성 증후군 또는 만성 골수단핵구성 백혈병을 치료하는데 사용하기 위한 tim-3 억제제 및 저메틸화제를 포함하는 조합물
EP4090770A1 (en) 2020-01-17 2022-11-23 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma
US20230086099A1 (en) 2020-01-30 2023-03-23 Ona Therapeutics, S.L. Combination therapy for treatment of cancer and cancer metastasis
CA3164559A1 (en) 2020-01-31 2021-08-05 Lars Mueller Methods of inducing neoepitope-specific t cells with a pd-1 axis binding antagonist and an rna vaccine
WO2021156360A1 (en) 2020-02-05 2021-08-12 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for discontinuing a treatment with a tyrosine kinase inhibitor (tki)
JP2023514152A (ja) 2020-02-06 2023-04-05 ブリストル-マイヤーズ スクイブ カンパニー Il-10およびその使用
EP4107173A1 (en) 2020-02-17 2022-12-28 Board of Regents, The University of Texas System Methods for expansion of tumor infiltrating lymphocytes and use thereof
JP2023514957A (ja) 2020-02-28 2023-04-12 オレガ・バイオテック Ctla4阻害剤及びil-17b阻害剤に基づく複合療法
AU2021225491A1 (en) 2020-02-28 2022-10-20 Novartis Ag A triple pharmaceutical combination comprising dabrafenib, an Erk inhibitor and a RAF inhibitor
US20230113705A1 (en) 2020-02-28 2023-04-13 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for diagnosing, prognosing and managing treatment of breast cancer
CA3170369A1 (en) 2020-03-05 2022-04-14 Michal Shahar Methods and compositions for treating cancer with immune cells
CN115768465A (zh) 2020-03-06 2023-03-07 Ona疗法有限公司 抗cd36抗体及其治疗癌症的用途
MX2022010912A (es) 2020-03-06 2022-11-09 Celgene Quanticel Res Inc Combinacion de un inhibidor de desmetilasa-1 especifica de lisina (lsd-1) y nivolumab para usarse en el tratamiento de cancer de pulmon de celulas peque?as (sclc) o cancer de pulmon de celulas no peque?as escamosas (sqnsclc).
EP3878446A1 (en) 2020-03-09 2021-09-15 Universite De Geneve Hsd11b1 inhibitors for use in immunotherapy and uses thereof
WO2021194942A1 (en) 2020-03-23 2021-09-30 Bristol-Myers Squibb Company Anti-ccr8 antibodies for treating cancer
WO2021191870A1 (en) 2020-03-27 2021-09-30 Dcprime B.V. Ex vivo use of modified cells of leukemic origin for enhancing the efficacy of adoptive cell therapy
EP4126824A1 (en) 2020-03-31 2023-02-08 Theravance Biopharma R&D IP, LLC Substituted pyrimidines and methods of use
KR20230004635A (ko) 2020-04-21 2023-01-06 노파르티스 아게 Csf-1r에 의해 조절되는 질병을 치료하기 위한 투여 요법
CA3176356A1 (en) 2020-04-22 2021-10-28 Anne BROOKS Systems and methods for coordinating manufacturing of cells for patient-specific immunotherapy
KR102623161B1 (ko) * 2020-10-08 2024-01-09 고려대학교 산학협력단 Pd-l1 친화도가 증가된 pd-1 변이체
US20230212256A1 (en) 2020-05-21 2023-07-06 Board Of Regents, The University Of Texas System T cell receptors with vgll1 specificity and uses thereof
EP4157319A1 (en) 2020-05-28 2023-04-05 Modernatx, Inc. Use of mrnas encoding ox40l, il-23 and il-36gamma for treating cancer
WO2021247836A1 (en) 2020-06-03 2021-12-09 Board Of Regents, The University Of Texas System Methods for targeting shp-2 to overcome resistance
US20210387983A1 (en) 2020-06-10 2021-12-16 Theravance Biopharma R&D Ip, Llc Crystalline alk5 inhibitors and uses thereof
MX2022015872A (es) 2020-06-11 2023-05-16 Provention Bio Inc Metodos y composiciones para prevenir diabetes tipo 1.
TW202214857A (zh) 2020-06-19 2022-04-16 法商昂席歐公司 新型結合核酸分子及其用途
CN115916199A (zh) 2020-06-23 2023-04-04 诺华股份有限公司 包含3-(1-氧代异吲哚啉-2-基)哌啶-2,6-二酮衍生物的给药方案
UY39298A (es) 2020-06-26 2022-01-31 Amgen Inc Muteínas de il-10 y proteínas de fusión de las mismas
EP4171617A1 (en) 2020-06-30 2023-05-03 Mendus B.V. Use of leukemia-derived cells in ovarian cancer vaccines
MX2023000197A (es) 2020-07-07 2023-02-22 BioNTech SE Arn terapeutico para el cancer positivo para vph.
WO2022009157A1 (en) 2020-07-10 2022-01-13 Novartis Ag Lhc165 and spartalizumab combinations for treating solid tumors
US11787775B2 (en) 2020-07-24 2023-10-17 Genentech, Inc. Therapeutic compounds and methods of use
WO2022023379A1 (en) 2020-07-28 2022-02-03 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for preventing and treating a cancer
EP4188549A1 (en) 2020-08-03 2023-06-07 Novartis AG Heteroaryl substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
AU2021331476A1 (en) 2020-08-28 2023-05-04 Bristol-Myers Squibb Company Lag-3 antagonist therapy for hepatocellular carcinoma
JP2023538955A (ja) 2020-08-31 2023-09-12 ブリストル-マイヤーズ スクイブ カンパニー 細胞局在シグネチャーおよび免疫療法
WO2022043557A1 (en) 2020-08-31 2022-03-03 Advanced Accelerator Applications International Sa Method of treating psma-expressing cancers
WO2022043558A1 (en) 2020-08-31 2022-03-03 Advanced Accelerator Applications International Sa Method of treating psma-expressing cancers
EP4208482A1 (en) 2020-09-02 2023-07-12 Pharmabcine Inc. Combination therapy of a pd-1 antagonist and an antagonist for vegfr-2 for treating patients with cancer
CA3192509A1 (en) 2020-09-24 2022-03-31 Yogita Krishnamachari Stable formulations of programmed death receptor 1 (pd-1) antibodies and hyaluronidase variants and fragments thereof and methods of use thereof
CN112285224A (zh) * 2020-10-02 2021-01-29 朱吉安 一种抗pd-1单克隆抗体药物的质量标准检测方法
KR20230080460A (ko) 2020-10-05 2023-06-07 브리스톨-마이어스 스큅 컴퍼니 단백질을 농축시키는 방법
WO2022076596A1 (en) 2020-10-06 2022-04-14 Codiak Biosciences, Inc. Extracellular vesicle-aso constructs targeting stat6
WO2022086957A1 (en) 2020-10-20 2022-04-28 Genentech, Inc. Peg-conjugated anti-mertk antibodies and methods of use
MX2023004493A (es) 2020-10-23 2023-05-10 Bristol Myers Squibb Co Terapia de agonista del gen-3 de activacion del linfocito (lag-3) para cancer de pulmon.
WO2022084531A1 (en) 2020-10-23 2022-04-28 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating glioma
WO2022093981A1 (en) 2020-10-28 2022-05-05 Genentech, Inc. Combination therapy comprising ptpn22 inhibitors and pd-l1 binding antagonists
EP4236960A1 (en) 2020-10-28 2023-09-06 Ikena Oncology, Inc. Combination of an ahr inhibitor with a pdx inhibitor or doxorubicine
CA3196539A1 (en) 2020-11-04 2022-05-12 Chi-Chung Li Dosing for treatment with anti-cd20/anti-cd3 bispecific antibodies
KR20230095113A (ko) 2020-11-04 2023-06-28 제넨테크, 인크. 항-cd20/항-cd3 이중특이적 항체들과 항-cd79b 항체 약물 접합체들을 이용한 치료를 위한 투약
KR20230100732A (ko) 2020-11-04 2023-07-05 제넨테크, 인크. 항-cd20/항-cd3 이중특이성 항체의 피하 투여
WO2022097060A1 (en) 2020-11-06 2022-05-12 Novartis Ag Cd19 binding molecules and uses thereof
EP4243839A1 (en) 2020-11-13 2023-09-20 Catamaran Bio, Inc. Genetically modified natural killer cells and methods of use thereof
WO2022101484A1 (en) 2020-11-16 2022-05-19 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for predicting and treating uveal melanoma
US20230416830A1 (en) 2020-11-16 2023-12-28 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for predicting and treating uveal melanoma
US20240024320A1 (en) 2020-11-17 2024-01-25 Seagen Inc. Methods of treating cancer with a combination of tucatinib and an anti-pd-1/anti-pd-l1 antibody
WO2022115611A1 (en) 2020-11-25 2022-06-02 Catamaran Bio, Inc. Cellular therapeutics engineered with signal modulators and methods of use thereof
US20220168293A1 (en) 2020-12-02 2022-06-02 Pfizer Inc. Time to resolution of axitinib-related adverse events
AU2021392630A1 (en) 2020-12-02 2023-06-22 Genentech, Inc. Methods and compositions for neoadjuvant and adjuvant urothelial carcinoma therapy
WO2022120179A1 (en) 2020-12-03 2022-06-09 Bristol-Myers Squibb Company Multi-tumor gene signatures and uses thereof
MX2023006604A (es) 2020-12-04 2023-06-19 Tidal Therapeutics Inc Lipidos cationicos ionizables y nanoparticulas lipidicas, y metodos de sintesis y uso de los mismos.
TW202237119A (zh) 2020-12-10 2022-10-01 美商住友製藥腫瘤公司 Alk﹘5抑制劑和彼之用途
WO2022135667A1 (en) 2020-12-21 2022-06-30 BioNTech SE Therapeutic rna for treating cancer
TW202245808A (zh) 2020-12-21 2022-12-01 德商拜恩迪克公司 用於治療癌症之治療性rna
WO2022135666A1 (en) 2020-12-21 2022-06-30 BioNTech SE Treatment schedule for cytokine proteins
WO2022146948A1 (en) 2020-12-28 2022-07-07 Bristol-Myers Squibb Company Subcutaneous administration of pd1/pd-l1 antibodies
WO2022146947A1 (en) 2020-12-28 2022-07-07 Bristol-Myers Squibb Company Antibody compositions and methods of use thereof
CA3205538A1 (en) 2021-01-19 2022-07-28 Han XIAO Bone-specific delivery of polypeptides
KR20230135075A (ko) 2021-01-22 2023-09-22 멘두스 비.브이. 종양 백신접종 방법
EP4284510A1 (en) 2021-01-29 2023-12-06 Novartis AG Dosage regimes for anti-cd73 and anti-entpd2 antibodies and uses thereof
TW202241508A (zh) 2021-01-29 2022-11-01 美商艾歐凡斯生物治療公司 細胞介素相關之腫瘤浸潤性淋巴球組合物及方法
US20240109899A1 (en) 2021-02-04 2024-04-04 Bristol-Myers Squibb Company Benzofuran compounds as sting agonists
GB202102396D0 (en) 2021-02-19 2021-04-07 Adc Therapeutics Sa Molecular adjuvant
IL305795A (en) * 2021-03-10 2023-11-01 B G Negev Technologies & Applications Ltd At Ben Gurion Univ Reporter cells expressing chimeric proteins for use in determining the presence and or activity of immune barrier molecules
JP2024510989A (ja) 2021-03-12 2024-03-12 メンドゥス・ベスローテン・フェンノートシャップ ワクチン接種方法及びcd47遮断薬の使用
US20240165094A1 (en) 2021-03-17 2024-05-23 Institut National de la Santé et de la Recherche Médicale Methods and compositions for treating melanoma
WO2022195551A1 (en) 2021-03-18 2022-09-22 Novartis Ag Biomarkers for cancer and methods of use thereof
TW202304506A (zh) 2021-03-25 2023-02-01 日商安斯泰來製藥公司 涉及抗claudin 18.2抗體的組合治療以治療癌症
US20240181052A1 (en) 2021-03-29 2024-06-06 Juno Therapeutics, Inc. Methods for dosing and treatment with a combination of a checkpoint inhibitor therapy and a car t cell therapy
WO2022212876A1 (en) 2021-04-02 2022-10-06 The Regents Of The University Of California Antibodies against cleaved cdcp1 and uses thereof
TW202304979A (zh) 2021-04-07 2023-02-01 瑞士商諾華公司 抗TGFβ抗體及其他治療劑用於治療增殖性疾病之用途
PE20240327A1 (es) 2021-04-13 2024-02-22 Nuvalent Inc Heterociclos con sustitucion amino para tratar canceres con mutaciones de egfr
WO2022219080A1 (en) 2021-04-14 2022-10-20 INSERM (Institut National de la Santé et de la Recherche Médicale) New method to improve nk cells cytotoxicity
EP4326903A1 (en) 2021-04-23 2024-02-28 Inserm (Institut National De La Sante Et De La Recherche Medicale) Methods and compositions for treating cell senescence accumulation related disease
JP2024516230A (ja) 2021-04-30 2024-04-12 ジェネンテック, インコーポレイテッド がんのための治療及び診断方法並びに組成物
AU2021443318A1 (en) 2021-04-30 2023-09-07 F. Hoffmann-La Roche Ag Dosing for combination treatment with anti-cd20/anti-cd3 bispecific antibody and anti-cd79b antibody drug conjugate
AR125874A1 (es) 2021-05-18 2023-08-23 Novartis Ag Terapias de combinación
CN117412767A (zh) 2021-05-25 2024-01-16 雪绒花免疫公司 C-x-c基序趋化因子受体6(cxcr6)结合分子及其使用方法
WO2022251359A1 (en) 2021-05-26 2022-12-01 Theravance Biopharma R&D Ip, Llc Bicyclic inhibitors of alk5 and methods of use
TW202313117A (zh) 2021-06-03 2023-04-01 美商欣爍克斯公司 包含il-2接合物及西妥昔單抗(cetuximab)之頭頸癌組合療法
GB202107994D0 (en) 2021-06-04 2021-07-21 Kymab Ltd Treatment of cancer
CN117915948A (zh) 2021-06-18 2024-04-19 建新公司 抗TGF-β抗体配制品及其用途
BR112023026966A2 (pt) 2021-07-02 2024-03-12 Hoffmann La Roche Métodos para tratar um indivíduo com melanoma, para alcançar uma resposta clínica, para tratar um indivíduo com linfoma não hodgkin, para tratar uma população de indivíduos com linfoma não hodgkin e para tratar um indivíduo com câncer colorretal metastático
KR20240046323A (ko) 2021-07-13 2024-04-08 비온테크 에스이 암에 대한 병용 요법에 있어서 cd40 및 cd137에 대한 다중특이 결합제
EP4377351A1 (en) 2021-07-28 2024-06-05 F. Hoffmann-La Roche AG Methods and compositions for treating cancer
JP2024527049A (ja) 2021-07-28 2024-07-19 ジェネンテック, インコーポレイテッド がんを治療するための方法及び組成物
WO2023007472A1 (en) 2021-07-30 2023-02-02 ONA Therapeutics S.L. Anti-cd36 antibodies and their use to treat cancer
JP2024531910A (ja) 2021-08-04 2024-09-03 ザ リージェンツ オブ ザ ユニバーシティ オブ コロラド,ア ボディー コーポレイト Lat活性化キメラ抗原受容体t細胞及びその使用方法
MX2024002281A (es) 2021-08-23 2024-05-20 Immunitas Therapeutics Inc Anticuerpos anti-cd161 y usos de los mismos.
KR20240051162A (ko) 2021-09-02 2024-04-19 도이체스크레브스포르슝스젠트룸스티프퉁데스외펜트리헨레크츠 부작용이 감소된 항-cecam6 항체
EP4398889A1 (en) 2021-09-10 2024-07-17 Leap Therapeutics, Inc. Combination therapy
WO2023051926A1 (en) 2021-09-30 2023-04-06 BioNTech SE Treatment involving non-immunogenic rna for antigen vaccination and pd-1 axis binding antagonists
TW202321308A (zh) 2021-09-30 2023-06-01 美商建南德克公司 使用抗tigit抗體、抗cd38抗體及pd—1軸結合拮抗劑治療血液癌症的方法
WO2023057882A1 (en) 2021-10-05 2023-04-13 Pfizer Inc. Combinations of azalactam compounds with a pd-1 axis binding antagonist for the treatment of cancer
EP4413117A1 (en) 2021-10-05 2024-08-14 Cytovia Therapeutics, Llc. Natural killer cells and methods of use thereof
IL311771A (en) 2021-10-06 2024-05-01 BioNTech SE Multispecific binding agents against PD-L1 and CD137 in combination
TW202333802A (zh) 2021-10-11 2023-09-01 德商拜恩迪克公司 用於肺癌之治療性rna(二)
TW202330612A (zh) 2021-10-20 2023-08-01 日商武田藥品工業股份有限公司 靶向bcma之組合物及其使用方法
WO2023076880A1 (en) 2021-10-25 2023-05-04 Board Of Regents, The University Of Texas System Foxo1-targeted therapy for the treatment of cancer
CA3234821A1 (en) 2021-10-28 2023-05-04 Suman Kumar VODNALA Methods for culturing immune cells
MX2024005053A (es) 2021-10-29 2024-05-10 Bristol Myers Squibb Co Terapia con antagonista del gen de activacion de linfocitos 3 (lag-3) para cancer hematologico.
WO2023078900A1 (en) 2021-11-03 2023-05-11 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating triple negative breast cancer (tnbc)
WO2023079428A1 (en) 2021-11-03 2023-05-11 Pfizer Inc. Combination therapies using tlr7/8 agonist
WO2023080900A1 (en) 2021-11-05 2023-05-11 Genentech, Inc. Methods and compositions for classifying and treating kidney cancer
WO2023083439A1 (en) 2021-11-09 2023-05-19 BioNTech SE Tlr7 agonist and combinations for cancer treatment
KR20240103007A (ko) 2021-11-12 2024-07-03 노파르티스 아게 폐암 치료를 위한 병용 요법
TW202340212A (zh) 2021-11-24 2023-10-16 美商建南德克公司 治療性化合物及其使用方法
WO2023097195A1 (en) 2021-11-24 2023-06-01 Genentech, Inc. Therapeutic indazole compounds and methods of use in the treatment of cancer
IL313439A (en) 2021-12-16 2024-08-01 Valerio Therapeutics New conjugated nucleic acid molecules and their uses
WO2023122573A1 (en) 2021-12-20 2023-06-29 Synthorx, Inc. Head and neck cancer combination therapy comprising an il-2 conjugate and pembrolizumab
WO2023118165A1 (en) 2021-12-21 2023-06-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating melanoma
WO2023130081A1 (en) 2021-12-30 2023-07-06 Neoimmunetech, Inc. Method of treating a tumor with a combination of il-7 protein and vegf antagonist
WO2023133424A2 (en) * 2022-01-05 2023-07-13 TCR2 Therapeutics Inc. Compositions and methods for tcr reprogramming using fusion proteins and anti-pd-1 fusion peptides
MX2024008831A (es) 2022-01-26 2024-07-25 Bristol Myers Squibb Company Terapia combinada para carcinoma hepatocelular.
WO2023147488A1 (en) 2022-01-28 2023-08-03 Iovance Biotherapeutics, Inc. Cytokine associated tumor infiltrating lymphocytes compositions and methods
AU2023226078A1 (en) 2022-02-25 2024-08-22 Bristol-Myers Squibb Company Combination therapy for colorectal carcinoma.
WO2023168404A1 (en) 2022-03-04 2023-09-07 Bristol-Myers Squibb Company Methods of treating a tumor
WO2023170606A1 (en) 2022-03-08 2023-09-14 Alentis Therapeutics Ag Use of anti-claudin-1 antibodies to increase t cell availability
WO2023178329A1 (en) 2022-03-18 2023-09-21 Bristol-Myers Squibb Company Methods of isolating polypeptides
AU2022450448A1 (en) 2022-04-01 2024-10-10 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2023196988A1 (en) 2022-04-07 2023-10-12 Modernatx, Inc. Methods of use of mrnas encoding il-12
WO2023196987A1 (en) 2022-04-07 2023-10-12 Bristol-Myers Squibb Company Methods of treating tumor
US20230326022A1 (en) 2022-04-08 2023-10-12 Bristol-Myers Squibb Company Machine Learning Identification, Classification, and Quantification of Tertiary Lymphoid Structures
EP4257609A1 (en) 2022-04-08 2023-10-11 iOmx Therapeutics AG Combination therapies based on pd-1 inhibitors and sik3 inhibitors
WO2023198116A1 (en) * 2022-04-14 2023-10-19 Beigene Switzerland Gmbh Stable high concentration arginine formulations containing pd-1 antibody and methods of use thereof
WO2023201369A1 (en) 2022-04-15 2023-10-19 Iovance Biotherapeutics, Inc. Til expansion processes using specific cytokine combinations and/or akti treatment
WO2023211972A1 (en) 2022-04-28 2023-11-02 Medical University Of South Carolina Chimeric antigen receptor modified regulatory t cells for treating cancer
WO2023214325A1 (en) 2022-05-05 2023-11-09 Novartis Ag Pyrazolopyrimidine derivatives and uses thereof as tet2 inhibitors
CN114920830B (zh) * 2022-05-07 2023-05-16 北京大学 Vκ4-1-IgLC多肽及其用途
WO2023219613A1 (en) 2022-05-11 2023-11-16 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2023218046A1 (en) 2022-05-12 2023-11-16 Genmab A/S Binding agents capable of binding to cd27 in combination therapy
WO2023230554A1 (en) 2022-05-25 2023-11-30 Pfizer Inc. Combination of a braf inhibitor, an egfr inhibitor, and a pd-1 antagonist for the treatment of braf v600e-mutant, msi-h/dmmr colorectal cancer
WO2023235847A1 (en) 2022-06-02 2023-12-07 Bristol-Myers Squibb Company Antibody compositions and methods of use thereof
WO2023240058A2 (en) 2022-06-07 2023-12-14 Genentech, Inc. Prognostic and therapeutic methods for cancer
US20240002331A1 (en) 2022-06-08 2024-01-04 Tidal Therapeutics, Inc. Ionizable cationic lipids and lipid nanoparticles, and methods of synthesis and use thereof
US11786531B1 (en) 2022-06-08 2023-10-17 Beigene Switzerland Gmbh Methods of treating B-cell proliferative disorder
WO2023241659A1 (en) * 2022-06-16 2023-12-21 Beigene, Ltd. Methods of treating lymphoma using anti-tigit antibodies
GB202209518D0 (en) 2022-06-29 2022-08-10 Snipr Biome Aps Treating & preventing E coli infections
TW202417042A (zh) 2022-07-13 2024-05-01 美商建南德克公司 用抗fcrh5/抗cd3雙特異性抗體進行治療之給藥
WO2024020432A1 (en) 2022-07-19 2024-01-25 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
EP4310197A1 (en) 2022-07-21 2024-01-24 Fundación para la Investigación Biomédica del Hospital Universitario Puerta de Hierro Majadahonda Method for identifying lung cancer patients for a combination treatment of immuno- and chemotherapy
WO2024023740A1 (en) 2022-07-27 2024-02-01 Astrazeneca Ab Combinations of recombinant virus expressing interleukin-12 with pd-1/pd-l1 inhibitors
WO2024028794A1 (en) 2022-08-02 2024-02-08 Temple Therapeutics BV Methods for treating endometrial and ovarian hyperproliferative disorders
WO2024033399A1 (en) 2022-08-10 2024-02-15 Institut National de la Santé et de la Recherche Médicale Sigmar1 ligand for the treatment of pancreatic cancer
WO2024033400A1 (en) 2022-08-10 2024-02-15 Institut National de la Santé et de la Recherche Médicale Sk2 inhibitor for the treatment of pancreatic cancer
WO2024041652A1 (en) * 2022-08-25 2024-02-29 Beigene, Ltd. Methods of cancer treatment
WO2024041651A1 (en) * 2022-08-25 2024-02-29 Beigene, Ltd. Methods of cancer treatment using anti-pd1 antibodies in combination with anti-tim3 antibodies and anti-lag3 antibodies
WO2024044675A1 (en) 2022-08-25 2024-02-29 Beigene, Ltd. Methods of cancer treatment using anti-pd1 antibodies in combination with anti-tim3 antibodies
WO2024049949A1 (en) 2022-09-01 2024-03-07 Genentech, Inc. Therapeutic and diagnostic methods for bladder cancer
WO2024056716A1 (en) 2022-09-14 2024-03-21 Institut National de la Santé et de la Recherche Médicale Methods and pharmaceutical compositions for the treatment of dilated cardiomyopathy
WO2024069009A1 (en) 2022-09-30 2024-04-04 Alentis Therapeutics Ag Treatment of drug-resistant hepatocellular carcinoma
WO2024077095A1 (en) 2022-10-05 2024-04-11 Genentech, Inc. Methods and compositions for classifying and treating bladder cancer
WO2024077166A1 (en) 2022-10-05 2024-04-11 Genentech, Inc. Methods and compositions for classifying and treating lung cancer
WO2024086827A2 (en) 2022-10-20 2024-04-25 Repertoire Immune Medicines, Inc. Cd8 t cell targeted il2
WO2024084034A1 (en) 2022-10-21 2024-04-25 Institut National de la Santé et de la Recherche Médicale Methods and pharmaceutical compositions for the treatment of osteoarthritis
TW202426505A (zh) 2022-10-25 2024-07-01 美商建南德克公司 癌症之治療及診斷方法
WO2024102722A1 (en) 2022-11-07 2024-05-16 Neoimmunetech, Inc. Methods of treating a tumor with an unmethylated mgmt promoter
WO2024112571A2 (en) 2022-11-21 2024-05-30 Iovance Biotherapeutics, Inc. Two-dimensional processes for the expansion of tumor infiltrating lymphocytes and therapies therefrom
WO2024110905A1 (en) 2022-11-24 2024-05-30 Beigene, Ltd. Anti-cea antibody drug conjugates and methods of use
WO2024116140A1 (en) 2022-12-01 2024-06-06 Medimmune Limited Combination therapy for treatment of cancer comprising anti-pd-l1 and anti-cd73 antibodies
WO2024115725A1 (en) 2022-12-01 2024-06-06 BioNTech SE Multispecific antibody against cd40 and cd137 in combination therapy with anti-pd1 ab and chemotherapy
WO2024124044A1 (en) 2022-12-07 2024-06-13 The Brigham And Women’S Hospital, Inc. Compositions and methods targeting sat1 for enhancing anti¬ tumor immunity during tumor progression
WO2024126457A1 (en) 2022-12-14 2024-06-20 Astellas Pharma Europe Bv Combination therapy involving bispecific binding agents binding to cldn18.2 and cd3 and immune checkpoint inhibitors
WO2024137589A2 (en) 2022-12-20 2024-06-27 Genentech, Inc. Methods of treating pancreatic cancer with a pd-1 axis binding antagonist and an rna vaccine
WO2024137776A1 (en) 2022-12-21 2024-06-27 Bristol-Myers Squibb Company Combination therapy for lung cancer
WO2024148243A1 (en) 2023-01-06 2024-07-11 Lassen Therapeutics 1, Inc. Anti-il-18bp antibodies
WO2024148241A1 (en) 2023-01-06 2024-07-11 Lassen Therapeutics 1, Inc. Anti-il-18bp antibodies
WO2024150177A1 (en) 2023-01-11 2024-07-18 Advesya Treatment methods for solid tumors
WO2024151885A1 (en) 2023-01-13 2024-07-18 Iovance Biotherapeutics, Inc. Use of til as maintenance therapy for nsclc patients who achieved pr/cr after prior therapy
WO2024153168A2 (en) 2023-01-19 2024-07-25 Beigene, Ltd. Anti-cmet antibodies and methods of use
US20240294651A1 (en) 2023-01-30 2024-09-05 Kymab Limited Antibodies
WO2024175699A1 (en) 2023-02-23 2024-08-29 Imcheck Therapeutics Combination of btn3a activating antibody and immune checkpoint inhibitors
WO2024183637A1 (en) 2023-03-03 2024-09-12 Beigene Switzerland Gmbh Muc1 antibodies and methods of use
WO2024183635A1 (en) 2023-03-03 2024-09-12 Beigene, Ltd. Muc1 and cd16a antibodies and methods of use
WO2024184810A1 (en) 2023-03-06 2024-09-12 Beigene Switzerland Gmbh Anti-cldn6 and anti-cd3 multispecific antibodies and methods of use
WO2024184812A1 (en) 2023-03-06 2024-09-12 Beigene Switzerland Gmbh Anti-cldn6 antibodies and methods of use
WO2024184811A1 (en) 2023-03-06 2024-09-12 Beigene Switzerland Gmbh Anti-cd3 multispecific antibodies and methods of use
WO2024196952A1 (en) 2023-03-20 2024-09-26 Bristol-Myers Squibb Company Tumor subtype assessment for cancer therapy
WO2024200571A1 (en) 2023-03-28 2024-10-03 Institut National de la Santé et de la Recherche Médicale Method for discriminating mono-immunotherapy from combined immunotherapy in cancers
WO2024209072A1 (en) 2023-04-06 2024-10-10 Genmab A/S Multispecific binding agents against pd-l1 and cd137 for treating cancer

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006121168A1 (en) * 2005-05-09 2006-11-16 Ono Pharmaceutical Co., Ltd. Human monoclonal antibodies to programmed death 1(pd-1) and methods for treating cancer using anti-pd-1 antibodies alone or in combination with other immunotherapeutics
CN101355965A (zh) * 2005-06-08 2009-01-28 达纳-法伯癌症研究院 通过抑制程序性细胞死亡1(pd-1)途经治疗持续性感染和癌症的方法及组合物
CN102245640A (zh) * 2008-12-09 2011-11-16 霍夫曼-拉罗奇有限公司 抗-pd-l1抗体及它们用于增强t细胞功能的用途
CN102264762A (zh) * 2008-09-26 2011-11-30 达纳-法伯癌症研究公司 人抗pd-1、pd-l1和pd-l2的抗体及其应用

Family Cites Families (202)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE792533A (fr) 1971-12-09 1973-06-08 Int Chem & Nuclear Corp Nouvelles pyrazolo (1,5a) pyrimidines et leur procede de preparation
US4376110A (en) 1980-08-04 1983-03-08 Hybritech, Incorporated Immunometric assays using monoclonal antibodies
WO1988007089A1 (en) 1987-03-18 1988-09-22 Medical Research Council Altered antibodies
US5859205A (en) * 1989-12-21 1999-01-12 Celltech Limited Humanised antibodies
US5994514A (en) 1991-08-14 1999-11-30 Genentech, Inc. Immunoglobulin variants
AU4116793A (en) 1992-04-24 1993-11-29 Board Of Regents, The University Of Texas System Recombinant production of immunoglobulin-like domains in prokaryotic cells
CA2163345A1 (en) 1993-06-16 1994-12-22 Susan Adrienne Morgan Antibodies
CA2143491C (en) 1994-03-01 2011-02-22 Yasumasa Ishida A novel peptide related to human programmed cell death and dna encoding it
JP2778921B2 (ja) 1994-11-18 1998-07-23 三共株式会社 イミダゾピラゾール誘導体
US6194551B1 (en) 1998-04-02 2001-02-27 Genentech, Inc. Polypeptide variants
US6528624B1 (en) 1998-04-02 2003-03-04 Genentech, Inc. Polypeptide variants
GB9809951D0 (en) 1998-05-08 1998-07-08 Univ Cambridge Tech Binding molecules
US6737056B1 (en) 1999-01-15 2004-05-18 Genentech, Inc. Polypeptide variants with altered effector function
KR20060067983A (ko) 1999-01-15 2006-06-20 제넨테크, 인크. 효과기 기능이 변화된 폴리펩티드 변이체
HUP0202882A2 (en) 1999-08-23 2002-12-28 Dana Farber Cancer Inst Inc Novel b7-4 molecules and uses therefor
IL147972A0 (en) 1999-08-23 2002-09-12 Dana Farber Cancer Inst Inc Ge Pd-1, a receptor for b7-4 and uses therefor
CA2379421A1 (en) 1999-08-27 2001-03-08 Abbott Laboratories Sulfonylphenylpyrazole compounds useful as cox-2 inhibitors
KR20020088406A (ko) 1999-09-17 2002-11-27 애보트 게엠베하 운트 콤파니 카게 치료제로서의 피라졸로피리미딘
PL358215A1 (en) * 2000-03-24 2004-08-09 Micromet Ag Multifunctional polypeptides comprising a binding site to an epitope of the nkg2d receptor complex
JP2003531149A (ja) 2000-04-13 2003-10-21 ザ・ロツクフエラー・ユニバーシテイ 抗体由来の免疫応答の増強
US20020094989A1 (en) 2000-10-11 2002-07-18 Hale Jeffrey J. Pyrrolidine modulators of CCR5 chemokine receptor activity
KR20030066657A (ko) 2000-11-15 2003-08-09 오노 야꾸힝 고교 가부시키가이샤 Pd-1 결손 마우스 및 그 용도
ATE489395T1 (de) 2000-12-12 2010-12-15 Medimmune Llc Moleküle mit längeren halbwertszeiten, zusammensetzungen und deren verwendung
CA2433018A1 (en) 2000-12-21 2002-06-27 Joel C. Barrish Thiazolyl inhibitors of tec family tyrosine kinases
US20030133939A1 (en) 2001-01-17 2003-07-17 Genecraft, Inc. Binding domain-immunoglobulin fusion proteins
EP1366067B1 (en) 2001-03-07 2012-09-26 Merck Patent GmbH Expression technology for proteins containing a hybrid isotype antibody moiety
ES2251582T3 (es) 2001-03-09 2006-05-01 Pfizer Products Inc. Compuestos antiinflamatorios de bencimidazol.
AR036993A1 (es) 2001-04-02 2004-10-20 Wyeth Corp Uso de agentes que modulan la interaccion entre pd-1 y sus ligandos en la submodulacion de respuestas inmunologicas
WO2003004497A1 (fr) 2001-07-05 2003-01-16 Sumitomo Pharmaceuticals Company, Limited Compose heterocyclique
US7662925B2 (en) 2002-03-01 2010-02-16 Xencor, Inc. Optimized Fc variants and methods for their generation
US7317091B2 (en) 2002-03-01 2008-01-08 Xencor, Inc. Optimized Fc variants
DE10161767T1 (de) 2002-07-03 2018-06-07 Honjo Tasuku Immunopotenzierende Zusammensetzungen, die einen Anti-PD-L1 Antikörper enthalten
KR101050700B1 (ko) 2002-08-26 2011-07-20 다케다 야쿠힌 고교 가부시키가이샤 칼슘 수용체 조절 화합물 및 이의 용도
CN1771231B (zh) 2002-08-26 2011-05-25 武田药品工业株式会社 钙受体调节性化合物及其用途
EP1578447A4 (en) 2002-10-31 2009-06-03 Genentech Inc METHODS AND COMPOSITIONS THAT CAN INCREASE ANTIBODY PRODUCTION
ATE514713T1 (de) * 2002-12-23 2011-07-15 Wyeth Llc Antikörper gegen pd-1 und ihre verwendung
EP2368578A1 (en) 2003-01-09 2011-09-28 Macrogenics, Inc. Identification and engineering of antibodies with variant Fc regions and methods of using same
US7960512B2 (en) * 2003-01-09 2011-06-14 Macrogenics, Inc. Identification and engineering of antibodies with variant Fc regions and methods of using same
US7563869B2 (en) 2003-01-23 2009-07-21 Ono Pharmaceutical Co., Ltd. Substance specific to human PD-1
US8084582B2 (en) 2003-03-03 2011-12-27 Xencor, Inc. Optimized anti-CD20 monoclonal antibodies having Fc variants
US20060183746A1 (en) 2003-06-04 2006-08-17 Currie Kevin S Certain imidazo[1,2-a]pyrazin-8-ylamines and method of inhibition of Bruton's tyrosine kinase by such compounds
US7405295B2 (en) 2003-06-04 2008-07-29 Cgi Pharmaceuticals, Inc. Certain imidazo[1,2-a]pyrazin-8-ylamines and method of inhibition of Bruton's tyrosine kinase by such compounds
US7393848B2 (en) 2003-06-30 2008-07-01 Cgi Pharmaceuticals, Inc. Certain heterocyclic substituted imidazo[1,2-A]pyrazin-8-ylamines and methods of inhibition of Bruton's tyrosine kinase by such compounds
CN1860118A (zh) 2003-07-29 2006-11-08 Irm责任有限公司 作为蛋白激酶抑制剂的化合物和组合物
WO2005018572A2 (en) 2003-08-22 2005-03-03 Biogen Idec Ma Inc. Improved antibodies having altered effector function and methods for making the same
US20060134105A1 (en) * 2004-10-21 2006-06-22 Xencor, Inc. IgG immunoglobulin variants with optimized effector function
WO2005047290A2 (en) 2003-11-11 2005-05-26 Cellular Genomics Inc. Imidazo[1,2-a] pyrazin-8-ylamines as kinase inhibitors
US20050249723A1 (en) 2003-12-22 2005-11-10 Xencor, Inc. Fc polypeptides with novel Fc ligand binding sites
GB0400440D0 (en) 2004-01-09 2004-02-11 Isis Innovation Receptor modulators
CA2580981C (en) 2004-09-22 2013-10-22 Kirin Beer Kabushiki Kaisha Stabilized human igg4 antibodies
WO2006053121A2 (en) 2004-11-10 2006-05-18 Cgi Pharmaceuticals, Inc. Imidazo[1 , 2-a] pyrazin-8-ylamines useful as modulators of kinase activity
AU2005316540A1 (en) 2004-12-16 2006-06-22 Vertex Pharmaceuticals Incorporated Pyrid-2-ones useful as inhibitors of Tec family protein kinases for the treatment of inflammatory, proliferative and immunologically-mediated diseases
TW200639163A (en) 2005-02-04 2006-11-16 Genentech Inc RAF inhibitor compounds and methods
TW200716551A (en) 2005-03-10 2007-05-01 Cgi Pharmaceuticals Inc Certain substituted amides, method of making, and method of use thereof
DK1907424T3 (en) 2005-07-01 2015-11-09 Squibb & Sons Llc HUMAN MONOCLONAL ANTIBODIES TO PROGRAMMED death ligand 1 (PD-L1)
US7691885B2 (en) 2005-08-29 2010-04-06 Vertex Pharmaceuticals Incorporated Pyridones useful as inhibitors of kinases
AU2006284900A1 (en) 2005-08-29 2007-03-08 Vertex Pharmaceuticals Incorporated 3, 5-disubstituted pyrid-2-ones useful as inhibitors of Tec family of non-receptor tyrosine kinases
WO2007026720A1 (ja) 2005-08-31 2007-03-08 Taisho Pharmaceutical Co., Ltd. 縮環ピラゾール誘導体
EP1919919A1 (en) 2005-09-01 2008-05-14 Astellas Pharma Inc. Pyridazinone derivatives used for the treatment of pain
RU2008127486A (ru) 2005-12-08 2010-01-20 Милленниум Фармасьютикалз, Инк. (Us) Бициклические соединения с ингибиторной активностью в отношении киназы
RU2008133161A (ru) 2006-01-13 2010-02-20 Фармасайкликс, Инк. (Us) Ингибиторы тирозин киназ и их применение
RU2429244C2 (ru) * 2006-03-23 2011-09-20 Байоарктик Ньюросайенс Аб Улучшенные селективные в отношении протофибрилл антитела и их применение
JP5271895B2 (ja) 2006-05-15 2013-08-21 メルク・シャープ・アンド・ドーム・コーポレーション 抗糖尿病性の二環式化合物
EP2865381A1 (en) 2006-05-18 2015-04-29 Pharmacyclics, Inc. ITK inhibitors for treating blood cell malignancies
TWI398252B (zh) 2006-05-26 2013-06-11 Novartis Ag 吡咯并嘧啶化合物及其用途
CN101104640A (zh) 2006-07-10 2008-01-16 苏州大学 抗人pd-l1单克隆抗体制备及应用
JP2010502751A (ja) 2006-09-11 2010-01-28 シージーアイ ファーマシューティカルズ,インコーポレイティド キナーゼ阻害物質、およびキナーゼ阻害物質の使用および同定方法
PE20081370A1 (es) 2006-09-11 2008-11-28 Cgi Pharmaceuticals Inc Determinadas amidas sustituidas, metodo de elaboracion y metodo de uso de las mismas
AR063946A1 (es) 2006-09-11 2009-03-04 Cgi Pharmaceuticals Inc Determinadas pirimidinas sustituidas, el uso de las mismas para el tratamiento de enfermedades mediadas por la inhibicion de la actividad de btk y composiciones farmaceuticas que las comprenden.
AR063706A1 (es) 2006-09-11 2009-02-11 Cgi Pharmaceuticals Inc Determinadas amidas sustituidas, el uso de las mismas para el tratamiento de enfermedades mediadas por la inhibicion de la actividad de btk y composiciones farmaceuticas que las comprenden.
EP2201840B1 (en) 2006-09-22 2011-11-02 Pharmacyclics, Inc. Inhibitors of Bruton's Tyrosine Kinase
WO2008045627A2 (en) 2006-10-06 2008-04-17 Irm Llc Protein kinase inhibitors and methods for using thereof
CA2668286C (en) 2006-11-03 2014-09-16 Pharmacyclics, Inc. Bruton's tyrosine kinase activity probe and method of using
CN101730699A (zh) 2007-03-21 2010-06-09 百时美施贵宝公司 可用于治疗增殖性、变应性、自身免疫性和炎症性疾病的稠合杂环化合物
WO2008144253A1 (en) 2007-05-14 2008-11-27 Irm Llc Protein kinase inhibitors and methods for using thereof
WO2008145142A1 (en) * 2007-05-31 2008-12-04 Genmab A/S Stable igg4 antibodies
EP2170959B1 (en) 2007-06-18 2013-10-02 Merck Sharp & Dohme B.V. Antibodies to human programmed death receptor pd-1
WO2009024531A1 (en) 2007-08-17 2009-02-26 INSERM (Institut National de la Santé et de la Recherche Médicale) Method for treating and diagnosing hematologic malignancies
CL2008002793A1 (es) 2007-09-20 2009-09-04 Cgi Pharmaceuticals Inc Compuestos derivados de amidas sustituidas, inhibidores de la actividad de btk; composicion farmaceutica que los comprende; utiles en el tratamiento del cancer, trastornos oseos, enfermedades autoinmunes, entre otras
JO3076B1 (ar) * 2007-10-17 2017-03-15 Janssen Alzheimer Immunotherap نظم العلاج المناعي المعتمد على حالة apoe
AU2008314632B2 (en) 2007-10-19 2015-05-28 Celgene Avilomics Research, Inc. Heteroaryl compounds and uses thereof
US7989465B2 (en) 2007-10-19 2011-08-02 Avila Therapeutics, Inc. 4,6-disubstituted pyrimidines useful as kinase inhibitors
ES2499017T3 (es) 2007-10-23 2014-09-26 F. Hoffmann-La Roche Ag Nuevos inhibidores de quinasa
WO2009077334A1 (en) 2007-12-14 2009-06-25 F. Hoffmann-La Roche Ag Novel imidazo[1,2-a]pyridine and imidazo[1,2-b]pyridazine derivatives
DK2242749T3 (da) 2008-02-05 2013-06-17 Hoffmann La Roche Nye pyridinoner og pyridazinoner
PL2250279T3 (pl) 2008-02-08 2016-11-30 Przeciwciała anty-ifnar1 o zmniejszonym powinowactwie do liganda fc
US8168757B2 (en) 2008-03-12 2012-05-01 Merck Sharp & Dohme Corp. PD-1 binding proteins
ES2554615T3 (es) 2008-05-06 2015-12-22 Gilead Connecticut, Inc. Amidas sustituidas, método de preparación y utilización como inhibidores de Btk
SG10201510696RA (en) 2008-06-27 2016-01-28 Celgene Avilomics Res Inc Heteroaryl compounds and uses thereof
US8338439B2 (en) 2008-06-27 2012-12-25 Celgene Avilomics Research, Inc. 2,4-disubstituted pyrimidines useful as kinase inhibitors
CN102083819B (zh) 2008-07-02 2014-07-09 霍夫曼-拉罗奇有限公司 作为激酶抑制剂的新型苯基吡嗪酮
CN102066370B (zh) 2008-07-15 2014-05-14 霍夫曼-拉罗奇有限公司 苯基-咪唑并吡啶类和哒嗪类
EP2307025B1 (en) 2008-07-16 2017-09-20 Pharmacyclics LLC Inhibitors of bruton's tyrosine kinase for the treatment of solid tumors
ES2461494T3 (es) 2008-07-18 2014-05-20 F. Hoffmann-La Roche Ag Nuevas fenilimidazopirazinas
EP2323665B1 (en) 2008-07-24 2013-06-19 Bristol-Myers Squibb Company Fused heterocyclic compounds useful as kinase modulators
CN102203125A (zh) 2008-08-25 2011-09-28 安普利穆尼股份有限公司 Pd-1拮抗剂及其使用方法
NZ621143A (en) 2008-09-05 2016-08-26 Celgene Avilomics Res Inc Algorithm for designing irreversible inhibitors
JP5794917B2 (ja) 2008-09-12 2015-10-14 アイシス・イノベーション・リミテッドIsis Innovationlimited Pd−1特異抗体およびその使用
EP2342229A1 (en) 2008-09-12 2011-07-13 ISIS Innovation Limited Pd-1 specific antibodies and uses thereof
KR101050829B1 (ko) 2008-10-02 2011-07-20 서울대학교산학협력단 항 pd-1 항체 또는 항 pd-l1 항체를 포함하는 항암제
AU2009308675A1 (en) 2008-10-31 2010-05-06 Genentech, Inc. Pyrazolopyrimidine JAK inhibitor compounds and methods
US20120028981A1 (en) 2008-11-05 2012-02-02 Principia Biopharma Inc. Kinase Knockdown Via Electrophilically Enhanced Inhibitors
EP2365970B1 (en) 2008-11-12 2018-03-21 Gilead Connecticut, Inc. Pyridazinones and their use as btk inhibitors
KR101721707B1 (ko) * 2008-11-28 2017-03-30 에모리 유니버시티 감염 및 종양 치료 방법
US8426428B2 (en) 2008-12-05 2013-04-23 Principia Biopharma, Inc. EGFR kinase knockdown via electrophilically enhanced inhibitors
WO2010068788A1 (en) 2008-12-10 2010-06-17 Cgi Pharmaceuticals, Inc. Heterocyclic amides as btk inhibitors
WO2010068810A2 (en) 2008-12-10 2010-06-17 Cgi Pharmaceuticals, Inc. Certain substituted amides, method of making, and method of use thereof
WO2010068806A1 (en) 2008-12-10 2010-06-17 Cgi Pharmaceuticals, Inc. Amide derivatives as btk inhibitors in the treatment of allergic, autoimmune and inflammatory disorders as well as cancer
CN102325753B (zh) 2008-12-19 2014-09-10 百时美施贵宝公司 用作激酶抑制剂的咔唑甲酰胺化合物
US20100197924A1 (en) 2008-12-22 2010-08-05 Millennium Pharmaceuticals, Inc. Preparation of aminotetralin compounds
EP3255047B1 (en) 2009-01-06 2021-06-30 Dana-Farber Cancer Institute, Inc. Pyrimido-diazepinone kinase scaffold compounds and uses in treating disorders
JP5844159B2 (ja) * 2009-02-09 2016-01-13 ユニヴェルシテ デクス−マルセイユUniversite D’Aix−Marseille Pd−1抗体およびpd−l1抗体ならびにその使用
US8299077B2 (en) 2009-03-02 2012-10-30 Roche Palo Alto Llc Inhibitors of Bruton's tyrosine kinase
EP2421854B1 (en) 2009-04-24 2014-07-23 F.Hoffmann-La Roche Ag Inhibitors of bruton's tyrosine kinase
EP2424368B1 (en) 2009-04-29 2014-12-31 Locus Pharmaceuticals, Inc. Pyrrolotriazine compounds
JP2012529535A (ja) 2009-06-12 2012-11-22 ブリストル−マイヤーズ スクイブ カンパニー キナーゼモジュレーターとして有用なニコチンアミド化合物
AR077468A1 (es) 2009-07-09 2011-08-31 Array Biopharma Inc Compuestos de pirazolo (1,5 -a) pirimidina sustituidos como inhibidores de trk- quinasa
US8846673B2 (en) 2009-08-11 2014-09-30 Bristol-Myers Squibb Company Azaindazoles as kinase inhibitors and use thereof
US9493578B2 (en) * 2009-09-02 2016-11-15 Xencor, Inc. Compositions and methods for simultaneous bivalent and monovalent co-engagement of antigens
PL2473049T3 (pl) 2009-09-04 2019-07-31 Biogen Ma Inc. Inhibitory kinazy tyrozynowej brutona
EP2485589A4 (en) 2009-09-04 2013-02-06 Biogen Idec Inc HETEROARYARY INHIBITORS OF BTK
US7741330B1 (en) 2009-10-12 2010-06-22 Pharmacyclics, Inc. Pyrazolo-pyrimidine inhibitors of Bruton's tyrosine kinase
JP5774595B2 (ja) * 2009-10-28 2015-09-09 ヤンセン バイオテツク,インコーポレーテツド 抗glp−1r抗体及びそれらの使用
CN102711810B (zh) * 2009-11-30 2015-04-22 詹森生物科技公司 效应子功能已消除的抗体Fc区突变体
US10053513B2 (en) * 2009-11-30 2018-08-21 Janssen Biotech, Inc. Antibody Fc mutants with ablated effector functions
WO2011103584A2 (en) * 2010-02-19 2011-08-25 Xencor, Inc. Novel ctla4-ig immunoadhesins
JP2013523098A (ja) 2010-03-29 2013-06-17 ザイムワークス,インコーポレイテッド 強化又は抑制されたエフェクター機能を有する抗体
RU2017112518A (ru) 2010-05-07 2019-01-25 Джилид Коннектикут, Инк. Пиридоновые и азапиридоновые соединения и способы применения
MY189483A (en) 2010-05-31 2022-02-16 Ono Pharmaceutical Co Purinone derivative
CA3113343A1 (en) 2010-06-03 2011-12-08 Pharmacyclics Llc Use of inhibitors of bruton's tyrosine kinase (btk) in the treatment of follicular lymphoma
WO2011159857A1 (en) 2010-06-16 2011-12-22 Bristol-Myers Squibb Company Carboline carboxamide compounds useful as kinase inhibitors
MY162132A (en) 2010-06-23 2017-05-31 Hanmi Science Co Ltd Novel fused pyrimidine derivatives for inhibition of tyrosine kinase activity
US20120053189A1 (en) 2010-06-28 2012-03-01 Pharmacyclics, Inc. Btk inhibitors for the treatment of immune mediated conditions
US20120100166A1 (en) * 2010-07-15 2012-04-26 Zyngenia, Inc. Ang-2 Binding Complexes and Uses Thereof
CN103096716B (zh) 2010-08-10 2016-03-02 西建阿维拉米斯研究公司 Btk抑制剂的苯磺酸盐
AR082590A1 (es) 2010-08-12 2012-12-19 Hoffmann La Roche Inhibidores de la tirosina-quinasa de bruton
BR112013007499A2 (pt) 2010-09-01 2016-07-12 Genentech Inc piridazinonas - métodos de criação e usos
WO2012031004A1 (en) 2010-09-01 2012-03-08 Gilead Connecticut, Inc. Pyridinones/pyrazinones, method of making, and method of use thereof
WO2012083370A1 (en) * 2010-12-22 2012-06-28 Cephalon Australia Pty Ltd Modified antibody with improved half-life
HUE041335T2 (hu) 2011-03-29 2019-05-28 Roche Glycart Ag Antitest FC-variánsok
MX341076B (es) * 2011-03-31 2016-08-04 Merck Sharp & Dohme Formulaciones estables de anticuerpos para el receptor humano pd-1 de meurte programada y tratamientos relacionados.
CN103889962B (zh) 2011-04-01 2017-05-03 犹他大学研究基金会 作为受体酪氨酸激酶btk抑制剂的取代的n‑(3‑(嘧啶‑4‑基)苯基)丙烯酰胺类似物
CA2760174A1 (en) 2011-12-01 2013-06-01 Pharmascience Inc. Protein kinase inhibitors and uses thereof
CN103608040B (zh) * 2011-04-20 2017-03-01 米迪缪尼有限公司 结合b7‑h1和pd‑1的抗体和其他分子
WO2012143522A1 (en) 2011-04-20 2012-10-26 Glaxo Group Limited Tetrahydropyrazolo [1,5 -a] pyrimidine as anti -tuberculosis compounds
CN103582637B (zh) 2011-05-17 2015-08-12 弗·哈夫曼-拉罗切有限公司 酪氨酸激酶抑制剂
US9376438B2 (en) 2011-05-17 2016-06-28 Principia Biopharma, Inc. Pyrazolopyrimidine derivatives as tyrosine kinase inhibitors
JP5974084B2 (ja) 2011-05-17 2016-08-23 プリンシピア バイオファーマ インコーポレイテッド チロシンキナーゼ阻害剤
WO2012158810A1 (en) 2011-05-17 2012-11-22 Principia Biopharma Inc. Tyrosine kinase inhibitors
ES2693647T3 (es) * 2011-06-06 2018-12-13 Novo Nordisk A/S Anticuerpos terapéuticos
DK2718270T3 (da) 2011-06-10 2022-08-01 Merck Patent Gmbh Sammensætninger og fremgangsmåder til fremstillingen af pyrimidin- og pyridinforbindelser med btk-hæmmende aktivitet
ES2677367T3 (es) 2011-06-22 2018-08-01 INSERM (Institut National de la Santé et de la Recherche Médicale) Anticuerpos anti-Axl y usos de los mismos
AU2012282229B2 (en) 2011-07-08 2015-05-07 Novartis Ag Novel pyrrolo pyrimidine derivatives
PE20190262A1 (es) * 2011-08-01 2019-02-25 Genentech Inc Metodos para tratar el cancer por el uso de antagonistas de union al eje pd-1 e inhibidores de mek
SI2785375T1 (sl) 2011-11-28 2020-11-30 Merck Patent Gmbh Protitelesa proti PD-L1 in uporabe le-teh
JP6226752B2 (ja) 2012-02-09 2017-11-08 中外製薬株式会社 抗体のFc領域改変体
EP2844289B1 (en) 2012-04-30 2019-07-17 MedImmune, LLC Molecules with reduced effector function and extended half-lives, compositions, and uses thereof
SG11201407190TA (en) 2012-05-15 2014-12-30 Bristol Myers Squibb Co Cancer immunotherapy by disrupting pd-1/pd-l1 signaling
CN115093480A (zh) 2012-05-31 2022-09-23 索伦托药业有限公司 与pd-l1结合的抗原结合蛋白
CA2877516A1 (en) * 2012-07-03 2014-01-03 Janssen Alzheimer Immunotherapy C-terminal and central epitope a-beta antibodies
CN104994873B (zh) 2012-10-04 2017-12-22 达纳-法伯癌症研究所公司 人单克隆抗‑pd‑l1抗体和使用方法
US20140377269A1 (en) * 2012-12-19 2014-12-25 Adimab, Llc Multivalent antibody analogs, and methods of their preparation and use
AR093984A1 (es) 2012-12-21 2015-07-01 Merck Sharp & Dohme Anticuerpos que se unen a ligando 1 de muerte programada (pd-l1) humano
TWI682941B (zh) 2013-02-01 2020-01-21 美商再生元醫藥公司 含嵌合恆定區之抗體
LT2840892T (lt) * 2013-02-20 2018-07-25 Regeneron Pharmaceuticals, Inc. Nežmogaus tipo gyvūnai su modifikuotomis imunoglobulino sunkiųjų grandinių sekomis
CA2904377C (en) * 2013-03-15 2021-07-13 Regeneron Pharmaceuticals, Inc. Il-33 antagonists and uses thereof
MX367918B (es) 2013-04-25 2019-09-11 Beigene Ltd Compuestos heterociclicos fusionados como inhibidores de proteina quinasa.
CA3175360C (en) * 2013-05-31 2024-05-28 Sorrento Therapeutics, Inc. Antigen binding proteins that bind pd-1
CN112457403B (zh) 2013-09-13 2022-11-29 广州百济神州生物制药有限公司 抗pd1抗体及其作为治疗剂与诊断剂的用途
EP3060251A4 (en) 2013-10-25 2017-12-06 Pharmacyclics LLC Treatment using bruton's tyrosine kinase inhibitors and immunotherapy
JOP20200094A1 (ar) 2014-01-24 2017-06-16 Dana Farber Cancer Inst Inc جزيئات جسم مضاد لـ pd-1 واستخداماتها
KR102130600B1 (ko) 2014-07-03 2020-07-08 베이진 엘티디 Pd-l1 항체와 이를 이용한 치료 및 진단
CN106687446B (zh) 2014-07-18 2020-04-28 百济神州(北京)生物科技有限公司 作为t790m/wt-egfr的选择性和不可逆的激酶抑制剂的5-氨基-4-氨甲酰基-吡唑化合物及其用途
TW201618775A (zh) 2014-08-11 2016-06-01 艾森塔製藥公司 Btk抑制劑、pi3k抑制劑、jak-2抑制劑、pd-1抑制劑及/或pd-l1抑制劑之治療組合物
US10035802B2 (en) 2014-08-14 2018-07-31 Teva Pharmaceuticals Usa, Inc. Solid state forms of ibrutinib
TW201625304A (zh) 2014-10-24 2016-07-16 美國禮來大藥廠 泌尿上皮癌之療法
WO2016087994A1 (en) 2014-12-05 2016-06-09 Acerta Pharma B.V. Btk inhibitors to treat solid tumors through modulation of the tumor microenvironment
US10485797B2 (en) 2014-12-18 2019-11-26 Principia Biopharma Inc. Treatment of pemphigus
WO2016105582A1 (en) 2014-12-24 2016-06-30 Nunn Philip A Compositions for ileo-jejunal drug delivery
US9139653B1 (en) * 2015-04-30 2015-09-22 Kymab Limited Anti-human OX40L antibodies and methods of treatment
ES2789500T5 (es) 2015-05-29 2023-09-20 Hoffmann La Roche Procedimientos terapéuticos y de diagnóstico para el cáncer
WO2017024465A1 (en) 2015-08-10 2017-02-16 Innovent Biologics (Suzhou) Co., Ltd. Pd-1 antibodies
WO2017046746A1 (en) 2015-09-15 2017-03-23 Acerta Pharma B.V. Therapeutic combinations of a btk inhibitor and a gitr binding molecule, a 4-1bb agonist, or an ox40 agonist
WO2017059224A2 (en) 2015-10-01 2017-04-06 Gilead Sciences, Inc. Combination of a btk inhibitor and a checkpoint inhibitor for treating cancers
CN109475536B (zh) * 2016-07-05 2022-05-27 百济神州有限公司 用于治疗癌症的PD-l拮抗剂和RAF抑制剂的组合
KR20230162137A (ko) 2016-08-16 2023-11-28 베이진 스위찰랜드 게엠베하 (s)-7-(1-아크릴로일피페리딘-4-일)-2-(4-페녹시페닐)-4,5,6,7-테트라-하이드로피라졸로 [1,5-a] 피리미딘-3-카르복스아미드의 제조 및 그 용도
CN118252927A (zh) 2016-08-19 2024-06-28 百济神州有限公司 使用包含btk抑制剂的组合产品治疗癌症
AU2017317227B2 (en) * 2016-08-26 2024-08-01 Beigene, Ltd. Anti-Tim-3 antibodies and use thereof
US10793632B2 (en) 2016-08-30 2020-10-06 Xencor, Inc. Bispecific immunomodulatory antibodies that bind costimulatory and checkpoint receptors
EP3519051B1 (en) 2016-09-27 2021-09-22 Beigene, Ltd. Treatment of cancers using combination comprising parp inhibitors
PE20191034A1 (es) 2016-10-14 2019-08-05 Xencor Inc Proteinas de fusion heterodimericas biespecificas que contienen proteinas de fusion fc il-15/il-15r y fragmentos de anticuerpo pd-1
CN110461847B (zh) 2017-01-25 2022-06-07 百济神州有限公司 (S)-7-(1-(丁-2-炔酰基)哌啶-4-基)-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺的结晶形式、其制备及用途
WO2018193105A1 (en) 2017-04-20 2018-10-25 Adc Therapeutics Sa Combination therapy
AU2018290532A1 (en) 2017-06-26 2019-11-21 Beigene, Ltd. Immunotherapy for hepatocellular carcinoma
WO2019034009A1 (en) 2017-08-12 2019-02-21 Beigene, Ltd. BTK INHIBITOR WITH ENHANCED DOUBLE SELECTIVITY
WO2019108795A1 (en) 2017-11-29 2019-06-06 Beigene Switzerland Gmbh Treatment of indolent or aggressive b-cell lymphomas using a combination comprising btk inhibitors
EP3749366A4 (en) 2018-02-09 2021-11-10 BeiGene, Ltd. IMMUNOTHERAPY FOR UROTHELIAL CARCINOMA
GB201803746D0 (en) 2018-03-08 2018-04-25 Ultrahuman Eight Ltd PD1 binding agents
WO2019183226A1 (en) 2018-03-21 2019-09-26 Mei Pharma, Inc. Combination therapy
US20220249491A1 (en) 2019-06-10 2022-08-11 Beigene Switzerland Gmbh Oral solid tablet comprising bruton's tyrosine kinase inhibitor and preparation method therefor
CN113950327A (zh) 2019-06-10 2022-01-18 百济神州瑞士有限责任公司 口服胶囊剂及其制备方法
EP4041304A4 (en) * 2019-09-11 2023-09-27 BeiGene, Ltd. TREATMENT OF CANCER USING A COMBINATION COMPRISING A MULTI-TYROSINE KINASE INHIBITOR AND IMMUNE BULLETIN INHIBITOR

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006121168A1 (en) * 2005-05-09 2006-11-16 Ono Pharmaceutical Co., Ltd. Human monoclonal antibodies to programmed death 1(pd-1) and methods for treating cancer using anti-pd-1 antibodies alone or in combination with other immunotherapeutics
CN101355965A (zh) * 2005-06-08 2009-01-28 达纳-法伯癌症研究院 通过抑制程序性细胞死亡1(pd-1)途经治疗持续性感染和癌症的方法及组合物
CN102264762A (zh) * 2008-09-26 2011-11-30 达纳-法伯癌症研究公司 人抗pd-1、pd-l1和pd-l2的抗体及其应用
CN102245640A (zh) * 2008-12-09 2011-11-16 霍夫曼-拉罗奇有限公司 抗-pd-l1抗体及它们用于增强t细胞功能的用途

Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11186637B2 (en) 2013-09-13 2021-11-30 Beigene Switzerland Gmbh Anti-PD1 antibodies and their use as therapeutics and diagnostics
US11673951B2 (en) 2013-09-13 2023-06-13 Beigene Switzerland Gmbh Anti-PD1 antibodies and their use as therapeutics and diagnostics
US11512132B2 (en) 2014-07-03 2022-11-29 Beigene, Ltd. Anti-PD-L1 antibodies and their use as therapeutics and diagnostics
US11534431B2 (en) 2016-07-05 2022-12-27 Beigene Switzerland Gmbh Combination of a PD-1 antagonist and a RAF inhibitor for treating cancer
CN109475536A (zh) * 2016-07-05 2019-03-15 百济神州有限公司 用于治疗癌症的PD-l拮抗剂和RAF抑制剂的组合
US11701357B2 (en) 2016-08-19 2023-07-18 Beigene Switzerland Gmbh Treatment of B cell cancers using a combination comprising Btk inhibitors
CN107840887A (zh) * 2016-09-21 2018-03-27 基石药业(苏州)有限公司 一种新的pd‑1单克隆抗体
CN107840887B (zh) * 2016-09-21 2022-03-25 基石药业(苏州)有限公司 一种新的pd-1单克隆抗体
CN110087730B (zh) * 2016-09-27 2023-03-28 百济神州(苏州)生物科技有限公司 使用包含parp抑制剂的组合产品治疗癌症
CN110087730A (zh) * 2016-09-27 2019-08-02 百济神州有限公司 使用包含parp抑制剂的组合产品治疗癌症
CN110214153B (zh) * 2016-11-18 2024-03-29 法国施维雅药厂 抗pd-1抗体及组合物
CN110214153A (zh) * 2016-11-18 2019-09-06 西福根有限公司 抗pd-1抗体及组合物
WO2018113258A1 (zh) * 2016-12-22 2018-06-28 安源医药科技(上海)有限公司 抗pd-1抗体及其用途
US11161904B2 (en) 2016-12-22 2021-11-02 Ampsource Biopharma Shanghai Inc. Anti-PD-1 antibody and use thereof
US11555038B2 (en) 2017-01-25 2023-01-17 Beigene, Ltd. Crystalline forms of (S)-7-(1-(but-2-ynoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide, preparation, and uses thereof
US10815303B2 (en) 2017-03-29 2020-10-27 Shanghai Biomed-Union Biotechnology Co., Ltd. Fusion protein for restoring the functions of failing immune cells and application thereof
WO2018176505A1 (zh) * 2017-03-29 2018-10-04 上海科医联创生物科技有限公司 一种恢复衰竭性免疫细胞功能的融合蛋白及其应用
WO2018192089A1 (zh) 2017-04-20 2018-10-25 苏州思坦维生物技术股份有限公司 拮抗抑制人pd-1抗原与其配体结合的单克隆抗体及其制备方法与应用
US11345754B2 (en) 2017-04-20 2022-05-31 Acroimmune Biopharma Co., Ltd. Monoclonal antibody antagonizing and inhibiting the binding of human PD-1 antigen to its ligand, preparation method therefor and application thereof
US11597768B2 (en) 2017-06-26 2023-03-07 Beigene, Ltd. Immunotherapy for hepatocellular carcinoma
CN110799543A (zh) * 2017-06-26 2020-02-14 百济神州有限公司 肝细胞癌的免疫治疗
WO2019001417A1 (en) * 2017-06-26 2019-01-03 Beigene, Ltd. IMMUNOTHERAPY FOR HEPATOCELLULAR CARCINOMA
WO2019101062A1 (zh) * 2017-11-24 2019-05-31 长春百克生物科技股份公司 重组疫苗及其应用
US11786529B2 (en) 2017-11-29 2023-10-17 Beigene Switzerland Gmbh Treatment of indolent or aggressive B-cell lymphomas using a combination comprising BTK inhibitors
CN112351794A (zh) * 2018-02-09 2021-02-09 百济神州有限公司 用于尿路上皮癌的免疫治疗方法
CN109452229B (zh) * 2018-11-19 2021-10-22 百奥赛图(北京)医药科技股份有限公司 狗源化pd-1基因改造动物模型的制备方法及应用
CN109452229A (zh) * 2018-11-19 2019-03-12 北京百奥赛图基因生物技术有限公司 狗源化pd-1基因改造动物模型的制备方法及应用
WO2020143749A1 (zh) 2019-01-10 2020-07-16 迈威(上海)生物科技有限公司 重组抗人pd-1抗体及其应用
WO2021047623A1 (en) * 2019-09-11 2021-03-18 Beigene, Ltd. Treatment of cancer using a combination comprising multi-tyrosine kinase inhibitor and immune checkpoint inhibitor
WO2024012364A1 (en) * 2022-07-12 2024-01-18 Beigene Switzerland Gmbh Preparation methods for a highly concentrated pd1 antibody solution by ultrafiltration/diafiltration (uf/df)
WO2024012584A1 (en) * 2022-07-15 2024-01-18 Beigene Switzerland Gmbh Methods of cancer treatment using anti-tigit antibodies
WO2024165043A1 (en) * 2023-02-08 2024-08-15 Beigene Switzerland Gmbh Preparation methods for a highly concentrated pd1 antibody solution by applying single-pass tangential flow filtration (sptff)

Also Published As

Publication number Publication date
US9217034B2 (en) 2015-12-22
IL272867A (en) 2020-04-30
EP3702373A3 (en) 2020-11-11
US10519235B2 (en) 2019-12-31
JP2016533763A (ja) 2016-11-04
EA201690567A1 (ru) 2016-08-31
HK1217501A1 (zh) 2017-01-13
EP3702373B1 (en) 2022-08-24
CA2924172C (en) 2020-06-30
NL301252I2 (nl) 2024-01-04
EP3044234A4 (en) 2017-08-09
IL244514A0 (en) 2016-04-21
US20180111995A1 (en) 2018-04-26
NO2023045I1 (no) 2023-12-07
EP4130044A1 (en) 2023-02-08
US20230303689A1 (en) 2023-09-28
HRP20221262T1 (hr) 2022-12-09
HUE049281T2 (hu) 2020-09-28
US11673951B2 (en) 2023-06-13
RS63571B1 (sr) 2022-10-31
PT3044234T (pt) 2020-05-27
EP3044234A1 (en) 2016-07-20
CN107011441B (zh) 2020-12-01
US9988450B2 (en) 2018-06-05
DK3702373T3 (da) 2022-09-12
SG11201601844TA (en) 2016-04-28
CN112457403B (zh) 2022-11-29
CN112552401A (zh) 2021-03-26
US9834606B2 (en) 2017-12-05
EP3702373A2 (en) 2020-09-02
TW201538525A (zh) 2015-10-16
HUS2300041I1 (hu) 2023-12-28
SI3702373T1 (sl) 2022-11-30
HUE060420T2 (hu) 2023-02-28
CN107090041B (zh) 2018-11-16
AU2020201069A1 (en) 2020-03-05
BR112016005408A2 (pt) 2018-01-16
AU2013400609A9 (en) 2020-03-05
MX2016003292A (es) 2016-06-24
CA3078121A1 (en) 2015-03-19
AU2013400609A8 (en) 2016-07-21
IL244514B (en) 2020-03-31
CY1125652T1 (el) 2024-02-16
CA3080200A1 (en) 2015-03-19
EP3044234B1 (en) 2020-03-04
US20150315274A1 (en) 2015-11-05
ZA201601953B (en) 2017-06-28
IL296026B1 (en) 2024-06-01
ES2927567T3 (es) 2022-11-08
LT3702373T (lt) 2022-11-10
US8735553B1 (en) 2014-05-27
IL296026B2 (en) 2024-10-01
NZ718643A (en) 2020-02-28
TWI636995B (zh) 2018-10-01
US20210230274A1 (en) 2021-07-29
AU2013400609B2 (en) 2019-11-14
BR112016005408B1 (pt) 2023-03-21
KR102100419B1 (ko) 2020-04-14
EP3044234B9 (en) 2020-08-26
IL296026A (en) 2022-10-01
US11186637B2 (en) 2021-11-30
IL284258A (en) 2021-07-29
US20150079109A1 (en) 2015-03-19
PL3702373T3 (pl) 2022-12-05
EP3702373B9 (en) 2022-11-23
CN112457403A (zh) 2021-03-09
AU2013400609A1 (en) 2016-05-05
CN112552401B (zh) 2023-08-25
AU2013400609B9 (en) 2020-03-05
PT3702373T (pt) 2022-09-27
CN107090041A (zh) 2017-08-25
CN108715615B (zh) 2020-11-27
ES2792183T3 (es) 2020-11-10
EA034666B1 (ru) 2020-03-04
WO2015035606A1 (en) 2015-03-19
CY2023025I1 (el) 2024-02-16
BR112016005408A8 (pt) 2023-01-10
FR24C1001I1 (fr) 2024-02-23
IL284258B (en) 2022-10-01
CA2924172A1 (en) 2015-03-19
JP6623353B2 (ja) 2019-12-25
AU2020201069B2 (en) 2022-03-24
RS63571B9 (sr) 2023-02-28
US20180251551A1 (en) 2018-09-06
IL284258B2 (en) 2023-02-01
IL312577A (en) 2024-07-01
CN108715615A (zh) 2018-10-30
PL3044234T3 (pl) 2020-10-19
US20200216535A1 (en) 2020-07-09
CN105531288B (zh) 2020-12-11
IL272867B (en) 2021-07-29
DK3044234T3 (da) 2020-05-18
CN107011441A (zh) 2017-08-04
US20220119524A1 (en) 2022-04-21
AU2022204171A1 (en) 2022-07-07
KR20160044063A (ko) 2016-04-22

Similar Documents

Publication Publication Date Title
US11186637B2 (en) Anti-PD1 antibodies and their use as therapeutics and diagnostics
CN106604742B (zh) 抗pd-l1抗体及其作为治疗剂及诊断剂的用途
JP2019048804A (ja) 抗pd−1抗体並びにその治療及び診断のための使用

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1217501

Country of ref document: HK

TA01 Transfer of patent application right

Effective date of registration: 20200616

Address after: 83 kangyao South Road, Zhongxin knowledge city, Huangpu District, Guangzhou City, Guangdong Province

Applicant after: Baiji Shenzhou (Guangzhou) Biotechnology Co., Ltd

Address before: Greater Cayman, Cayman Islands

Applicant before: BEIGENE, Ltd.

TA01 Transfer of patent application right
GR01 Patent grant
GR01 Patent grant
TR01 Transfer of patent right

Effective date of registration: 20201228

Address after: No. 83, kangyao South Road, Huangpu District, Guangzhou City, Guangdong Province, 510555

Patentee after: Guangzhou Baiji Shenzhou biopharmaceutical Co.,Ltd.

Address before: 510000 83 kangyao South Road, Zhongxin knowledge city, Huangpu District, Guangzhou City, Guangdong Province

Patentee before: Baiji Shenzhou (Guangzhou) Biotechnology Co., Ltd

TR01 Transfer of patent right