CN101899114A - 抗pd-1抗体及其用途 - Google Patents
抗pd-1抗体及其用途 Download PDFInfo
- Publication number
- CN101899114A CN101899114A CN2010101700224A CN201010170022A CN101899114A CN 101899114 A CN101899114 A CN 101899114A CN 2010101700224 A CN2010101700224 A CN 2010101700224A CN 201010170022 A CN201010170022 A CN 201010170022A CN 101899114 A CN101899114 A CN 101899114A
- Authority
- CN
- China
- Prior art keywords
- seq
- ser
- antibody
- gly
- val
- 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.)
- Pending
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [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
- C07K16/2818—Immunoglobulins [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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
- C07K2317/622—Single chain antibody (scFv)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
Abstract
本发明公开内容提供了能够作为PD-1(程序性死亡1)激动剂和/或拮抗剂的抗体和抗原结合片段,由此总体调节免疫应答,特别是由TcR和CD28介导的那些免疫应答。所公开的组合物及方法可用于例如治疗自身免疫病、炎性疾病、***反应、移植物排斥、癌症以及其它免疫***紊乱。
Description
本申请是国际申请日为2003年12月22日的国际申请PCT/IB2003/006304进入中国、申请号为200380109929.8的题为“抗PD-1抗体及其用途”的发明专利申请的分案申请。
技术领域
技术领域涉及受程序性死亡1(PD-1)受体调控的免疫应答的调节。
背景技术
适应性免疫应答包括称为T细胞和B细胞的两大类淋巴细胞的激活、选择和克隆增殖。在遭遇抗原之后,T细胞增殖并分化为抗原特异性效应细胞,而B细胞增殖并分化为抗体分泌性细胞。
T细胞激活是需要T细胞和呈递抗原细胞(APC)之间的数个信号传导事件的多步过程。为使T细胞激活发生,必须将两类信号递送给静息T细胞。第一类是由抗原特异性T细胞受体(TcR)介导的,并赋予免疫应答特异性。第二种共刺激类型,调控着应答的量级并且是通过T细胞上的辅助受体递送的。
初级共刺激信号是通过活化CD28受体经与其配体B7-1或B7-2的接合而递送的。相反,抑制性CTLA-4受体与相同的B7-1或B7-2配体的接合,则导致T细胞应答的削弱。从而,CTLA-4信号拮抗由CD28所介导的共刺激。在高抗原浓度下,CD28共刺激胜过CTLA-4的抑制效应。CD28和CTLA-4表达的时序调节维持了激活和抑制信号之间的平衡,并确保了有效免疫应答的形成,而同时预防了自身免疫性的发展。
最近业已鉴定了CD28和CTLA-4及其B-7样配体的分子同系物。ICOS为CD28-样共刺激受体。PD-1(程序性死亡1)为抑制性受体和CTLA-4的相似物。本发明公开内容涉及由PD-1受体所介导的免疫应答的调节。
PD-1为50-55kDa的I型跨膜受体,其最初是在经历激活诱导的细胞凋亡的T细胞系中鉴定的。PD-1表达于T细胞、B细胞和巨噬细胞之上。PD-1的配体为B7家族成员PD-L1(B7-H1)和PD-L2(B7-DC)。
PD-1是免疫球蛋白(Ig)超家族成员,在其胞外区含有单个Ig V-样结构域。PD-1胞浆结构域含有两个酪氨酸,其中最接近于膜的酪氨酸(小鼠PD-1中的VAYEEL)位于ITIM(基于免疫受体酪氨酸的抑制基序)之内。PD-1上ITIM的存在预示着该分子通过募集胞浆磷酸酶发挥作用以削弱抗原受体的信号传导。人和鼠PD-1蛋白共有大约60%的氨基酸同一性,具有保守的四个潜在的N-糖基化位点以及限定Ig-V结构域的残基。胞浆区中的ITIM以及羧基末端酪氨酸(人和小鼠中的TEYATI)周围的ITIM-样基序在人和鼠直向同源物(orthologue)之间也是保守的。
PD-1表达于激活的T细胞、B细胞和单核细胞之上。实验数据暗示了PD-1与其配体在下调中央和外周免疫应答中的相互作用。特别是,野生型T细胞中而非PD-1缺陷型T细胞中的增殖在PD-L1的存在下受到抑制。另外,PD-1缺陷型小鼠表现出自身免疫表型。C57BL/6小鼠中的PD-1缺陷导致慢性进行性狼疮样肾小球肾炎和关节炎。在Balb/c小鼠中,PD-1缺陷由于心组织特异性自身反应性抗体的存在而引起严重的心肌病。
一般而言,存在着提供用于免疫紊乱的安全且有效的治疗方法的需要,所述免疫紊乱例如自身免疫病、炎性疾病、***反应、移植物排斥、癌症、免疫缺陷症以及其它免疫***相关紊乱。这些紊乱中所涉及的免疫应答的调节可通过操纵PD-1途径而实现。
发明内容
本发明公开内容提供了可作为PD-1激动剂和/或拮抗剂起作用,由此调节受PD-1调控的免疫应答的抗体。本发明公开内容还提供了包含新的抗原结合片段的抗-PD-1抗体。本发明的抗-PD-1抗体能够:(a)特异性结合于PD-1,包括人PD-1;(b)阻断PD-1与其天然配体的相互作用;或(c)发挥两种功能。此外,所述抗体可能拥有免疫调节性质,即,它们可能有效地调节与PD-1相关的免疫应答的下调。依赖于使用方法和期望效果,抗体可用于增强或者抑制免疫应答。
所述抗体的非限制性举例说明性实施方案有PD1-17、PD1-28、PD1-33、PD1-35和PD1-F2。其它实施方案包括PD1-17、PD1-28、PD1-33、PD1-35或PD1-F2中Fv片段的VH和/或VL结构域。更多的实施方案包括这些VH和VL结构域中任一个的一个或多个互补决定区(CDR)。其它实施方案包括PD1-17、PD1-28、PD1-33、PD1-35或PD1-F2中VH结构域的H3片段。
本发明公开内容也提供了包含PD-1抗体的组合物,及其在调节免疫应答的方法中的用途,包括治疗人或动物的方法。在特别的实施方案中,通过增强或减弱由TcR/CD28介导的T细胞应答,抗-PD-1抗体可用于治疗或预防免疫紊乱。对本发明组合物的治疗敏感的紊乱包括但不限于类风湿关节炎、多发性硬化、炎性肠病、Crohn氏病、***性红斑狼疮、I型糖尿病、移植物排斥、移植物抗宿主疾病、过度增生性免疫紊乱、癌症以及传染病。
另外,抗-PD-1抗体可在诊断上用于检测生物学样品中的PD-1或其片段。所检测的PD-1的量可能与PD-1的表达水平相关,其依次又与受试者中免疫细胞(如激活的T细胞、B细胞和单核细胞)的激活状态相关。
本发明公开内容也提供了分离的核酸,其包含编码来自PD1-17、PD1-28、PD1-33、PD1-35或PD1-F2的Fv片段的VH或VL结构域的序列。同样提供的有这样的分离核酸,其包含编码来自本发明公开的VH和VL结构域中任一个的一个或多个CDR的序列。本发明公开内容也提供了包含此类核酸的载体和宿主细胞。
本发明公开内容还提供了生产新的VH和VL结构域和/或功能性抗体的方法,所述功能性抗体包括衍生自PD1-17、PD1-28、PD1-33、PD1-35或PD1-F2的VH或VL结构域的此类结构域的全部或一部分。
本发明公开内容的另外方面将在下面的说明中部分阐明,并且部分地将会由于所述说明而显而易见,或者可通过实施本发明而了解。本发明示于所附的权利要求书中并在其中特别指出,且本发明公开内容不应当解释为以任何方式限制权利要求的范围。以下详述包括本发明多种实施方案的例示性代表,它们并非用于限制所请求保护的发明。附图构成本说明书的一部分,并且,连同所述说明,仅用于举例说明多种实施方案而非限制本发明。引述参考文献并非认可这些参考文献是本发明的现有技术。
附图说明
图1A和1B显示了如通过噬菌体ELISA所测定的scFv抗体与人PD-1的反应性。
图2A-2C显示了如通过ELISA所测定的IgG-转化的抗体与人或小鼠PD-1的反应性。
图3显示了ELISA结果,证明所选的PD-1抗体抑制PD-L1与PD-1的结合。
图4显示了ELISA结果,证明免疫调节性PD-1抗体与PD-1上的不同位点结合,如通过交叉阻断ELISA分析所测定的那样。
图5显示了T细胞增殖测定的结果,证明由TcR和抗-PD-1抗体PD1-17或PD-L1.Fc进行共接合使增殖下降。由TcR和抗-PD-1J110进行共接合对增殖没有影响。
图6证明可溶形式的PD1-17促进的原代T细胞的增殖。
具体实施方式
定义
如本发明公开内容所用,术语“抗体”是指免疫球蛋白或其片段或衍生物,并且涵盖包含抗原结合位点的任何多肽,而不论其是在体外或是在体内生产的。该术语包括但不限于多克隆的、单克隆的、单特异性的、多特异性的、非特异性的、人源化的、单链的、嵌合的、合成的、重组的、杂交的、突变的以及移植的抗体。除非如“完整抗体”中那样由术语“完整”另行修饰,为了本发明公开内容的目的,术语“抗体”也包括抗体片段如Fab、F(ab′)2、Fv、scFv、Fd、dAb,以及保留抗原结合功能即特异性结合PD-1能力的其它抗体片段。一般地,此类片段将包含抗原结合结构域。
术语“抗原结合结构域”、“抗原结合片段”以及“结合片段”是指抗体分子的一部分,其包含负责抗体和抗原之间特异性结合的氨基酸。在抗原大的情况下,抗原结合结构域可能仅与抗原的一部分结合。抗原分子中负责与抗原结合结构域特异性相互作用的部分被称为“表位”或“抗原决定簇”。
抗原结合结构域一般地包含抗体轻链可变区(VL)和抗体重链可变区(VH),不过,它并非必需两者都包含。例如,所谓的Fd抗体片段仅由VH结构域组成,但仍保留了完整抗体的一些抗原结合功能。
术语“所有组成成分(repertoire)”是指遗传上多样性的核苷酸集合,其全部或部分地衍生自编码所表达的免疫球蛋白的序列。所述序列是通过例如H链的V、D和J区段以及例如L链的V和J区段的体内重排产生的。备选地,所述序列可通过体外刺激而由细胞系产生,响应于该刺激发生重排。备选地,部分或所有序列可通过核苷酸合成、随机诱变以及其它方法,如美国专利No.5,565,332中所公开的那样,通过将未重排的V区段与D和J区段组合而获得。
术语“特异性相互作用”和“特异性结合”是指两分子形成在生理条件下相对稳定的复合物。特异性结合以高亲和力以及低度到中度的结合量为特征,这有别于通常具有低亲和力与中度到高度的结合量的非特异性结合。一般地,当亲和常数KA高于106M-1或更优选高于108M-1时,认为结合是特异性的。如必要,可通过改变结合条件降低非特异性结合而基本上不影响特异性结合。熟练技术人员可利用常规技术优化合适的结合条件,如抗体的浓度、溶液的离子强度、温度、允许结合的时间、封闭剂(如血清清蛋白、乳酪蛋白)的浓度等。举例说明性的条件示于实施例1、2、4、6和7中。
短语“基本上如...中所示”意味着本发明相关的CDR、VH或VL结构域在指定区域(如CDR)上与所示序列完全相同或者仅具有不重要的区别。不重要的区别包括次要的氨基酸变化,例如在指定区域的序列中取代任意5个氨基酸中的1个或2个。
术语“PD-1活性”是指与PD-1相关的一种或多种免疫调节活性。例如,PD-1为TcR/CD28介导的免疫应答的负调节物。体内和体外评估PD-1活性的操作在实施例8、9和10中描述。
术语“调节”、“免疫调节的”及其同源词是指因与抗-PD-1抗体的相互作用所致的与T细胞应答下调相关的PD-1活性的下降或上升,其中所述下降或上升是相对于不存在相同抗体下的PD-1活性而言的。活性的下降或上升优选为至少大约10%、20%、30%、40%、50%、60%、70%、80%、90%或更多。当PD-1活性下降时,术语“调节的”及“调节”与术语“抑制的”及“抑制”是可互换的。当PD-1上升时,术语“调节的”及“调节”与术语“激活的”及“激活”是可互换的。PD-1的活性可利用如实施例8和9中所描述的T细胞增殖测定来定量确定。
术语“治疗”和“治疗方法”既指治疗性治疗又指预防/预防性措施。需要治疗的那些个体可包括早已患有特殊医学紊乱的个体,以及可能最终患有所述紊乱的那些个体(即需要预防性措施的那些个体)。
术语“有效量”是指足以降低PD-1活性的剂量或量,以实现患者症状的改善或达到期望的生物学结果,例如提高T细胞的溶细胞活性、诱导免疫耐受、降低或提高与T细胞介导的免疫应答的负调控相关的PD-1活性等。
术语“分离的”是指基本上脱离其天然环境的分子。例如,分离的蛋白基本上不含来自得到它的细胞或组织源的细胞材料或其它蛋白。术语“分离的”也指其中分离的蛋白足够纯以至于能够作为药物组合物施用的制剂,或者至少70-80%(w/w)纯,更优选至少80-90%(w/w)纯,甚至更优选90-95%纯,并且最优选至少95%、96%、97%、98%、99%或100%(w/w)纯。
抗-PD-1抗体
本发明公开内容提供了包含新型抗原结合片段的抗-PD-1抗体。
一般而言,例如,可利用传统的杂交瘤技术(Kohler和Milstein(1975)Nature,256:495-499)、重组DNA方法(美国专利No.4,816,567)或由抗体文库实施的噬菌体展示(Clackson等(1991)Nature,352:624-628;Marks等(1991)J.Mol.Biol.,222:581-597)制备抗体。关于其它抗体生产技术,也参见Antibodies:A LaboratoryManual,Harlow等编,Cold Spring Harbor Laboratory,1988。本发明不局限于任何特定的来源、起源物种、生产方法。
完整抗体,也称为免疫球蛋白,一般是四聚体糖基化蛋白,由两条大约各25kDa的轻(L)链以及两条大约各50kDa的重(H)链组成。抗体中发现了两类轻链,命名为λ链和κ链。依赖于重链恒定结构域的氨基酸序列,免疫球蛋白可分配为5大类:A、D、E、G和M,并且其中有数种可进一步划分为亚类(同种型),如IgG1、IgG2、IgG3、IgG4、IgA1和IgA2。
不同类型免疫球蛋白的亚基结构和三维构象是本领域众所周知的。关于抗体结构的综述,见Harlow等,同前。简言之,每条轻链由N-末端可变结构域(VL)和恒定结构域(CL)组成。每条重链由N-末端可变结构域(VH)、三或四个恒定结构域(CH)、以及铰链区组成。最接近于VH的CH结构域被命名为CH1。VH和VL结构域由四个具有相对保守序列的区域组成,称为构架区(FR1、FR2、FR3和FR4),它们构成三个高变序列区域的支架,所述高变序列区域称为互补决定区(CDR)。CDR含有大多数负责与抗原特异性相互作用的残基。三个CDR被称为CDR1、CDR2和CDR3。重链上的CDR组分被称为H1、H2和H 3,而轻链上的CDR组分被相应地称为L1、L2和L3。CDR3,并且特别是H3,是抗原结合结构域内分子多样性的最大来源。例如,H3可短至2个氨基酸残基或者多于26个。
Fab片段(抗原结合片段)由通过恒定区之间的二硫键共价连接的VH-CH1和VL-CL结构域组成。为克服在宿主细胞中共表达时Fv中非共价连接的VH和VL结构域解离的倾向,可构建所谓的单链(sc)Fv片段(scFv)。在scFv中,柔性且足够长的多肽或者将VH的C-末端连接于VL的N-末端,或者将VL的C-末端连接于VH的N-末端。最常见地,利用15个残基的(Gly4Ser)3肽作为接头,但其它接头也是本领域公知的。
抗体多样性是编码可变区的多个种系基因组合装配以及多种体细胞事件的结果。体细胞事件包括V基因区段与D和J基因区段重组以制备完整VH区,以及V和J基因区段重组以制备完整VL区。重组过程本身是不精确的,导致V(D)J接合处氨基酸的丢失或添加。这些多样化机制出现在抗原暴露之前的发育B细胞之中。抗原刺激后,B细胞中表达的抗体基因经历体细胞突变。
根据种系基因区段的估计数、这些区段的随机重组以及随机VH-VL配对,可生产最多1.6×107个不同的抗体(Fundamental Immunology,第3版,Paul编,Raven Press,New York,NY,1993)。若考虑有助于抗体多样性的其它过程(如体细胞突变),则认为可潜在地产生1×1010以上的不同抗体(Immunoglobulin Genes,第2版,Jonio等编,Academic Press,San Diego,CA,1995)。由于这许多过程参与抗体的多样性,独立产生的抗体在CDR区将具有完全相同或者甚至基本上相似的氨基酸序列是非常不可能的。
本发明公开内容提供了新的来源于人免疫球蛋白基因文库的CDR。携带CDR的结构通常将是抗体重链或轻链或其部分,其中CDR位于对应于天然存在的VH及VL的CDR的位置上。例如,免疫球蛋白可变结构域的结构和定位可如Kabat等,Sequences of Proteins ofImmunological Interest,No.91-3242,National Institutes ofHealth Publications,Bethesda,MD,1991中所述确定。
抗-PD-1抗体、其scFv片段、VH和VL结构域及CDR的DNA和氨基酸序列示于序列表之中,并如表1中所列的那样列举。抗体特别的非限制性举例说明性的实施方案被称为PD1-17、PD1-28、PD1-33、PD1-35和PD1-F2。举例说明性实施方案的VH和VL结构域内每一个CDR的位置列于表2和3中。
表1:VH和VL结构域以及CDR的DNA和氨基酸(AA)序列
表2:重链CDR的位置
表3:轻链CDR的位置
抗-PD-1抗体也任选地包含抗体恒定区或其部分。例如,VL结构域可在其C末端附着有抗体轻链恒定结构域,包括人Cκ或Cλ链。类似地,基于VH结构域的特异性抗原结合结构域可附着有全部或部分免疫球蛋白重链,所述重链来源于任何抗体同种型如IgG、IgA、IgE和IgM以及任何同种型亚类,包括但不限于IgG1和IgG4。在例示性的实施方案中,PD1-17、PD1-28、PD1-33和PD1-35抗体包含人IgG1λ重链和轻链的C-末端片段,而PD1-F2包含人IgG1κ重链和轻链的C-末端片段。C-末端片段的DNA和氨基酸序列是本领域众所周知的(参见如Kabat等,Sequences of Proteins of Immunological Interest,No.91-3242,National Institutes of Health Publications,Bethesda,MD,1991)。非限制性的例示性序列示于表4。
表4
C-末端区 | DNA | 氨基酸 |
IgG1重链 | SEQ ID NO:44 | SEQ ID NO:45 |
λ轻链 | SEQ ID NO:42 | SEQ ID NO:43 |
κ轻链 | SEQ ID NO:57 | SEQ ID NO:58 |
某些实施方案包括来自PD1-17、PD1-28、PD1-33、PD1-35和PD1-F2的Fv片段的VH和/或VL结构域。另外的实施方案包括任何这些VH和VL结构域的至少一个CDR。包含SEQ ID NO:2、SEQ ID NO:4、SEQ ID NO:6、SEQ ID NO:8、SEQ ID NO:10、SEQ ID NO:12、SEQ ID NO:14、SEQ ID NOs:16-40、SEQ ID NO:47或SEQ ID NO:49中所示的至少一个CDR序列的抗体涵盖在本发明的范围之内。例如,一实施方案包括选自PD1-17、PD1-28、PD1-33、PD1-35和PD1-F2中至少之一的抗体的VH结构域的H3片段。
在某些实施方案中,VH和/或VL结构域可被种系化(germlined),也就是利用常规的分子生物学技术突变这些结构域的构架区(FRs),以匹配由种系细胞产生的那些结构域。在其它实施方案中,构架序列保持与共有的种系序列趋异。
在某些实施方案中,抗体特异性结合位于人PD-1胞外结构域内的表位。推定的胞外结构域由SEQ ID NO:41(Swissport登录号Q15116)中从大约氨基酸21到大约氨基酸170的序列组成。在某些其它实施方案中,抗体特异性结合位于小鼠PD-1胞外结构域内的表位,亲和力大于107M-1,并且优选大于108M-1。小鼠PD-1的氨基酸序列示于SEQ IDNO:56(登录号NM_008798),并且总体上与其人对应物有大约60%的同一性。在另一些实施方案中,本发明的抗体结合于PD-1的PD-L-结合结构域。
预期本发明的抗体也与其它蛋白结合,例如,包括包含全部或部分PD-1胞外结构域的重组蛋白。
本领域普通技术人员将会认识到本发明的抗体可用于检测、测量和抑制稍微不同于PD-1的蛋白。预期抗体将保留结合特异性,只要靶蛋白包含与SEQ ID NO:41所示序列中任何至少100、80、60、40或20个邻接氨基酸的序列具有至少大约60%、70%、80%、90%、95%或更高同一性的序列。同一性百分比是由标准比对算法确定的,例如Altshul等(1990)J.Mol.Biol.,215:403-410中所示的Basic LocalAlignment Tool(BLAST),Needleman等(1970)J.Mol.Biol.,48:444-453的算法或者Meyers等(1988)Comput.Appl.Biosci.,4:11-17的算法。
除了序列同源性分析之外,可进行表位作图(参见如EpitopeMapping Protocols,ed.Morris,Humana Press,1996)以及二级和三级结构分析,以鉴定所公开的抗体及其与抗原的复合物所采取的特定3D结构。此类方法包括但不限于X射线晶体学(Engstom(1974)Biochem.Exp.Biol.,11:7-13)以及本文所公开抗体的实际表现的计算机建模(Fletterick等(1986)Computer Graphics and MolecularModeling,in Current Communications in Molecular Biology,ColdSpring Harbor Laboratory,Cold Spring Harbor,NY)。
衍生物
本发明公开内容也提供了用于获得特异于PD-1的抗体的方法。此类抗体中的CDR并不局限于表1中所鉴定的VH和VL的具体序列,并且可包括保留了特异性结合PD-1能力的这些序列的变体。此类变体可由熟练技术人员利用本领域众所周知的技术由表1中所列的序列得到。例如,可在FRs和/或CDRs中进行氨基酸取代、缺失或添加。尽管FRs中的变化通常被设计用于改善抗体的稳定性和免疫原性,但CDRs中的变化一般被设计用于提高抗体对其靶的亲和力。FRs变体也包括天然存在的免疫球蛋白同种异型。此类提高亲和力的变化可通过常规技术凭经验确定,所述技术包括改变CDR并测试抗体对其靶的亲和力。例如,可在所公开的任一CDR内进行保守氨基酸取代。可依据AntibodyEngineering,第2版,Oxford University Press,Borrebaeck编,1995中描述的方法进行各种改变。这些包括但不限于通过取代序列内编码功能上等同的氨基酸残基的不同密码子而改变了的核苷酸序列,由此产生“沉默”变化。例如,非极性氨基酸包括丙氨酸、亮氨酸、异亮氨酸、缬氨酸、脯氨酸、苯丙氨酸、色氨酸和甲硫氨酸。极性中性氨基酸包括甘氨酸、丝氨酸、苏氨酸、半胱氨酸、酪氨酸、天冬酰胺和谷氨酰胺。带正电荷的(碱性)氨基酸包括精氨酸、赖氨酸和组氨酸。带负电荷的(酸性)氨基酸包括天冬氨酸和谷氨酸。序列内的氨基酸取代可选自该氨基酸所属类别的其它成员(见表5)。此外,多肽中的任何天然残基也可用丙氨酸取代(参见如MacLennan等(1998)Acta Physiol.Scand.Suppl.643:55-67;Sasaki等(1998)Adv.Biophys.35:1-24)。
本发明抗体的衍生物和类似物可通过本领域众所周知的各种技术生产,包括重组及合成法(Maniatis(1990)Molecular Cloning,ALaboratory Manual,第二版,Cold Spring Harbor Laboratory,ColdSpring Harbor,NY,以及Bodansky等(1995)The Practice ofPeptide Synthesis,第二版,Spring Verlag,Berlin,德国)。
表5
原始残基 | 例示性取代 | 一般的取代 |
Ala(A) | Val,Leu,Ile | Val |
Arg(R) | Lys,Gln,Asn | Lys |
Asn(N) | Gln | Gln |
Asp(D) | Glu | Glu |
Cys(C) | Ser,Ala | Ser |
Gln(Q) | Asn | Asn |
Gly(G) | Pro,Ala | Ala |
His(H) | Asn,Gln,Lys,Arg | Arg |
Ile(I) | Leu,Val,Met,Ala,Phe,正亮氨酸 | Leu |
Leu(L) | 正亮氨酸,Ile,Val,Met,Ala,Phe | Ile |
Lys(K) | Arg,1,4-二氨基丁酸,Gln,Asn | Arg |
Met(M) | Leu,Phe,Ile | Leu |
Phe(F) | Leu,Val,Ile,Ala,Tyr | Leu |
Pro(P) | Ala | Gly |
Ser(S) | Thr,Ala,Cys | Thr |
Thr(T) | Ser | Ser |
Trp(W) | Tyr,Phe | Tyr |
Tyr(Y) | Trp,Phe,Thr,Ser | Phe |
Val(V) | Ile,Met,Leu,Phe,Ala,正亮氨酸 | Leu |
在一个实施方案中,用于制备作为本发明VH结构域的氨基酸序列变体的VH结构域的方法包括在本文所公开的VH结构域的氨基酸序列中添加、缺失、取代或***一个或多个氨基酸的步骤,任选地将如此提供的VH结构域与一个或多个VL结构域组合,并测试VH结构域或VH/VL组合或多个VH/VL组合对PD-1的特异性结合,或者,并任选地测试此抗原结合结构域调节PD-1活性的能力。VL结构域可具有完全相同于或基本上如根据表1所示的氨基酸序列。
可采用类似的方法,其中将本文公开的VL结构域的一个或多个序列变体与一个或多个VH结构域组合。
本发明公开内容的另一方面提供了制备与PD-1特异性结合的抗原结合片段的方法。所述方法包括:
(a)提供编码VH结构域的起始核酸所有组成成分,其中VH结构域包括将要被取代的CDR3或者缺失CDR3编码区;
(b)将所述所有组成成分与编码基本上如本文所示的VHCDR3(即H3)氨基酸序列的供体核酸组合,从而将供体核酸***到所述所有组成成分的CDR3区,以提供编码VH结构域的核酸的产物所有组成成分;
(c)表达产物所有组成成分的核酸;
(d)选择特异于PD-1的结合片段;和
(e)回收该特异性结合片段或编码它的核酸。
再次地,可采用类似的方法,其中将本发明的VLCDR3(即L3)与编码VL结构域的核酸所有组成成分组合,其中VL结构域包括将要被取代的CDR3或者缺失CDR3编码区。供体核酸可选自编码基本上如SEQ IDNO:17-40或SEQ ID NO:50-55中所示氨基酸序列的核酸。
可利用重组DNA技术将编码本发明CDR(如CDR3)的序列引入到缺失各自CDR(如CDR3)的可变结构域所有组成成分中,例如使用由Marks等(Bio/Technology(1992)10:779-783)描述的方法学。特别地,指向或邻近于可变结构域区域5′端的共有引物可与人VH基因的第三构架区的共有引物联合使用,以提供缺失CDR3的VH可变结构域所有组成成分。可将所述所有组成成分与特定抗体的CDR3组合。利用类似的技术,衍生自CDR3的序列可与缺失CDR3的VH或VL结构域所有组成成分改组,并将改组的完整VH或VL结构域与同源的VL或VH结构域组合,以制备本发明的PD-1特异性抗体。然后所述所有组成成分可在合适的宿主***如噬菌体展示***中展示,例如在WO 92/01047中所描述的,从而可选择合适的抗原结合片段。
类似的改组或组合技术也由Stemmer(Nature(1994)370:389-391)公开,他描述了与β-内酰胺酶基因有关的技术,但评论说该途径可用于产生抗体。
在另一实施方案中,利用一个或多个所选VH和/或VL基因的随机诱变,人们可产生携带衍生自本文所公开的序列的一个或多个序列的新型VH或VL区。一种这样的技术即易错PCR由Gram等(Proc.Nat.Acad.Sci.U.S.A.(1992)89:3576-3580)描述。
可使用的另一种方法是直接诱变VH或VL基因的CDRs。此类技术由Barbas等(Proc.Nat.Acad.Sci.U.S.A.(1994)91:3809-3813)以及Schier等(J.Mol.Biol.(1996)263:551-567)公开。
类似地,可将一个或多个、或者所有三个CDRs移植到VH或VL结构域所有组成成分中,然后筛选特异于PD-1的抗原结合片段。
免疫球蛋白可变结构域的一部分将包含至少一个基本上如本文所示的CDRs,和任选地来自如本文所示的scFv片段的间插构架区。所述部分可包括FR1和FR4中任一或两者的至少大约50%,50%为FR1C-末端的50%和FR4N-末端的50%。可变结构域基本部分N-末端或C-末端另外的残基可以是通常不与天然存在的可变结构域区结合的那些残基。例如,通过重组DNA技术构建抗体可能导致引入由接头编码的N-或C-末端残基,引入所述接头是为了易化克隆或其它操作步骤的。其它操作步骤包括引入接头以将可变结构域连接于另一蛋白序列,包括免疫球蛋白重链恒定区、其它可变结构域(例如,在微型双功能(diabody)抗体的生产中)、或者如下文更为详细讨论的蛋白标记。
尽管实施例中举例说明的实施方案包括VH和VL结构域的“匹配”配对,熟练技术人员将会认识到备选的实施方案可包括仅含来自VL或VH结构域的单个CDR的抗原结合片段。可利用两者中的任一单链特异性结合结构域筛选互补结构域,其能够形成能够与例如PD-1结合的两结构域特异性抗原结合片段。筛选可利用WO 92/01047中公开的所谓的等级双组合方法通过噬菌体展示筛选法完成,其中利用含H或L链克隆的个体菌落感染编码另一链(L或H)的完整克隆文库,并按照所述的噬菌体展示技术对所得的两链特异性结合结构域进行选择。
可将本文描述的抗-PD1抗体连接于另一个功能分子,如另一个肽或蛋白(清蛋白、另一个抗体等)、毒素、放射性同位素、细胞毒性剂或细胞抑制剂。例如,可通过化学交联或通过重组方法连接抗体。也可将抗体连接于多种非蛋白聚合物的一种,如聚乙二醇、聚丙二醇或聚氧化烯,其中以美国专利Nos.4,640,835;4,496,689;4,301,144;4,670,417;4,791,192或4,179,337中所示的方式进行。抗体可通过与聚合物共价缀合而化学修饰,例如,以提高其循环半衰期。例示性的聚合物以及附着它们的方法也显示在美国专利Nos.4,766,106;4,179,337;4,495,285和4,609,546中。
也可改变所公开的抗体以使之具有不同于天然模式的糖基化模式。例如,可缺失一个或多个碳水化合物部分和/或向原始抗体中添加一个或多个糖基化位点。向本文公开的抗体中添加糖基化位点可通过改变氨基酸序列,以使之含有本领域公知的糖基化位点共有序列来完成。增加抗体上的碳水化合物部分数目的另一种手段是通过将糖苷化学或酶促偶联于所述抗体的氨基酸残基。此类方法描述在WO 87/05330和Aplin等(1981)CRC Crit.Rev.Biochem.,22:259-306中。从抗体中除去任何碳水化合物部分可化学或酶促完成,例如,如由Hakimuddin等(1987)Arch.Biochem.Biophys.,259:52;和Edge等(1981)Anal.Biochem.,118:131以及由Thotakura等(1987)Meth.Enzymol.,138:350所述的那样。抗体也可用可检测或功能性标记予以标记。可检测标记包括放射性标记如131I或99Tc,它们也可利用常规化学附着于抗体。可检测标记也包括酶标记如辣根过氧化物酶或碱性磷酸酶。可检测标记还包括化学部分如生物素,它可介由与特异性同源的可检测部分如标记的抗生物素蛋白予以检测。
其中CDR序列仅不显著地有别于SEQ ID NO:2、SEQ ID NO:4、SEQ ID NO:6、SEQ ID NO:8、SEQ ID NO:10、SEQ ID NO:12、SEQID NO:14、SEQ ID NOs:16-40、SEQ ID NO:47或SEQ ID NO:49中所示那些的抗体涵盖在本发明的范围之内。一般地,氨基酸由具有相似电荷、疏水性或立体化学特征的相关氨基酸取代。此类取代将落入技术人员的普通技术之内。与CDRs中不同,在FRs中可进行更多的基本变化,而不会不利地影响抗体的结合性质。FRs的变化包括但不限于:人源化非人来源的,或工程改造某些对于抗原接触或对于稳定结合位点重要的构架残基,例如,改变恒定区的类或亚类,改变可能变更效应子功能如Fc受体结合的特定氨基酸残基,例如美国专利Nos.5,624,821和5,648,260以及Lund等(1991)J.Immun.147:2657-2662和Morgan等(1995)Immunology 86:319-324中所描述的那样,或者改变可产生恒定区的物种。
本领域技术人员将会认识到上文所述的修饰并非是详尽无遗的,并且在本发明公开内容的教导下,许多其它修饰对熟练技术人员而言将会是显而易见的。
核酸、克隆和表达***
本发明公开内容还提供了编码所公开的抗体的分离的核酸。所述核酸可包括DNA或RNA,并且可以是全部或部分合成或重组的。提及的如本文所示的核苷酸序列涵盖了具有指定序列的DNA分子,并且涵盖了具有指定序列且其中U取代了T的RNA分子,除非上下文另有要求。
本文提供的核酸包括本文公开的CDR、VH结构域和/或VL结构域的编码序列。
本发明公开内容也提供了质粒、载体、噬菌粒、转录盒或表达盒形式的构建体,其包含编码本文公开的CDR、VH结构域和/或VL结构域的至少一种核酸。
本发明公开内容还提供了包含上述一种或多种构建体的宿主细胞。
同样提供的有编码任何CDR(H1、H2、H3、L1、L2或L3)、VH或VL结构域的核酸,以及制备所述编码产物的方法。所述方法包括由所述编码核酸表达所述编码产物。表达可通过在合适的条件下培养含所述核酸的重组宿主细胞实现。通过表达生产后,可利用任何合适的技术分离和/或纯化VH或VL结构域或特异性结合成员,然后适当地使用。
抗原结合片段、VH和/或VL结构域、以及编码核酸分子和载体可以以基本上纯或均质的形式,由其天然环境中分离和/或纯化,或者在核酸的情况下,除了编码具有所需功能的多肽的序列之外,不含或基本上不含其他来源的核酸或基因。
用于在多种不同宿主细胞中克隆和表达多肽的***是本领域众所周知的。有关适合于生产抗体的细胞,见Gene Expression Systems,Academic Press,Fernandez等编,1999。简言之,合适的宿主细胞包括细菌、植物细胞、哺乳动物细胞以及酵母和杆状病毒***。本领域可获得的用于表达异源多肽的哺乳动物细胞系包括中国仓鼠卵巢细胞、HeLa细胞、幼仓鼠肾细胞、NS0小鼠骨髓瘤细胞等等。常见的细菌宿主为大肠杆菌(E.coli)。可利用任何与本发明相容的蛋白表达***生产所公开的抗体。合适的表达***包括Gene ExpressionSystems,Academic Press,Fernandez等编,1999中所描述的转基因动物。
可选择或构建合适的载体,从而它们含有合适的调控序列,包括启动子序列、终止子序列、多腺苷酰化序列、增强子序列、标记基因以及其它适当的序列。载体可以是质粒或病毒,如适当的噬菌体或噬菌粒。有关更多细节,参见例如Sambrook等,Molecular Cloning:ALaboratory Manual,第二版,Cold Spring Harbor Laboratory Press,1989。许多用于核酸操作的已知技术和方案在Current Protocols inMolecular Biology,第二版,Ausubel等编,John Wiley & Sons,1992中有详细描述,例如,制备核酸构建体、诱变、测序、将DNA引入到细胞中和基因表达,以及蛋白分析。
本发明公开内容的另一方面提供了包含如此处所公开的核酸的宿主细胞。又在另一方面提供了包括将此核酸引入到宿主细胞中的方法。所述引入可采用任何可获得的技术。对于真核细胞,合适的技术可包括磷酸钙转染、DEAE-葡聚糖、电穿孔、脂质体介导的转染以及使用逆转录病毒或其它病毒转导,例如痘苗病毒,或者对昆虫细胞而言使用杆状病毒。对于细菌细胞,合适的技术可包括氯化钙转化、电穿孔以及使用噬菌体转染。在将核酸引入到细胞中之后,可通过例如在基因表达的条件下培养宿主细胞而使得或允许由所述核酸表达。
使用方法
所公开的抗-PD-1抗体能够调节与PD-1相关的免疫应答的下调。在特别的实施方案中,所述免疫应答是由TcR/CD28介导的。所公开的抗体可作为PD-1的激动剂或拮抗剂起作用,这依赖于其使用方法。抗体可用于预防、诊断或治疗哺乳动物尤其是人的医学紊乱。本发明的抗体也可用于分离PD-1或表达PD-1的细胞。此外,所述抗体可用于治疗处于紊乱危险之中或易感、或具有与异常PD-1表达或功能相关的紊乱的受试者。
本发明的抗体可用在用以诱导对特定抗原(如治疗蛋白)的耐受的方法之中。在一个实施方案中,耐受是针对特定抗原通过共施用抗原和本发明的抗-PD-1抗体诱导的。例如,频繁接受因子VIII的患者产生此蛋白的抗体;本发明的抗-PD-1抗体联合重组因子VIII的共施用预期将导致针对此凝血因子的免疫应答的下调。
本发明的抗体能够在可能期望免疫应答水平下降的情形下使用,例如,在某些类型的变应性或***反应(如通过抑制IgE生产),自身免疫病(如类风湿关节炎、I型糖尿病、多发性硬化、炎性肠病、Crohn氏病以及***性红斑狼疮),组织、皮肤和器官移植物排斥,以及移植物抗宿主疾病(GVHD)中。
当期望免疫应答减小时,本发明的抗-PD-1抗体可用作为PD-1激动剂,以增强与PD-1相关的免疫应答的弱化。在这些实施方案中,需要正信号(即由抗原受体如TcR或BcR介导的)和负信号(即PD-1)之间的共呈递和物理邻近性。优选的距离小于或与天然存在的呈递抗原细胞的大小相当,也就是小于大约100μm;更优选地,小于大约50μm;并且最优选地,小于大约20μm。
在有些实施方案中,正(激活)和负(抑制)信号是由固定于固体支持物基质或载体上的配体或抗体提供的。在多种不同的实施方案中,固体支持物基质可由聚合物组成,如活化琼脂糖、葡聚糖、纤维素、聚偏1,1-二氟乙烯(PVDF)。备选地,固体支持物基质可以是以硅石或塑料聚合物为基础,如尼龙、涤纶、聚苯乙烯、聚丙烯酸酯、聚乙烯、聚四氟乙烯等。
可将所述基质植入到患者脾中。备选地,所述基质可用于离体温育由患者获得的T细胞,然后分离T细胞并植回到患者之中。所述基质也可由可生物降解的材料制成,例如聚乙醇酸、聚羟基链烷酸酯、胶原或明胶,从而它们能够被注射到患者的腹膜腔中,并在注射后经过一段时间溶解。可对所述载体塑形以模拟细胞(如珠子或小球体)。
在有些实施方案中,正信号是由T细胞活化的结合TcR的抗-CD3抗体递送的。活化抗-CD3抗体是本领域公知的(参见例如美国专利Nos.6,405,696和5,316,763)。活化TcR信号和负PD-1信号之间的比率是利用本领域公知的常规操作、或如实施例8、9和10中所述通过实验确定的。
在某些情形下,可能期望引发或增强患者的免疫应答,以治疗免疫紊乱或癌症。由所公开的方法治疗或预防的紊乱包括但不限于微生物(如细菌)、病毒(如全身性病毒感染如流感、病毒性皮肤病如疱疹或带状疱疹)或寄生物感染;以及癌症(如黑素瘤和***癌)。
用抗-PD-1抗体刺激T细胞激活增强了T-T细胞应答。在此类情况下,所述抗体作为PD-1拮抗剂起作用。从而,在有些实施方案中,可利用所述抗体抑制或降低与PD-1相关的下调活性,也就是与TcR/CD28介导的免疫应答的下调相关的活性。在这些实施方案中,所述抗体并不偶联于正信号如TcR介导的刺激,例如所述抗体为其可溶、未结合支持物的形式。如实施例中所证明的那样,阻断PD-1/PD-L与拮抗性抗-PD-1抗体的相互作用导致增强的T细胞增殖应答,这与PD-1途径在T-T相互作用中的下调作用一致。在各种实施方案中,所述抗体抑制PD-L与PD-1的结合,IC50小于10nM,并且更优选小于5nM,并且最优选小于1nM。PD-L结合的抑制可如实施例6中所述或使用本领域公知的技术测量。
本发明的抗体或抗体组合物以治疗有效量施用。一般地,治疗有效量可能随受试者的年龄、状况和性别、以及受试者医学状况的严重度而不同。抗体的治疗有效量在从大约0.001到大约30mg/kg体重的范围内变动,优选从大约0.01到大约25mg/kg体重,从大约0.1到大约20mg/kg体重,或者从大约1到大约10mg/kg。所述剂量可根据需要调整,以满足所观察到的治疗效果。合适的剂量是由治疗医师根据临床指征选择的。
所述抗体可作为大丸剂施用,以便在施药后最大时间长度内使得抗体的循环水平最大化。在大丸剂施用后也可使用连续输注。
也可从患者中分离免疫细胞(如激活的T细胞、B细胞或单核细胞),并与本发明的抗体离体(ex vivo)温育。在有些实施方案中,免疫应答可通过从受试者中取出免疫细胞,将所述免疫细胞与本发明的抗-PD-1抗体体外接触,同时伴有免疫细胞的活化(如通过抗TcR和/或BcR抗原受体的抗体)进行抑制。在此类实施方案中,所述抗-PD-1抗体应当以多价的形式使用,从而免疫细胞表面上的PD-1分子经与此类抗体结合而成为“交联的”。例如,可将所述抗-PD-1抗体结合到固体支持物如珠子上,或者介由第二抗体交联。然后可利用本领域公知的方法分离免疫细胞并再植入到患者中。
在另一个方面,本发明的抗体可用作为靶向剂用于将另一种治疗剂或细胞毒性剂(如毒素)递送给表达PD-1的细胞。所述方法包括施用偶联于治疗剂或细胞毒性剂的抗-PD-1抗体,或在允许所述抗体与PD-1结合的条件下施用。
本发明的抗体也可用于检测生物学样品中PD-1的存在。所检测的PD-1的量可能与PD-1的表达水平相关,其依次又与受试者中免疫细胞(如激活的T细胞、B细胞和单核细胞)的激活状态相关。
采用抗体的检测法是本领域众所周知的,并且包括,例如,ELISA、放射免疫测定、免疫印迹、蛋白印迹、免疫荧光、免疫沉淀。所述抗体可在诊断试剂盒中提供,所述试剂盒合并了一种或多种这些技术以检测PD-1。此种试剂盒可含有其它组分、包装、说明书或其它材料,以辅助检测所述蛋白。
当抗体旨在用于诊断目的时,可能期望修饰它们,例如用配体基团(例如生物素)或可检测的标记基团(例如荧光基团、放射性同位素或酶)修饰。如果需要,可利用常规技术标记本发明的抗体。例如,合适的可检测标记包括例如荧光团、发色团、放射性原子、电子密试剂、酶以及具有特异性结合配偶体的配体。酶一般通过其活性予以检测。例如,辣根过氧化物酶可通过其将四甲联苯胺(TMB)转化为可由分光光度计定量的蓝色色素的能力予以检测。关于检测,合适的结合配偶体包括但不限于:生物素与抗生物素蛋白或链霉抗生物素蛋白,IgG与蛋白A,以及本领域公知的众多受体-配体对。其它改变和可能性对本领域普通技术人员将会是非常显而易见的,并认为是本发明范围内的等同物。
本发明的抗体可在筛选方法中用于鉴定能有效作为治疗剂的PD-1途径的抑制剂。在此筛选测定中,通过组合PD-1和本发明的抗体形成第一结合混合物;并测量所述第一结合混合物中的结合量(M0)。也通过组合PD-1、抗体、以及待筛选化合物或试剂形成第二结合混合物,并测量所述第二结合混合物中的结合量(M1)。待测化合物可以是另一种抗-PD-1抗体,如实施例中所举例说明的那样。然后比较所述第一及第二结合混合物中的结合量,例如,通过计算M1/M0比率进行比较。如果观察到第二结合混合物中的结合与第一结合混合物相比下降,则认为所述化合物或试剂能够调节与PD-1相关的免疫应答的下调。结合混合物的配制和优化落在本领域技术水平之内,此类结合混合物也可以含有必要的缓冲液和盐以增强或优化结合,并且另外的对照测定可包含在本发明的筛选测定中。这样可鉴定发现使PD-1抗体结合降低至少约10%(即,M1/M0<0.9)、优选大于约30%的化合物,然后,如果需要,如下文所述在其它测定或动物模型中对其进行改善紊乱能力的第二次筛选。PD-1与抗体之间的结合强度可利用以下技术测量,例如,酶联免疫吸附测定(ELISA),放射免疫测定(RIA),基于表面等离子体共振的技术(如Biacore),这些全部都是本领域众所周知的技术。
然后可如实施例中所述或在动物模型(一般地参见ImmunologicDefects in Laboratory Animals,Gershwin等编,Plenum Press,1981)中体外测试所述化合物,例如,如以下的动物模型:SWR×NZB(SNF1)转基因小鼠模型(Uner等(1998)J.Autoimmune.11(3):233-240),KRN转基因小鼠(K/BxN)模型(Ji等(1999)Immunol.Rev.169:139);SLE模型NZB×NZW(B/W)小鼠(Riemekasten等(2001)ArthritisRheum.,44(10):2435-2445);多发性硬化模型小鼠实验性自身免疫性脑炎(EAE)(Tuohy等(1988)J.Immunol.141:1126-1130,Sobel等(1984)J.Immunol.132:2393-2401,以及Traugott,Cell Immunol.(1989)119:114-129);糖尿病NOD小鼠模型(Baxter等.(1991)Autoimmunity,9(1):61-67)等等)。
例如根据动物试验所确定的初步剂量以及用于人类施用的剂量比例换算是根据本领域公认的操作进行的。毒性和疗效可通过细胞培养物或实验动物中的标准药学操作确定。由细胞培养物测定或动物研究获得的数据可用于配制用于人的剂量范围。在一个实验动物模型中所达到的治疗有效剂量可利用本领域公知的换算因子予以换算以用于另一个动物,包括人(参见如Freireich等(1966)Cancer Chemother.Reports,50(4):219-244)。
药物组合物和施用方法
本发明公开内容提供了包含抗-PD-1抗体的组合物。此类组合物可能适合于制药用途以及向患者施用。所述组合物一般包括一种或多种本发明的抗体以及药学上可接受的赋形剂。短语“药学上可接受的赋形剂”包括与药物施用相容的任何及所有溶剂、分散介质、涂层、抗细菌剂和抗真菌剂、等渗剂以及吸收延迟剂等。此类介质和试剂对药学活性物质的用途是本领域众所周知的。所述组合物也可以含有其它提供补充的、附加的或增强的治疗功能的活性化合物。所述药物组合物也可连同施用说明书一起包含在容器、包装或分配器中。
本发明的药物组合物被配制为与其期望的施用途径相容。实现施用的方法是本领域普通技术人员公知的。例如,施用可以是静脉内、腹膜内、肌内、腔内、皮下或经皮。也有可能获得可局部或口服施用、或能够跨粘膜输送的组合物。
用于真皮内或皮下应用的溶液或悬浮液一般包括一种或多种如下成分:无菌稀释剂如注射用水、盐溶液、固定油、聚乙二醇、甘油、丙二醇或其它合成溶剂;抗细菌剂如苄醇或羟苯甲酸甲酯;抗氧化剂如抗坏血酸或亚硫酸氢钠;螯合剂如乙二胺四乙酸;缓冲液如乙酸盐、柠檬酸盐或磷酸盐;以及用于调整张力的试剂如氯化钠或葡萄糖。pH可用酸或碱调节,例如盐酸或氢氧化钠。此类制剂可封装在由玻璃或塑料制成的安瓿、一次性注射器或多剂量小瓶中。
适合于注射的药物组合物包括无菌水溶液或分散体,以及用于临时制备无菌可注射溶液或分散体的无菌粉末。对于静脉内施用,合适的载体包括生理盐水、制菌水、Cremophor EL(BASF,Parsippany,NJ)或磷酸缓冲盐溶液(PBS)。在所有情况下,所述组合物必需是无菌的,并且应当是存在容易的可注射性程度的流体。它在制造和贮藏条件下应当是稳定的,并且必需抗微生物如细菌和真菌的污染作用加以保存。微生物作用的预防可通过多种抗细菌剂和抗真菌剂实现,例如,对羟基苯甲酸酯、氯丁醇、苯酚、抗坏血酸、硫柳汞等。在许多情况下,组合物中将优选包括等渗剂,例如糖,多元醇如甘露糖醇、山梨糖醇以及氯化钠。载体可以是溶剂或分散介质,例如,含有水、乙醇、多羟基化合物(例如,甘油、丙二醇和液体聚乙二醇等)以及它们合适的混合物。例如,合适流动性可通过使用涂层如卵磷脂,在分散体的情况下通过维持所需的粒径和/或通过使用表面活性剂得以维持。可注射组合物的延迟吸收可通过将延迟吸收的试剂例如单硬脂酸铝和明胶包含到组合物中实现。
口服组合物一般包含惰性稀释剂或可食载体。可将它们封装到明胶胶囊中或压缩成片剂。为口服施用,可将抗体与赋形剂组合,并以片剂、锭剂或胶囊的形式使用。药学上相容的结合剂和/或佐剂材料可作为组合物的一部分包括在内。所述片剂、药丸、胶囊、锭剂等可含有如下任一成分或具有相似性质的化合物:粘合剂如微晶纤维素、黄蓍树胶或明胶;赋形剂如淀粉或乳糖;崩解剂如褐藻酸、Primogel或玉米淀粉;润滑剂如硬脂酸镁或Sterotes;助流剂如胶体二氧化硅;增甜剂如蔗糖或糖精;或调味剂如胡椒薄荷、水杨酸甲酯或橙味调味剂(orange Havoring)。
全身性施用也可以是通过跨粘膜或经皮手段。为了跨粘膜或经皮施用,制剂中使用与待穿过的屏障相称的渗透剂。此类渗透剂通常是本领域公知的,并且包括,例如去污剂、胆汁盐和梭链孢酸衍生物。例如,跨粘膜施用可通过使用糖锭、鼻腔喷雾、吸入剂或栓剂完成。例如,在抗体包含Fc部分的情况下,组合物可能(如美国专利No.6,030,613中所述介由FcRn受体介导的途径)能够跨肠、口或肺粘膜输送。对于经皮施用,可将活性化合物配制成如本领域普遍公知的软膏、油膏、凝胶或乳膏。为了通过吸入施用,可以气雾剂喷雾的形式由压缩容器或分配器递送抗体,所述容器或分配器含有合适的推进剂例如气体如二氧化碳或雾化器。
在某些实施方案中,本文公开的抗体与将会保护该化合物防止由体内迅速消除的载体一起制备,例如缓释制剂,包括植入物和微囊化递送***。可使用可生物降解的生物相容性聚合物如乙烯乙酸乙烯酯、聚酐、聚乙醇酸、胶原、聚原酸酯以及聚乳酸。用于制备此类制剂的方法对本领域技术人员将会是显而易见的。含有本文公开的抗体的脂质体悬浮液也可用作为药学上可接受的载体。这些可根据本领域技术人员公知的方法制备,例如,如美国专利No.4,522,811中所述的那样。
以剂量单位形式配制口服或肠胃外组合物可能是有利的,以易化施用和剂量的一致性。如本文所用的术语“剂量单位形式”是指适合作为待治疗受试者的单位剂量的物理上不连续的单位;每个单位含有预定量的经计算与所需药物载体相结合产生期望疗效的活性化合物。
本发明组合物的毒性和疗效可通过细胞培养物或实验动物中的标准药学方法确定,例如用以确定LD50(对50%群体致死的剂量)和ED50(在50%群体中治疗有效的剂量)的方法。毒性和疗效之间的剂量比率是治疗指数,且其可表达为LD50/ED50比率。优选呈现出大治疗指数的组合物。
对于本发明中所用的任何组合物,治疗有效剂量最初可由细胞培养物测定来估计。合适的生物测定的实例包括DNA复制测定、细胞因子释放测定、基于转录的测定、PD-1/PD-L1结合测定、肌酸激酶测定、基于前脂肪细胞(pre-adipocyte)分化的测定、基于脂肪细胞中葡萄糖吸收的测定、免疫学测定、其它例如实施例中所描述的测定。由细胞培养物测定和动物研究获得的数据可用于配制用于人的剂量范围。可在动物模型中配制剂量,以获得包括IC50(即实现半数最大症状抑制的抗体浓度)的循环血浆浓度范围。例如,可通过高效液相层析测量血浆中的循环水平。可通过合适的生物测定监控任何特定剂量的效力。剂量优选处于具有少许毒性或无毒性的循环浓度的范围内。剂量可依赖于所采用的剂型和所使用的施用途径而变。
以下实施例并非以任何方式限制本发明的范围。本领域普通技术人员将会认识到能够进行众多修改和变动而不会改变本发明的精神或范围。此类修改和变动涵盖在本发明的范围之内。特此将本申请通篇所引述的所有参考文献、专利和公开的专利申请的全部内容并入作为参考。
实施例
实施例1:结合PD-1的ScFv的选择
利用扩大形式的由Vaughan等(Nature Biotech.(1996)14:309-314)描述的1.38×1010文库的scFv噬菌粒文库选择特异于人PD-1的抗体。将可溶性PD-1融合蛋白(20μg/ml的磷酸缓冲盐水(PBS)溶液)或对照融合蛋白(50μg/ml的PBS溶液)涂覆到微量滴定板孔中,4℃过夜。孔在PBS中洗涤并在MPBS(3%奶粉的PBS溶液)中于37℃封闭1小时。将纯化的噬菌体(1012转导单位(tu))在终体积100μl的3%MPBS中封闭1小时。添加封闭的噬菌体到封闭的对照融合蛋白孔,并温育1小时。然后将封闭且去选择(deselect)的噬菌体转移到涂覆有PD-1融合蛋白的封闭的孔中,并温育另外一个小时。孔用PBST(含0.1%v/v Tween 20的PBS)洗涤5次,然后用PBS洗涤5次。洗脱结合的噬菌体颗粒,并用于感染10ml指数生长的大肠杆菌TG1。使感染的细胞在2TY液体培养基中于37℃生长1小时,然后涂布到2TYAG板上,并于30℃温育过夜。将菌落从板上刮到10ml 2TY液体培养基中,并加入15%甘油于-70℃贮存。
用辅助噬菌体超感染来自第一轮淘选的甘油原种培养物,并进行拯救(rescue)以产生表达scFv抗体的噬菌体颗粒,用于第二轮淘选。以这种方式总共进行两轮淘选用于PD1-17的分离,除了在第二轮淘选中使用20μg/ml对照蛋白进行去选择。在三轮选择之后选到了克隆PD1-28、PD1-33和PD1-35。第二和第三轮的去选择是利用10μg/ml对照融合蛋白进行的。
鼠PD-1抗体是利用终浓度为100nM的生物素化鼠PD-1融合蛋白通过可溶性选择进行选择的。使用了如上文所述的scFv噬菌粒文库。对1ml 3%MPBS中的纯化的scFv噬菌体(1012tu)封闭30分钟,然后加入生物素化的抗原,并于室温下温育1小时。将噬菌体/抗原添加到250μl Dynal M280链霉抗生物素蛋白磁珠中,并室温下再温育15分钟,所述磁珠业已在1ml 3%MPBS中于37℃封闭1小时。珠子利用磁架捕获,并在1ml 3%MPBS/0.1%(v/v)Tween 20中洗涤4次,紧接着在PBS中洗涤3次。在末次PBS洗涤后,将珠子重悬于100μl PBS中,并用于感染5ml指数生长的大肠杆菌TG-1细胞。使感染的细胞于37℃温育1小时(30分钟静止,30分钟于250rpm振荡),然后涂布到2TYAG板上,并于30℃温育过夜。将长出的菌落从板上刮下,并如上文所述拯救噬菌体。如上所述进行第二轮可溶性选择。
实施例2:通过噬菌体ELISA确定抗体对PD-1的特异性
为确定抗体对PD-1的特异性,针对PD-1融合蛋白和对照蛋白进行了噬菌体ELISA。将来自选择产物的个体大肠杆菌菌落挑取到每孔含100μl 2TYAG培养基的96孔板中。向指数生长的培养物中添加感染复数(moi)为10的M13K07辅助噬菌体,并将板于37℃温育另外1小时。将板在台式离心机中以2000rpm离心10分钟。除去上清,并将细胞沉淀重悬于100μl 2TYAK中,并于30℃振荡温育过夜。第二天,将板以2000rpm离心10分钟,并将来自各孔的含噬菌体的上清液转移到新的96孔板中。在ELISA前,将噬菌体样品在终浓度为3%的MPBS中封闭。
将溶于PBS的0.5-2.5μg/ml人或小鼠PD-1融合蛋白和对照融合以及非融合蛋白于4℃过夜涂覆到96孔微量滴定板上。涂覆后,从孔中除去溶液,并使板在3%MPBS中封闭1小时。用PBS冲洗板,然后向各孔添加50μl预封闭的噬菌体。将板温育1小时,然后用PBST洗涤3次,紧接着用PBS洗涤3次。向各孔中加入50μl抗-M13-HRP缀合物(Pharmacia,Peapack,NJ)的1∶5000稀释液,并将板温育40-60分钟。各板用PBST洗涤3次,然后用PBS洗涤3次。向各孔添加50μlTMB底物,并温育样品直至显色。反应通过添加25μl 0.5M H2SO4终止。所产生的信号通过使用微量滴定板读数器在450nm处读取吸收度测量。表现出对PD-1融合蛋白而非对照融合蛋白的特异性结合的克隆从而得以鉴定和确认。
PD1-17scFv的特异性数据示于图1A。PD1-28、PD1-33和PD1-35scFv与人PD-1的反应性示于图1B(IgG1对照并不结合PD-1)。
实施例3:抗体克隆的鉴定
将结合PD-1的scFv的大肠杆菌克隆划线到2TYAG板上,并于30℃温育过夜。通过使用pCANTAB6载体序列寡核苷酸(oligos)扩增来自scFv克隆的VH和VL区对来自这些板的菌落进行测序。如实施例4中所述,测定了中和PD-L1与PD-1结合的独特的结合PD-1的克隆。scFv和IgG形式之间的序列差异归因于在由scFv转化为IgG期间由PCR引物所引入的变化。
实施例4:生化结合抑制测定和筛选
通过向指数生长的培养物中添加1mM IPTG并于30℃温育过夜来诱导ScFv生产。通过对来自过夜诱导的细菌沉淀进行渗透压休克获得粗制含scFv的周质提取物。将沉淀重悬于20%(w/v)蔗糖,50mMTris-HCl,pH 7.5,1mM EDTA,并在冰上冷却30分钟。通过离心除去细胞碎片,并通过层析纯化scFv,和将缓冲液交换成PBS。在96孔微量滴定板测定中测试了纯化的scFv(PD1-17、PD1-28、PD1-33和PD1-35)抑制生物素化的人PD-L1融合蛋白与固定在塑料上的人PD-1融合蛋白结合的能力。生物素化的PD-L1融合蛋白的结合是用AMDEX碱性磷酸酶检测的,并且所产生的信号是通过使用微量滴定板读数器在405nm处读取吸收度测量的。数据表达为总结合百分比,并试验了scFv浓度的滴定以建立作为计算的IC50值的克隆效价(clonepotency)。scFv和IgG抗体的克隆效价数据示于表5。
PD1-F2scFv如上文所述生产和纯化。以105细胞/孔向聚-D-赖氨酸涂覆的96孔微量滴定板中加入终体积为100μl的表达鼠PD-1的细胞。将细胞离心,并在PBS中洗涤两次,然后用300μl溶于PBS的1%BSA室温下封闭1小时。封闭的细胞在PBST中洗涤三次,之后添加25μl/孔测定缓冲液(0.05%BSA,0.05%Tween 20,溶于Dulbecco氏PBS中)或样品,接着是25μl 300ng/ml的生物素化鼠PD-L1融合蛋白。生物素化的PD-L1融合蛋白的结合是用Amdex碱性磷酸酶检测的,并且信号如上所述进行读取。PD1-F2scFv和IgG的效价示于表6。
表6:抗-PD-1ScFv和IgG抗体的效价
克隆 | ScFv IC50(nM) | IgG IC50(nM) |
PD1-17 | 726 | 2.5 |
PD1-28 | 560 | 1.4 |
PD1-33 | 74 | 1.8 |
PD1-35 | 85 | 2.3 |
PD1-F2 | 28 | 1.0 |
实施例5:ScFv向IgG的转化
来自scFv克隆的重链和轻链V区是利用克隆特异性引物通过PCR扩增的。PCR产物用合适的限制酶消化并亚克隆到含人IgG1重链恒定结构域的载体中(Takahashi等(1982)Cell 29,671)或含人λ或κ轻链恒定结构域的载体中(Hieter等.(1982)Nature 294,536)。根据VH和VL区段的种系确定是否利用κ或λ轻链恒定结构域进行转化(表7)。
表7:PD-1抗体克隆VH和VL区的种系
克隆 | VH种系 | VL种系 |
PD1-17 | DP-70 | DPL-8 |
PD1-28 | DP-14 | DPL-23 |
PD1-33 | DP-7 | DPL-11 |
PD1-35 | DP-65 | DPL-2 |
PD1-F2 | DP-47 | L12(K) |
质粒中V区结构域的***是通过来自个体大肠杆菌菌落的质粒DNA的测序验证的。通过标准技术由大肠杆菌培养物制备质粒,并利用标准技术将重链和轻链构建体共转染到真核细胞中。利用A蛋白琼脂糖凝胶(Pharmacia)纯化分泌的IgG,并将缓冲液交换成PBS。
抗-小鼠PD1抗体PD1-F2的结合亲和力是借助表面等离子体共振(SPR)***(BIAcore 3000)(Biacore,Piscataway,NJ)利用固定在CM5传感芯片上的鼠PD-1融合物确定的。流动细胞中PD1-F2的浓度范围从7.81到125nM变动,而抗-小鼠PD1抗体J43(eBioscience,SanDiego,CA)的浓度范围从25nM到500nM变动。PD1-F2的平衡常数KD是6.7×10-9M(KA=1.5×108M-1),而J43的KD是3.8×10-7M(KA=2.6×106M-1)。
抗-PD-1IgG结合人或鼠PD-1的能力测定如下。将ELISA板与2.5μg/m1人PD-1/IgG嵌合体温育过夜。用PBS/1%BSA洗涤板,并与测试抗体的系列稀释液在室温(RT)下温育2小时。洗涤后,添加饱和浓度的HRP缀合的山羊抗人抗体或HRP缀合的兔抗鼠抗体,并在室温下温育样品1小时。未结合的山羊和兔抗体利用PBS/1%BSA洗涤。测定利用TBM显色。结果表达为OD 405吸收度值,并示于图2A-2C。鼠抗人PD-1抗体J110是商业上可获得的(eBioscience,San Diego,CA),并包含在内用于比较。
实施例6:所选的PD-1抗体抑制PD-L1与PD-1的结合
进行抑制测定以评估抗体阻断PD-L1对PD-1的结合的能力。ELISA如实施例2中所述进行,并有改动。在与第一抗体抗-PD-1抗体室温下温育2小时后,添加固定浓度(1μg/ml)的生物素缀合的PD-L1-Ig,且样品于室温下再温育1小时。洗涤后,添加饱和浓度的抗生物素蛋白-HRP,并在室温下温育1小时。未结合的抗生物素蛋白-HRP利用PBS/1%BSA洗涤。测定利用TMB显色。
将结果与由J110获得的结果进行比较,如图3所示。抗人PD-1抗体J110和PD1-30并不抑制PD-L1与PD-1的结合。抗人抗体PD1-17、PD1-28、PD1-33和PD1-35以及抗小鼠抗体PD1-F2阻断PD-1/PD-L1相互作用。
实施例7:PD-1抗体识别PD-1上不同的位点
进行抑制测定以对由多种人抗人PD-1抗体所识别的位点进行作图。ELISA如实施例6中所述进行,并稍加改动。在与第一抗体室温下温育2小时后,添加固定浓度(0.25μg/ml)的生物素缀合的抗-PD-1抗体J110,且样品于室温下再温育1小时。洗涤后,添加饱和浓度的抗生物素蛋白-HRP,并在室温下温育1小时。未结合的抗生物素蛋白-HRP利用PBS/1%BSA洗涤。测定利用TMB显色。
如图4所示,抗人PD-1抗体(J110、J116、PD1-17、PD1-28、PD1-33和PD1-35)的结合限定了PD-1上至少两个不同的位点。交叉阻断结果显示J110和J116与完全相同或重叠的位点结合,而PD1-17、28、33和35与另一不同的位点结合。J116或J110对PD-1的结合阻断了J110的结合。相反,PD1-17、PD1-28、PD1-33和PD1-35的结合并不阻断J110的结合。这提示所测试的抗-PD-1抗体与至少两个不同的表位结合:一个被J110和J116识别,而另一个被PD1-17、PD1-28、PD1-33和PD1-35识别。
实施例8:PD-1接合导致T细胞应答下降
CD4+T细胞(5×104细胞/孔)用涂覆有抗hCD3+/-PD-L1-Fc或抗-PD-1(PD1-17或J110)的甲苯磺酰珠(Dynal,Great Neck,NY)刺激。融合蛋白的浓度或抗体效价如图5的X轴所示。72小时后,通过3H-胸苷掺入测定增殖。掺入的放射性利用LKB 1205板读数器测定。
如图5所示,抗-PD-1抗体PD1-17或PD-L1.Fc对PD-1的接合导致T细胞增殖下降。从而,PD1-17能够模拟PD-1配体并递送抑制信号。如下文所讨论的那样(实施例9),该抑制信号导致T细胞增殖和IL-2生产下降。抗体PD1-28、PD1-33和PD1-35具有与PD1-17相同的效应。所述效应是剂量依赖性的,因为在存在渐增浓度的PD1-17或PD-L1.Fc时细胞的激活导致T细胞增殖下降。对照抗-PD-1抗体J110(图5)或J116(数据未显示)并不抑制T细胞应答,并且提高J110的浓度对T细胞增殖具有极微的影响。为了比较,数值表示为抗-CD3应答的百分比。“100%”表示当细胞由抗-CD3/鼠IgG涂覆的小球体激活时所获得的CPMs。总而言之,这些结果表明有些但并非所有识别PD-1的抗体都可作为PD-1途径的激动剂起作用。
进行了更多的实验以弄清楚PD-1对T细胞应答的下调是否需要TcR/PD-1协同接合到单个(顺式(CIS))或不同(反式(TRANS))的细胞表面上。制备了两组小球体:一组含有抗-CD3和PD-L1.Fc(顺式),另一组含有抗-CD3或PD-L1.Fc(反式)。仅仅在PD-1和TcR两者都在相同表面(顺式)上被配体接合的条件下观察到通过PD-1的抑制。在测试的所有珠:细胞比率下,在TCR和PD-1信号被递送到不同的表面(反式)的条件下没有观察到抑制。
为排除反式实验中的空间位阻,利用抗-CD3抗体和B7.2.Fc设置了相似的测定。在这些测定中,在顺式和反式条件下都观察到T细胞应答的B7共刺激。总而言之,这些发现证明接近于TCR的PD-1是对T细胞激活的受体调节功能所必需的。因此,为调节T细胞应答,激活和抑制信号必须都由相同表面发出,无论所述表面是细胞的表面或是珠子的表面。
实施例9:抗体对PD-1接合的阻断导致增殖提高
为评估可溶性抗-PD-1抗体对增殖的影响,用抗-CD3/抗-CD28涂覆的珠子预活化CD4+T细胞48小时,收获,并在PD1-17、J110或对照IgG的存在下用所示浓度的PHA加10ng/ml IL-2再刺激。在开始培养时,以多种浓度添加各抗体。在72小时测量增殖。
结果证明PD1-17(图6)和PD1-35(数据未显示)促进了原代T细胞的增殖。对照抗体J110并不促进体外T细胞应答。所选的抗-PD1抗体,如由PD1-17和PD-35所例示的那样,抑制PD-1与其天然配体的相互作用,由此阻断负信号的递送。负信号的阻断也导致增殖和IL-2生产提高。
实施例10:紊乱的治疗
由PD-1调控的免疫应答的调节可用于期望免疫抑制效果或免疫应答增强的情形。本实施例描述了PD-1抗体作为PD-1激动剂或拮抗剂用于治疗分别处于疾病发作或具有确定的免疫紊乱或癌症的受试者的用途。
可能需要免疫应答增强的、处于癌症危险之中或患有癌症的受试者将会得益于PD-1拮抗剂的治疗,例如可溶形式的本发明的抗-PD-1抗体。最常见的,在门诊病人的环境下,以每周一次通过缓慢静脉内输注施用大约0.1-10mg/kg剂量的抗体。拮抗剂合适的治疗有效剂量是由治疗医师选择的,并且将在大约从1μg/kg到20mg/kg、从1μg/kg到10mg/kg、从1μg/kg到1mg/kg、从10μg/kg到1mg/kg、从10μg/kg到100μg/kg、从100μg到1mg/kg,以及从500μg/kg到5mg/kg的范围内变动。
也利用所述抗体预防和/或减轻涉及异常或不期望的免疫应答的疾病或状况的严重度和/或症状,例如在下文所例示的自身免疫紊乱中。
多发性硬化(MS)是中枢神经***疾病,它以髓鞘的炎症和丧失为特征。在用于多发性硬化的实验性自身免疫性脑炎(EAE)小鼠模型中(Tuohy等(J.Immunol.(1988)141:1126-1130),Sobel等(J.Immunol.(1984)132:2393-2401),以及Traugott(Cell Immunol.(1989)119:114-129),在诱发EAE之前(并且是连续地)用PD-1激动剂治疗小鼠预期将预防或延迟MS的发作。
关节炎是以关节中的炎症为特征的疾病。在用于类风湿关节炎的胶原诱发的关节炎(CIA)小鼠模型中(Courtenay等(Nature(1980)283:666-628)和Williams等(Immunol.(1995)84:433-439)),用PD-1激动剂治疗预期将预防或治疗类风湿关节炎(RA)或其它关节炎疾病。
***性红斑狼疮(SLE)是以自体抗体的存在为特征的自身免疫病。本发明的抗体和组合物可用作PD-1激动剂抑制自体反应性T细胞和B细胞的活性,并预防或治疗NZB×NZW小鼠(SLE小鼠模型)(Immunologic Defects in Laboratory Animals,Gershwin等编,Plenum Press,1981)或人的SLE或相关疾病。
预期本发明的PD-1抗体在离体治疗中将以每月一次或更低的频率作为PD-1激动剂施用。治疗持续时间将在一个月和数年之间的范围内变动。
为测试人体内所述抗体的临床功效,鉴定了患有黑素瘤、***癌、RA、SLE、MS、I型糖尿病的个体并随机化到治疗组中。治疗组包括安慰组和一到三个用PD-1激动剂(不同剂量)治疗的组。预期将对个体随访1至3年。预期接受治疗的个体将表现出改善。
根据本说明书内所引述的参考文献的教导,本说明书得到了最为彻底的理解,特此将它们全部全文并入作为参考。本说明书内的实施方案提供了本发明的实施方案的举例说明,而不应当解释为限制本发明的范围。熟练技术人员认识到许多其它实施方案为所请求保护的发明所涵盖,并期望本说明书和实施例仅仅被认为是例示性的,而本发明真正的范围和精神是由如下权利要求表示的。
序列表
<110>Collins,Mary et al.
<120>抗PD-1抗体及其用途
<130>08702.6098-00000
<160>58
<170>PatentIn version 3.1
<210>1
<211>384
<212>DNA
<213>智人(Homo sapiens)
<400>1
caggtgcagc tgcaggagtc gggcccagga gtggtgaagc cttcggggac cctgtccctc 60
acctgcgcta tttctggtgg ctccatcggc tctggtggct ccatcagaag tactaggtgg 120
tggagttggg tccgccagtc cccagggaag gggctggagt ggataggcga aatctatcat 180
agtgggagca ccaactacaa cccgtccctc aagagtcgcg tcaccatatc actagacaag 240
tctaggaatc acttctccct gaggctgaac tctgtgaccg ccgcggacac ggccgtttat 300
tactgtgcga gacaggacta cggtgactcc ggcgactggt acttcgatct gtggggcaag 360
gggacaatgg tcaccgtctc ctca 384
<210>2
<211>128
<212>PRT
<213>智人(Homo sapiens)
<400>2
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Val Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Gly Ser Ile Gly Ser Gly
20 25 30
Gly Ser Ile Arg Ser Thr Arg Trp Trp Ser Trp Val Arg Gln Ser Pro
35 40 45
Gly Lys Gly Leu Glu Trp Ile Gly Glu Ile Tyr His Ser Gly Ser Thr
50 55 60
Asn Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Leu Asp Lys
65 70 75 80
Ser Arg Asn His Phe Ser Leu Arg Leu Asn Ser Val Thr Ala Ala Asp
85 90 95
Thr Ala Val Tyr Tyr Cys Ala Arg Gln Asp Tyr Gly Asp Ser Gly Asp
100 105 110
Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Met Val Thr Val Ser Ser
115 120 125
<210>3
<211>330
<212>DNA
<213>智人(Homo sapiens)
<400>3
aattttatgc tgactcagcc ccactctgtg tcggagtctc cggggaagac ggtaaccatc 60
tcctgcaccc gcagcagtgg cagcattgcc agcaactctg tgcagtggta ccagcagcgc 120
ccgggcagtt cccccaccac tgtgatctat gaggataacc aaagaccctc tggggtccct 180
gatcggttct ctggctccat cgacagctcc tccaactctg cctccctcac cgtctctgga 240
ctgaagactg aggacgaggc tgactactac tgtcagtctt ctgatagcag cgctgtggta 300
ttcggcagtg ggaccaagct gaccgtccta 330
<210>4
<211>110
<212>PRT
<213>智人(Homo sapiens)
<400>4
Asn Phe Met Leu Thr Gln Pro His Ser Val Ser Glu Ser Pro Gly Lys
1 5 10 15
Thr Val Thr Ile Ser Cys Thr Arg Ser Ser Gly Ser Ile Ala Ser Asn
20 25 30
Ser Val Gln Trp Tyr Gln Gln Arg Pro Gly Ser Ser Pro Thr Thr Val
35 40 45
Ile Tyr Glu Asp Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Ile Asp Ser Ser Ser Asn Ser Ala Ser Leu Thr Val Ser Gly
65 70 75 80
Leu Lys Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Ser Asp Ser
85 90 95
Ser Ala Val Val Phe Gly Ser Gly Thr Lys Leu Thr Val Leu
100 105 110
<210>5
<211>357
<212>DNA
<213>智人(Homo sapiens)
<400>5
gaggtgcagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaagtc 60
tcctgcaagg cttctggtta cagatttacc agctacggca tcagctgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggatgg atcagcgctt acaatggtaa cacaaactac 180
gcacagaagc tccagggcag agtcaccatg accacagaca catccacgaa cacagcctac 240
atggagctga ggagcctgag atctgacgac acggccgtgt attactgtgc gagagacgcg 300
gattatagta gtgggtctgg gtactggggc cagggaaccc tggtcaccgt ctcctca 357
<210>6
<211>119
<212>PRT
<213>智人(Homo sapiens)
<400>6
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Arg Phe Thr Ser Tyr
20 25 30
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Ala Asp Tyr Ser Ser Gly Ser Gly Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210>7
<211>324
<212>DNA
<213>智人(Homo sapiens)
<400>7
tcctatgagc tgactcagcc accctcggtg tcagtgtccc caggacagac ggccaggatc 60
acctgttctg gagatgcatt gccaaagcaa tatgcttatt ggtaccagca gaagccaggc 120
caggcccctg tgatggttat atataaagac actgagaggc cctcagggat ccctgagcga 180
ttctctggct ccagctcagg gacaaaagtc acgttgacca tcagtggagt ccaggcagaa 240
gacgaggctg actattattg tcaatcagca gacaacagta ttacttatag ggtgttcggc 300
ggagggacca aggtcaccgt ccta 324
<210>8
<211>108
<212>PRT
<213>智人(Homo sapiens)
<400>8
Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln
1 5 10 15
Thr Ala Arg Ile Thr Cys Ser Gly Asp Ala Leu Pro Lys Gln Tyr Ala
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Met Val Ile Tyr
35 40 45
Lys Asp Thr Glu Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Thr Lys Val Thr Leu Thr Ile Ser Gly Val Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Ala Asp Asn Ser Ile Thr Tyr
85 90 95
Arg Val Phe Gly Gly Gly Thr Lys Val Thr Val Leu
100 105
<210>9
<211>357
<212>DNA
<213>智人(Homo sapiens)
<400>9
caggtgcagc tggtgcaatc tggggctgag gtgaagaaac ctggggcctc agtgagggtt 60
tcctgcaagg catctggata caccctcacc agttactata ttcactgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggaata atcaacccta gaggtgccac cataagctac 180
gcacagaagt tccagggcag agtcaccatg accagggaca cgtccacgag tacagtctac 240
atggaactga gaaacttgaa atctgaggac acggccctgt attactgtgc tactgcaggc 300
atctatggtt ttgactttga ctactggggc agaggaaccc tggtcaccgt ctcctca 357
<210>10
<211>119
<212>PRT
<213>智人(Homo sapiens)
<400>10
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Arg Val Ser Cys Lys Ala Ser Gly Tyr Thr Leu Thr Ser Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile Asn Pro Arg Gly Ala Thr Ile Ser Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Arg Asn Leu Lys Ser Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Thr Ala Gly Ile Tyr Gly Phe Asp Phe Asp Tyr Trp Gly Arg Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210>11
<211>333
<212>DNA
<213>智人(Homo sapiens)
<400>11
cagtctgccc tgactcagcc tgcctccgtg tctgggtctc ctgggcagtc gatcaccatc 60
tcctgcactg gaaccagtaa tgacgttggt ggttataatt atgtctcctg gtaccaacat 120
cacccaggca aagcccccaa actcatcatt tatgatgtca ctaaccggcc ctcaggggtt 180
tctgatcgct tctctggctc caagtctggc aacacggcct ccctgaccat ctctgggctc 240
ctggctgagg acgagggtga ttattactgc agctcataca caattgttac caatttcgag 300
gttcttttcg gcggagggac caagctgacc gtc 333
<210>12
<211>111
<212>PRT
<213>智人(Homo sapiens)
<400>12
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Asn Asp Val Gly Gly Tyr
20 25 30
Asn Tyr Val Ser Trp Tyr Gln His His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Ile Ile Tyr Asp Val Thr Asn Arg Pro Ser Gly Val Ser Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Leu Ala Glu Asp Glu Gly Asp Tyr Tyr Cys Ser Ser Tyr Thr Ile Val
85 90 95
Thr Asn Phe Glu Val Leu Phe Gly Gly Gly Thr Lys Leu Thr Val
100 105 110
<210>13
<211>381
<212>DNA
<213>智人(Homo sapiens)
<400>13
caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60
acctgcactg tctctggtgg ctccatcagc agtggtgctt attactggag ctggatccgc 120
cagcacccag ggaagggcct ggagtggatt gggtacatct attacaatgg gaacacgtac 180
tacaacccgt ccctcaggag tctagttacc atatcagtag acgcgtctaa gaaccagttc 240
tccctgaagc tgagctctgt gactgccgcg gacacggccg tctattactg tgcgagagcg 300
tctgattacg tttggggggg ttatcgttat atggatgctt ttgatatctg gggccgggga 360
accctggtca ccgtctcctc a 381
<210>14
<211>127
<212>PRT
<213>智人(Homo sapiens)
<400>14
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly
20 25 30
Ala Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Tyr Ile Tyr Tyr Asn Gly Asn Thr Tyr Tyr Asn Pro Ser
50 55 60
Leu Arg Ser Leu Val Thr Ile Ser Val Asp Ala Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Ala Ser Asp Tyr Val Trp Gly Gly Tyr Arg Tyr Met Asp
100 105 110
Ala Phe Asp Ile Trp Gly Arg Gly Thr Leu Ile Thr Val Ser Ser
115 120 125
<210>15
<211>336
<212>DNA
<213>智人(Homo sapiens)
<400>15
cagtctgtgc tgactcagcc accctcagcg tctgggaccc ccgggcagag ggtcaccatc 60
tcttgttctg gaagcaactc caacatcgga agtaattctg taaactggta ccagcagctc 120
ccaggaacgg cccccaaact cctcatctat ggtaataatc agcggccctc aggggtccct 180
gaccgattct ctggctccaa gtctggcacc tcagcctccc tggccatcag tgggctccag 240
tctgagaatg aggctgatta ttactgtgca gcatgggatg acagcctgaa tggtccggta 300
ttcggccgag ggaccaaggt caccgtccta ggtgag 336
<210>16
<211>112
<212>PRT
<213>智人(Homo sapiens)
<400>16
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Asn Ser Asn Ile Gly Ser Asn
20 25 30
Ser Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Gly Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln
65 70 75 80
Ser Glu Asn Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu
85 90 95
Asn Gly Pro Val Phe Gly Arg Gly Thr Lys Val Thr Val Leu Gly Glu
100 105 110
<210>17
<211>12
<212>PRT
<213>智人(Homo sapiens)
<400>17
Ser Gly Gly Ser Ile Arg Ser Thr Arg Trp Trp Ser
1 5 10
<210>18
<211>16
<212>PRT
<213>智人(Homo sapiens)
<400>18
Glu Ile Tyr His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210>19
<211>13
<212>PRT
<213>智人(Homo sapiens)
<400>19
Gln Asp Tyr Gly Asp Ser Gly Asp Trp Tyr Phe Asp Leu
1 5 10
<210>20
<211>13
<212>PRT
<213>智人(Homo sapiens)
<400>20
Thr Arg Ser Ser Gly Ser Ile Ala Ser Asn Ser Val Gln
1 5 10
<210>21
<211>7
<212>PRT
<213>智人(Homo sapiens)
<400>21
Glu Asp Asn Gln Arg Pro Ser
1 5
<210>22
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>22
Gln Ser Ser Asp Ser Ser Ala Val Val
1 5
<210>23
<211>5
<212>PRT
<213>智人(Homo sapiens)
<400>23
Ser Tyr Gly Ile Ser
1 5
<210>24
<211>17
<212>PRT
<213>智人(Homo sapiens)
<400>24
Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu Gln
1 5 10 15
Gly
<210>25
<211>10
<212>PRT
<213>智人(Homo sapiens)
<400>25
Asp Ala Asp Tyr Ser Ser Gly Ser Gly Tyr
1 5 10
<210>26
<211>11
<212>PRT
<213>智人(Homo sapiens)
<400>26
Ser Gly Asp Ala Leu Pro Lys Gln Tyr Ala Tyr
1 5 10
<210>27
<211>7
<212>PRT
<213>智人(Homo sapiens)
<400>27
Lys Asp Thr Glu Arg Pro Ser
1 5
<210>28
<211>11
<212>PRT
<213>智人(Homo sapiens)
<400>28
Gln Ser Ala Asp Asn Ser Ile Thr Tyr Arg Val
1 5 10
<210>29
<211>5
<212>PRT
<213>智人(Homo sapiens)
<400>29
Ser Tyr Tyr Ile His
1 5
<210>30
<211>17
<212>PRT
<213>智人(Homo sapiens)
<400>30
Ile Ile Asn Pro Arg Gly Ala Thr Ile Ser Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210>31
<211>10
<212>PRT
<213>智人(Homo sapiens)
<400>31
Ala Gly Ile Tyr Gly Phe Asp Phe Asp Tyr
1 5 10
<210>32
<211>14
<212>PRT
<213>智人(Homo sapiens)
<400>32
Thr Gly Thr Ser Asn Asp Val Gly Gly Tyr Asn Tyr Val Ser
1 5 10
<210>33
<211>7
<212>PRT
<213>智人(Homo sapiens)
<400>33
Asp Val Thr Asn Arg Pro Ser
1 5
<210>34
<211>12
<212>PRT
<213>智人(Homo sapiens)
<400>34
Ser Ser Tyr Thr Ile Val Thr Asn Phe Glu Val Leu
1 5 10
<210>35
<211>7
<212>PRT
<213>智人(Homo sapiens)
<400>35
Ser Gly Ala Tyr Tyr Trp Ser
1 5
<210>36
<211>16
<212>PRT
<213>智人(Homo sapiens)
<400>36
Tyr Ile Tyr Tyr Asn Gly Asn Thr Tyr Tyr Asn Pro Ser Leu Arg Ser
1 5 10 15
<210>37
<211>17
<212>PRT
<213>智人(Homo sapiens)
<400>37
Ala Ser Asp Tyr Val Trp Gly Gly Tyr Arg Tyr Met Asp Ala Phe Asp
1 5 10 15
Ile
<210>38
<211>13
<212>PRT
<213>智人(Homo sapiens)
<400>38
Ser Gly Ser Asn Ser Asn Ile Gly Ser Asn Ser Val Asn
1 5 10
<210>39
<211>7
<212>PRT
<213>智人(Homo sapiens)
<400>39
Gly Asn Asn Gln Arg Pro Ser
1 5
<210>40
<211>11
<212>PRT
<213>智人(Homo sapiens)
<400>40
Ala Ala Trp Asp Asp Ser Leu Asn Gly Pro Val
1 5 10
<210>41
<211>288
<212>PRT
<213>智人(Homo sapiens)
<400>41
Met Gln Ile Pro Gln Ala Pro Trp Pro Val Val Trp Ala Val Leu Gln
1 5 10 15
Leu Gly Trp Arg Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp
20 25 30
Asn Pro Pro Thr Phe Phe Pro Ala Leu Leu Val Val Thr Glu Gly Asp
35 40 45
Asn Ala Thr Phe Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val
50 55 60
Leu Asn Trp Tyr Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala
65 70 75 80
Ala Phe Pro Glu Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg
85 90 95
Val Thr Gln Leu Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg
100 105 110
Ala Arg Arg Asn Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu
115 120 125
Ala Pro Lys Ala Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val
130 135 140
Thr Glu Arg Arg Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro
145 150 155 160
Arg Pro Ala Gly Gln Phe Gln Thr Leu Val Val Gly Val Val Gly Gly
165 170 175
Leu Leu Gly Ser Leu Val Leu Leu Val Trp Val Leu Ala Val Ile Cys
180 185 190
Ser Arg Ala Ala Arg Gly Thr Ile Gly Ala Arg Arg Thr Gly Gln Pro
195 200 205
Leu Lys Glu Asp Pro Ser Ala Val Pro Val Phe Ser Val Asp Tyr Gly
210 215 220
Glu Leu Asp Phe Gln Trp Arg Glu Lys Thr Pro Glu Pro Pro Val Pro
225 230 235 240
Cys Val Pro Glu Gln Thr Glu Tyr Ala Thr Ile Val Phe Pro Ser Gly
245 250 255
Met Gly Thr Ser Ser Pro Ala Arg Arg Gly Ser Ala Asp Gly Pro Arg
260 265 270
Ser Ala Gln Pro Leu Arg Pro Glu Asp Gly His Cys Ser Trp Pro Leu
275 280 285
<210>42
<211>320
<212>DNA
<213>智人(Homo sapiens)
<400>42
gtcagcccaa ggctgccccc tcggtcactc tgttcccgcc ctcctctgag gagcttcaag 60
ccaacaaggc cacactggtg tgtctcataa gtgacttcta cccgggagcc gtgacagtgg 120
cctggaaggc agatagcagc cccgtcaagg cgggagtgga gaccaccaca ccctccaaac 180
aaagcaacaa caagtacgcg gccagcagct atctgagcct gacgcctgag cagtggaagt 240
cccacagaag ctacagctgc caggtcacgc atgaagggag caccgtggag aagacagtgg 300
cccctacaga atgttcatag 320
<210>43
<211>106
<212>PRT
<213>智人(Homo sapiens)
<400>43
Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser
1 5 10 15
Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp
20 25 30
Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro
35 40 45
Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn
50 55 60
Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys
65 70 75 80
Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val
85 90 95
Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
100 105
<210>44
<211>960
<212>DNA
<213>智人(Homo sapiens)
<400>44
cctccaccaa gggcccatcg gtcttccccc tggcaccctc ctccaagagc acctctgggg 60
gcacagcggc cctgggctgc ctggtcaagg actacttccc cgaaccggtg acggtgtcgt 120
ggaactcagg cgccctgacc agcggcgtgc acaccttccc ggctgtccta cagtcctcag 180
gactctactc cctcagcagc gtggtgaccg tgccctccag cagcttgggc acccagacct 240
acatctgcaa cgtgaatcac aagcccagca acaccaaggt ggacaagaaa gttgagccca 300
aatcttgtga caaaactcac acatgcccac cgtgcccagc acctgaactc ctggggggac 360
cgtcagtctt cctcttcccc ccaaaaccca aggacaccct catgatctcc cggacccctg 420
aggtcacatg cgtggtggtg gacgtgagcc acgaagaccc tgaggtcaag ttcaactggt 480
acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag cagtacaaca 540
gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg aatggcaagg 600
agtacaagtg caaggtctcc aacaaagccc tcccagcccc catcgagaaa accatctcca 660
aagccaaagg gcagccccga gaaccacagg tgtacaccct gcccccatcc cgggaggaga 720
tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctatccc agcgacatcg 780
ccgtggagtg ggagagcaat gggcagccgg agaacaacta caagaccacg cctcccgtgc 840
tggactccga cggctccttc ttcctctata gcaagctcac cgtggacaag agcaggtggc 900
agcaggggaa cgtcttctca tgctccgtga tgcatgaggc tctgcacaac cactacacgc 960
<210>45
<211>330
<212>PRT
<213>智人(Homo sapiens)
<400>45
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210>46
<211>366
<212>DNA
<213>智人(Homo sapiens)
<400>46
ggcgcgcact ccgaggtgca gctggtgcag tctgggggag gcgtggttca gcctgggagg 60
tccctgagac tctcctgtgc agcgtctgga ttcaccttta gtagctattg gatgagctgg 120
gtccgccagg ctccagggaa ggggctggag tgggtctcag ctattagtgg tagtggtggt 180
agcacatact acgcagactc cgtgaagggc cggttcacca tctccagaga caattccaag 240
aacacgctgt atctgcaaat gaacagccta agagccgagg acacggccgt atattactgt 300
gcgaaagaga actggggatc gtacttcgat ctctgggggc aagggaccac ggtcaccgtc 360
tcctca 366
<210>47
<211>125
<212>PRT
<213>智人(Homo sapiens)
<400>47
Gly Ala His Ser Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Val
1 5 10 15
Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr
20 25 30
Phe Ser Ser Tyr Trp Cys Asp Arg Met Ser Trp Val Arg Gln Ala Pro
35 40 45
Gly Lys Gly Leu Glu Trp Val Ser Ala Ile Ser Gly Ser Gly Gly Ser
50 55 60
Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
65 70 75 80
Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
85 90 95
Asp Thr Ala Val Tyr Tyr Cys Ala Lys Glu Asn Trp Gly Ser Tyr Phe
100 105 110
Asp Leu Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210>48
<211>332
<212>DNA
<213>智人(Homo sapiens)
<400>48
ggcgtgcact ccgacatcgt gatgacccag tctccttcca ccctgtctgc atctgtagga 60
gacagagtca ccatcacttg ccgggccagt cagggtatta gtagctggtt ggcctggtat 120
cagcagaaac cagggagagc ccctaaggtc ttgatctata aggcatctac tttagaaagt 180
ggggtcccat caaggttcag cggcagtgga tctgggacag atttcactct caccatcagc 240
agtctgcaac ctgaagattt tgcaacttac tactgtcaac agagttacag taccccgtgg 300
acgttcggcc aggggaccaa gctggaaatc aa 332
<210>49
<211>112
<212>PRT
<213>智人(Homo sapiens)
<400>49
Gly Val His Ser Asp Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser
1 5 10 15
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly
20 25 30
Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Arg Ala Pro
35 40 45
Lys Val Leu Ile Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr
85 90 95
Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
<210>50
<211>6
<212>PRT
<213>智人(Homo sapiens)
<400>50
Ser Ser Tyr Trp Met Ser
1 5
<210>51
<211>17
<212>PRT
<213>智人(Homo sapiens)
<400>51
Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210>52
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>52
Glu Asn Trp Gly Ser Tyr Phe Asp Leu
1 5
<210>53
<211>11
<212>PRT
<213>智人(Homo sapiens)
<400>53
Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala
1 5 10
<210>54
<211>7
<212>PRT
<213>智人(Homo sapiens)
<400>54
Lys Ala Ser Thr Leu Glu Ser
1 5
<210>55
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>55
Gln Gln Ser Tyr Ser Thr Pro Trp Thr
1 5
<210>56
<211>288
<212>PRT
<213>Murine
<400>56
Met Trp Val Arg Gln Val Pro Trp Ser Phe Thr Trp Ala Val Leu Gln
1 5 10 15
Leu Ser Trp Gln Ser Gly Trp Leu Leu Glu Val Pro Asn Gly Pro Trp
20 25 30
Arg Ser Leu Thr Phe Tyr Pro Ala Trp Leu Thr Val Ser Glu Gly Ala
35 40 45
Asn Ala Thr Phe Thr Cys Ser Leu Ser Asn Trp Ser Glu Asp Leu Met
50 55 60
Leu Asn Trp Asn Arg Leu Ser Pro Ser Asn Gln Thr Glu Lys Gln Ala
65 70 75 80
Ala Phe Cys Asn Gly Leu Ser Gln Pro Val Gln Asp Ala Arg Phe Gln
85 90 95
Ile Ile Gln Leu Pro Asn Arg His Asp Phe His Met Asn Ile Leu Asp
100 105 110
Thr Arg Arg Asn Asp Ser Gly Ile Tyr Leu Cys Gly Ala Ile Ser Leu
115 120 125
His Pro Lys Ala Lys Ile Glu Glu Ser Pro Gly Ala Glu Leu Val Val
130 135 140
Thr Glu Arg Ile Leu Glu Thr Ser Thr Arg Tyr Pro Ser Pro Ser Pro
145 150 155 160
Lys Pro Glu Gly Arg Phe Gln Gly Met Val Ile Gly Ile Met Ser Ala
165 170 175
Leu Val Gly Ile Pro Val Leu Leu Leu Leu Ala Trp Ala Leu Ala Val
180 185 190
Phe Cys Ser Thr Ser Met Ser Glu Ala Arg Gly Ala Gly Ser Lys Asp
195 200 205
Asp Thr Leu Lys Glu Glu Pro Ser Ala Ala Pro Val Pro Ser Val Ala
210 215 220
Tyr Glu Glu Leu Asp Phe Gln Gly Arg Glu Lys Thr Pro Glu Leu Pro
22 230 235 240
Thr Ala Cys Val His Thr Glu Tyr Ala Thr Ile Val Phe Thr Glu Gly
245 250 255
Leu Gly Ala Ser Ala Met Gly Arg Arg Gly Ser Ala Asp Gly Leu Gln
260 265 270
Gly Pro Arg Pro Pro Arg His Glu Asp Gly His Cys Ser Trp Pro Leu
275 280 285
<210>57
<211>321
<212>DNA
<213>智人(Homo sapiens)
<400>57
actgtggctg caccatctgt cttcatcttc ccgccatctg atgagcagtt gaaatctgga 60
actgcctctg ttgtgtgcct gctgaataac ttctatccca gagaggccaa agtacagtgg 120
aaggtggata acgccctcca atcgggtaac tcccaggaga gtgtcacaga gcaggacagc 180
aaggacagca cctacagcct cagcagcacc ctgacgctga gcaaagcaga ctacgagaaa 240
cacaaagtct acgcctgcga agtcacccat cagggcctga gctcgcccgt cacaaagagc 300
ttcaacaggg gagagtgtta g 321
<210>58
<211>108
<212>PRT
<213>智人(Homo sapiens)
<400>58
His Met Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
1 5 10 15
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
20 25 30
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
35 40 45
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
50 55 60
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
65 70 75 80
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
85 90 95
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
Claims (19)
1.分离的抗体,其包含
包含3个CDRs的VH结构域,以及包含3个CDRs的VL结构域;
其中所述抗体包含
(a)至少3个具有SEQ ID NO:23、SEQ ID NO:24和SEQ ID NO:25序列的VH结构域CDRs和至少3个具有SEQ ID NO:26、SEQ ID NO:27和SEQ ID NO:28序列的VL结构域CDRs;或
(b)至少3个具有SEQ ID NO:29、SEQ ID NO:30和SEQ ID NO:31序列的VH结构域CDRs和至少3个具有SEQ ID NO:32、SEQ ID NO:33和SEQ ID NO:34序列的VL结构域CDRs;或
(c)至少3个具有SEQ ID NO:35、SEQ ID NO:36和SEQ ID NO:37序列的VH结构域CDRs和至少3个具有SEQ ID NO:38、SEQ ID NO:39和SEQ ID NO:40序列的VL结构域CDRs;且
其中所述抗体特异性结合位于人PD-1胞外结构域内的表位,且
其中抗体与PD-1的胞外结构域特异性结合,其亲和常数大于107M-1。
2.权利要求1的抗体,其包含选自SEQ ID NO:6、SEQ ID NO:10或SEQ ID NO:14的氨基酸序列。
3.权利要求1的抗体,其包含选自SEQ ID NO:8、SEQ ID NO:12或SEQ ID NO:16的氨基酸序列。
4.权利要求1的抗体,其中抗体抑制PD-L与PD-1的结合,其IC50低于10nM。
5.权利要求1的抗体,其是Fab、F(ab′)2、Fv、scFv、Fd或dAb。
6.权利要求1的抗体,其中抗体是人的。
7.权利要求1的抗体,其中抗体为IgG1或IgG4。
8.权利要求7的抗体,其中抗体为IgG1λ或IgG1κ。
9.权利要求1的抗体,其中抗体包含:(a)SEQ ID NO:6的VH结构域和SEQ ID NO:8的VL结构域;或(b)SEQ ID NO:10的VH结构域和SEQ ID NO:12的VL结构域;或(c)SEQ ID NO:14的VH结构域和SEQ ID NO:16的VL结构域。
10.药物组合物,其包含权利要求1的抗体。
11.有效剂量的权利要求10的药物组合物在制备用于治疗或预防选自自身免疫紊乱、针对移植物的免疫应答、***反应和癌症的紊乱的药物中的用途。
12.权利要求11的用途,其中受试者是人。
13.分离的核酸,其编码权利要求1的抗体。
14.表达载体,其包含权利要求13的核酸。
15.宿主细胞,其包含权利要求14的载体。
16.权利要求15的宿主细胞,其中宿主细胞选自:大肠杆菌、中国仓鼠卵巢细胞、HeLa细胞和NS0细胞。
17.权利要求13的核酸,其中核酸编码SEQ ID NO:6、SEQ ID NO:8、SEQ ID NO:10、SEQ ID NO:12、SEQ ID NO:14或SEQ ID NO:16中所示的氨基酸序列。
18.权利要求17的核酸,其中核酸包含选自SEQ ID NO:5、SEQ IDNO:7、SEQ ID NO:9、SEQ ID NO:11、SEQ ID NO:13或SEQ ID NO:15的核苷酸序列。
19.制备权利要求1-9中任一项的的分离的抗体的方法,该方法包括:
(a)提供编码3个具有下述序列的VL结构域CDRs的核酸:
SEQ ID NO:26、SEQ ID NO:27和SEQ ID NO:28;或
SEQ ID NO:32、SEQ ID NO:33和SEQ ID NO:34;或
SEQ ID NO:38、SEQ ID NO:39和SEQ ID NO:40;
(b)将编码3个VH结构域CDRs的核酸的所有组成成分与编码3个VL结构域CDRs的核酸组合,以便提供核酸产物所有组成成分,所述核酸编码3个VL结构域CDRs和3个VH结构域CDRs的所有组成成分;
(c)表达产物所有组成成分的核酸;
(d)选择抗原结合片段,所述抗原结合片段包含特异性结合PD-1且从产物所有组成成分的核酸表达的可变结构域;和
(e)生产包含所述抗原结合片段的抗体。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US43535402P | 2002-12-23 | 2002-12-23 | |
US60/435354 | 2002-12-23 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2003801099298A Division CN1753912B (zh) | 2002-12-23 | 2003-12-22 | 抗pd-1抗体及其用途 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN101899114A true CN101899114A (zh) | 2010-12-01 |
Family
ID=32682224
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2003801099298A Expired - Fee Related CN1753912B (zh) | 2002-12-23 | 2003-12-22 | 抗pd-1抗体及其用途 |
CN2010101700224A Pending CN101899114A (zh) | 2002-12-23 | 2003-12-22 | 抗pd-1抗体及其用途 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2003801099298A Expired - Fee Related CN1753912B (zh) | 2002-12-23 | 2003-12-22 | 抗pd-1抗体及其用途 |
Country Status (14)
Country | Link |
---|---|
US (4) | US7488802B2 (zh) |
EP (1) | EP1576014B1 (zh) |
JP (2) | JP4511943B2 (zh) |
CN (2) | CN1753912B (zh) |
AT (1) | ATE514713T1 (zh) |
AU (2) | AU2003288675B2 (zh) |
BR (1) | BR0316880A (zh) |
CA (1) | CA2508660C (zh) |
ES (1) | ES2367430T3 (zh) |
HK (1) | HK1083510A1 (zh) |
IL (1) | IL169152A (zh) |
MX (1) | MXPA05006828A (zh) |
NO (1) | NO336442B1 (zh) |
WO (1) | WO2004056875A1 (zh) |
Cited By (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015035606A1 (en) * | 2013-09-13 | 2015-03-19 | Beigene, Ltd. | Anti-pd1 antibodies and their use as therapeutics and diagnostics |
CN104558177A (zh) * | 2013-10-25 | 2015-04-29 | 苏州思坦维生物技术有限责任公司 | 拮抗抑制程序性死亡受体pd-1与其配体结合的单克隆抗体及其编码序列与用途 |
WO2016015685A1 (zh) * | 2014-07-30 | 2016-02-04 | 珠海市丽珠单抗生物技术有限公司 | 抗pd-1抗体及其应用 |
CN107074947A (zh) * | 2014-08-05 | 2017-08-18 | 马布奎斯特公司 | 结合至pd‑1的免疫试剂 |
CN107438621A (zh) * | 2014-10-27 | 2017-12-05 | 新加坡科技研究局 | 抗pd‑1抗体 |
CN109152798A (zh) * | 2015-12-02 | 2019-01-04 | 斯特库比股份有限公司 | 特异于糖基化的pd-1的抗体及其使用方法 |
CN109311981A (zh) * | 2016-01-22 | 2019-02-05 | 马布奎斯特公司 | Pd1特异性抗体 |
US10428146B2 (en) | 2014-07-22 | 2019-10-01 | Cb Therapeutics, Inc. | Anti PD-1 antibodies |
US10435470B2 (en) | 2014-08-05 | 2019-10-08 | Cb Therapeutics, Inc. | Anti-PD-L1 antibodies |
CN110382536A (zh) * | 2017-01-20 | 2019-10-25 | 大有华夏生物医药集团有限公司 | 抗pd-1抗体及其用途 |
US10544225B2 (en) | 2014-07-03 | 2020-01-28 | Beigene, Ltd. | Anti-PD-L1 antibodies and their use as therapeutics and diagnostics |
US10864203B2 (en) | 2016-07-05 | 2020-12-15 | Beigene, Ltd. | Combination of a PD-1 antagonist and a RAF inhibitor for treating cancer |
CN113444165A (zh) * | 2011-10-17 | 2021-09-28 | Io生物技术公司 | 基于pd-l1的免疫疗法 |
CN113929782A (zh) * | 2014-09-16 | 2022-01-14 | 依奈特制药公司 | 对淋巴细胞中抑制途径的中和 |
CN114380909A (zh) * | 2015-03-30 | 2022-04-22 | 斯特库比股份有限公司 | 特异性针对糖基化的pd-l1的抗体及其使用方法 |
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 |
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 |
US11597768B2 (en) | 2017-06-26 | 2023-03-07 | Beigene, Ltd. | Immunotherapy for hepatocellular carcinoma |
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 |
Families Citing this family (1104)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7030219B2 (en) | 2000-04-28 | 2006-04-18 | Johns Hopkins University | B7-DC, Dendritic cell co-stimulatory molecules |
ATE481985T1 (de) | 2002-07-03 | 2010-10-15 | Ono Pharmaceutical Co | Immunpotenzierende zusammensetzungen |
US7488802B2 (en) * | 2002-12-23 | 2009-02-10 | Wyeth | Antibodies against PD-1 |
JP2007530029A (ja) * | 2004-03-26 | 2007-11-01 | クアーク・ファーマスーティカルス、インコーポレイテッド | アネキシンii及びその使用 |
SI1810026T1 (en) | 2004-10-06 | 2018-08-31 | Mayo Foundation For Medical Education And Research | B7-H1 and PD-1 in the treatment of renal cell carcinoma |
DK2161336T4 (en) | 2005-05-09 | 2017-04-24 | Ono Pharmaceutical Co | Human monoclonal antibodies for programmed death 1 (PD-1) and methods for treating cancer using anti-PD-1 antibodies alone or in combination with other immunotherapies |
AU2012204032B2 (en) * | 2005-06-08 | 2014-01-16 | Dana-Farber Cancer Institute, Inc. | Methods and compositions for the treatment of persistent infections and cancer by inhibiting the programmed cell death 1 (PD-1) pathway |
MX349137B (es) * | 2005-06-08 | 2017-07-13 | Dana-Farber Cancer Inst | Metodos y composiciones para el tratamiento de infecciones persistentes y cancer por inhibicion de la ruta de muerte celular programada (pd-1). |
EP1907424B1 (en) | 2005-07-01 | 2015-07-29 | E. R. Squibb & Sons, L.L.C. | Human monoclonal antibodies to programmed death ligand 1 (pd-l1) |
EP2347775B1 (en) | 2005-12-13 | 2020-04-15 | President and Fellows of Harvard College | Scaffolds for cell transplantation |
WO2007100098A1 (ja) | 2006-03-03 | 2007-09-07 | Kyoto University | 細胞表面機能分子の細胞外領域多量体 |
PL2772535T3 (pl) | 2006-05-31 | 2022-09-05 | Children's Medical Center Corporation | Mezenchymalne komórki macierzyste ABC5 dodatnie jako immunomodulatory |
CN105056226A (zh) | 2006-12-27 | 2015-11-18 | 埃默里大学 | 用于治疗传染病和肿瘤的组合物和方法 |
DK2155248T3 (en) | 2007-04-12 | 2015-09-14 | Brigham & Womens Hospital | Targeting abcb5 for cancer therapy |
PE20090321A1 (es) | 2007-06-04 | 2009-04-20 | Genentech Inc | Anticuerpos anti-notch1 nrr, metodo de preparacion y composicion farmaceutica |
AU2014201367B2 (en) * | 2007-06-18 | 2016-01-28 | Merck Sharp & Dohme B.V. | Antibodies to human programmed death receptor pd-1 |
PL2170959T3 (pl) | 2007-06-18 | 2014-03-31 | Merck Sharp & Dohme | Przeciwciała przeciwko ludzkiemu receptorowi programowanej śmierci PD-1 |
WO2009023566A2 (en) * | 2007-08-09 | 2009-02-19 | Genzyme Corporation | Method of treating autoimmune disease with mesenchymal stem cells |
US8263078B2 (en) | 2007-09-05 | 2012-09-11 | Inotek Pharmaceuticals Corporation | Antibodies against flagellin and uses thereof |
CN102006891B (zh) | 2008-02-13 | 2017-04-26 | 哈佛学院董事会 | 连续的细胞程序化装置 |
US8168757B2 (en) | 2008-03-12 | 2012-05-01 | Merck Sharp & Dohme Corp. | PD-1 binding proteins |
US9017660B2 (en) | 2009-11-11 | 2015-04-28 | Advaxis, Inc. | Compositions and methods for prevention of escape mutation in the treatment of Her2/neu over-expressing tumors |
US9650639B2 (en) | 2008-05-19 | 2017-05-16 | Advaxis, Inc. | Dual delivery system for heterologous antigens |
EP2288379A4 (en) | 2008-05-19 | 2012-08-08 | Advaxis | DOUBLE RELEASE SYSTEM FOR HETEROLOGIST ANTIGENE |
US20110223188A1 (en) * | 2008-08-25 | 2011-09-15 | Solomon Langermann | Targeted costimulatory polypeptides and methods of use to treat cancer |
AU2009288730B2 (en) | 2008-08-25 | 2013-06-20 | Amplimmune, Inc. | Compositions of PD-1 antagonists and methods of use |
US8927697B2 (en) * | 2008-09-12 | 2015-01-06 | Isis Innovation Limited | PD-1 specific antibodies and uses thereof |
EP2342228B1 (en) | 2008-09-12 | 2017-09-06 | Oxford University Innovation Limited | Pd-1 specific antibodies and uses thereof |
KR101814408B1 (ko) | 2008-09-26 | 2018-01-04 | 다나-파버 캔서 인스티튜트 인크. | 인간 항-pd-1, pd-l1, 및 pd-l2 항체 및 그의 용도 |
JP5840494B2 (ja) | 2008-10-02 | 2016-01-06 | エマージェント プロダクト デベロップメント シアトル, エルエルシー | Cd86アンタゴニストの多標的結合タンパク質 |
AU2009314556B2 (en) * | 2008-11-14 | 2016-08-04 | Children's Medical Center Corporation | Therapeutic and diagnostic methods relating to cancer stem cells |
US11542328B2 (en) | 2008-11-14 | 2023-01-03 | The Brigham And Women's Hospital, Inc. | Therapeutic and diagnostic methods relating to cancer stem cells |
CN102282265B (zh) | 2008-11-28 | 2020-07-24 | 埃默里大学 | 用于治疗传染病和肿瘤的方法 |
PL2376535T3 (pl) * | 2008-12-09 | 2017-09-29 | F.Hoffmann-La Roche Ag | Przeciwciała ANTY-PD-L1 i ich zastosowanie do nasilania działania limfocytów T |
ES2629337T3 (es) * | 2009-02-09 | 2017-08-08 | Inserm - Institut National De La Santé Et De La Recherche Médicale | Anticuerpos contra PD-1 y anticuerpos contra PD-L1 y usos de los mismos |
US20100239583A1 (en) * | 2009-03-04 | 2010-09-23 | Inotek Pharmaceuticals Corporation | Antibodies against flagellin and uses thereof |
WO2011041613A2 (en) * | 2009-09-30 | 2011-04-07 | Memorial Sloan-Kettering Cancer Center | Combination immunotherapy for the treatment of cancer |
US10016617B2 (en) | 2009-11-11 | 2018-07-10 | The Trustees Of The University Of Pennsylvania | Combination immuno therapy and radiotherapy for the treatment of Her-2-positive cancers |
WO2011100841A1 (en) * | 2010-02-16 | 2011-08-25 | Valorisation-Recherche, Limited Partnership | Pd-1 modulation and uses thereof for modulating hiv replication |
TW201134488A (en) * | 2010-03-11 | 2011-10-16 | Ucb Pharma Sa | PD-1 antibodies |
US8993731B2 (en) | 2010-03-11 | 2015-03-31 | Ucb Biopharma Sprl | PD-1 antibody |
AU2011230537C1 (en) | 2010-03-26 | 2018-08-02 | Trustees Of Dartmouth College | Vista regulatory T cell mediator protein, vista binding agents and use thereof |
US20150231215A1 (en) | 2012-06-22 | 2015-08-20 | Randolph J. Noelle | VISTA Antagonist and Methods of Use |
US10745467B2 (en) | 2010-03-26 | 2020-08-18 | The Trustees Of Dartmouth College | VISTA-Ig for treatment of autoimmune, allergic and inflammatory disorders |
JP2013532153A (ja) | 2010-06-18 | 2013-08-15 | ザ ブリガム アンド ウィメンズ ホスピタル インコーポレイテッド | 慢性免疫病に対する免疫治療のためのtim−3およびpd−1に対する二重特異性抗体 |
US8907053B2 (en) | 2010-06-25 | 2014-12-09 | Aurigene Discovery Technologies Limited | Immunosuppression modulating compounds |
US9783578B2 (en) | 2010-06-25 | 2017-10-10 | Aurigene Discovery Technologies Limited | Immunosuppression modulating compounds |
US8906649B2 (en) | 2010-09-27 | 2014-12-09 | Janssen Biotech, Inc. | Antibodies binding human collagen II |
WO2012047583A2 (en) * | 2010-09-27 | 2012-04-12 | Janssen Biotech, Inc. | Antibodies binding human collagen ii |
CN107412756A (zh) | 2010-10-01 | 2017-12-01 | 宾夕法尼亚大学理事会 | 李斯特菌疫苗载体用于在寄生虫感染的个体中扭转免疫无应答的用途 |
KR102157971B1 (ko) | 2010-10-06 | 2020-09-18 | 프레지던트 앤드 펠로우즈 오브 하바드 칼리지 | 재료에 기초한 세포 치료를 위한 주사 가능한 기공 형성 하이드로겔 |
AU2012229218B2 (en) | 2011-03-11 | 2017-03-02 | Advaxis, Inc. | Listeria-based adjuvants |
HUE039209T2 (hu) | 2011-03-31 | 2018-12-28 | Merck Sharp & Dohme | Antitestek stabil formulációi emberi programozott halálreceptor PD-1 ellen és ezzel kapcsolatos kezelések |
EP2699603B1 (en) | 2011-04-19 | 2016-03-02 | The United States of America As Represented by the Secretary Department of Health and Human Services | Human monoclonal antibodies specific for glypican-3 and use thereof |
KR101970025B1 (ko) | 2011-04-20 | 2019-04-17 | 메디뮨 엘엘씨 | B7-h1 및 pd-1과 결합하는 항체 및 다른 분자들 |
US9096642B2 (en) | 2011-06-08 | 2015-08-04 | Aurigene Discovery Technologies Limited | Therapeutic compounds for immunomodulation |
US10081684B2 (en) | 2011-06-28 | 2018-09-25 | Whitehead Institute For Biomedical Research | Using sortases to install click chemistry handles for protein ligation |
EP3812387A1 (en) | 2011-07-21 | 2021-04-28 | Sumitomo Dainippon Pharma Oncology, Inc. | Heterocyclic protein kinase inhibitors |
ES2893855T3 (es) | 2011-08-11 | 2022-02-10 | Ono Pharmaceutical Co | Agente terapéutico para enfermedades autoinmunes que comprende agonista de PD-1 |
CN104159911A (zh) | 2012-03-07 | 2014-11-19 | 奥瑞基尼探索技术有限公司 | 作为免疫调节剂的模拟肽化合物 |
SG10201700392UA (en) | 2012-03-12 | 2017-03-30 | Advaxis Inc | Suppressor cell function inhibition following listeria vaccine treatment |
KR20140142736A (ko) | 2012-03-29 | 2014-12-12 | 오리진 디스커버리 테크놀로지스 리미티드 | 인간의 pd1의 bc 루프로부터의 면역조절 사이클릭 화합물 |
WO2013155493A1 (en) | 2012-04-12 | 2013-10-17 | Yale University | Methods of treating inflammatory and autoimmune diseases and disorders |
AU2013249366B2 (en) | 2012-04-16 | 2018-02-01 | President And Fellows Of Harvard College | Mesoporous silica compositions for modulating immune responses |
US9856320B2 (en) * | 2012-05-15 | 2018-01-02 | Bristol-Myers Squibb Company | Cancer immunotherapy by disrupting PD-1/PD-L1 signaling |
EP3553086A1 (en) * | 2012-05-31 | 2019-10-16 | Sorrento Therapeutics Inc. | Antigen binding proteins that bind pd-l1 |
IL289834B1 (en) | 2012-06-13 | 2024-03-01 | Incyte Holdings Corp | Conversion of tricyclic compounds as FGFR inhibitors |
US9890215B2 (en) | 2012-06-22 | 2018-02-13 | King's College London | Vista modulators for diagnosis and treatment of cancer |
CN112587658A (zh) | 2012-07-18 | 2021-04-02 | 博笛生物科技有限公司 | 癌症的靶向免疫治疗 |
US10034938B2 (en) | 2012-08-30 | 2018-07-31 | Amgen Inc. | Method for treating melanoma using a herpes simplex virus and an immune checkpoint inhibitor |
CN105246507B (zh) | 2012-09-07 | 2019-01-25 | 达特茅斯大学理事会 | 用于诊断和治疗癌症的vista调节剂 |
WO2014122271A1 (en) | 2013-02-07 | 2014-08-14 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for predicting the survival time of patients suffering from diffuse large b-cell lymphomas |
ES2814962T3 (es) | 2013-02-20 | 2021-03-29 | Novartis Ag | Fijación eficaz como objetivo de la leucemia humana primaria utilizando células T modificadas con receptor de antígeno quimérico anti-CD123 |
CN111139256A (zh) | 2013-02-20 | 2020-05-12 | 诺华股份有限公司 | 使用人源化抗EGFRvIII嵌合抗原受体治疗癌症 |
ME03041B (me) | 2013-03-06 | 2018-10-20 | Astrazeneca Ab | Inhibitori hinazolina aktivirajućih mutantnih oblika receptora epidermalnog faktora rasta |
WO2014165082A2 (en) * | 2013-03-13 | 2014-10-09 | Medimmune, Llc | Antibodies and methods of detection |
US9308236B2 (en) | 2013-03-15 | 2016-04-12 | Bristol-Myers Squibb Company | Macrocyclic inhibitors of the PD-1/PD-L1 and CD80(B7-1)/PD-L1 protein/protein interactions |
UY35468A (es) | 2013-03-16 | 2014-10-31 | Novartis Ag | Tratamiento de cáncer utilizando un receptor quimérico de antígeno anti-cd19 |
EP2981821B2 (en) | 2013-04-02 | 2021-11-03 | Merck Sharp & Dohme Corp. | Immunohistochemical assay for detecting expression of programmed death ligand 1 (pd-l1) in tumor tissue |
US10532050B2 (en) | 2013-04-09 | 2020-01-14 | Lixte Biotechnology, Inc. | Formulations of oxabicycloheptanes and oxabicycloheptenes |
AU2014254019B2 (en) | 2013-04-18 | 2018-09-27 | Armo Biosciences, Inc. | Methods of using interleukin-10 for treating diseases and disorders |
SG10201708520YA (en) | 2013-04-19 | 2017-12-28 | Incyte Corp | Bicyclic heterocycles as fgfr inhibitors |
WO2014179664A2 (en) | 2013-05-02 | 2014-11-06 | Anaptysbio, Inc. | Antibodies directed against programmed death-1 (pd-1) |
EP2994530A4 (en) | 2013-05-10 | 2016-11-16 | Whitehead Biomedical Inst | PROTEIN MODIFICATION OF LIVING CELLS USING SORTASE |
EP3546484B1 (en) | 2013-05-10 | 2021-09-08 | Whitehead Institute for Biomedical Research | In vitro production of red blood cells with sortaggable proteins |
WO2014194293A1 (en) | 2013-05-30 | 2014-12-04 | Amplimmune, Inc. | Improved methods for the selection of patients for pd-1 or b7-h4 targeted therapies, and combination therapies thereof |
CN111423511B (zh) | 2013-05-31 | 2024-02-23 | 索伦托药业有限公司 | 与pd-1结合的抗原结合蛋白 |
US9823255B2 (en) | 2013-06-17 | 2017-11-21 | Armo Biosciences, Inc. | Method for assessing protein identity and stability |
CN111593414A (zh) | 2013-08-05 | 2020-08-28 | 特韦斯特生物科学公司 | 从头合成的基因文库 |
CA2920539C (en) | 2013-08-08 | 2024-01-02 | Cytune Pharma | Combined pharmaceutical composition |
SI3444271T1 (sl) | 2013-08-08 | 2022-03-31 | Cytune Pharma | Modulokini na osnovi IL-15 in IL-15Ralfa sushi domene |
WO2015026634A1 (en) | 2013-08-20 | 2015-02-26 | Merck Sharp & Dohme Corp. | Treating cancer with a combination of a pd-1 antagonist and dinaciclib |
AR097306A1 (es) | 2013-08-20 | 2016-03-02 | Merck Sharp & Dohme | Modulación de la inmunidad tumoral |
JP6509867B2 (ja) | 2013-08-30 | 2019-05-08 | アルモ・バイオサイエンシーズ・インコーポレイテッド | 疾患及び障害を治療するためにインターロイキン−10を使用する方法 |
KR20160075506A (ko) | 2013-09-06 | 2016-06-29 | 오리진 디스커버리 테크놀로지스 리미티드 | 면역조절제로서 사이클릭 펩티도미메틱 화합물 |
PL3363790T3 (pl) | 2013-09-06 | 2020-07-27 | Aurigene Discovery Technologies Limited | Pochodne 1,2,4-oksadiazolu jako immunomodulatory |
JP2016532711A (ja) | 2013-09-06 | 2016-10-20 | オーリジーン ディスカバリー テクノロジーズ リミテッドAurigene Discovery Technologies Limited | 免疫調節剤としての1,3,4−オキサジアゾール及び1,3,4−チアジアゾールの誘導体 |
US10077305B2 (en) * | 2013-09-10 | 2018-09-18 | Medimmune Limited | Antibodies against PD-1 and uses thereof |
EP3757130A1 (en) | 2013-09-26 | 2020-12-30 | Costim Pharmaceuticals Inc. | Methods for treating hematologic cancers |
CA2987519A1 (en) | 2013-11-01 | 2015-05-07 | Yale University | Delivery vehicles |
WO2015066413A1 (en) | 2013-11-01 | 2015-05-07 | Novartis Ag | Oxazolidinone hydroxamic acid compounds for the treatment of bacterial infections |
ES2862139T3 (es) | 2013-11-11 | 2021-10-07 | Armo Biosciences Inc | Procedimientos de uso de Interleucina 10 para el tratamiento de enfermedades y trastornos |
US20150140036A1 (en) | 2013-11-13 | 2015-05-21 | Novartis Institutes For Biomedical Research, Inc. | Low, immune enhancing, dose mtor inhibitors and uses thereof |
US10556024B2 (en) | 2013-11-13 | 2020-02-11 | Whitehead Institute For Biomedical Research | 18F labeling of proteins using sortases |
EP3079772B1 (en) | 2013-12-10 | 2020-02-05 | Merck Sharp & Dohme Corp. | Immunohistochemical proximity assay for pd-1 positive cells and pd-ligand positive cells in tumor tissue |
SI3081576T1 (sl) | 2013-12-12 | 2019-12-31 | Shanghai Hengrui Pharmaceutical Co., Ltd., | Protitelo PD-1, njegov antigen-vezavni fragment in njegova medicinska uporaba |
EP3084003A4 (en) | 2013-12-17 | 2017-07-19 | Merck Sharp & Dohme Corp. | Ifn-gamma gene signature biomarkers of tumor response to pd-1 antagonists |
JP6779785B2 (ja) | 2013-12-19 | 2020-11-04 | ノバルティス アーゲー | ヒトメソテリンキメラ抗原受容体およびその使用 |
US11014987B2 (en) | 2013-12-24 | 2021-05-25 | Janssen Pharmaceutics Nv | Anti-vista antibodies and fragments, uses thereof, and methods of identifying same |
EP3087098B1 (en) | 2013-12-24 | 2020-04-08 | Janssen Pharmaceutica NV | Anti-vista antibodies and fragments |
CA2936377A1 (en) | 2014-01-10 | 2015-07-16 | Shanghai Birdie Biotech, Inc. | Compounds and compositions for treating egfr expressing tumors |
JO3517B1 (ar) | 2014-01-17 | 2020-07-05 | Novartis Ag | ان-ازاسبيرو الكان حلقي كبديل مركبات اريل-ان مغايرة وتركيبات لتثبيط نشاط shp2 |
TWI681969B (zh) * | 2014-01-23 | 2020-01-11 | 美商再生元醫藥公司 | 針對pd-1的人類抗體 |
TWI680138B (zh) | 2014-01-23 | 2019-12-21 | 美商再生元醫藥公司 | 抗pd-l1之人類抗體 |
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 |
ES2783026T3 (es) | 2014-02-04 | 2020-09-16 | Pfizer | Combinación de un antagonista de PD-1 y un agonista de 4-1BB para el tratamiento de cáncer |
EP3102605B1 (en) | 2014-02-04 | 2018-11-14 | Pfizer Inc | Combination of a pd-1 antagonist and a vegfr inhibitor for treating cancer |
US20170037125A1 (en) | 2014-02-04 | 2017-02-09 | Incyte Corporation | Combination of a pd-1 antagonist and an ido1 inhibitor for treating cancer |
EP3114144A1 (en) | 2014-03-05 | 2017-01-11 | Bristol-Myers Squibb Company | Treatment of renal cancer using a combination of an anti-pd-1 antibody and another anti-cancer agent |
CN113583129A (zh) | 2014-03-14 | 2021-11-02 | 诺华股份有限公司 | 针对lag-3的抗体分子及其用途 |
EP3119423B1 (en) | 2014-03-15 | 2022-12-14 | Novartis AG | Treatment of cancer using chimeric antigen receptor |
PE20161371A1 (es) | 2014-03-24 | 2016-12-21 | Novartis Ag | Compuestos organicos de monobactam para el tratamiento de infecciones bacterianas |
RU2718542C2 (ru) | 2014-04-07 | 2020-04-08 | Новартис Аг | Лечение злокачественной опухоли с использованием химерного рецептора антигена против cd19 |
JP7348708B2 (ja) * | 2014-04-30 | 2023-09-21 | プレジデント・アンド・フェロウズ・オブ・ハーバード・カレッジ | 組み合わせワクチン装置および癌細胞を殺滅する方法 |
MX2016014753A (es) | 2014-05-15 | 2017-03-06 | Bristol Myers Squibb Co | Tratamiento de cancer de pulmon con el uso de una combinacion de un anticuerpo de muerte anti-programada 1 (anti-pd-1) y otro agente anti-cancerigeno. |
SG11201609770TA (en) | 2014-05-23 | 2016-12-29 | Eisai R&D Man Co Ltd | Combination therapies for the treatment of cancer |
WO2015181624A2 (en) | 2014-05-28 | 2015-12-03 | Idenix Pharmaceuticals, Inc | Nucleoside derivatives for the treatment of cancer |
SG11201609721WA (en) | 2014-05-28 | 2016-12-29 | Agenus Inc | Anti-gitr antibodies and methods of use thereof |
WO2015187295A2 (en) | 2014-06-02 | 2015-12-10 | Armo Biosciences, Inc. | Methods of lowering serum cholesterol |
WO2015187835A2 (en) | 2014-06-06 | 2015-12-10 | Bristol-Myers Squibb Company | Antibodies against glucocorticoid-induced tumor necrosis factor receptor (gitr) and uses thereof |
CA2951885C (en) | 2014-06-11 | 2023-07-04 | Kathy A. Green | Use of vista agonists and antagonists to suppress or enhance humoral immunity |
US10092645B2 (en) | 2014-06-17 | 2018-10-09 | Medimmune Limited | Methods of treatment with antagonists against PD-1 and PD-L1 in combination with radiation therapy |
RU2735958C2 (ru) | 2014-06-19 | 2020-11-11 | Регенерон Фармасьютикалз, Инк. | Животные, отличные от человека, имеющие гуманизированный ген 1 запрограммированной гибели клеток |
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 |
CN105440135A (zh) | 2014-09-01 | 2016-03-30 | 博笛生物科技有限公司 | 用于***的抗-pd-l1结合物 |
CA2954446A1 (en) | 2014-07-09 | 2016-01-14 | Shanghai Birdie Biotech, Inc. | Anti-pd-l1 combinations for treating tumors |
PL3169341T3 (pl) | 2014-07-16 | 2019-12-31 | Transgene Sa | Wirus onkolityczny do ekspresji modulatorów punktu kontroli immunologicznej |
CA2955084C (en) | 2014-07-16 | 2023-08-29 | Transgene Sa | Combination of oncolytic virus with immune checkpoint modulators |
SG10201913696YA (en) | 2014-07-18 | 2020-03-30 | Advaxis Inc | Combination of a pd-1 antagonist and a listeria-based vaccine for treating prostate cancer |
ES2805475T3 (es) | 2014-07-21 | 2021-02-12 | Novartis Ag | Tratamiento del cáncer utilizando un receptor antigénico quimérico de CD33 |
WO2016014530A1 (en) | 2014-07-21 | 2016-01-28 | Novartis Ag | Combinations of low, immune enhancing. doses of mtor inhibitors and cars |
US11542488B2 (en) | 2014-07-21 | 2023-01-03 | Novartis Ag | Sortase synthesized chimeric antigen receptors |
US20170209492A1 (en) | 2014-07-31 | 2017-07-27 | Novartis Ag | Subset-optimized chimeric antigen receptor-containing t-cells |
US9982052B2 (en) | 2014-08-05 | 2018-05-29 | MabQuest, SA | Immunological reagents |
CN107001316A (zh) | 2014-08-06 | 2017-08-01 | 诺华股份有限公司 | 作为抗菌剂的喹诺酮衍生物 |
WO2016025880A1 (en) | 2014-08-14 | 2016-02-18 | Novartis Ag | Treatment of cancer using gfr alpha-4 chimeric antigen receptor |
TW202140557A (zh) | 2014-08-19 | 2021-11-01 | 瑞士商諾華公司 | 使用cd123嵌合抗原受體治療癌症 |
CA2955676A1 (en) | 2014-08-25 | 2016-03-03 | Pfizer Inc. | Combination of a pd-1 antagonist and an alk inhibitor for treating cancer |
US9535074B2 (en) | 2014-09-08 | 2017-01-03 | Merck Sharp & Dohme Corp. | Immunoassay for soluble PD-L1 |
WO2016040892A1 (en) | 2014-09-13 | 2016-03-17 | Novartis Ag | Combination therapies |
CA2961636A1 (en) | 2014-09-17 | 2016-03-24 | Boris ENGELS | Targeting cytotoxic cells with chimeric receptors for adoptive immunotherapy |
US10053683B2 (en) | 2014-10-03 | 2018-08-21 | Whitehead Institute For Biomedical Research | Intercellular labeling of ligand-receptor interactions |
AU2015327868A1 (en) | 2014-10-03 | 2017-04-20 | Novartis Ag | Combination therapies |
KR20170068504A (ko) | 2014-10-08 | 2017-06-19 | 노파르티스 아게 | 키메라 항원 수용체 요법에 대한 치료 반응성을 예측하는 바이오마커 및 그의 용도 |
MA41044A (fr) | 2014-10-08 | 2017-08-15 | Novartis Ag | Compositions et procédés d'utilisation pour une réponse immunitaire accrue et traitement contre le cancer |
ES2908056T3 (es) | 2014-10-10 | 2022-04-27 | Idera Pharmaceuticals Inc | Tratamiento del cáncer por agonistas del TLR9 con inhibidores del punto de control |
US9732119B2 (en) | 2014-10-10 | 2017-08-15 | Bristol-Myers Squibb Company | Immunomodulators |
CN107001478B (zh) | 2014-10-14 | 2022-01-11 | 诺华股份有限公司 | 针对pd-l1的抗体分子及其用途 |
KR20170068553A (ko) | 2014-10-14 | 2017-06-19 | 아르모 바이오사이언시스 인코포레이티드 | 인터류킨-15 조성물 및 이의 용도 |
EP3209320B1 (en) | 2014-10-22 | 2023-03-08 | Armo Biosciences, Inc. | Methods of using interleukin-10 for treating diseases and disorders |
SG11201702723VA (en) | 2014-10-29 | 2017-05-30 | Five Prime Therapeutics Inc | Combination therapy for cancer |
JP7305300B2 (ja) | 2014-11-05 | 2023-07-10 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | 併用免疫療法 |
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 |
KR20170080697A (ko) | 2014-11-13 | 2017-07-10 | 더 존스 홉킨스 유니버시티 | 관문 차단 및 미소부수체 불안정성 |
US9856292B2 (en) | 2014-11-14 | 2018-01-02 | Bristol-Myers Squibb Company | Immunomodulators |
AU2015347015B2 (en) | 2014-11-14 | 2019-02-14 | Novartis Ag | Antibody drug conjugates |
JP6891112B2 (ja) | 2014-11-20 | 2021-06-18 | プロメガ コーポレイションPromega Corporation | 免疫チェックポイントの調節因子を評価するためのシステム及び方法 |
US20180334490A1 (en) | 2014-12-03 | 2018-11-22 | Qilong H. Wu | Methods for b cell preconditioning in car therapy |
JP2017537927A (ja) | 2014-12-04 | 2017-12-21 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | がん(骨髄腫)を処置するための抗cs1および抗pd1抗体の併用 |
EP3226900A4 (en) | 2014-12-05 | 2018-09-19 | Immunext, Inc. | Identification of vsig8 as the putative vista receptor and its use thereof to produce vista/vsig8 modulators |
EP3226688B1 (en) | 2014-12-05 | 2020-07-01 | Merck Sharp & Dohme Corp. | Tricyclic compounds as inhibitors of mutant idh enzymes |
EP3226689B1 (en) | 2014-12-05 | 2020-01-15 | Merck Sharp & Dohme Corp. | Novel tricyclic compounds as inhibitors of mutant idh enzymes |
EP3226690B1 (en) | 2014-12-05 | 2020-05-20 | Merck Sharp & Dohme Corp. | Novel tricyclic compounds as inhibitors of mutant idh enzymes |
TWI595006B (zh) | 2014-12-09 | 2017-08-11 | 禮納特神經系統科學公司 | 抗pd-1抗體類和使用彼等之方法 |
KR102457921B1 (ko) | 2014-12-09 | 2022-10-25 | 리제너론 파마슈티칼스 인코포레이티드 | 인간화 분화 클러스터 274 유전자를 갖는 비인간 동물 |
KR20170086661A (ko) | 2014-12-09 | 2017-07-26 | 머크 샤프 앤드 돔 코포레이션 | Pd-1 길항제에 대한 반응의 유전자 시그너처 바이오마커를 유도하기 위한 시스템 및 방법 |
PE20171044A1 (es) | 2014-12-16 | 2017-07-19 | Novartis Ag | COMPUESTOS DE ISOXAZOL DE ACIDO HIDROXAMICO COMO INHIBIDORES DE LpxC |
US9861680B2 (en) | 2014-12-18 | 2018-01-09 | Bristol-Myers Squibb Company | Immunomodulators |
SG11201704975SA (en) | 2014-12-18 | 2017-07-28 | Amgen Inc | Stable frozen herpes simplex virus formulation |
US9944678B2 (en) | 2014-12-19 | 2018-04-17 | Bristol-Myers Squibb Company | Immunomodulators |
EP3234193B1 (en) | 2014-12-19 | 2020-07-15 | Massachusetts Institute of Technology | Molecular biomarkers for cancer immunotherapy |
WO2016100882A1 (en) | 2014-12-19 | 2016-06-23 | Novartis Ag | Combination therapies |
PT3240801T (pt) | 2014-12-31 | 2021-02-18 | Checkmate Pharmaceuticals Inc | Imunoterapia antitumoral combinada |
JP2018506526A (ja) | 2015-01-29 | 2018-03-08 | ボード オブ トラスティーズ オブ ミシガン ステイト ユニバーシティBoard Of Trustees Of Michigan State University | クリプティックポリペプチドおよびその使用 |
CA3012602A1 (en) | 2015-01-30 | 2016-08-04 | President And Fellows Of Harvard College | Peritumoral and intratumoral materials for cancer therapy |
WO2016126608A1 (en) | 2015-02-02 | 2016-08-11 | Novartis Ag | Car-expressing cells against multiple tumor antigens and uses thereof |
WO2016126615A1 (en) | 2015-02-03 | 2016-08-11 | Armo Biosciences, Inc. | Methods of using interleukin-10 for treating diseases and disorders |
US20160222060A1 (en) | 2015-02-04 | 2016-08-04 | Bristol-Myers Squibb Company | Immunomodulators |
MX2017010673A (es) | 2015-02-20 | 2018-03-21 | Incyte Corp | Heterociclos biciclicos como inhibidores de receptores del factor de crecimiento fibroblastico (fgfr). |
MA41551A (fr) | 2015-02-20 | 2017-12-26 | Incyte Corp | Hétérocycles bicycliques utilisés en tant qu'inhibiteurs de fgfr4 |
CA2977767A1 (en) | 2015-02-26 | 2016-09-01 | Merck Patent Gmbh | Pd-1 / pd-l1 inhibitors for the treatment of cancer |
BR112017018872A2 (pt) | 2015-03-04 | 2018-05-29 | Eisai R&D Man Co Ltd | combinação de um antagonista pd-1 e eribulina para tratamento de câncer |
KR20170122809A (ko) | 2015-03-04 | 2017-11-06 | 머크 샤프 앤드 돔 코포레이션 | 암을 치료하기 위한 pd-1 길항제 및 vegfr/fgfr/ret 티로신 키나제 억제제의 조합 |
BR112017018964A2 (pt) | 2015-03-06 | 2018-05-22 | Beyondspring Pharmaceuticals Inc | uso de plinabulin e métodos para tratar tumor cerebral |
RU2736045C2 (ru) | 2015-03-06 | 2020-11-11 | Бейондспринг Фармасьютикалс, Инк. | Способ лечения рака, ассоциированного с мутацией ras |
BR112017018908A2 (pt) | 2015-03-10 | 2018-04-17 | Aduro Biotech, Inc. | composições e métodos para ativar a sinalização dependente do "estimulador do gene de interferon |
CA3220902A1 (en) | 2015-03-10 | 2016-09-15 | Aurigene Discovery Technologies Limited | 1,2,4-oxadiazole and thiadiazole compounds as immunomodulators |
US9809625B2 (en) | 2015-03-18 | 2017-11-07 | Bristol-Myers Squibb Company | Immunomodulators |
WO2016154177A2 (en) | 2015-03-23 | 2016-09-29 | Jounce Therapeutics, Inc. | Antibodies to icos |
ES2820768T3 (es) | 2015-04-03 | 2021-04-22 | Xoma Technology Ltd | Tratamiento del cáncer usando inhibidores de TGF-beta y PD-1 |
WO2016164580A1 (en) | 2015-04-07 | 2016-10-13 | Novartis Ag | Combination of chimeric antigen receptor therapy and amino pyrimidine derivatives |
EP3280464A4 (en) | 2015-04-10 | 2018-09-26 | President and Fellows of Harvard College | Immune cell trapping devices and methods for making and using the same |
WO2016168133A1 (en) | 2015-04-17 | 2016-10-20 | Merck Sharp & Dohme Corp. | Blood-based biomarkers of tumor sensitivity to pd-1 antagonists |
MY188749A (en) | 2015-04-17 | 2021-12-28 | Bristol Myers Squibb Co | Compositions comprising a combination of nivolumab and ipilimumab |
JP7114457B2 (ja) | 2015-04-17 | 2022-08-08 | ザ トラスティーズ オブ ザ ユニバーシティ オブ ペンシルバニア | キメラ抗原受容体発現細胞の有効性および増殖を改善するための方法 |
US9981239B2 (en) | 2015-04-21 | 2018-05-29 | Twist Bioscience Corporation | Devices and methods for oligonucleic acid library synthesis |
EP3286211A1 (en) | 2015-04-23 | 2018-02-28 | Novartis AG | Treatment of cancer using chimeric antigen receptor and protein kinase a blocker |
KR20170140316A (ko) | 2015-04-28 | 2017-12-20 | 브리스톨-마이어스 스큅 컴퍼니 | 항-pd-1 항체를 사용한 pd-l1-양성 흑색종의 치료 |
KR20170138555A (ko) | 2015-04-28 | 2017-12-15 | 브리스톨-마이어스 스큅 컴퍼니 | 항-pd-1 항체 및 항-ctla-4 항체를 사용한 pd-l1-음성 흑색종의 치료 |
EP3736287A1 (en) | 2015-05-11 | 2020-11-11 | The Johns Hopkins University | Autoimmune antibodies for use in inhibiting cancer cell growth |
US10815264B2 (en) | 2015-05-27 | 2020-10-27 | Southern Research Institute | Nucleotides for the treatment of cancer |
WO2016191751A1 (en) | 2015-05-28 | 2016-12-01 | Bristol-Myers Squibb Company | Treatment of pd-l1 positive lung cancer using an anti-pd-1 antibody |
JP7121496B2 (ja) | 2015-05-28 | 2022-08-18 | アルモ・バイオサイエンシーズ・インコーポレイテッド | 癌治療で使用するためのペグ化インターロイキン-10 |
RU2017145558A (ru) | 2015-05-29 | 2019-07-01 | Мерк Шарп И Доум Корп. | Комбинация антагониста pd-1 и олигонуклеотида типа cpg-c для лечения рака |
CN107849144B (zh) | 2015-05-29 | 2021-09-17 | 艾吉纳斯公司 | 抗-ctla-4抗体及其使用方法 |
WO2016196389A1 (en) | 2015-05-29 | 2016-12-08 | Bristol-Myers Squibb Company | Treatment of renal cell carcinoma |
CN115554399A (zh) | 2015-05-31 | 2023-01-03 | 源生公司 | 用于免疫疗法的组合组合物 |
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 |
TW201709929A (zh) | 2015-06-12 | 2017-03-16 | 宏觀基因股份有限公司 | 治療癌症的聯合療法 |
JP2018516969A (ja) | 2015-06-12 | 2018-06-28 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | Pd−1およびcxcr4シグナル伝達経路の組合せ遮断による癌の処置 |
MY193229A (en) | 2015-06-16 | 2022-09-26 | Merck Patent Gmbh | Pd-l1 antagonist combination treatments |
CN107849145B (zh) * | 2015-06-16 | 2021-10-26 | 基因泰克公司 | 抗cd3抗体及其使用方法 |
EP3310813A1 (en) | 2015-06-17 | 2018-04-25 | Novartis AG | Antibody drug conjugates |
CN114133448A (zh) * | 2015-06-23 | 2022-03-04 | 纪念斯隆-凯特琳癌症中心 | 新型pd-1免疫调节剂 |
US11009509B2 (en) | 2015-06-24 | 2021-05-18 | Janssen Pharmaceutica Nv | Anti-VISTA antibodies and fragments |
BR112017028530A2 (pt) | 2015-07-02 | 2018-08-28 | Celgene Corp | terapia combinada para tratamento de cânceres hematológicos e tumores sólidos |
GB201511790D0 (en) | 2015-07-06 | 2015-08-19 | Iomet Pharma Ltd | Pharmaceutical compound |
JP7014706B2 (ja) | 2015-07-13 | 2022-02-01 | サイトメックス セラピューティクス インコーポレイテッド | 抗pd-1抗体、活性化可能抗pd-1抗体、およびその使用方法 |
KR20180027563A (ko) | 2015-07-13 | 2018-03-14 | 비욘드스프링 파마수티컬스, 인코포레이티드. | 플리나불린 조성물 |
WO2017011666A1 (en) | 2015-07-14 | 2017-01-19 | Bristol-Myers Squibb Company | Method of treating cancer using immune checkpoint inhibitor |
US10786547B2 (en) | 2015-07-16 | 2020-09-29 | Biokine Therapeutics Ltd. | Compositions, articles of manufacture and methods for treating cancer |
EP3322448A4 (en) | 2015-07-16 | 2019-03-06 | Bioxcel Therapeutics, Inc. | NOVEL METHOD FOR THE TREATMENT OF CANCER WITH IMMUNOMODULATION |
WO2017015427A1 (en) | 2015-07-21 | 2017-01-26 | Novartis Ag | Methods for improving the efficacy and expansion of immune cells |
CN106699888B (zh) * | 2015-07-28 | 2020-11-06 | 上海昀怡健康科技发展有限公司 | 一种pd-1抗体及其制备方法和应用 |
ES2878188T3 (es) | 2015-07-29 | 2021-11-18 | Novartis Ag | Terapias de combinación que comprenden moléculas de anticuerpos contra LAG-3 |
KR20180034426A (ko) | 2015-07-29 | 2018-04-04 | 노파르티스 아게 | 암의 치료에서의 항 pd-1 및 항 m-csf 항체의 조합 용도 |
BR112018001640A2 (pt) | 2015-07-29 | 2018-09-18 | Novartis Ag | combinação de antagonista da pd-1 com um inibidor de egfr |
EP3878465A1 (en) | 2015-07-29 | 2021-09-15 | Novartis AG | Combination therapies comprising antibody molecules to tim-3 |
PL3328419T3 (pl) | 2015-07-30 | 2021-12-27 | Macrogenics, Inc. | Cząsteczki wiążące pd-1 i sposoby ich zastosowania |
WO2017021911A1 (en) | 2015-08-04 | 2017-02-09 | Glaxosmithkline Intellectual Property Development Limited | Combination treatments and uses and methods thereof |
CA2994635A1 (en) | 2015-08-04 | 2017-02-09 | Glaxosmithkline Intellectual Property Development Limited | Combination treatments and uses and methods thereof |
US20190010231A1 (en) | 2015-08-07 | 2019-01-10 | Pieris Pharmaceuticals Gmbh | Novel fusion polypeptide specific for lag-3 and pd-1 |
WO2017025871A1 (en) | 2015-08-07 | 2017-02-16 | Glaxosmithkline Intellectual Property Development Limited | Combination therapy comprising anti ctla-4 antibodies |
WO2017024465A1 (en) * | 2015-08-10 | 2017-02-16 | Innovent Biologics (Suzhou) Co., Ltd. | Pd-1 antibodies |
RU2729830C2 (ru) * | 2015-08-11 | 2020-08-12 | Уси Байолоджикс (Кайман) Инк. | Новые анти-pd-1 антитела |
EP3344644A4 (en) | 2015-08-13 | 2019-02-27 | Merck Sharp & Dohme Corp. | CYCLIC DI-NUCLEOTIDE COMPOUNDS AS STING AGONISTS |
US11453697B1 (en) | 2015-08-13 | 2022-09-27 | Merck Sharp & Dohme Llc | Cyclic di-nucleotide compounds as sting agonists |
WO2017031242A1 (en) | 2015-08-20 | 2017-02-23 | Sutro Biopharma, Inc. | Anti-tim-3 antibodies, compositions comprising anti-tim-3 antibodies and methods of making and using anti-tim-3 antibodies |
EP3341012A4 (en) | 2015-08-25 | 2019-03-20 | Armo Biosciences, Inc. | METHOD FOR USE OF INTERLEUKIN-10 FOR THE TREATMENT OF ILLNESSES AND SUFFERING |
ES2955775T3 (es) | 2015-08-27 | 2023-12-07 | Inst Nat Sante Rech Med | Métodos para predecir el tiempo de supervivencia de pacientes que padecen cáncer de pulmón |
US10323091B2 (en) | 2015-09-01 | 2019-06-18 | Agenus Inc. | Anti-PD-1 antibodies and methods of use thereof |
JP7074341B2 (ja) | 2015-09-02 | 2022-05-24 | イムテップ エス.アー.エス. | 抗lag-3抗体 |
US11747346B2 (en) | 2015-09-03 | 2023-09-05 | Novartis Ag | Biomarkers predictive of cytokine release syndrome |
US20170114098A1 (en) | 2015-09-03 | 2017-04-27 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles and uses thereof |
EA201890763A1 (ru) | 2015-09-18 | 2018-08-31 | Твист Байосайенс Корпорейшн | Библиотеки вариантных олигонуклеиновых кислот и их синтез |
CN113604546A (zh) | 2015-09-22 | 2021-11-05 | 特韦斯特生物科学公司 | 用于核酸合成的柔性基底 |
WO2017055327A1 (en) | 2015-09-29 | 2017-04-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for quantifying the population of endothelial cells in a tissue sample |
KR20180054824A (ko) | 2015-09-29 | 2018-05-24 | 셀진 코포레이션 | Pd-1 결합 단백질 및 이의 사용 방법 |
ES2839212T3 (es) | 2015-09-29 | 2021-07-05 | Inst Nat Sante Rech Med | Métodos para determinar el estado metabólico de linfomas B |
WO2017055319A1 (en) | 2015-09-29 | 2017-04-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for quantifying the population of b cells in a tissue sample |
WO2017055321A1 (en) | 2015-09-29 | 2017-04-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for quantifying the population of fibroblasts in a tissue sample |
WO2017055320A1 (en) | 2015-09-29 | 2017-04-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for quantifying the population of cytotoxic lymphocytes in a tissue sample |
WO2017055322A1 (en) | 2015-09-29 | 2017-04-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for quantifying the population of neutrophils in a tissue sample |
WO2017055326A1 (en) | 2015-09-29 | 2017-04-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for quantifying the population of myeloid dendritic cells in a tissue sample |
WO2017055324A1 (en) | 2015-09-29 | 2017-04-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for quantifying the population of cells of monocytic origin in a tissue sample |
WO2017055325A1 (en) | 2015-09-29 | 2017-04-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for quantifying the population of nk cells in a tissue sample |
US20190054090A1 (en) | 2015-10-01 | 2019-02-21 | Gilead Sciences, Inc. | Combination of a btk inhibitor and a checkpoint inhibitor for treating cancers |
EP4218833A1 (en) | 2015-10-01 | 2023-08-02 | Whitehead Institute for Biomedical Research | Labeling of antibodies |
MA43018B1 (fr) | 2015-10-02 | 2021-11-30 | Hoffmann La Roche | Anticorps anti-pd1 et procédés d'utilisation |
CN108137699B (zh) | 2015-10-02 | 2022-05-27 | 豪夫迈·罗氏有限公司 | 对pd1和tim3特异性的双特异性抗体 |
WO2017062619A2 (en) | 2015-10-08 | 2017-04-13 | Macrogenics, Inc. | Combination therapy for the treatment of cancer |
WO2017060397A1 (en) | 2015-10-09 | 2017-04-13 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for predicting the survival time of subjects suffering from melanoma metastases |
WO2017066561A2 (en) | 2015-10-16 | 2017-04-20 | President And Fellows Of Harvard College | Regulatory t cell pd-1 modulation for regulating t cell effector immune responses |
EP3365062A4 (en) | 2015-10-19 | 2019-07-17 | Cold Genesys, Inc. | METHODS OF TREATING SOLID OR LYMPHATIC TUMORS BY POLYTHERAPY |
CN108350505A (zh) | 2015-10-22 | 2018-07-31 | 震动疗法股份有限公司 | 用于测定icos表达的基因标志 |
CN105238762A (zh) * | 2015-10-26 | 2016-01-13 | 无锡傲锐东源生物科技有限公司 | 抗pd-1蛋白单克隆抗体杂交瘤细胞及其产生的抗pd-1单克隆抗体和应用 |
MA44334A (fr) | 2015-10-29 | 2018-09-05 | Novartis Ag | Conjugués d'anticorps comprenant un agoniste du récepteur de type toll |
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 |
MX2018005517A (es) | 2015-11-02 | 2018-11-09 | Five Prime Therapeutics Inc | Polipeptidos del dominio extracelular de cd80 y su uso en el tratamiento del cancer. |
EP3370768B9 (en) | 2015-11-03 | 2022-03-16 | Janssen Biotech, Inc. | Antibodies specifically binding pd-1 and their uses |
CA3003969A1 (en) | 2015-11-06 | 2017-05-11 | Orionis Biosciences Nv | Bi-functional chimeric proteins and uses thereof |
KR20180071386A (ko) | 2015-11-18 | 2018-06-27 | 브리스톨-마이어스 스큅 컴퍼니 | 항-pd-1 항체 및 항-ctla-4 항체의 조합물을 사용하는 폐암의 치료 |
EP3380523A1 (en) | 2015-11-23 | 2018-10-03 | Five Prime Therapeutics, Inc. | Fgfr2 inhibitors alone or in combination with immune stimulating agents in cancer treatment |
KR20180083944A (ko) | 2015-12-02 | 2018-07-23 | 아게누스 인코포레이티드 | 항체 및 이의 사용 방법 |
MX363780B (es) | 2015-12-03 | 2019-04-03 | Glaxosmithkline Ip Dev Ltd | Dinucleótidos de purina cíclica como moduladores del estimulador de los genes de interferón. |
WO2017098421A1 (en) | 2015-12-08 | 2017-06-15 | Glaxosmithkline Intellectual Property Development Limited | Benzothiadiazine compounds |
CN105837692A (zh) * | 2015-12-10 | 2016-08-10 | 苏州佰通生物科技有限公司 | 一种阻断免疫检测点的嵌合抗原受体及其应用 |
AR107781A1 (es) | 2015-12-14 | 2018-06-06 | Macrogenics Inc | Moléculas biespecíficas que tienen inmunorreactividad con pd-1 y ctla-4, y métodos de uso de las mismas |
WO2017106062A1 (en) | 2015-12-15 | 2017-06-22 | Merck Sharp & Dohme Corp. | Novel compounds as indoleamine 2,3-dioxygenase inhibitors |
CA3006984C (en) | 2015-12-15 | 2023-10-17 | Oncoimmune, Inc. | Chimeric and humanized anti-human ctla4 monoclonal antibodies and uses thereof |
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 |
EP3389712B1 (en) | 2015-12-17 | 2024-04-10 | Novartis AG | Antibody molecules to pd-1 and uses thereof |
WO2017103895A1 (en) | 2015-12-18 | 2017-06-22 | Novartis Ag | Antibodies targeting cd32b and methods of use thereof |
ES2954153T3 (es) | 2015-12-22 | 2023-11-20 | Regeneron Pharma | Combinación de anticuerpos anti-PD-1 y anticuerpos biespecíficos anti-CD20/anti-CD3 para tratar el cáncer |
TWI767896B (zh) | 2015-12-22 | 2022-06-21 | 美商英塞特公司 | 作為免疫調節劑之雜環化合物 |
EP3393504A1 (en) | 2015-12-22 | 2018-10-31 | Novartis AG | Mesothelin chimeric antigen receptor (car) and antibody against pd-l1 inhibitor for combined use in anticancer therapy |
CN105669864B (zh) | 2015-12-23 | 2018-10-16 | 杭州尚健生物技术有限公司 | 抗人程序性死亡受体1抗体及其制备方法和用途 |
US20200264165A1 (en) | 2016-01-04 | 2020-08-20 | Inserm (Institut National De La Sante Et De Larecherche Medicale) | Use of pd-1 and tim-3 as a measure for cd8+ cells in predicting and treating renal cell carcinoma |
CN106943596A (zh) | 2016-01-07 | 2017-07-14 | 博笛生物科技(北京)有限公司 | 用于***的抗-cd20组合 |
CN106943598A (zh) | 2016-01-07 | 2017-07-14 | 博笛生物科技(北京)有限公司 | 用于***的抗-her2组合 |
CN115252792A (zh) | 2016-01-07 | 2022-11-01 | 博笛生物科技有限公司 | 用于***的抗-egfr组合 |
BR112018013761A2 (pt) | 2016-01-08 | 2018-12-11 | Celgene Corp | compostos antiproliferativos e suas composições farmacêuticas e usos |
KR20180100565A (ko) | 2016-01-08 | 2018-09-11 | 셀진 코포레이션 | 2-(4-클로로페닐)-n-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-2,2-디플루오로아세트아미드의 제형 |
TWI733734B (zh) | 2016-01-08 | 2021-07-21 | 美商西建公司 | 2-(4-氯苯基)-n-((2-(2,6-二氧六氫吡啶-3-基)-1-氧基異吲哚啉-5-基)甲基)-2,2-二氟乙醯胺之固體型式,及其醫藥組合物及用途 |
CA3009001A1 (en) | 2016-01-11 | 2017-07-20 | Universitat Zurich | Immune-stimulating humanized monoclonal antibodies against human interleukin-2, and fusion proteins thereof |
US11214617B2 (en) | 2016-01-22 | 2022-01-04 | MabQuest SA | Immunological reagents |
JP6970099B2 (ja) | 2016-01-28 | 2021-11-24 | アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル | ガンの処置のための方法及び医薬組成物 |
WO2017129763A1 (en) | 2016-01-28 | 2017-08-03 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for the treatment of signet ring cell gastric cancer |
JP6902040B2 (ja) | 2016-01-28 | 2021-07-14 | アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル | 免疫チェックポイント阻害剤の効力を増強する方法 |
WO2017133175A1 (en) * | 2016-02-04 | 2017-08-10 | Nanjing Legend Biotech Co., Ltd. | Engineered mammalian cells for cancer therapy |
CA3013554A1 (en) | 2016-02-05 | 2017-08-10 | Orionis Biosciences Nv | Targeted therapeutic agents and uses thereof |
CN115531609A (zh) | 2016-02-06 | 2022-12-30 | 哈佛学院校长同事会 | 重塑造血巢以重建免疫 |
SG11201806583XA (en) | 2016-02-08 | 2018-09-27 | Beyondspring Pharmaceuticals Inc | Compositions containing tucaresol or its analogs |
CN109069626A (zh) | 2016-02-12 | 2018-12-21 | 詹森药业有限公司 | 抗-vista(b7h5)抗体 |
AU2017219254B2 (en) | 2016-02-17 | 2019-12-12 | Novartis Ag | TGFbeta 2 antibodies |
WO2017140821A1 (en) | 2016-02-19 | 2017-08-24 | Novartis Ag | Tetracyclic pyridone compounds as antivirals |
CA3013333A1 (en) | 2016-02-26 | 2017-08-31 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Antibodies having specificity for btla and uses thereof |
EP3423488A4 (en) | 2016-02-29 | 2019-11-06 | Foundation Medicine, Inc. | METHOD FOR THE TREATMENT OF CANCER |
CN109153714A (zh) | 2016-03-04 | 2019-01-04 | 诺华股份有限公司 | 表达多重嵌合抗原受体(car)分子的细胞及其用途 |
US10143746B2 (en) | 2016-03-04 | 2018-12-04 | Bristol-Myers Squibb Company | Immunomodulators |
WO2017155981A1 (en) | 2016-03-07 | 2017-09-14 | Massachusetts Institute Of Technology | Protein-chaperoned t-cell vaccines |
EP3426271A4 (en) | 2016-03-10 | 2019-10-16 | Cold Genesys, Inc. | METHODS OF TREATING SOLID OR LYMPHATIC TUMORS BY POLYTHERAPY |
WO2017153952A1 (en) | 2016-03-10 | 2017-09-14 | Glaxosmithkline Intellectual Property Development Limited | 5-sulfamoyl-2-hydroxybenzamide derivatives |
WO2017160599A1 (en) | 2016-03-14 | 2017-09-21 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Use of cd300b antagonists to treat sepsis and septic shock |
AU2017234163B2 (en) | 2016-03-15 | 2023-01-19 | Mersana Therapeutics, Inc. | NaPi2b-targeted antibody-drug conjugates and methods of use thereof |
WO2017160975A1 (en) * | 2016-03-16 | 2017-09-21 | Bristol-Myers Squibb Company | Methods of diagnosing and treating lupus |
US20210309965A1 (en) | 2016-03-21 | 2021-10-07 | Dana-Farber Cancer Institute, Inc. | T-cell exhaustion state-specific gene expression regulators and uses thereof |
WO2017165683A1 (en) | 2016-03-23 | 2017-09-28 | Novartis Ag | Cell secreted minibodies and uses thereof |
DK3433257T3 (da) | 2016-03-24 | 2024-01-02 | Novartis Ag | Alkynylnukleosidanaloger som hæmmere af human rhinovirus |
WO2017165778A1 (en) | 2016-03-24 | 2017-09-28 | Millennium Pharmaceuticals, Inc. | Methods of treating gastrointestinal immune-related adverse events in immune oncology treatments |
TW201735949A (zh) | 2016-03-24 | 2017-10-16 | 千禧製藥公司 | 治療抗ctla4及抗pd-1組合治療中的胃腸道免疫相關不良事件之方法 |
EP3436066A1 (en) | 2016-04-01 | 2019-02-06 | Checkmate Pharmaceuticals, Inc. | Fc receptor-mediated drug delivery |
EP3225253A1 (en) | 2016-04-01 | 2017-10-04 | Deutsches Krebsforschungszentrum Stiftung des Öffentlichen Rechts | Cancer therapy with an oncolytic virus combined with a checkpoint inhibitor |
CN107286242B (zh) | 2016-04-01 | 2019-03-22 | 中山康方生物医药有限公司 | 抗pd-1的单克隆抗体 |
US10358463B2 (en) | 2016-04-05 | 2019-07-23 | Bristol-Myers Squibb Company | Immunomodulators |
US11209441B2 (en) | 2016-04-05 | 2021-12-28 | Bristol-Myers Squibb Company | Cytokine profiling analysis |
CN109563081A (zh) | 2016-04-07 | 2019-04-02 | 葛兰素史克知识产权开发有限公司 | 可用作蛋白调节剂的杂环酰胺类 |
US10981901B1 (en) | 2016-04-07 | 2021-04-20 | Glaxosmithkline Intellectual Property Development Limited | Heterocyclic amides useful as protein modulators |
AU2017249698B2 (en) | 2016-04-13 | 2023-03-09 | Vivia Biotech, S.L | Ex vivo bite-activated T cells |
CN109789201B (zh) | 2016-04-15 | 2023-06-16 | 伊穆奈克斯特股份有限公司 | 抗人vista抗体及其用途 |
WO2017192874A1 (en) | 2016-05-04 | 2017-11-09 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Albumin-binding immunomodulatory compositions and methods of use thereof |
PE20190106A1 (es) | 2016-05-05 | 2019-01-15 | Glaxosmithkline Ip No 2 Ltd | Inhibidores del potenciador del homologo zeste 2 |
TWI755395B (zh) | 2016-05-13 | 2022-02-21 | 美商再生元醫藥公司 | 抗-pd-1抗體與輻射治療癌症之組合 |
EP3243832A1 (en) | 2016-05-13 | 2017-11-15 | F. Hoffmann-La Roche AG | Antigen binding molecules comprising a tnf family ligand trimer and pd1 binding moiety |
CA3023881A1 (en) | 2016-05-13 | 2017-11-16 | Orionis Biosciences Nv | Therapeutic targeting of non-cellular structures |
EP3454887B1 (en) | 2016-05-13 | 2021-01-20 | Orionis Biosciences BV | Targeted mutant interferon-beta and uses thereof |
AU2017266298B2 (en) | 2016-05-18 | 2024-01-04 | Boehringer Ingelheim International Gmbh | Anti PD-1 and anti-LAG3 antibodies for cancer treatment |
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 |
JP7194022B2 (ja) | 2016-05-20 | 2022-12-21 | イーライ リリー アンド カンパニー | Notch阻害剤とPD-1またはPD-L1阻害剤との併用療法 |
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 |
EP3463452A1 (en) | 2016-05-24 | 2019-04-10 | Institut National de la Sante et de la Recherche Medicale (INSERM) | Methods and pharmaceutical compositions for the treatment of non small cell lung cancer (nsclc) that coexists with chronic obstructive pulmonary disease (copd) |
WO2017202949A1 (en) | 2016-05-25 | 2017-11-30 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating cancers |
KR20230091191A (ko) | 2016-05-27 | 2023-06-22 | 아게누스 인코포레이티드 | 항-tim-3 항체 및 이의 사용 방법 |
KR20190008962A (ko) | 2016-06-02 | 2019-01-25 | 브리스톨-마이어스 스큅 컴퍼니 | 림프종 치료에서의 항-cd30 항체와 조합된 항-pd-1 항체의 용도 |
DK3463436T3 (da) | 2016-06-02 | 2023-12-18 | Ultimovacs Asa | Vaccine i kombination med en immuncheckpoint-hæmmer til anvendelse i cancerbehandling |
ES2954139T3 (es) | 2016-06-02 | 2023-11-20 | Bristol Myers Squibb Co | Bloqueo de PD-1 con nivolumab en el linfoma de Hodgkin refractario |
KR20190015407A (ko) | 2016-06-03 | 2019-02-13 | 브리스톨-마이어스 스큅 컴퍼니 | 재발성 소세포 폐암의 치료 방법에 사용하기 위한 항-pd-1 항체 |
CN109476754A (zh) | 2016-06-03 | 2019-03-15 | 百时美施贵宝公司 | 抗-pd-1抗体在治疗结肠直肠癌患者中的用途 |
EP3464369A1 (en) | 2016-06-03 | 2019-04-10 | Bristol-Myers Squibb Company | Anti-pd-1 antibody for use in a method of treating a tumor |
SG11201810872UA (en) | 2016-06-06 | 2019-01-30 | Beyondspring Pharmaceuticals Inc | Composition and method for reducing neutropenia |
WO2017212423A1 (en) | 2016-06-08 | 2017-12-14 | Glaxosmithkline Intellectual Property Development Limited | Chemcical compounds |
BR112018075598A2 (pt) | 2016-06-08 | 2019-03-26 | Glaxosmithkline Intellectual Property Development Limited | compostos químicos |
WO2017218533A1 (en) | 2016-06-13 | 2017-12-21 | Torque Therapeutics, Inc. | Methods and compositions for promoting immune cell function |
WO2017216705A1 (en) | 2016-06-14 | 2017-12-21 | Novartis Ag | Crystalline form of (r)-4-(5-(cyclopropylethynyl)isoxazol-3-yl)-n-hydroxy-2-methyl-2-(methylsulfonyl)butanamide as an antibacterial agent |
EP4257613A3 (en) * | 2016-06-14 | 2023-12-13 | Xencor, Inc. | Bispecific checkpoint inhibitor antibodies |
WO2017216686A1 (en) | 2016-06-16 | 2017-12-21 | Novartis Ag | 8,9-fused 2-oxo-6,7-dihydropyrido-isoquinoline compounds as antivirals |
WO2017216685A1 (en) | 2016-06-16 | 2017-12-21 | Novartis Ag | Pentacyclic pyridone compounds as antivirals |
SG11201810509PA (en) | 2016-06-20 | 2018-12-28 | Kymab Ltd | Anti-pd-l1 antibodies |
AU2017281285C1 (en) | 2016-06-20 | 2022-05-12 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
WO2017223422A1 (en) | 2016-06-24 | 2017-12-28 | Infinity Pharmaceuticals, Inc. | Combination therapies |
US11098077B2 (en) | 2016-07-05 | 2021-08-24 | Chinook Therapeutics, Inc. | Locked nucleic acid cyclic dinucleotide compounds and uses thereof |
IL264186B1 (en) | 2016-07-12 | 2024-04-01 | Revolution Medicines Inc | 2,5-dimutomers of 3-methylpyrazines and 2,5,6-dimutomers of 3-methylpyrazines as allosteric SHP2 inhibitors |
WO2018011166A2 (en) | 2016-07-12 | 2018-01-18 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for quantifying the population of myeloid dendritic cells in a tissue sample |
WO2018013797A1 (en) | 2016-07-13 | 2018-01-18 | President And Fellows Of Harvard College | Antigen-presenting cell-mimetic scaffolds and methods for making and using the same |
EP3487503A1 (en) | 2016-07-20 | 2019-05-29 | GlaxoSmithKline Intellectual Property Development Limited | Isoquinoline derivatives as perk inhibitors |
KR102565885B1 (ko) | 2016-07-20 | 2023-08-09 | 유니버시티 오브 유타 리서치 파운데이션 | Cd229 car t 세포 및 이의 사용 방법 |
WO2018023025A1 (en) | 2016-07-28 | 2018-02-01 | Novartis Ag | Combination therapies of chimeric antigen receptors adn pd-1 inhibitors |
CN109562282A (zh) | 2016-07-29 | 2019-04-02 | 伊莱利利公司 | 用于治疗癌症的使用merestinib和抗-pd-l1或抗-pd-1抑制剂的组合疗法 |
EP3490548A4 (en) | 2016-08-01 | 2020-04-15 | Molecular Templates, Inc. | ADMINISTRATION OF HYPOXIA-ACTIVATED DRUGS IN COMBINATION WITH IMMUNOMODULATORS FOR THE TREATMENT OF CANCER |
US11649289B2 (en) | 2016-08-04 | 2023-05-16 | Glaxosmithkline Intellectual Property Development Limited | Anti-ICOS and anti-PD-1 antibody combination therapy |
WO2018027524A1 (en) | 2016-08-09 | 2018-02-15 | Innovent Biologics (Suzhou) Co., Ltd. | Pd-1 antibody formulation |
WO2018029336A1 (en) | 2016-08-12 | 2018-02-15 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for determining whether a subject was administered with an activator of the ppar beta/delta pathway. |
JP6854340B2 (ja) | 2016-08-22 | 2021-04-07 | ツイスト バイオサイエンス コーポレーション | デノボ合成された核酸ライブラリ |
CN106977602B (zh) * | 2016-08-23 | 2018-09-25 | 中山康方生物医药有限公司 | 一种抗pd1单克隆抗体、其药物组合物及其用途 |
CN106967172B (zh) | 2016-08-23 | 2019-01-08 | 康方药业有限公司 | 抗ctla4-抗pd-1 双功能抗体、其药物组合物及其用途 |
WO2018035710A1 (en) | 2016-08-23 | 2018-03-01 | Akeso Biopharma, Inc. | Anti-ctla4 antibodies |
WO2018045177A1 (en) | 2016-09-01 | 2018-03-08 | Chimera Bioengineering, Inc. | Gold optimized car t-cells |
TW201811788A (zh) | 2016-09-09 | 2018-04-01 | 瑞士商諾華公司 | 作為抗病毒劑之多環吡啶酮化合物 |
US20190218294A1 (en) | 2016-09-09 | 2019-07-18 | Bristol-Myers Squibb Company | Use of an anti-pd-1 antibody in combination with an anti-mesothelin antibody in cancer treatment |
AU2017322501A1 (en) | 2016-09-09 | 2019-03-28 | Laboratoire Francais Du Fractionnement Et Des Biotechnologies | Combination of an anti-CD20 antibody, PI3 kinase-delta inhibitor, and anti-PD-1 or anti-PD-L1 antibody for treating hematological cancers |
WO2018046738A1 (en) | 2016-09-12 | 2018-03-15 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for predicting the survival time of patients suffering from cancer |
WO2018046736A1 (en) | 2016-09-12 | 2018-03-15 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for predicting the survival time of patients suffering from cancer |
UA124631C2 (uk) | 2016-09-14 | 2021-10-20 | Еббві Байотерапьютікс Інк. | Антитіло до pd-1 |
JP2019533645A (ja) | 2016-09-16 | 2019-11-21 | ザ・ジョンズ・ホプキンス・ユニバーシティー | 標的組織および細胞内送達のための増大した粘膜浸透のタンパク質ナノケージ |
JP2019531284A (ja) | 2016-09-19 | 2019-10-31 | セルジーン コーポレイション | Pd−1結合タンパク質を使用して免疫障害を治療する方法 |
JP2019534859A (ja) | 2016-09-19 | 2019-12-05 | セルジーン コーポレイション | Pd−1結合タンパク質を使用して白斑を治療する方法 |
KR102217487B1 (ko) | 2016-09-21 | 2021-02-23 | 트위스트 바이오사이언스 코포레이션 | 핵산 기반 데이터 저장 |
RU2759334C2 (ru) | 2016-09-21 | 2021-11-12 | Нексткьюр, Инк. | Антитела против siglec-15 и способы их применения |
WO2018057585A1 (en) | 2016-09-21 | 2018-03-29 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Chimeric antigen receptor (car) that targets chemokine receptor ccr4 and its use |
WO2018055080A1 (en) | 2016-09-22 | 2018-03-29 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for reprograming immune environment in a subject in need thereof |
JP7274413B2 (ja) | 2016-09-23 | 2023-05-16 | マレンゴ・セラピューティクス,インコーポレーテッド | ラムダ及びカッパ軽鎖を含む多重特異性抗体分子 |
JOP20190061A1 (ar) | 2016-09-28 | 2019-03-26 | Novartis Ag | مثبطات بيتا-لاكتاماز |
RS62410B1 (sr) | 2016-10-04 | 2021-10-29 | Merck Sharp & Dohme | Benzo[b]tiofenska jedinjenja kao agonisti sting |
JP2019530704A (ja) | 2016-10-06 | 2019-10-24 | ファイザー・インコーポレイテッド | がんの処置のためのアベルマブの投与レジメン |
US10525083B2 (en) | 2016-10-07 | 2020-01-07 | Novartis Ag | Nucleic acid molecules encoding chimeric antigen receptors comprising a CD20 binding domain |
MA46529A (fr) | 2016-10-11 | 2019-08-21 | Agenus Inc | Anticorps anti-lag-3 et leurs procédés d'utilisation |
JP2019530706A (ja) | 2016-10-14 | 2019-10-24 | メルク・シャープ・アンド・ドーム・コーポレーションMerck Sharp & Dohme Corp. | 尿路上皮がんを治療するための、pd−1アンタゴニスト及びエリブリンの組合せ |
WO2018071576A1 (en) | 2016-10-14 | 2018-04-19 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Treatment of tumors by inhibition of cd300f |
WO2018073753A1 (en) | 2016-10-18 | 2018-04-26 | Novartis Ag | Fused tetracyclic pyridone compounds as antivirals |
WO2018075447A1 (en) | 2016-10-19 | 2018-04-26 | The Trustees Of Columbia University In The City Of New York | Combination of braf inhibitor, talimogene laherparepvec, and immune checkpoint inhibitor for use in the treatment cancer (melanoma) |
WO2018077893A1 (en) | 2016-10-24 | 2018-05-03 | Orionis Biosciences Nv | Targeted mutant interferon-gamma and uses thereof |
CN110099925A (zh) | 2016-10-28 | 2019-08-06 | 百时美施贵宝公司 | 使用抗pd-1抗体治疗尿道上皮癌的方法 |
MA49863A (fr) | 2016-11-01 | 2020-06-17 | Anaptysbio Inc | Anticorps dirigés contre la mort programmée 1 (pd -1) |
CA3041183A1 (en) | 2016-11-02 | 2018-05-11 | Engmab Sarl | Bispecific antibody against bcma and cd3 and an immunological drug for combined use in treating multiple myeloma |
WO2018083087A2 (en) | 2016-11-02 | 2018-05-11 | Glaxosmithkline Intellectual Property (No.2) Limited | Binding proteins |
EP3535300A1 (en) | 2016-11-03 | 2019-09-11 | Bristol-Myers Squibb Company | Activatable anti-ctla-4 antibodies and uses thereof |
US10342785B2 (en) | 2016-11-04 | 2019-07-09 | Askat Inc. | Use of EP4 receptor antagonists for the treatment of NASH-associated liver cancer |
KR102526034B1 (ko) | 2016-11-07 | 2023-04-25 | 브리스톨-마이어스 스큅 컴퍼니 | 면역조정제 |
IT201600111877A1 (it) * | 2016-11-07 | 2018-05-07 | Biouniversa Srl | Anti-BAG3 antibodies in combination with inhibitors of immune check-point for therapeutic use |
US20190345500A1 (en) | 2016-11-14 | 2019-11-14 | |Nserm (Institut National De La Santé Et De La Recherche Médicale) | Methods and pharmaceutical compositions for modulating stem cells proliferation or differentiation |
WO2018094275A1 (en) | 2016-11-18 | 2018-05-24 | Tolero Pharmaceuticals, Inc. | Alvocidib prodrugs and their use as protein kinase inhibitors |
EP3541825A1 (en) | 2016-11-21 | 2019-09-25 | Idenix Pharmaceuticals LLC. | Cyclic phosphate substituted nucleoside derivatives for the treatment of liver diseases |
US11135307B2 (en) | 2016-11-23 | 2021-10-05 | Mersana Therapeutics, Inc. | Peptide-containing linkers for antibody-drug conjugates |
WO2018101448A1 (en) | 2016-11-30 | 2018-06-07 | Kyowa Hakko Kirin Co., Ltd. | Method of treating cancer using anti-ccr4 antibody and anti-pd-1 antibody |
BR112019011370A2 (pt) | 2016-12-01 | 2019-10-15 | Glaxosmithkline Ip Dev Ltd | terapia de combinação |
CN110234342A (zh) | 2016-12-01 | 2019-09-13 | 葛兰素史密斯克莱知识产权发展有限公司 | 组合疗法 |
EP3548083A1 (en) | 2016-12-03 | 2019-10-09 | Juno Therapeutics, Inc. | Methods for modulation of car-t cells |
MA50948A (fr) | 2016-12-07 | 2020-10-14 | Agenus Inc | Anticorps et procédés d'utilisation de ceux-ci |
IL266918B2 (en) | 2016-12-07 | 2024-03-01 | Agenus Inc | Anti-CTLA-4 antibodies and methods of using them |
TWI808955B (zh) | 2016-12-22 | 2023-07-21 | 美商英塞特公司 | 作為免疫調節劑之雜環化合物 |
CN110366564B (zh) * | 2016-12-23 | 2023-07-07 | 瑞美德生物医药科技有限公司 | 使用与程序性死亡1(pd-1)结合的抗体的免疫疗法 |
JP2020501589A (ja) | 2016-12-23 | 2020-01-23 | ウイルツ・バイオロジクス・リミテッド | がんの治療 |
WO2018122245A1 (en) | 2016-12-28 | 2018-07-05 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods of predicting the survival time of patients suffering from cms3 colorectal cancer |
WO2018122249A1 (en) | 2016-12-28 | 2018-07-05 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for predicting the survival time of patients suffering from a microsatellite stable colorectal cancer |
JP2020503363A (ja) | 2017-01-06 | 2020-01-30 | ビヨンドスプリング ファーマシューティカルズ,インコーポレイテッド | チューブリン結合化合物およびその治療的使用 |
MX2019008207A (es) | 2017-01-09 | 2019-12-11 | Tesaro Inc | Métodos para tratar el cáncer con anticuerpos anti-pd-1. |
WO2018129497A1 (en) | 2017-01-09 | 2018-07-12 | Bioxcel Therapeutics, Inc. | Predictive and diagnostic methods for prostate cancer |
EA201991696A1 (ru) | 2017-01-13 | 2020-02-05 | Эйдженус Инк. | Т-клеточные рецепторы, связывающиеся с ny-eso-1, и способы их применения |
WO2018134279A1 (en) | 2017-01-18 | 2018-07-26 | Pieris Pharmaceuticals Gmbh | Novel fusion polypeptides specific for lag-3 and pd-1 |
EP3570870A1 (en) | 2017-01-20 | 2019-11-27 | Novartis AG | Combination therapy for the treatment of cancer |
JP7240320B2 (ja) | 2017-01-23 | 2023-03-15 | レヴォリューション・メディスンズ,インコーポレイテッド | アロステリックshp2阻害剤としてのピリジン化合物 |
CN110446709B (zh) | 2017-01-23 | 2023-09-12 | 锐新医药公司 | 作为变构shp2抑制剂的二环化合物 |
US10434095B2 (en) | 2017-01-27 | 2019-10-08 | Celgene Corporation | 3-(1-oxo-4-((4-((3-oxomorpholino)methyl)benzyl)oxy)isoindolin-2-yl)piperidine-2,6-dione and isotopologues thereof |
AU2018217120B2 (en) | 2017-02-01 | 2024-02-08 | Beyondspring Pharmaceuticals, Inc. | Method of reducing neutropenia |
JOP20190187A1 (ar) | 2017-02-03 | 2019-08-01 | Novartis Ag | مترافقات عقار جسم مضاد لـ ccr7 |
JP2020506727A (ja) | 2017-02-06 | 2020-03-05 | オリオンズ バイオサイエンス エヌブイ | 標的化キメラタンパク質及びその使用 |
US10906985B2 (en) | 2017-02-06 | 2021-02-02 | Orionis Biosciences, Inc. | Targeted engineered interferon and uses thereof |
WO2018146148A1 (en) | 2017-02-07 | 2018-08-16 | INSERM (Institut National de la Santé et de la Recherche Médicale) | A method for predicting the response to checkpoint blockade cancer immunotherapy |
WO2018146128A1 (en) | 2017-02-07 | 2018-08-16 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Detection of kit polymorphism for predicting the response to checkpoint blockade cancer immunotherapy |
SI3579874T1 (sl) | 2017-02-10 | 2021-11-30 | Novartis Ag | 1-(4-amino-5-bromo-6-(1 h-pirazol-1-yl)pyrimidin-2-il)-1 h-pirazol-4-ol in njegova uporaba v zdravljenju raka |
EP3582855A1 (en) | 2017-02-15 | 2019-12-25 | GlaxoSmithKline Intellectual Property Development Limited | Combination treatment for cancer |
WO2018151820A1 (en) | 2017-02-16 | 2018-08-23 | Elstar Therapeutics, Inc. | Multifunctional molecules comprising a trimeric ligand and uses thereof |
CA3054289A1 (en) | 2017-02-21 | 2018-08-30 | Regeneron Pharmaceuticals, Inc. | Anti-pd-1 antibodies for treatment of lung cancer |
WO2018156777A1 (en) * | 2017-02-22 | 2018-08-30 | Sutro Biopharma, Inc. | Pd-1/tim-3 bi-specific antibodies, compositions thereof, and methods of making and using the same |
KR20190119107A (ko) | 2017-02-22 | 2019-10-21 | 트위스트 바이오사이언스 코포레이션 | 핵산 기반 데이터 저장 |
JP7132232B2 (ja) | 2017-02-24 | 2022-09-06 | マクロジェニクス,インコーポレーテッド | Cd137及び腫瘍抗原に結合できる二重特異性結合分子並びにその使用 |
EP3585782A1 (en) | 2017-02-27 | 2020-01-01 | GlaxoSmithKline Intellectual Property Development Limited | Heterocyclic amides as kinase inhibitors |
US20180271996A1 (en) | 2017-02-28 | 2018-09-27 | Mersana Therapeutics, Inc. | Combination therapies of her2-targeted antibody-drug conjugates |
WO2018162944A1 (en) * | 2017-03-04 | 2018-09-13 | Shenzhen Runshin Bioscience | Recombinant antibodies to programmed death 1 (pd-1) and uses therefor |
US11179413B2 (en) | 2017-03-06 | 2021-11-23 | Novartis Ag | Methods of treatment of cancer with reduced UBB expression |
WO2018167778A1 (en) | 2017-03-12 | 2018-09-20 | Yeda Research And Development Co. Ltd. | Methods of diagnosing and prognosing cancer |
WO2018167780A1 (en) | 2017-03-12 | 2018-09-20 | Yeda Research And Development Co. Ltd. | Methods of prognosing and treating cancer |
AU2018234810B2 (en) | 2017-03-15 | 2023-05-11 | Pandion Operations, Inc. | Targeted immunotolerance |
EP3595674A4 (en) | 2017-03-15 | 2020-12-16 | Twist Bioscience Corporation | BANKS OF VARIANTS OF IMMUNOLOGICAL SYNAPSE AND THEIR SYNTHESIS |
CN110461346A (zh) | 2017-03-15 | 2019-11-15 | 美国安进公司 | 溶瘤病毒单独或与检查点抑制剂组合用于治疗癌症的用途 |
EP3600427A1 (en) | 2017-03-24 | 2020-02-05 | INSERM - Institut National de la Santé et de la Recherche Médicale | Methods and compositions for treating melanoma |
WO2018183928A1 (en) | 2017-03-31 | 2018-10-04 | Bristol-Myers Squibb Company | Methods of treating tumor |
US20200031944A1 (en) | 2017-03-31 | 2020-01-30 | Five Prime Therapeutics, Inc. | Combination therapy for cancer using anti-gitr antibodies |
CN106987631A (zh) * | 2017-04-01 | 2017-07-28 | 武汉赛云博生物科技有限公司 | 一种用于pd‑1/pd‑l1阻断治疗伴随诊断的免疫组测序技术 |
WO2018185618A1 (en) | 2017-04-03 | 2018-10-11 | Novartis Ag | Anti-cdh6 antibody drug conjugates and anti-gitr antibody combinations and methods of treatment |
DK3606946T3 (da) | 2017-04-03 | 2022-10-24 | Hoffmann La Roche | Immunkonjugater af et anti-PD-1-antistof med et muteret IL-2 eller med IL-15 |
TWI747215B (zh) | 2017-04-05 | 2021-11-21 | 瑞士商赫孚孟拉羅股份公司 | 特異性結合至pd1至lag3的雙特異性抗體 |
US11603407B2 (en) | 2017-04-06 | 2023-03-14 | Regeneron Pharmaceuticals, Inc. | Stable antibody formulation |
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. |
AU2018251987A1 (en) | 2017-04-14 | 2019-12-05 | Cg Oncology, Inc. | Methods of treating bladder cancer |
CN108728444A (zh) | 2017-04-18 | 2018-11-02 | 长春华普生物技术股份有限公司 | 免疫调节性多核苷酸及其应用 |
IL270021B (en) | 2017-04-18 | 2022-08-01 | Tempest Therapeutics Inc | Bicyclic compounds and their use in cancer treatment |
WO2018195283A1 (en) | 2017-04-19 | 2018-10-25 | Elstar Therapeutics, Inc. | Multispecific molecules and uses thereof |
CA3060516A1 (en) | 2017-04-21 | 2018-10-25 | Sillajen, Inc. | Oncolytic vaccinia virus and checkpoint inhibitor combination therapy |
CN108794467A (zh) | 2017-04-27 | 2018-11-13 | 博笛生物科技有限公司 | 2-氨基-喹啉衍生物 |
AR111419A1 (es) | 2017-04-27 | 2019-07-10 | Novartis Ag | Compuestos fusionados de indazol piridona como antivirales |
US20200179511A1 (en) | 2017-04-28 | 2020-06-11 | Novartis Ag | Bcma-targeting agent, and combination therapy with a gamma secretase inhibitor |
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 |
AU2018260545B2 (en) | 2017-04-28 | 2023-11-23 | Marengo Therapeutics, Inc. | Multispecific molecules comprising a non-immunoglobulin heterodimerization domain and uses thereof |
UY37695A (es) | 2017-04-28 | 2018-11-30 | Novartis Ag | Compuesto dinucleótido cíclico bis 2’-5’-rr-(3’f-a)(3’f-a) y usos del mismo |
WO2018201056A1 (en) | 2017-04-28 | 2018-11-01 | Novartis Ag | Cells expressing a bcma-targeting chimeric antigen receptor, and combination therapy with a gamma secretase inhibitor |
PL3618863T3 (pl) | 2017-05-01 | 2023-11-06 | Agenus Inc. | Przeciwciała anty- tigit i sposoby ich zastosowania |
JOP20190260A1 (ar) | 2017-05-02 | 2019-10-31 | Merck Sharp & Dohme | صيغ ثابتة لأجسام مضادة لمستقبل الموت المبرمج 1 (pd-1) وطرق استخدامها |
JP7382232B2 (ja) | 2017-05-02 | 2023-11-16 | メルク・シャープ・アンド・ドーム・エルエルシー | 抗lag3抗体の製剤および抗lag3抗体と抗pd-1抗体との共製剤 |
AR111658A1 (es) | 2017-05-05 | 2019-08-07 | Novartis Ag | 2-quinolinonas tricíclicas como agentes antibacteriales |
EP3621624B1 (en) | 2017-05-12 | 2023-08-30 | Merck Sharp & Dohme LLC | Cyclic di-nucleotide compounds as sting agonists |
JOP20190256A1 (ar) | 2017-05-12 | 2019-10-28 | Icahn School Med Mount Sinai | فيروسات داء نيوكاسل واستخداماتها |
SG10202107880XA (en) | 2017-05-12 | 2021-09-29 | Harpoon Therapeutics Inc | Mesothelin binding proteins |
US11685787B2 (en) | 2017-05-16 | 2023-06-27 | Bristol-Myers Squibb Company | Treatment of cancer with anti-GITR agonist antibodies |
AR111760A1 (es) | 2017-05-19 | 2019-08-14 | Novartis Ag | Compuestos y composiciones para el tratamiento de tumores sólidos mediante administración intratumoral |
AU2018273914A1 (en) | 2017-05-24 | 2019-11-14 | Pandion Operations, Inc. | Targeted immunotolerance |
US20200362058A1 (en) | 2017-05-24 | 2020-11-19 | Novartis Ag | Antibody-cytokine engrafted proteins and methods of use |
AU2018274216A1 (en) | 2017-05-24 | 2019-12-12 | Novartis Ag | Antibody-cytokine engrafted proteins and methods of use in the treatment of cancer |
WO2018215937A1 (en) | 2017-05-24 | 2018-11-29 | Novartis Ag | Interleukin-7 antibody cytokine engrafted proteins and methods of use in the treatment of cancer |
AR111960A1 (es) | 2017-05-26 | 2019-09-04 | Incyte Corp | Formas cristalinas de un inhibidor de fgfr y procesos para su preparación |
AU2018277559A1 (en) | 2017-05-30 | 2019-10-17 | Bristol-Myers Squibb Company | Compositions comprising a combination of an anti-LAG-3 antibody, a PD-1 pathway inhibitor, and an immunotherapeutic agent |
DK3631454T3 (da) | 2017-05-30 | 2023-12-04 | Bristol Myers Squibb Co | Behandling af lag-3 positive tumorer |
JP7301002B2 (ja) | 2017-05-30 | 2023-06-30 | ブリストル-マイヤーズ スクイブ カンパニー | 抗lag-3抗体または抗lag-3抗体および抗pd-1もしくは抗pd-l1抗体を含む組成物 |
EP3630836A1 (en) | 2017-05-31 | 2020-04-08 | Elstar Therapeutics, Inc. | Multispecific molecules that bind to myeloproliferative leukemia (mpl) protein and uses thereof |
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 |
WO2018222685A1 (en) | 2017-05-31 | 2018-12-06 | Stcube & Co., Inc. | Methods of treating cancer using antibodies and molecules that immunospecifically bind to btn1a1 |
WO2018223040A1 (en) | 2017-06-01 | 2018-12-06 | Bristol-Myers Squibb Company | Methods of treating a tumor using an anti-pd-1 antibody |
CA3065929A1 (en) | 2017-06-01 | 2018-12-06 | Michael Wayne SAVILLE | Bispecific antibodies that bind cd123 and cd3 |
WO2018223004A1 (en) | 2017-06-01 | 2018-12-06 | Xencor, Inc. | Bispecific antibodies that bind cd20 and cd3 |
WO2018222989A1 (en) | 2017-06-02 | 2018-12-06 | The Penn State Research Foundation | Ceramide nanoliposomes, compositions and methods of using for immunotherapy |
MX2019014268A (es) | 2017-06-02 | 2020-08-03 | Juno Therapeutics Inc | Artículos de manufactura y métodos para tratamiento usando terapia celular adoptiva. |
KR20200026209A (ko) | 2017-06-06 | 2020-03-10 | 주식회사 에스티큐브앤컴퍼니 | Btn1a1 또는 btn1a1-리간드에 결합하는 항체 및 분자를 사용하여 암을 치료하는 방법 |
WO2018225093A1 (en) | 2017-06-07 | 2018-12-13 | Glaxosmithkline Intellectual Property Development Limited | Chemical compounds as atf4 pathway inhibitors |
BR112019025325A2 (pt) | 2017-06-09 | 2020-06-23 | Glaxosmithkline Intellectual Property Development Limited | Métodos para tratar câncer, para fabricar um anticorpo anti-icos ou porção de ligação a antígeno do mesmo, para fabricar um anticorpo anti-pd1 ou porção de ligação a antígeno do mesmo, para fabricar um anticorpo anti-pdl1 ou porção de ligação a antígeno do mesmo, anticorpo anti-icos ou fragmento de ligação a antígeno do mesmo e um anticorpo anti-pd1 ou fragmento de ligação a antígeno do mesmo, anticorpo anti-icos ou fragmento de ligação a antígeno do mesmo e um anticorpo anti-pd-l1 ou fragmento de ligação a antígeno do mesmo, uso de um anticorpo anti-icos ou porção de ligação a antígeno do mesmo e um anticorpo anti-pd1 ou porção de ligação a antígeno do mesmo, polinucleotídeo, vetor, e, célula hospedeira |
BR112019024291A2 (pt) | 2017-06-09 | 2020-07-28 | Providence Health & Services-Oregon | utilização de cd39 e de cd103 para a identificação de células t tumorais humanas reativas para o tratamento do câncer |
WO2018231864A1 (en) | 2017-06-12 | 2018-12-20 | Twist Bioscience Corporation | Methods for seamless nucleic acid assembly |
CA3066744A1 (en) | 2017-06-12 | 2018-12-20 | Twist Bioscience Corporation | Methods for seamless nucleic acid assembly |
WO2018229715A1 (en) | 2017-06-16 | 2018-12-20 | Novartis Ag | Compositions comprising anti-cd32b antibodies and methods of use thereof |
EP3641739A1 (en) | 2017-06-20 | 2020-04-29 | Institut Curie | Inhibitor of suv39h1 histone methyltransferase for use in cancer combination therapy |
WO2018235056A1 (en) | 2017-06-22 | 2018-12-27 | Novartis Ag | IL-1BETA BINDING ANTIBODIES FOR USE IN THE TREATMENT OF CANCER |
CN110785187B (zh) | 2017-06-22 | 2024-04-05 | 诺华股份有限公司 | 针对cd73的抗体分子及其用途 |
EA202090103A1 (ru) | 2017-06-22 | 2020-04-24 | Селджин Корпорейшн | Лечение гепатоцеллюлярной карциномы, которая характеризуется вирусной инфекцией гепатита b |
WO2018237173A1 (en) | 2017-06-22 | 2018-12-27 | Novartis Ag | ANTIBODY MOLECULES DIRECTED AGAINST CD73 AND CORRESPONDING USES |
AU2018287519B2 (en) | 2017-06-22 | 2021-07-22 | Novartis Ag | IL-1beta binding antibodies for use in treating cancer |
WO2018232725A1 (en) | 2017-06-23 | 2018-12-27 | Birdie Biopharmaceuticals, Inc. | PHARMACEUTICAL COMPOSITIONS |
EP3642220A1 (en) | 2017-06-23 | 2020-04-29 | Bristol-Myers Squibb Company | Immunomodulators acting as antagonists of pd-1 |
JP2020529862A (ja) * | 2017-06-25 | 2020-10-15 | システィミューン, インク.Systimmune, Inc. | 抗pd−1抗体とその作製及び使用方法 |
CA3066747A1 (en) | 2017-06-27 | 2019-01-03 | Novartis Ag | Dosage regimens for anti-tim-3 antibodies and uses thereof |
MX2019015155A (es) | 2017-06-29 | 2020-08-03 | Juno Therapeutics Inc | Modelo de raton para valorar toxicidades asociadas con inmunoterapias. |
EP4201399A3 (en) | 2017-06-30 | 2023-08-09 | Celgene Corporation | Compositions and methods of use of 2-(4-chlorophenyl)-n-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl) methyl) -2,2-difluoroacetamide |
BR112020000122A2 (pt) | 2017-07-03 | 2020-07-07 | Glaxosmithkline Intellectual Property Development Limited | derivados da n-(3-(2-(4-clorofenóxi)acetamido)biciclo[1.1.1] pentan-1-il)-2-ciclobutano-1-carboxamida e compostos relacionados como inibidores do atf4 para tratamento contra o câncer e outras doenças |
BR112020000086A2 (pt) | 2017-07-03 | 2020-07-07 | Glaxosmithkline Intellectual Property Development Limited | derivados de 2-(4-clorofenóxi)-n-((1-(2-(4-clorofenóxi) etinazetidin-3-il) metil) acetamida e compostos relacionados como inibidores de atf4 para tratamento de câncer e outras doenças |
EP3651766A1 (en) | 2017-07-10 | 2020-05-20 | Celgene Corporation | Antiproliferative compounds and methods of use thereof |
WO2019016174A1 (en) | 2017-07-18 | 2019-01-24 | Institut Gustave Roussy | METHOD FOR ASSESSING RESPONSE TO TARGETING DRUG PD-1 / PDL-1 MEDICINES |
WO2019018730A1 (en) | 2017-07-20 | 2019-01-24 | Novartis Ag | DOSAGE REGIMES FOR ANTI-LAG3 ANTIBODIES AND USES THEREOF |
EP3658173A1 (en) | 2017-07-25 | 2020-06-03 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for modulating monocytopoiesis |
WO2019021208A1 (en) | 2017-07-27 | 2019-01-31 | Glaxosmithkline Intellectual Property Development Limited | USEFUL INDAZOLE DERIVATIVES AS PERK INHIBITORS |
EP3658914A1 (en) | 2017-07-28 | 2020-06-03 | Bristol-Myers Squibb Company | Predictive peripheral blood biomarker for checkpoint inhibitors |
WO2019027858A1 (en) | 2017-08-04 | 2019-02-07 | Merck Sharp & Dohme Corp. | BENZO [B] STING THIOPHEN AGONISTS FOR THE TREATMENT OF CANCER |
WO2019027857A1 (en) | 2017-08-04 | 2019-02-07 | Merck Sharp & Dohme Corp. | COMBINATIONS OF PD-1 ANTAGONISTS AND STING BENZO [B] THIOPHENIC AGONISTS FOR THE TREATMENT OF CANCER |
AU2018323462A1 (en) | 2017-08-28 | 2020-03-26 | Bristol-Myers Squibb Company | TIM-3 antagonists for the treatment and diagnosis of cancers |
JP7387585B2 (ja) | 2017-09-04 | 2023-11-28 | アジェナス インコーポレイテッド | 混合系統白血病(mll)特異的ホスホペプチドに結合するt細胞受容体およびその使用方法 |
MX2020002612A (es) | 2017-09-07 | 2020-07-13 | Univ Res Inst Inc Augusta | Anticuerpos de la proteina de muerte celular programada 1. |
CN111344017A (zh) | 2017-09-07 | 2020-06-26 | 锐新医药公司 | 治疗癌症的shp2抑制剂组合物和方法 |
TW201922721A (zh) | 2017-09-07 | 2019-06-16 | 英商葛蘭素史克智慧財產發展有限公司 | 化學化合物 |
EP3681906A4 (en) | 2017-09-11 | 2021-06-09 | Twist Bioscience Corporation | GPCR-BINDING PROTEINS AND THEIR SYNTHESIS |
WO2019053617A1 (en) | 2017-09-12 | 2019-03-21 | Glaxosmithkline Intellectual Property Development Limited | CHEMICAL COMPOUNDS |
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 |
EP3684410A1 (en) | 2017-09-19 | 2020-07-29 | Institut Curie | Agonist of aryl hydrocarbon receptor for use in cancer combination therapy |
CN109554349B (zh) * | 2017-09-27 | 2022-06-24 | 亘喜生物科技(上海)有限公司 | Pd-1基因表达沉默的工程化免疫细胞 |
WO2019061324A1 (en) | 2017-09-29 | 2019-04-04 | Curis Inc. | CRYSTALLINE FORMS OF IMMUNOMODULATORS |
KR20200058506A (ko) | 2017-10-03 | 2020-05-27 | 브리스톨-마이어스 스큅 컴퍼니 | 면역조정제 |
WO2019069270A1 (en) | 2017-10-05 | 2019-04-11 | Glaxosmithkline Intellectual Property Development Limited | GENERATOR STIMULATOR MODULATORS (STING) INTERFERON |
WO2019069269A1 (en) | 2017-10-05 | 2019-04-11 | Glaxosmithkline Intellectual Property Development Limited | INTERFERON GENE STIMULATOR MODULATORS USEFUL IN THE TREATMENT OF HIV |
CA3074802A1 (en) * | 2017-10-10 | 2019-04-18 | Numab Therapeutics AG | Antibodies targeting pdl1 and methods of use thereof |
JP2020536872A (ja) | 2017-10-11 | 2020-12-17 | オーリジーン ディスカバリー テクノロジーズ リミテッドAurigene Discovery Technologies Limited | 3−置換1,2,4−オキサジアゾールの結晶形態 |
KR20200070295A (ko) | 2017-10-12 | 2020-06-17 | 레볼루션 메디슨즈, 인크. | 알로스테릭 shp2 억제제로서의 피리딘, 피라진 및 트리아진 화합물 |
KR20200064132A (ko) | 2017-10-15 | 2020-06-05 | 브리스톨-마이어스 스큅 컴퍼니 | 종양을 치료하는 방법 |
EP3697434A1 (en) | 2017-10-18 | 2020-08-26 | Vivia Biotech, S.L. | Bite-activated car-t cells |
US10894242B2 (en) | 2017-10-20 | 2021-01-19 | Twist Bioscience Corporation | Heated nanowells for polynucleotide synthesis |
US20210040205A1 (en) | 2017-10-25 | 2021-02-11 | Novartis Ag | Antibodies targeting cd32b and methods of use thereof |
KR20200116077A (ko) | 2017-11-01 | 2020-10-08 | 주노 쎄러퓨티크스 인코퍼레이티드 | B 세포 성숙 항원에 특이적인 키메라 항원 수용체 및 암호화 폴리뉴클레오타이드 |
CA3080904A1 (en) | 2017-11-01 | 2019-05-09 | Juno Therapeutics, Inc. | Antibodies and chimeric antigen receptors specific for b-cell maturation antigen |
WO2019089412A1 (en) | 2017-11-01 | 2019-05-09 | Merck Sharp & Dohme Corp. | Novel substituted tetrahydroquinolin compounds as indoleamine 2,3-dioxygenase (ido) inhibitors |
US20210132042A1 (en) | 2017-11-01 | 2021-05-06 | Juno Therapeutics, Inc. | Methods of assessing or monitoring a response to a cell therapy |
US11497734B2 (en) | 2017-11-03 | 2022-11-15 | Aurigene Discovery Technologies Limited | Dual inhibitors of TIM-3 and PD-1 pathways |
CN111315397A (zh) | 2017-11-06 | 2020-06-19 | 百时美施贵宝公司 | ***的方法 |
CA3081675A1 (en) | 2017-11-06 | 2019-05-09 | Aurigene Discovery Technologies Limited | Conjoint therapies for immunomodulation |
JP2021501221A (ja) | 2017-11-10 | 2021-01-14 | アーモ・バイオサイエンシーズ・インコーポレイテッドArmo Biosciences,Inc. | 免疫チェックポイント経路阻害剤と併用したインターロイキン−10の組成物および使用方法 |
WO2019099314A1 (en) | 2017-11-14 | 2019-05-23 | Merck Sharp & Dohme Corp. | Novel substituted biaryl compounds as indoleamine 2,3-dioxygenase (ido) inhibitors |
WO2019099294A1 (en) | 2017-11-14 | 2019-05-23 | Merck Sharp & Dohme Corp. | Novel substituted biaryl compounds as indoleamine 2,3-dioxygenase (ido) inhibitors |
TW201922291A (zh) | 2017-11-16 | 2019-06-16 | 瑞士商諾華公司 | 組合療法 |
AR113696A1 (es) | 2017-11-17 | 2020-06-03 | Merck Sharp & Dohme | Anticuerpos específicos para el transcrito similar a la inmunoglobulina tipo 3 (ilt3) y sus usos |
US20210079015A1 (en) | 2017-11-17 | 2021-03-18 | Novartis Ag | Novel dihydroisoxazole compounds and their use for the treatment of hepatitis b |
CA3083158A1 (en) | 2017-11-24 | 2019-05-31 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Methods and compositions for treating cancers |
US11638760B2 (en) | 2017-11-27 | 2023-05-02 | Mersana Therapeutics, Inc. | Pyrrolobenzodiazepine antibody conjugates |
MX2020005651A (es) | 2017-11-30 | 2020-10-28 | Novartis Ag | Receptor de antigeno quimerico dirigido a bcma y usos del mismo. |
US10946068B2 (en) | 2017-12-06 | 2021-03-16 | Pandion Operations, Inc. | IL-2 muteins and uses thereof |
US10174091B1 (en) | 2017-12-06 | 2019-01-08 | Pandion Therapeutics, Inc. | IL-2 muteins |
WO2019113464A1 (en) | 2017-12-08 | 2019-06-13 | Elstar Therapeutics, Inc. | Multispecific molecules and uses thereof |
US11946094B2 (en) | 2017-12-10 | 2024-04-02 | Augusta University Research Institute, Inc. | Combination therapies and methods of use thereof |
MX2020006273A (es) | 2017-12-15 | 2020-09-14 | Revolution Medicines Inc | Compuestos policiclicos como inhibidores alostericos de shp2. |
WO2019118937A1 (en) | 2017-12-15 | 2019-06-20 | Juno Therapeutics, Inc. | Anti-cct5 binding molecules and methods of use thereof |
JP2021507906A (ja) | 2017-12-20 | 2021-02-25 | ノバルティス アーゲー | 抗ウイルス剤としての融合三環式ピラゾロ−ジヒドロピラジニル−ピリドン化合物 |
EP3727401A4 (en) | 2017-12-20 | 2022-04-06 | Merck Sharp & Dohme Corp. | CYCLIC DINUCLEOTIDE COMPOUNDS USED AS STING AGONISTS |
JP2021506883A (ja) | 2017-12-21 | 2021-02-22 | メルサナ セラピューティクス インコーポレイテッド | ピロロベンゾジアゼピン抗体結合体 |
CN109966487B (zh) * | 2017-12-28 | 2023-08-25 | 上海复宏汉霖生物制药有限公司 | 一种包含抗pd-l1单克隆抗体的药物配制剂 |
US20210072244A1 (en) | 2018-01-04 | 2021-03-11 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma resistant |
US11324774B2 (en) | 2018-01-05 | 2022-05-10 | Augusta University Research Institute, Inc. | Compositions of oral alkaline salts and metabolic acid inducers and uses thereof |
EP3737408A1 (en) | 2018-01-08 | 2020-11-18 | Novartis AG | Immune-enhancing rnas for combination with chimeric antigen receptor therapy |
BR112020013144A2 (pt) | 2018-01-12 | 2020-12-08 | Bristol-Myers Squibb Company | Terapia de combinação com anticorpos anti-il-8 e anti-corpos anti-pd-1 para tratamento do câncer |
US20210363242A1 (en) | 2018-01-16 | 2021-11-25 | Bristol-Myers Squibb Company | Methods of treating cancer with antibodies against tim3 |
KR20200112904A (ko) | 2018-01-22 | 2020-10-05 | 브리스톨-마이어스 스큅 컴퍼니 | 암을 치료하는 조성물 및 방법 |
EP3743061A1 (en) | 2018-01-22 | 2020-12-02 | Pascal Biosciences Inc. | Cannabinoids and derivatives for promoting immunogenicity of tumor and infected cells |
BR112020014929A2 (pt) | 2018-01-23 | 2020-12-08 | Nextcure, Inc. | Composição farmacêutica, métodos para aumentar, para reduzir, para intensificar ou induzir uma resposta imune em um indivíduo, molécula, anticorpo monoclonal ou fragmento de ligação ao antígeno do mesmo, ácido nucleico, anticorpo monoclonal anti-b7h4 ou fragmento de ligação ao antígeno do mesmo, anticorpo anti-b7h4 ou fragmento de ligação ao antígeno do mesmo, cadeias leve e pesada de anticorpo anti-b7h4, e, cadeias leve e pesada de anticorpo |
JP7350015B2 (ja) | 2018-01-24 | 2023-09-25 | ビヨンドスプリング ファーマシューティカルズ,インコーポレイテッド | プリナブリンの投与による血小板減少症を軽減するための組成物および方法 |
US20210069246A1 (en) | 2018-01-31 | 2021-03-11 | Celgene Corporation | Combination therapy using adoptive cell therapy and checkpoint inhibitor |
WO2019152660A1 (en) | 2018-01-31 | 2019-08-08 | Novartis Ag | Combination therapy using a chimeric antigen receptor |
JP2021511793A (ja) | 2018-01-31 | 2021-05-13 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | Lag3に結合する抗原結合部位を含む二重特異性抗体 |
US20200405806A1 (en) | 2018-02-08 | 2020-12-31 | Bristol-Myers Squibb Company | Combination of a tetanus toxoid, anti-ox40 antibody and/or anti-pd-1 antibody to treat tumors |
TW202340257A (zh) | 2018-02-09 | 2023-10-16 | 日商小野藥品工業股份有限公司 | 雙特異性抗體 |
NL2020422B1 (en) | 2018-02-12 | 2019-08-19 | Stichting Het Nederlands Kanker Inst Antoni Van Leeuwenhoek Ziekenhuis | Methods for Predicting Treatment Outcome and/or for Selecting a Subject Suitable for Immune Checkpoint Therapy. |
EP3752203A1 (en) | 2018-02-13 | 2020-12-23 | Novartis AG | Chimeric antigen receptor therapy in combination with il-15r and il15 |
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 |
CN112384515A (zh) | 2018-02-27 | 2021-02-19 | 因赛特公司 | 作为a2a/a2b抑制剂的咪唑并嘧啶和***并嘧啶 |
JP2021514982A (ja) | 2018-02-28 | 2021-06-17 | ノバルティス アーゲー | インドール−2−カルボニル化合物及びb型肝炎治療のためのそれらの使用 |
US20210002373A1 (en) | 2018-03-01 | 2021-01-07 | Nextcure, Inc. | KLRG1 Binding Compositions and Methods of Use Thereof |
TWI708787B (zh) | 2018-03-02 | 2020-11-01 | 美商美國禮來大藥廠 | Pd-1促效劑抗體及其用途 |
CN111867679A (zh) | 2018-03-06 | 2020-10-30 | 居里研究所 | 用于癌症联合治疗的setdb1组蛋白甲基转移酶抑制剂 |
JP2021517589A (ja) | 2018-03-12 | 2021-07-26 | アンセルム(アンスティチュート・ナシオナル・ドゥ・ラ・サンテ・エ・ドゥ・ラ・ルシェルシュ・メディカル) | 癌の治療のための化学免疫療法を増強するためのカロリー制限模倣物の使用 |
US20210238280A1 (en) | 2018-03-14 | 2021-08-05 | Elstar Therapeutics, Inc. | Multifunctional molecules that bind to calreticulin and uses thereof |
EP3765516A2 (en) | 2018-03-14 | 2021-01-20 | Elstar Therapeutics, Inc. | Multifunctional molecules and uses thereof |
CA3093407A1 (en) | 2018-03-23 | 2019-09-26 | Bristol-Myers Squibb Company | Antibodies against mica and/or micb and uses thereof |
WO2019185792A1 (en) | 2018-03-29 | 2019-10-03 | Philogen S.P.A | Cancer treatment using immunoconjugates and immune check-point inhibitors |
CN108530537B (zh) * | 2018-03-29 | 2019-07-02 | 中国人民解放军军事科学院军事医学研究院 | Pd-1/pd-l1信号通路抑制剂 |
WO2019191676A1 (en) | 2018-03-30 | 2019-10-03 | Bristol-Myers Squibb Company | Methods of treating tumor |
WO2019195063A1 (en) | 2018-04-03 | 2019-10-10 | Merck Sharp & Dohme Corp. | Aza-benzothiophene compounds as sting agonists |
WO2019195124A1 (en) | 2018-04-03 | 2019-10-10 | Merck Sharp & Dohme Corp. | Benzothiophenes and related compounds as sting agonists |
EP3774903A1 (en) | 2018-04-04 | 2021-02-17 | Bristol-Myers Squibb Company | Anti-cd27 antibodies and uses thereof |
WO2019193540A1 (en) | 2018-04-06 | 2019-10-10 | Glaxosmithkline Intellectual Property Development Limited | Heteroaryl derivatives of formula (i) as atf4 inhibitors |
WO2019193541A1 (en) | 2018-04-06 | 2019-10-10 | Glaxosmithkline Intellectual Property Development Limited | Bicyclic aromatic ring derivatives of formula (i) as atf4 inhibitors |
JP2021521182A (ja) | 2018-04-12 | 2021-08-26 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | Cd73アンタゴニストとpd−1/pd−l1軸アンタゴニストの組み合わせ治療 |
US20210147547A1 (en) | 2018-04-13 | 2021-05-20 | Novartis Ag | Dosage Regimens For Anti-Pd-L1 Antibodies And Uses Thereof |
EP3781550A1 (en) | 2018-04-17 | 2021-02-24 | Tempest Therapeutics, Inc. | Bicyclic carboxamides and methods of use thereof |
EP3781599A1 (en) | 2018-04-18 | 2021-02-24 | Xencor, Inc. | Pd-1 targeted heterodimeric fusion proteins containing il-15/il-15ra fc-fusion proteins and pd-1 antigen binding domains and uses thereof |
KR20210003170A (ko) | 2018-04-18 | 2021-01-11 | 젠코어 인코포레이티드 | IL-15/IL-15Rα 이종이량체 Fc 융합 단백질 및 이의 용도 |
EP3781687A4 (en) | 2018-04-20 | 2022-02-09 | Merck Sharp & Dohme Corp. | NEW RIG-I SUBSTITUTED AGONISTS: COMPOSITIONS AND METHODS THEREOF |
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 |
WO2019207030A1 (en) | 2018-04-26 | 2019-10-31 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for predicting a response with an immune checkpoint inhibitor in a patient suffering from a lung cancer |
US20210047405A1 (en) | 2018-04-27 | 2021-02-18 | Novartis Ag | Car t cell therapies with enhanced efficacy |
WO2019213282A1 (en) | 2018-05-01 | 2019-11-07 | Novartis Ag | Biomarkers for evaluating car-t cells to predict clinical outcome |
CR20200590A (es) | 2018-05-04 | 2021-04-26 | Incyte Corp | Formas sólidas de un inhibidor de fgfr y procesos para prepararlas |
US11174257B2 (en) | 2018-05-04 | 2021-11-16 | Incyte Corporation | Salts of an FGFR inhibitor |
US20210363216A1 (en) | 2018-05-14 | 2021-11-25 | Immunocore Limited | Bifunctional binding polypeptides |
GB201807924D0 (en) | 2018-05-16 | 2018-06-27 | Ctxt Pty Ltd | Compounds |
MX2020012376A (es) | 2018-05-18 | 2021-03-09 | Incyte Corp | Derivados de pirimidina fusionados como inhibidores de los receptores de adenosina a2a/a2b. |
WO2019222706A1 (en) | 2018-05-18 | 2019-11-21 | Twist Bioscience Corporation | Polynucleotides, reagents, and methods for nucleic acid hybridization |
HRP20230449T1 (hr) | 2018-05-23 | 2023-07-21 | Celgene Corporation | Antiproliferativni spojevi i bispecifična protutijela protiv bcma i cd3 za kombiniranu upotrebu |
KR20210024454A (ko) | 2018-05-23 | 2021-03-05 | 셀진 코포레이션 | 다발성 골수종의 치료 및 4-(4-(4-(((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-4-일)옥시)메틸)벤질)피페라진-1-일)-3-플루오로벤조니트릴에 대한 바이오마커의 용도 |
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 |
US11352320B2 (en) | 2018-05-31 | 2022-06-07 | Merck Sharp & Dohme Corp. | Substituted [1.1.1] bicyclo compounds as indoleamine 2,3-dioxygenase inhibitors |
WO2019229699A1 (en) | 2018-05-31 | 2019-12-05 | Novartis Ag | Hepatitis b antibodies |
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 |
US20210205449A1 (en) | 2018-06-01 | 2021-07-08 | Novartis Ag | Dosing of a bispecific antibody that bind cd123 and cd3 |
JP7398396B2 (ja) | 2018-06-01 | 2023-12-14 | ノバルティス アーゲー | Bcmaに対する結合分子及びその使用 |
US11555071B2 (en) | 2018-06-03 | 2023-01-17 | Lamkap Bio Beta Ltd. | Bispecific antibodies against CEACAM5 and CD47 |
BR112020025048A2 (pt) | 2018-06-13 | 2021-04-06 | Novartis Ag | Receptores de antígeno quimérico de bcma e usos dos mesmos |
KR20210035805A (ko) | 2018-06-15 | 2021-04-01 | 플래그쉽 파이어니어링 이노베이션스 브이, 인크. | 세포후 신호전달 인자의 조절을 통한 면역 활성의 증가 |
CN112533629A (zh) | 2018-06-19 | 2021-03-19 | 阿尔莫生物科技股份有限公司 | 结合使用il-10药剂与嵌合抗原受体细胞疗法的组合物和方法 |
AU2019288276A1 (en) | 2018-06-20 | 2021-01-14 | Incyte Corporation | Anti-PD-1 antibodies and uses thereof |
TW202005985A (zh) | 2018-06-21 | 2020-02-01 | 美商再生元醫藥公司 | 用雙特異性抗CD3xMUC16抗體及抗PD-1抗體治療癌症的方法 |
WO2020005068A2 (en) | 2018-06-29 | 2020-01-02 | Stichting Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis | Gene signatures and method for predicting response to pd-1 antagonists and ctla-4 antagonists, and combination thereof |
EP3818083A2 (en) | 2018-07-03 | 2021-05-12 | Elstar Therapeutics, Inc. | Anti-tcr antibody molecules and uses thereof |
CR20210073A (es) * | 2018-07-04 | 2021-05-12 | Cytoimmune Therapeutics Inc | Composiciones y métodos para inmunoterapia dirigida a flt3, pd-1 y / o pd-l1 |
US20210253528A1 (en) | 2018-07-09 | 2021-08-19 | Glaxosmithkline Intellectual Property Development Limited | Chemical compounds |
CA3103385A1 (en) | 2018-07-10 | 2020-01-16 | Novartis Ag | 3-(5-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and their use in the treatment of ikaros family zinc finger 2 (ikzf2)-dependent diseases |
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 |
GB201811408D0 (en) | 2018-07-12 | 2018-08-29 | F Star Beta Ltd | CD137 Binding Molecules |
US20210277135A1 (en) | 2018-07-13 | 2021-09-09 | Bristol-Myers Squibb Company | Ox-40 agonist, pd-1 pathway inhibitor and ctla-4 inhibitor combination for use in a method of treating a cancer or a solid tumor |
EP3827020A1 (en) | 2018-07-24 | 2021-06-02 | Amgen Inc. | Combination of lilrb1/2 pathway inhibitors and pd-1 pathway inhibitors |
WO2020021465A1 (en) | 2018-07-25 | 2020-01-30 | Advanced Accelerator Applications (Italy) S.R.L. | Method of treatment of neuroendocrine tumors |
KR20210040080A (ko) | 2018-07-26 | 2021-04-12 | 브리스톨-마이어스 스큅 컴퍼니 | 암의 치료를 위한 lag-3 조합 요법 |
WO2020021061A1 (en) | 2018-07-26 | 2020-01-30 | Pieris Pharmaceuticals Gmbh | Humanized anti-pd-1 antibodies and uses thereof |
WO2020030634A1 (en) | 2018-08-06 | 2020-02-13 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating cancers |
WO2020030571A1 (en) | 2018-08-06 | 2020-02-13 | Glaxosmithkline Intellectual Property Development Limited | Combinations of a pd-1 antibody and a tlr4 modulator and uses thereof |
WO2020031107A1 (en) | 2018-08-08 | 2020-02-13 | Glaxosmithkline Intellectual Property Development Limited | Chemical compounds |
JP2021534101A (ja) | 2018-08-09 | 2021-12-09 | ヴェルソー セラピューティクス, インコーポレイテッド | Ccr2及びcsf1rを標的とするためのオリゴヌクレオチド組成物ならびにその使用 |
CN112955221A (zh) | 2018-08-27 | 2021-06-11 | 皮里斯制药有限公司 | 包含cd137/her2双特异性试剂和pd-1轴抑制剂的组合疗法及其用途 |
WO2020044206A1 (en) | 2018-08-29 | 2020-03-05 | Glaxosmithkline Intellectual Property Development Limited | Heterocyclic amides as kinase inhibitors for use in the treatment cancer |
WO2020047462A2 (en) | 2018-08-30 | 2020-03-05 | HCW Biologics, Inc. | Methods of treating aging-related disorders |
US11401324B2 (en) | 2018-08-30 | 2022-08-02 | HCW Biologics, Inc. | Single-chain chimeric polypeptides and uses thereof |
CA3108949A1 (en) | 2018-08-30 | 2020-03-05 | HCW Biologics, Inc. | Multi-chain chimeric polypeptides and uses thereof |
WO2020044252A1 (en) | 2018-08-31 | 2020-03-05 | Novartis Ag | Dosage regimes for anti-m-csf antibodies and uses thereof |
WO2020047345A1 (en) | 2018-08-31 | 2020-03-05 | Yale University | Compositions and methods of using cell-penetrating antibodies in combination with immune checkpoint modulators |
WO2020048942A1 (en) | 2018-09-04 | 2020-03-12 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for enhancing cytotoxic t lymphocyte-dependent immune responses |
WO2020049534A1 (en) | 2018-09-07 | 2020-03-12 | Novartis Ag | Sting agonist and combination therapy thereof for the treatment of cancer |
KR20210057726A (ko) | 2018-09-07 | 2021-05-21 | 화이자 인코포레이티드 | 항-αvβ8 항체 및 그의 조성물 및 용도 |
WO2020053742A2 (en) | 2018-09-10 | 2020-03-19 | Novartis Ag | Anti-hla-hbv peptide antibodies |
KR20230170813A (ko) | 2018-09-12 | 2023-12-19 | 노파르티스 아게 | 항바이러스 피리도피라진디온 화합물 |
JP2022501361A (ja) | 2018-09-19 | 2022-01-06 | アルパイン イミューン サイエンシズ インコーポレイテッド | バリアントcd80融合タンパク質および関連構築物の方法および使用 |
JP2022511337A (ja) | 2018-09-19 | 2022-01-31 | インサーム (インスティテュート ナショナル デ ラ サンテ エ デ ラ ルシェルシェ メディカル) | 免疫チェックポイント治療に抵抗性のある癌の治療のための方法および医薬組成物 |
MX2021003554A (es) | 2018-09-25 | 2021-05-27 | Harpoon Therapeutics Inc | Proteinas de union a dll3 y metodos de uso. |
AU2019346645A1 (en) | 2018-09-27 | 2021-04-29 | Marengo Therapeutics, Inc. | CSF1R/CCR2 multispecific antibodies |
EP3856779A1 (en) | 2018-09-28 | 2021-08-04 | Novartis AG | Cd22 chimeric antigen receptor (car) therapies |
WO2020069409A1 (en) | 2018-09-28 | 2020-04-02 | Novartis Ag | Cd19 chimeric antigen receptor (car) and cd22 car combination therapies |
JP2022502385A (ja) | 2018-09-29 | 2022-01-11 | ノバルティス アーゲー | Shp2の活性を阻害するための化合物の製造方法 |
US20220040183A1 (en) | 2018-10-01 | 2022-02-10 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of inhibitors of stress granule formation for targeting the regulation of immune responses |
MA53822A (fr) | 2018-10-03 | 2021-08-11 | Xencor Inc | Protéines de fusion fc hétérodimères d'il -12 |
WO2020076799A1 (en) | 2018-10-09 | 2020-04-16 | Bristol-Myers Squibb Company | Anti-mertk antibodies for treating cancer |
US11066404B2 (en) | 2018-10-11 | 2021-07-20 | Incyte Corporation | Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors |
US11377477B2 (en) | 2018-10-12 | 2022-07-05 | Xencor, Inc. | PD-1 targeted IL-15/IL-15RALPHA fc fusion proteins and uses in combination therapies thereof |
CN112867803A (zh) | 2018-10-16 | 2021-05-28 | 诺华股份有限公司 | 单独的或与免疫标志物组合的肿瘤突变负荷作为生物标志物用于预测对靶向疗法的应答 |
WO2020079692A1 (en) | 2018-10-17 | 2020-04-23 | Biolinerx Ltd. | Treatment of metastatic pancreatic adenocarcinoma |
US20210340240A1 (en) | 2018-10-18 | 2021-11-04 | INSERM (Institut National de la Santé et de la Recherche Médicale | Combination of a big-h3 antagonist and an immune checkpoint inhibitor for the treatment of solid tumor |
WO2020081928A1 (en) | 2018-10-19 | 2020-04-23 | Bristol-Myers Squibb Company | Combination therapy for melanoma |
AU2019366321A1 (en) | 2018-10-22 | 2021-05-13 | Glaxosmithkline Intellectual Property Development Limited | Dosing |
KR20210081384A (ko) | 2018-10-23 | 2021-07-01 | 브리스톨-마이어스 스큅 컴퍼니 | 종양을 치료하는 방법 |
KR20210084546A (ko) | 2018-10-29 | 2021-07-07 | 메르사나 테라퓨틱스, 인코포레이티드 | 펩티드 함유 링커를 갖는 시스테인 조작된 항체-약물 접합체 |
EP3873532A1 (en) | 2018-10-31 | 2021-09-08 | Novartis AG | Dc-sign antibody drug conjugates |
WO2020092854A2 (en) | 2018-11-01 | 2020-05-07 | Juno Therapeutics, Inc. | Chimeric antigen receptors specific for g protein-coupled receptor class c group 5 member d (gprc5d) |
EP3873943A2 (en) | 2018-11-01 | 2021-09-08 | Juno Therapeutics, Inc. | Methods for treatment using chimeric antigen receptors specific for b-cell maturation antigen |
US20210395240A1 (en) | 2018-11-01 | 2021-12-23 | Merck Sharp & Dohme Corp. | Novel substituted pyrazole compounds as indoleamine 2,3-dioxygenase inhibitors |
EP3877366A4 (en) | 2018-11-06 | 2022-08-24 | Merck Sharp & Dohme Corp. | NOVEL SUBSTITUTED TRICYCLIC COMPOUNDS AS INDOLAMINE-2,3-DIOXYGENASE INHIBITORS |
WO2020102375A1 (en) | 2018-11-14 | 2020-05-22 | Regeneron Pharmaceuticals, Inc. | Intralesional administration of pd-1 inhibitors for treating skin cancer |
TW202028222A (zh) | 2018-11-14 | 2020-08-01 | 美商Ionis製藥公司 | Foxp3表現之調節劑 |
AU2019379325A1 (en) | 2018-11-16 | 2021-06-03 | Genexine, 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 |
KR20210093946A (ko) | 2018-11-16 | 2021-07-28 | 아르퀼 인코포레이티드 | 암의 치료를 위한 제약 조합물 |
JP2022513062A (ja) | 2018-11-16 | 2022-02-07 | ジュノー セラピューティクス インコーポレイテッド | B細胞悪性腫瘍を処置するために、操作されたt細胞を投薬する方法 |
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 |
WO2020106560A1 (en) | 2018-11-20 | 2020-05-28 | Merck Sharp & Dohme Corp. | Substituted amino triazolopyrimidine and amino triazolopyrazine adenosine receptor antagonists, pharmaceutical compositions and their use |
BR112021009078A8 (pt) | 2018-11-20 | 2023-02-07 | Merck Sharp & Dohme | Antagonistas substituídos de receptor de adenosina de aminotriazolopirimidina e aminotriazolopirazina, composições farmacêuticas e seus usos |
EP3883964A1 (en) | 2018-11-20 | 2021-09-29 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Bispecific antibody targeting transferrin receptor 1 and soluble antigen |
JP2022511437A (ja) | 2018-11-26 | 2022-01-31 | デバイオファーム インターナショナル エス.エー. | Hiv感染の組み合わせ治療 |
US20220018828A1 (en) | 2018-11-28 | 2022-01-20 | Inserm (Institut National De La Santé Et La Recherche Médicale | Methods and kit for assaying lytic potential of immune effector cells |
WO2020112581A1 (en) | 2018-11-28 | 2020-06-04 | Merck Sharp & Dohme Corp. | Novel substituted piperazine amide compounds as indoleamine 2, 3-dioxygenase (ido) inhibitors |
IL283487B1 (en) | 2018-11-30 | 2024-03-01 | Glaxosmithkline Ip Dev Ltd | Compounds useful in curing HIV |
JOP20210116A1 (ar) | 2018-11-30 | 2023-01-30 | Merck Sharp & Dohme | مشتقات أمينو ترايازولو كوينازولين بها استبدال في الموضع-9 كمضادات مستقبل أدينوزين، تركيبات صيدلانية واستخدامها |
US20220088070A1 (en) | 2018-11-30 | 2022-03-24 | Juno Therapeutics, Inc. | Methods for treatment using adoptive cell therapy |
AU2019391097A1 (en) | 2018-12-04 | 2021-05-20 | Sumitomo Pharma Oncology, Inc. | CDK9 inhibitors and polymorphs thereof for use as agents for treatment of cancer |
WO2020115262A1 (en) | 2018-12-07 | 2020-06-11 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of cd26 and cd39 as new phenotypic markers for assessing maturation of foxp3+ t cells and uses thereof for diagnostic purposes |
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 |
TW202039459A (zh) | 2018-12-11 | 2020-11-01 | 美商施萬生物製藥研發 Ip有限責任公司 | Alk5 抑制劑 |
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 |
US20220047556A1 (en) | 2018-12-17 | 2022-02-17 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of sulconazole as a furin inhibitor |
GB201820547D0 (en) | 2018-12-17 | 2019-01-30 | Oxford Univ Innovation | Modified antibodies |
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 |
CN113271945A (zh) | 2018-12-20 | 2021-08-17 | 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和药物组合 |
US11618776B2 (en) | 2018-12-20 | 2023-04-04 | Xencor, Inc. | Targeted heterodimeric Fc fusion proteins containing IL-15/IL-15RA and NKG2D antigen binding domains |
WO2020128613A1 (en) | 2018-12-21 | 2020-06-25 | Novartis Ag | Use of il-1beta binding antibodies |
CN113227137A (zh) | 2018-12-21 | 2021-08-06 | 诺华股份有限公司 | IL-1β抗体在骨髓增生异常综合征的治疗或预防中的用途 |
JP2022515188A (ja) | 2018-12-21 | 2022-02-17 | エイム・イムノテック・インコーポレイテッド | がん治療のための組成物および方法 |
WO2020128637A1 (en) | 2018-12-21 | 2020-06-25 | Novartis Ag | Use of il-1 binding antibodies in the treatment of a msi-h cancer |
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 |
CN113227138A (zh) | 2018-12-21 | 2021-08-06 | 诺华股份有限公司 | IL-1β结合抗体的用途 |
WO2020127965A1 (en) | 2018-12-21 | 2020-06-25 | Onxeo | New conjugated nucleic acid molecules and their uses |
CR20210324A (es) | 2018-12-21 | 2021-07-14 | Novartis Ag | Anticuerpos anti-pmel 17 y conjugados de los mismos |
EP3902529A1 (en) | 2018-12-27 | 2021-11-03 | Amgen Inc. | Lyophilized virus formulations |
EP3906415A1 (en) | 2019-01-03 | 2021-11-10 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for enhancing cd8+ t cell-dependent immune responses in subjects suffering from cancer |
JP2022516989A (ja) | 2019-01-09 | 2022-03-03 | セルジーン コーポレイション | (s)-4-(4-(4-(((2-(2,6-ジオキソピペリジン-3-イル)-1-オキソイソインドリン-4-イル)オキシ)メチル)ベンジル)ピペラジン-1-イル)-3-フルオロベンゾニトリルを含む医薬組成物及びその使用方法 |
WO2020146440A1 (en) | 2019-01-09 | 2020-07-16 | Celgene Corporation | Antiproliferative compounds and second active agents for use in treating multiple myeloma |
EA202191620A1 (ru) | 2019-01-09 | 2021-11-01 | Селджин Корпорейшн | Твердые формы, содержащие (s)-4-(4-(4-(((2-(2,6-диоксопиперидин-3-ил)-1-оксоизоиндолин-4-ил)окси)метил)бензил)пиперазин-1-ил)-3-фторбензонитрил и его соли, и содержащие их композиции и способы их применения |
MX2021008525A (es) | 2019-01-15 | 2021-11-12 | Univ Nantes | Polipeptidos de interleucina-34 (il-34) mutados y sus usos en terapia. |
JP2022518207A (ja) | 2019-01-17 | 2022-03-14 | ジョージア テック リサーチ コーポレイション | 酸化コレステロールを含有する薬物送達システム |
TWI829857B (zh) | 2019-01-29 | 2024-01-21 | 美商英塞特公司 | 作為a2a / a2b抑制劑之吡唑并吡啶及***并吡啶 |
US20220096651A1 (en) | 2019-01-29 | 2022-03-31 | Juno Therapeutics, Inc. | Antibodies and chimeric antigen receptors specific for receptor tyrosine kinase like orphan receptor 1 (ror1) |
EP3918332A1 (en) | 2019-01-30 | 2021-12-08 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for identifying whether a subject suffering from a cancer will achieve a response with an immune-checkpoint inhibitor |
WO2020161083A1 (en) | 2019-02-04 | 2020-08-13 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for modulating blood-brain barrier |
KR20210146290A (ko) | 2019-02-12 | 2021-12-03 | 스미토모 다이니폰 파마 온콜로지, 인크. | 헤테로시클릭 단백질 키나제 억제제를 포함하는 제제 |
CN113395967A (zh) | 2019-02-12 | 2021-09-14 | 诺华股份有限公司 | 包含tno155和pd-1抑制剂的药物组合 |
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 |
AU2020222346B2 (en) | 2019-02-15 | 2021-12-09 | Novartis Ag | Substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof |
SG11202108702XA (en) | 2019-02-15 | 2021-09-29 | Incyte Corp | Cyclin-dependent kinase 2 biomarkers and uses thereof |
MX2021009763A (es) | 2019-02-15 | 2021-09-08 | Novartis Ag | Derivados de 3-(1-oxo-5-(piperidin-4-il)isoindolin-2-il)piperidina -2,6-diona y usos de los mismos. |
US20220107320A1 (en) | 2019-02-15 | 2022-04-07 | Incelldx, Inc. | Assaying Bladder-Associated Samples, Identifying and Treating Bladder-Associated Neoplasia, and Kits for Use Therein |
WO2020168197A1 (en) | 2019-02-15 | 2020-08-20 | Incyte Corporation | Pyrrolo[2,3-d]pyrimidinone compounds as cdk2 inhibitors |
WO2020169472A2 (en) | 2019-02-18 | 2020-08-27 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods of inducing phenotypic changes in macrophages |
US20220088075A1 (en) | 2019-02-22 | 2022-03-24 | The Trustees Of The University Of Pennsylvania | Combination therapies of egfrviii chimeric antigen receptors and pd-1 inhibitors |
EP3938506A4 (en) * | 2019-02-26 | 2022-12-14 | Twist Bioscience Corporation | VARIANT NUCLEIC ACID LIBRARIES FOR OPTIMIZATION OF ANTIBODIES |
CA3137361A1 (en) | 2019-02-28 | 2020-09-03 | Regeneron Pharmaceuticals, Inc. | Administration of pd-1 inhibitors for treating skin cancer |
WO2020180959A1 (en) | 2019-03-05 | 2020-09-10 | Incyte Corporation | Pyrazolyl pyrimidinylamine compounds as cdk2 inhibitors |
SG11202108449SA (en) | 2019-03-05 | 2021-09-29 | Amgen Inc | Use of oncolytic viruses for the treatment of cancer |
SG11202109003QA (en) | 2019-03-06 | 2021-09-29 | Regeneron Pharma | Il-4/il-13 pathway inhibitors for enhanced efficacy in treating cancer |
US11628162B2 (en) | 2019-03-08 | 2023-04-18 | Incyte Corporation | Methods of treating cancer with an FGFR inhibitor |
WO2020183011A1 (en) | 2019-03-14 | 2020-09-17 | Institut Curie | Htr1d inhibitors and uses thereof in the treatment of cancer |
EA202192555A1 (ru) | 2019-03-19 | 2021-11-25 | Фундасио Привада Институт Д'Инвестигасио Онколохика Де Валь Эброн | Комбинированная терапия для лечения рака |
JP2022525149A (ja) | 2019-03-20 | 2022-05-11 | スミトモ ダイニッポン ファーマ オンコロジー, インコーポレイテッド | ベネトクラクスが失敗した急性骨髄性白血病(aml)の処置 |
US11712433B2 (en) | 2019-03-22 | 2023-08-01 | Sumitomo Pharma Oncology, Inc. | Compositions comprising PKM2 modulators and methods of treatment using the same |
WO2020198676A1 (en) | 2019-03-28 | 2020-10-01 | Bristol-Myers Squibb Company | Methods of treating tumor |
EP3946625A1 (en) | 2019-03-28 | 2022-02-09 | Bristol-Myers Squibb Company | Methods of treating tumor |
WO2020205560A1 (en) | 2019-03-29 | 2020-10-08 | Incyte Corporation | Sulfonylamide compounds as cdk2 inhibitors |
CA3134439A1 (en) | 2019-03-29 | 2020-10-08 | Institut Curie | Interleukin-2 variants with modified biological activity |
TW202102543A (zh) | 2019-03-29 | 2021-01-16 | 美商安進公司 | 溶瘤病毒在癌症新輔助療法中之用途 |
JP2022527972A (ja) | 2019-04-02 | 2022-06-07 | アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル | 前悪性病変を有する患者において癌を予測及び予防する方法 |
US20220177465A1 (en) | 2019-04-04 | 2022-06-09 | Merck Sharp & Dohme Corp. | Inhibitors of histone deacetylase-3 useful for the treatment of cancer, inflammation, neurodegeneration diseases and diabetes |
EP3952850A1 (en) | 2019-04-09 | 2022-02-16 | Institut National de la Santé et de la Recherche Médicale (INSERM) | Use of sk2 inhibitors in combination with immune checkpoint blockade therapy for the treatment of cancer |
EP3956446A1 (en) | 2019-04-17 | 2022-02-23 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treatment of nlrp3 inflammasome mediated il-1beta dependent disorders |
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 |
US11440914B2 (en) | 2019-05-01 | 2022-09-13 | Incyte Corporation | Tricyclic amine compounds as CDK2 inhibitors |
US11447494B2 (en) | 2019-05-01 | 2022-09-20 | Incyte Corporation | Tricyclic amine compounds as CDK2 inhibitors |
MA55805A (fr) | 2019-05-03 | 2022-03-09 | Flagship Pioneering Innovations V Inc | Métodes de modulation de l'activité immunitaire |
AU2019444218A1 (en) | 2019-05-07 | 2021-11-25 | Immunicom, Inc. | Increasing responses to checkpoint inhibitors by extracorporeal apheresis |
CA3136568A1 (en) | 2019-05-13 | 2020-11-19 | Regeneron Pharmaceuticals, Inc. | Combination of pd-1 inhibitors and lag-3 inhibitors for enhanced efficacy in treating cancer |
EP3969438A1 (en) | 2019-05-16 | 2022-03-23 | Stingthera, Inc. | Oxoacridinyl acetic acid derivatives and methods of use |
EP3969452A1 (en) | 2019-05-16 | 2022-03-23 | Stingthera, Inc. | Benzo[b][1,8]naphthyridine acetic acid derivatives and methods of use |
EP3972992A4 (en) | 2019-05-20 | 2023-07-19 | Pandion Operations, Inc. | ANTI-MADCAM IMMUNE TOLERANCE |
US20220241412A1 (en) | 2019-05-24 | 2022-08-04 | Pfizer Inc. | Combination therapies using cdk inhibitors |
JP2022534967A (ja) | 2019-05-30 | 2022-08-04 | ブリストル-マイヤーズ スクイブ カンパニー | 多腫瘍遺伝子シグネチャーおよびその使用 |
US20220233691A1 (en) | 2019-05-30 | 2022-07-28 | Bristol-Myers Squibb Company | Cell localization signature and combination therapy |
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 |
EP3980460A2 (en) * | 2019-06-05 | 2022-04-13 | AnaptysBio, Inc. | Pd-1 agonist and method of using same |
US20210038684A1 (en) | 2019-06-11 | 2021-02-11 | Alkermes Pharma Ireland Limited | Compositions and Methods for Cancer Immunotherapy |
EP3983004A1 (en) | 2019-06-14 | 2022-04-20 | TILT Biotherapeutics Oy | Oncolytic adenovirus and checkpoint inhibitor combination therapy |
CA3143680A1 (en) | 2019-06-18 | 2020-12-24 | Janssen Sciences Ireland Unlimited Company | Combination of hepatitis b virus (hbv) vaccines and anti-pd-1 or anti-pd-l1 antibody |
WO2020255009A2 (en) | 2019-06-18 | 2020-12-24 | Janssen Sciences Ireland Unlimited Company | Combination of hepatitis b virus (hbv) vaccines and anti-pd-1 antibody |
AU2020298294A1 (en) | 2019-06-21 | 2022-02-17 | Twist Bioscience Corporation | Barcode-based nucleic acid sequence assembly |
US11738052B2 (en) | 2019-06-21 | 2023-08-29 | HCW Biologics, Inc. | Multi-chain chimeric polypeptides and uses thereof |
WO2020260547A1 (en) | 2019-06-27 | 2020-12-30 | Rigontec Gmbh | Design method for optimized rig-i ligands |
EP3994270A1 (en) | 2019-07-02 | 2022-05-11 | Fred Hutchinson Cancer Research Center | Recombinant ad35 vectors and related gene therapy improvements |
CN114302878A (zh) | 2019-07-03 | 2022-04-08 | 大日本住友制药肿瘤公司 | 酪氨酸激酶非受体1(tnk1)抑制剂及其用途 |
EP3998081A4 (en) | 2019-07-05 | 2023-07-12 | Ono Pharmaceutical Co., Ltd. | TREATMENT OF BLOOD CANCER WITH PD-1/CD3 DUAL SPECIFICITY PROTEIN |
WO2021007269A1 (en) | 2019-07-09 | 2021-01-14 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
CN110384657A (zh) * | 2019-07-15 | 2019-10-29 | 三峡大学 | 靶向PD-L1载miR-34a微泡的制备方法及在制备抑制***的药物上的应用 |
GB201910305D0 (en) | 2019-07-18 | 2019-09-04 | Ctxt Pty Ltd | Compounds |
GB201910304D0 (en) | 2019-07-18 | 2019-09-04 | Ctxt Pty Ltd | Compounds |
US11083705B2 (en) | 2019-07-26 | 2021-08-10 | Eisai R&D Management Co., Ltd. | Pharmaceutical composition for treating tumor |
CN114514032A (zh) | 2019-08-02 | 2022-05-17 | 兰提欧派普有限公司 | 用于治疗癌症的血管紧张素2型(at2)受体激动剂 |
CN114585623A (zh) | 2019-08-02 | 2022-06-03 | 梅尔莎纳医疗公司 | 双[N-((5-氨基甲酰基)-1H-苯并[d]咪唑-2-基)吡唑-5-甲酰胺]衍生物和相关化合物作为STING(干扰素基因刺激物)激动剂用于治疗癌症 |
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 |
JPWO2021025140A1 (zh) | 2019-08-08 | 2021-02-11 | ||
MX2022001732A (es) | 2019-08-12 | 2022-05-06 | Purinomia Biotech Inc | Metodos y composiciones para promover y potenciar la respuesta inmunitaria mediada por linfocitos t dirigida a la adcc de las celulas con expresion de cd39. |
KR20220064369A (ko) | 2019-08-14 | 2022-05-18 | 인사이트 코포레이션 | Cdk2 저해제로서의 이미다졸릴 피리디미딘일아민 화합물 |
GB201912107D0 (en) | 2019-08-22 | 2019-10-09 | Amazentis Sa | Combination |
KR20220053007A (ko) | 2019-08-30 | 2022-04-28 | 아게누스 인코포레이티드 | 항-cd96 항체 및 이의 사용 방법 |
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 |
WO2021055630A1 (en) | 2019-09-17 | 2021-03-25 | Bial- Biotech Investments, Inc. | Substituted, saturated and unsaturated n-heterocyclic carboxamides and related compounds for their use in the treatment of medical disorders |
MX2022003237A (es) | 2019-09-17 | 2022-07-04 | Bial R&D Invest S A | Imidazol carboxamidas sustituidas y su uso en el tratamiento de trastornos medicos. |
CN114761386A (zh) | 2019-09-17 | 2022-07-15 | 比亚尔R&D投资股份公司 | 作为酸性神经酰胺酶抑制剂的经取代n-杂环甲酰胺及其作为药物的用途 |
TW202124446A (zh) | 2019-09-18 | 2021-07-01 | 瑞士商諾華公司 | 與entpd2抗體之組合療法 |
BR112022004995A2 (pt) | 2019-09-18 | 2022-06-21 | Lamkap Bio Alpha AG | Anticorpos biespecíficos contra ceacam5 e cd3 |
WO2021053559A1 (en) | 2019-09-18 | 2021-03-25 | Novartis Ag | Entpd2 antibodies, combination therapies, and methods of using the antibodies and combination therapies |
CR20220107A (es) | 2019-09-18 | 2022-04-25 | Novartis Ag | Proteínas de fusión nkg2d y sus usos |
US20220348653A1 (en) | 2019-09-22 | 2022-11-03 | Bristol-Myers Squibb Company | Quantitative Spatial Profiling for LAG-3 Antagonist Therapy |
US20220339249A1 (en) | 2019-09-25 | 2022-10-27 | Bristol-Myers Squibb Company | Composite biomarker for cancer therapy |
JP2022549495A (ja) | 2019-09-25 | 2022-11-25 | シージェン インコーポレイテッド | 造血器がんの治療のための抗cd30 adc、抗pd-1、および化学療法剤の併用 |
US11667613B2 (en) | 2019-09-26 | 2023-06-06 | Novartis Ag | Antiviral pyrazolopyridinone compounds |
AU2020355614A1 (en) | 2019-09-27 | 2022-04-14 | Glaxosmithkline Intellectual Property Development Limited | Antigen binding proteins |
AU2020358726A1 (en) | 2019-10-01 | 2022-04-07 | Silverback Therapeutics, Inc. | Combination therapy with immune stimulatory conjugates |
EP3800201A1 (en) | 2019-10-01 | 2021-04-07 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Cd28h stimulation enhances nk cell killing activities |
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 |
EP4037700A2 (en) | 2019-10-03 | 2022-08-10 | Xencor, Inc. | Targeted il-12 heterodimeric fc-fusion proteins |
US20220363776A1 (en) | 2019-10-04 | 2022-11-17 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical composition for the treatment of ovarian cancer, breast cancer or pancreatic cancer |
CR20220170A (es) | 2019-10-11 | 2022-10-10 | Incyte Corp | Aminas bicíclicas como inhibidoras de la cdk2 |
TW202128757A (zh) | 2019-10-11 | 2021-08-01 | 美商建南德克公司 | 具有改善之特性的 PD-1 標靶 IL-15/IL-15Rα FC 融合蛋白 |
JP2022552324A (ja) | 2019-10-14 | 2022-12-15 | インサイト・コーポレイション | Fgfr阻害剤としての二環式複素環 |
WO2021076728A1 (en) | 2019-10-16 | 2021-04-22 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
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 |
MX2022004769A (es) | 2019-10-21 | 2022-05-16 | Novartis Ag | Inhibidores de tim-3 y sus usos. |
CN114786679A (zh) | 2019-10-21 | 2022-07-22 | 诺华股份有限公司 | 具有维奈托克和tim-3抑制剂的组合疗法 |
EP4048304A1 (en) | 2019-10-22 | 2022-08-31 | Institut Curie | Immunotherapy targeting tumor neoantigenic peptides |
NL2024108B1 (en) | 2019-10-26 | 2021-07-19 | Vitroscan B V | Methods and apparatus for measuring immune-cell mediated anti-tumoroid responses |
MX2022005187A (es) | 2019-10-28 | 2022-07-27 | Shanghai Inst Materia Medica Cas | Compuesto de ácido oxocarboxílico heterocíclico de cinco miembros y el uso médico del mismo. |
JP2023500575A (ja) | 2019-10-29 | 2023-01-10 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 癌を治療するためのPD-1アンタゴニスト、VEGFR/FGFR/RETチロシンキナーゼ阻害剤、及びCBP/β-カテニン阻害剤の組合せ |
WO2021083959A1 (en) | 2019-10-29 | 2021-05-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating uveal melanoma |
JP2022553821A (ja) | 2019-11-05 | 2022-12-26 | ブリストル-マイヤーズ スクイブ カンパニー | M-タンパク質アッセイおよびその使用 |
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 |
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 |
CA3160479A1 (en) | 2019-11-08 | 2021-05-14 | Bristol-Myers Squibb Company | Lag-3 antagonist therapy for melanoma |
PE20230407A1 (es) | 2019-11-11 | 2023-03-07 | Incyte Corp | Sales y formas cristalinas de un inhibidor de pd-1/pd-l1 |
US20220395553A1 (en) | 2019-11-14 | 2022-12-15 | Cohbar, Inc. | Cxcr4 antagonist peptides |
WO2021102343A1 (en) | 2019-11-22 | 2021-05-27 | Sumitomo Dainippon Pharma Oncology, Inc. | Solid dose pharmaceutical composition |
AU2020385400A1 (en) | 2019-11-22 | 2022-06-09 | Theravance Biopharma R&D Ip, Llc | Substituted 1,5-naphthyridines or quinolines as ALK5 inhibitors |
EP3824954A1 (en) | 2019-11-22 | 2021-05-26 | Centre National de la Recherche Scientifique | Device, apparatus and method for minibeam radiation therapy |
AU2020394441A1 (en) | 2019-11-26 | 2022-06-02 | Novartis Ag | CD19 and CD22 chimeric antigen receptors and uses thereof |
WO2021108025A1 (en) | 2019-11-26 | 2021-06-03 | Massachusetts Institute Of Technology | Cell-based cancer vaccines and cancer therapies |
EP3831849A1 (en) | 2019-12-02 | 2021-06-09 | LamKap Bio beta AG | Bispecific antibodies against ceacam5 and cd47 |
BR112022010664A2 (pt) | 2019-12-04 | 2022-08-16 | Incyte Corp | Derivados de um inibidor de fgfr |
AU2020397956A1 (en) | 2019-12-04 | 2022-07-07 | Orna Therapeutics, Inc. | Circular RNA compositions and methods |
US11897891B2 (en) | 2019-12-04 | 2024-02-13 | Incyte Corporation | Tricyclic heterocycles as FGFR inhibitors |
US20230074558A1 (en) | 2019-12-06 | 2023-03-09 | Mersana Therapeutics, Inc. | Dimeric compounds as sting agonists |
US11897950B2 (en) | 2019-12-06 | 2024-02-13 | Augusta University Research Institute, Inc. | Osteopontin monoclonal antibodies |
AU2020399976A1 (en) | 2019-12-09 | 2022-06-30 | Merck Sharp & Dohme B.V. | Combination therapy with LIV1-ADC and PD-1 antagonist |
US20230114107A1 (en) | 2019-12-17 | 2023-04-13 | Flagship Pioneering Innovations V, Inc. | Combination anti-cancer therapies with inducers of iron-dependent cellular disassembly |
KR20220118481A (ko) | 2019-12-19 | 2022-08-25 | 브리스톨-마이어스 스큅 컴퍼니 | Dgk 억제제 및 체크포인트 길항제의 조합물 |
WO2021123243A1 (en) | 2019-12-19 | 2021-06-24 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and vaccine compositions to treat cancers |
KR20220116257A (ko) | 2019-12-20 | 2022-08-22 | 노파르티스 아게 | 골수섬유증 및 골수이형성 증후군을 치료하기 위한, 데시타빈 또는 항 pd-1 항체 스파르탈리주맙을 포함하거나 또는 포함하지 않는, 항 tim-3 항체 mbg453 및 항 tgf-베타 항체 nis793의 조합물 |
EP4084821A2 (en) | 2020-01-03 | 2022-11-09 | Marengo Therapeutics, Inc. | Multifunctional molecules that bind to cd33 and uses thereof |
EP4085060A1 (en) | 2020-01-03 | 2022-11-09 | Incyte Corporation | Combination therapy comprising a2a/a2b and pd-1/pd-l1 inhibitors |
WO2021144426A1 (en) | 2020-01-17 | 2021-07-22 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma |
IL293752A (en) | 2020-01-17 | 2022-08-01 | Novartis Ag | A combination containing a tim-3 inhibitor and a substance that causes hypomethylation for use in the treatment of myeloplastic syndrome or chronic myelomonocytic leukemia |
BR112022014849A2 (pt) | 2020-01-28 | 2022-10-11 | Genentech Inc | Métodos de tratamento de um tumor sólido, métodos para induzir a proliferação de células t, para induzir a proliferação de células nk e para induzir a produção de ifny |
IL295093A (en) | 2020-01-30 | 2022-09-01 | Ona Therapeutics S L | Combined treatment for cancer and cancer metastases |
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) |
KR20220139915A (ko) | 2020-02-06 | 2022-10-17 | 브리스톨-마이어스 스큅 컴퍼니 | Il-10 및 그의 용도 |
CA3169231A1 (en) | 2020-02-11 | 2021-08-19 | HCW Biologics, Inc. | Methods of treating age-related and inflammatory diseases |
WO2021163298A1 (en) | 2020-02-11 | 2021-08-19 | HCW Biologics, Inc. | Methods of activating regulatory t cells |
WO2021163299A1 (en) | 2020-02-11 | 2021-08-19 | HCW Biologics, Inc. | Chromatography resin and uses thereof |
KR20220148846A (ko) | 2020-02-28 | 2022-11-07 | 노파르티스 아게 | 다브라페닙, erk 억제제, 및 raf 억제제를 포함하는 삼중 약학적 조합물 |
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 |
WO2021171264A1 (en) | 2020-02-28 | 2021-09-02 | Novartis Ag | Dosing of a bispecific antibody that binds cd123 and cd3 |
WO2022074464A2 (en) | 2020-03-05 | 2022-04-14 | Neotx Therapeutics Ltd. | Methods and compositions for treating cancer with immune cells |
KR20230017165A (ko) | 2020-03-06 | 2023-02-03 | 인사이트 코포레이션 | Axl/mer 및 pd-1/pd-l1 억제제를 포함하는 병행 요법 |
AU2021232158A1 (en) | 2020-03-06 | 2022-09-29 | Ona Therapeutics, S.L. | Anti-CD36 antibodies and their use to treat cancer |
WO2021177822A1 (en) | 2020-03-06 | 2021-09-10 | Stichting Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis | Modulating anti-tumor immunity |
US20230093147A1 (en) | 2020-03-09 | 2023-03-23 | President And Fellows Of Harvard College | Methods and compositions relating to improved combination therapies |
CA3172423A1 (en) | 2020-03-20 | 2021-03-22 | Alex WESSELHOEFT | Circular rna compositions and methods |
AU2021244200A1 (en) | 2020-03-23 | 2022-11-24 | Bristol-Myers Squibb Company | Anti-CCR8 antibodies for treating cancer |
EP4126824A1 (en) | 2020-03-31 | 2023-02-08 | Theravance Biopharma R&D IP, LLC | Substituted pyrimidines and methods of use |
CA3179800A1 (en) | 2020-04-10 | 2021-10-14 | Juno Therapeutics, Inc. | Methods and uses related to cell therapy engineered with a chimeric antigen receptor targeting b-cell maturation antigen |
WO2021209357A1 (en) | 2020-04-14 | 2021-10-21 | Glaxosmithkline Intellectual Property Development Limited | Combination treatment for cancer involving anti-icos and anti-pd1 antibodies, optionally further involving anti-tim3 antibodies |
EP4136112A1 (en) | 2020-04-14 | 2023-02-22 | GlaxoSmithKline Intellectual Property Development Limited | Combination treatment for cancer |
IL297165A (en) | 2020-04-16 | 2022-12-01 | Incyte Corp | Soysag tricyclic CRS inhibitors |
JP2023523193A (ja) | 2020-04-21 | 2023-06-02 | ノバルティス アーゲー | Csf-1rにより調節される疾患を治療するための投与レジメン |
TW202206100A (zh) | 2020-04-27 | 2022-02-16 | 美商西健公司 | 癌症之治療 |
US20230174666A1 (en) | 2020-04-29 | 2023-06-08 | HCW Biologics, Inc. | Anti-cd26 proteins and uses thereof |
US20230181756A1 (en) | 2020-04-30 | 2023-06-15 | Novartis Ag | Ccr7 antibody drug conjugates for treating cancer |
WO2021224186A1 (en) | 2020-05-04 | 2021-11-11 | Institut Curie | New pyridine derivatives as radiosensitizers |
CA3181538A1 (en) | 2020-05-05 | 2021-11-11 | Teon Therapeutics, Inc. | Cannabinoid receptor type 2 (cb2) modulators and uses thereof |
TW202202493A (zh) | 2020-05-06 | 2022-01-16 | 美商默沙東藥廠 | Il4i1抑制劑及使用方法 |
WO2021231526A1 (en) | 2020-05-13 | 2021-11-18 | Incyte Corporation | Fused pyrimidine compounds as kras inhibitors |
CA3178260A1 (en) | 2020-05-13 | 2021-11-18 | Massachusetts Institute Of Technology | Compositions of polymeric microdevices and their use in cancer immunotherapy |
WO2021234110A1 (en) | 2020-05-20 | 2021-11-25 | Institut Curie | Single domain antibodies and their use in cancer therapies |
CA3168738A1 (en) | 2020-05-26 | 2021-12-02 | Matthew G. Fury | Methods of treating cervical cancer by administering a pd-1 inhibitor |
MX2022014943A (es) | 2020-05-26 | 2023-03-08 | Inst Nat Sante Rech Med | Polipéptidos de coronavirus 2 causante del síndrome respiratorio agudo severo (sars-cov-2) y usos de los mismos para propositos de vacuna. |
WO2021242794A2 (en) | 2020-05-29 | 2021-12-02 | President And Fellows Of Harvard College | Living cells engineered with polyphenol-functionalized biologically active nanocomplexes |
CA3184756A1 (en) | 2020-06-01 | 2021-12-09 | HCW Biologics, Inc. | Methods of treating aging-related disorders |
WO2021247003A1 (en) | 2020-06-01 | 2021-12-09 | HCW Biologics, Inc. | Methods of treating aging-related disorders |
US11767353B2 (en) | 2020-06-05 | 2023-09-26 | Theraly Fibrosis, Inc. | Trail compositions with reduced immunogenicity |
TW202214623A (zh) | 2020-06-10 | 2022-04-16 | 美商施萬生物製藥研發 Ip有限責任公司 | 結晶型alk5抑制劑及其用途 |
AU2021288224A1 (en) | 2020-06-11 | 2023-01-05 | Novartis Ag | ZBTB32 inhibitors and uses thereof |
AR122644A1 (es) | 2020-06-19 | 2022-09-28 | Onxeo | Nuevas moléculas de ácido nucleico conjugado y sus usos |
KR20230027056A (ko) | 2020-06-23 | 2023-02-27 | 노파르티스 아게 | 3-(1-옥소이소인돌린-2-일)피페리딘-2,6-디온 유도체를 포함하는 투약 요법 |
WO2021262969A1 (en) | 2020-06-24 | 2021-12-30 | The General Hospital Corporation | Materials and methods of treating cancer |
US20230293530A1 (en) | 2020-06-24 | 2023-09-21 | Yeda Research And Development Co. Ltd. | Agents for sensitizing solid tumors to treatment |
JP2023531512A (ja) | 2020-06-25 | 2023-07-24 | セルジーン コーポレーション | 併用療法を用いて癌を治療するための方法 |
EP4172184A2 (en) | 2020-06-26 | 2023-05-03 | Amgen Inc. | Il-10 muteins and fusion proteins thereof |
CN116096906A (zh) | 2020-06-29 | 2023-05-09 | 旗舰创业创新五公司 | 工程化以促进萨诺传递的病毒及其在治疗癌症中的用途 |
US20230235408A1 (en) | 2020-06-30 | 2023-07-27 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for predicting the risk of recurrence and/or death of patients suffering from a solid cancer after preoperative adjuvant therapies |
JP2023531290A (ja) | 2020-06-30 | 2023-07-21 | アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル | 術前補助療法及び根治手術後の固形がんを患っている患者の再発及び/又は死亡のリスクを予測するための方法 |
EP4178548A1 (en) | 2020-07-07 | 2023-05-17 | Celgene Corporation | Pharmaceutical compositions comprising (s)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)m ethyl) benzyl)piperazin-1-yl)-3-fluorobenzonitrile and methods of using the same |
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 |
EP4189395A1 (en) | 2020-07-28 | 2023-06-07 | Institut National de la Santé et de la Recherche Médicale (INSERM) | 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 |
CN116134155A (zh) | 2020-08-26 | 2023-05-16 | 瑞泽恩制药公司 | 通过施用pd-1抑制剂治疗癌症的方法 |
AU2021333779A1 (en) | 2020-08-26 | 2023-04-13 | Marengo Therapeutics, Inc. | Methods of detecting TRBC1 or TRBC2 |
WO2022047093A1 (en) | 2020-08-28 | 2022-03-03 | Incyte Corporation | Vinyl imidazole compounds as inhibitors of kras |
BR112023003427A2 (pt) | 2020-08-28 | 2023-03-21 | Bristol Myers Squibb Co | Terapia com antagonista de lag-3 para carcinoma hepatocelular |
EP4204020A1 (en) | 2020-08-31 | 2023-07-05 | Advanced Accelerator Applications International S.A. | Method of treating psma-expressing cancers |
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 |
CA3189987A1 (en) | 2020-09-02 | 2022-03-10 | Pharmabcine Inc. | Combination therapy of a pd-1 antagonist and an antagonist for vegfr-2 for treating patients with cancer |
JP2023542490A (ja) | 2020-09-03 | 2023-10-10 | リジェネロン・ファーマシューティカルズ・インコーポレイテッド | Pd-1阻害剤を投与することによりがん疼痛を処置する方法 |
WO2022072783A1 (en) | 2020-10-02 | 2022-04-07 | Incyte Corporation | Bicyclic dione compounds as inhibitors of kras |
US20230374160A1 (en) | 2020-10-02 | 2023-11-23 | Regeneron Pharmaceuticals, Inc. | Combination of antibodies for treating cancer with reduced cytokine release syndrome |
JP2023544410A (ja) | 2020-10-05 | 2023-10-23 | ブリストル-マイヤーズ スクイブ カンパニー | タンパク質を濃縮するための方法 |
WO2022079270A1 (en) | 2020-10-16 | 2022-04-21 | Université D'aix-Marseille | Anti-gpc4 single domain antibodies |
CA3196243A1 (en) | 2020-10-20 | 2022-04-28 | Angela Marinetti | Metallic trans-(n-heterocyclic carbene)-amine-platinum complexes and uses thereof for treating cancer |
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 |
CA3196496A1 (en) | 2020-10-23 | 2022-04-28 | Laurence David TOMS | Lag-3 antagonist therapy for lung cancer |
JP2023549678A (ja) | 2020-10-28 | 2023-11-29 | イケナ オンコロジー, インコーポレイテッド | AHR阻害剤のPDx阻害剤またはドキソルビシンとの組み合わせ |
CN116390757A (zh) | 2020-10-28 | 2023-07-04 | 卫材R&D管理有限公司 | 用于***的药物组合物 |
US11866434B2 (en) | 2020-11-06 | 2024-01-09 | Incyte Corporation | Process for making a PD-1/PD-L1 inhibitor and salts and crystalline forms thereof |
CA3199095A1 (en) | 2020-11-06 | 2022-05-12 | Novartis Ag | Cd19 binding molecules and uses thereof |
TW202233615A (zh) | 2020-11-06 | 2022-09-01 | 美商英塞特公司 | Pd—1/pd—l1抑制劑之結晶形式 |
US11780836B2 (en) | 2020-11-06 | 2023-10-10 | Incyte Corporation | Process of preparing a PD-1/PD-L1 inhibitor |
IL302402A (en) | 2020-11-08 | 2023-06-01 | Seagen Inc | Combined treatment |
CA3200878A1 (en) | 2020-11-12 | 2022-05-19 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Antibodies conjugated or fused to the receptor-binding domain of the sars-cov-2 spike protein and uses thereof for vaccine purposes |
WO2022101463A1 (en) | 2020-11-16 | 2022-05-19 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of the last c-terminal residues m31/41 of zikv m ectodomain for triggering apoptotic cell death |
EP4244392A1 (en) | 2020-11-16 | 2023-09-20 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Methods and compositions for predicting and treating uveal melanoma |
EP4244391A1 (en) | 2020-11-16 | 2023-09-20 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for predicting and treating uveal melanoma |
JP2023550402A (ja) | 2020-11-18 | 2023-12-01 | アンスティテュ・クリー | ビグアニジンの二量体及びその治療的使用 |
TW202227089A (zh) | 2020-11-30 | 2022-07-16 | 大陸商杭州阿諾生物醫藥科技有限公司 | 用於治療pik3ca突變癌症的組合療法 |
WO2022120179A1 (en) | 2020-12-03 | 2022-06-09 | Bristol-Myers Squibb Company | Multi-tumor gene signatures and uses thereof |
CA3201219A1 (en) | 2020-12-04 | 2022-06-09 | Mir Ali | Ionizable cationic lipids and lipid nanoparticles, and methods of synthesis and use thereof |
EP4259149A1 (en) | 2020-12-08 | 2023-10-18 | Infinity Pharmaceuticals, Inc. | Eganelisib for use in the treatment of pd-l1 negative cancer |
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 |
WO2022130206A1 (en) | 2020-12-16 | 2022-06-23 | Pfizer Inc. | TGFβr1 INHIBITOR COMBINATION THERAPIES |
KR20230121772A (ko) | 2020-12-18 | 2023-08-21 | 람카프 바이오 베타 엘티디. | Ceacam5 및 cd47에 대한 이중특이적 항체 |
WO2022135666A1 (en) | 2020-12-21 | 2022-06-30 | BioNTech SE | Treatment schedule for cytokine proteins |
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 |
WO2022135667A1 (en) | 2020-12-21 | 2022-06-30 | BioNTech SE | Therapeutic rna for treating cancer |
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 |
KR20230157940A (ko) | 2020-12-29 | 2023-11-17 | 인사이트 코포레이션 | A2a/a2b 저해제, pd-1/pd-l1 저해제 및 항-cd73 항체를포함하는 병용 요법 |
CA3204162A1 (en) | 2021-01-11 | 2022-07-14 | Robert Kastelein | Compositions and methods related to receptor pairing |
JP2024505428A (ja) | 2021-01-14 | 2024-02-06 | アンスティテュ キュリー | Her2単一ドメイン抗体バリアントおよびそのcar |
WO2022162569A1 (en) | 2021-01-29 | 2022-08-04 | Novartis Ag | Dosage regimes for anti-cd73 and anti-entpd2 antibodies and uses thereof |
EP4284919A1 (en) | 2021-01-29 | 2023-12-06 | Iovance Biotherapeutics, Inc. | Methods of making modified tumor infiltrating lymphocytes and their use in adoptive cell therapy |
WO2022165403A1 (en) | 2021-02-01 | 2022-08-04 | Yale University | Chemotherapeutic bioadhesive particles with immunostimulatory molecules for cancer treatment |
TW202241494A (zh) | 2021-02-10 | 2022-11-01 | 大陸商同潤生物醫藥(上海)有限公司 | 治療腫瘤的方法和組合 |
EP4291243A1 (en) | 2021-02-12 | 2023-12-20 | Synthorx, Inc. | Lung cancer combination therapy with il-2 conjugates and an anti-pd-1 antibody or antigen-binding fragment thereof |
CN116917273A (zh) | 2021-03-02 | 2023-10-20 | 葛兰素史克知识产权发展有限公司 | 作为dnmt1抑制剂的经取代的吡啶 |
JP2024510947A (ja) | 2021-03-05 | 2024-03-12 | レアダルティス、ソシエダッド リミターダ | 三量体ポリペプチドおよびがん治療におけるその使用 |
WO2022189618A1 (en) | 2021-03-12 | 2022-09-15 | Institut Curie | Nitrogen-containing heterocycles as radiosensitizers |
EP4308118A1 (en) | 2021-03-17 | 2024-01-24 | Institut National de la Santé et de la Recherche Médicale (INSERM) | Methods and compositions for treating melanoma |
WO2022195551A1 (en) | 2021-03-18 | 2022-09-22 | Novartis Ag | Biomarkers for cancer and methods of use thereof |
CA3212571A1 (en) | 2021-03-19 | 2022-09-22 | Trained Therapeutix Discovery, Inc. | Compounds for regulating trained immunity, and their methods of use |
KR20230159590A (ko) | 2021-03-23 | 2023-11-21 | 리제너론 파아마슈티컬스, 인크. | Pd-1 억제제를 투여함에 의한 면역억제 또는 면역손상된 환자에서 암을 치료하는 방법 |
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 |
KR20240005700A (ko) | 2021-03-29 | 2024-01-12 | 주노 쎄러퓨티크스 인코퍼레이티드 | 체크포인트 억제제 요법 및 car t 세포 요법의 조합을 사용한 투여 및 치료 방법 |
WO2022208353A1 (en) | 2021-03-31 | 2022-10-06 | Glaxosmithkline Intellectual Property Development Limited | Antigen binding proteins and combinations thereof |
CA3214085A1 (en) | 2021-03-31 | 2022-10-06 | Darby Rye Schmidt | Thanotransmission polypeptides and their use in treating cancer |
EP4314068A1 (en) | 2021-04-02 | 2024-02-07 | 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 |
AU2022254104A1 (en) | 2021-04-08 | 2023-10-26 | Nurix Therapeutics, Inc. | Combination therapies with cbl-b inhibitor compounds |
GB2623199A (en) | 2021-04-08 | 2024-04-10 | Marengo Therapeutics Inc | Multifunctional molecules binding to TCR and uses thereof |
IL307556A (en) | 2021-04-09 | 2023-12-01 | Seagen Inc | Cancer treatment methods using antibodies against TIGIT |
EP4323405A1 (en) | 2021-04-12 | 2024-02-21 | Incyte Corporation | Combination therapy comprising an fgfr inhibitor and a nectin-4 targeting agent |
TW202309022A (zh) | 2021-04-13 | 2023-03-01 | 美商努法倫特公司 | 用於治療具egfr突變之癌症之胺基取代雜環 |
EP4322938A1 (en) | 2021-04-14 | 2024-02-21 | Institut National de la Santé et de la Recherche Médicale (INSERM) | New method to improve nk cells cytotoxicity |
BR112023021475A2 (pt) | 2021-04-16 | 2023-12-19 | Novartis Ag | Conjugados anticorpo-fármaco e métodos para produzir os mesmos |
AR125396A1 (es) | 2021-04-20 | 2023-07-12 | Seagen Inc | Modulación de citotoxicidad celular dependiente de anticuerpos |
WO2022223791A1 (en) | 2021-04-23 | 2022-10-27 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating cell senescence accumulation related disease |
WO2022227015A1 (en) | 2021-04-30 | 2022-11-03 | Merck Sharp & Dohme Corp. | Il4i1 inhibitors and methods of use |
EP4337763A1 (en) | 2021-05-10 | 2024-03-20 | Institut Curie | Methods for the treatment of cancer, inflammatory diseases and autoimmune diseases |
AU2022272835A1 (en) | 2021-05-13 | 2023-11-02 | Foundation For Biomedical Research And Innovation At Kobe | Anti-human pd-1 agonist antibody and pharmaceutical composition comprising the antibody for treating or preventing inflammatory diseases |
AR125874A1 (es) | 2021-05-18 | 2023-08-23 | Novartis Ag | Terapias de combinación |
WO2022242737A1 (zh) | 2021-05-21 | 2022-11-24 | 天津立博美华基因科技有限责任公司 | 药物组合及其用途 |
WO2022251359A1 (en) | 2021-05-26 | 2022-12-01 | Theravance Biopharma R&D Ip, Llc | Bicyclic inhibitors of alk5 and methods of use |
WO2022254337A1 (en) | 2021-06-01 | 2022-12-08 | Novartis Ag | Cd19 and cd22 chimeric antigen receptors and uses thereof |
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 |
AU2022288058A1 (en) | 2021-06-07 | 2023-11-16 | Agonox, Inc. | Cxcr5, pd-1, and icos expressing tumor reactive cd4 t cells and their use |
CA3220155A1 (en) | 2021-06-09 | 2022-12-15 | Incyte Corporation | Tricyclic heterocycles as fgfr inhibitors |
US11939331B2 (en) | 2021-06-09 | 2024-03-26 | Incyte Corporation | Tricyclic heterocycles as FGFR inhibitors |
KR20240026507A (ko) | 2021-06-29 | 2024-02-28 | 플래그쉽 파이어니어링 이노베이션스 브이, 인크. | 타노트랜스미션을 촉진시키도록 엔지니어링된 면역 세포 및 이의 용도 |
WO2023280790A1 (en) | 2021-07-05 | 2023-01-12 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Gene signatures for predicting survival time in patients suffering from renal cell carcinoma |
CA3224674A1 (en) | 2021-07-07 | 2023-01-12 | Pei Gan | Tricyclic compounds as inhibitors of kras |
CA3225254A1 (en) | 2021-07-13 | 2023-01-19 | BioNTech SE | Multispecific binding agents against cd40 and cd137 in combination therapy for cancer |
CA3224841A1 (en) | 2021-07-14 | 2023-01-19 | Zhenwu Li | Tricyclic compounds as inhibitors of kras |
WO2023004287A1 (en) | 2021-07-19 | 2023-01-26 | Regeneron Pharmaceuticals, Inc. | Combination of checkpoint inhibitors and an oncolytic virus for treating cancer |
AU2022320051A1 (en) | 2021-07-30 | 2024-01-25 | ONA Therapeutics S.L. | Anti-cd36 antibodies and their use to treat cancer |
WO2023010080A1 (en) | 2021-07-30 | 2023-02-02 | Seagen Inc. | Treatment for cancer |
WO2023012147A1 (en) | 2021-08-03 | 2023-02-09 | F. Hoffmann-La Roche Ag | Bispecific antibodies and methods of use |
WO2023015198A1 (en) | 2021-08-04 | 2023-02-09 | Genentech, Inc. | Il15/il15r alpha heterodimeric fc-fusion proteins for the expansion of nk cells in the treatment of solid tumours |
CA3227880A1 (en) | 2021-08-05 | 2023-02-09 | Marios SOTIROPOULOS | Scanning dynamic device for minibeams production |
IL310662A (en) | 2021-08-23 | 2024-04-01 | Immunitas Therapeutics Inc | Anti-CD161 antibodies and their uses |
US20230174555A1 (en) | 2021-08-31 | 2023-06-08 | Incyte Corporation | Naphthyridine compounds as inhibitors of kras |
WO2023034530A1 (en) | 2021-09-02 | 2023-03-09 | Teon Therapeutics, Inc. | Methods of improving growth and function of immune cells |
AU2022341239A1 (en) | 2021-09-08 | 2024-03-21 | Redona Therapeutics, Inc. | Papd5 and/or papd7 inhibiting 4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivatives |
WO2023039243A2 (en) * | 2021-09-13 | 2023-03-16 | Achelois Biopharma, Inc. | Hepatitis b virus antivirus (hbv-antivirus) compositions and methods of use |
WO2023041744A1 (en) | 2021-09-17 | 2023-03-23 | Institut Curie | Bet inhibitors for treating pab1 deficient cancer |
WO2023049697A1 (en) | 2021-09-21 | 2023-03-30 | Incyte Corporation | Hetero-tricyclic compounds as inhibitors of kras |
WO2023051926A1 (en) | 2021-09-30 | 2023-04-06 | BioNTech SE | Treatment involving non-immunogenic rna for antigen vaccination and pd-1 axis binding antagonists |
US20230143938A1 (en) | 2021-10-01 | 2023-05-11 | Incyte Corporation | Pyrazoloquinoline kras inhibitors |
TW202327595A (zh) | 2021-10-05 | 2023-07-16 | 美商輝瑞大藥廠 | 用於治療癌症之氮雜內醯胺化合物的組合 |
WO2023057534A1 (en) | 2021-10-06 | 2023-04-13 | Genmab A/S | 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) |
US11939328B2 (en) | 2021-10-14 | 2024-03-26 | Incyte Corporation | Quinoline compounds as inhibitors of KRAS |
WO2023077034A1 (en) | 2021-10-28 | 2023-05-04 | Lyell Immunopharma, Inc. | Methods for culturing immune cells |
IL309227A (en) | 2021-10-29 | 2024-02-01 | Bristol Myers Squibb Co | LAG-3 antagonist therapy for hematological cancer |
WO2023081730A1 (en) | 2021-11-03 | 2023-05-11 | Teon Therapeutics, Inc. | 4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide derivatives as cannabinoid cb2 receptor modulators for the treatment of cancer |
WO2023079428A1 (en) | 2021-11-03 | 2023-05-11 | Pfizer Inc. | Combination therapies using tlr7/8 agonist |
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) |
WO2023083439A1 (en) | 2021-11-09 | 2023-05-19 | BioNTech SE | Tlr7 agonist and combinations for cancer treatment |
WO2023086812A1 (en) * | 2021-11-11 | 2023-05-19 | Regeneron Pharmaceuticals, Inc. | Cd20-pd1 binding molecules and methods of use thereof |
TW202319073A (zh) | 2021-11-12 | 2023-05-16 | 瑞士商諾華公司 | 用於治療肺癌的組合療法 |
WO2023088968A1 (en) | 2021-11-17 | 2023-05-25 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Universal sarbecovirus vaccines |
WO2023089032A1 (en) | 2021-11-19 | 2023-05-25 | Institut Curie | Methods for the treatment of hrd cancer and brca-associated cancer |
WO2023091746A1 (en) | 2021-11-22 | 2023-05-25 | Incyte Corporation | Combination therapy comprising an fgfr inhibitor and a kras inhibitor |
WO2023097211A1 (en) | 2021-11-24 | 2023-06-01 | The University Of Southern California | Methods for enhancing immune checkpoint inhibitor therapy |
US20230203010A1 (en) | 2021-12-03 | 2023-06-29 | Incyte Corporation | Bicyclic amine cdk12 inhibitors |
WO2023099763A1 (en) | 2021-12-03 | 2023-06-08 | Institut Curie | Sirt6 inhibitors for use in treating resistant hrd cancer |
US20230183251A1 (en) | 2021-12-10 | 2023-06-15 | Incyte Corporation | Bicyclic amines as cdk12 inhibitors |
WO2023111203A1 (en) | 2021-12-16 | 2023-06-22 | Onxeo | 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 |
AR128043A1 (es) | 2021-12-22 | 2024-03-20 | Incyte Corp | Sales y formas sólidas de un inhibidor de fgfr y procesos para su preparación |
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 |
WO2023133280A1 (en) | 2022-01-07 | 2023-07-13 | Regeneron Pharmaceuticals, Inc. | Methods of treating recurrent ovarian cancer with bispecific anti-muc16 x anti-cd3 antibodies alone or in combination with anti-pd-1 antibodies |
WO2023147371A1 (en) | 2022-01-26 | 2023-08-03 | Bristol-Myers Squibb Company | Combination therapy for hepatocellular carcinoma |
WO2023147488A1 (en) | 2022-01-28 | 2023-08-03 | Iovance Biotherapeutics, Inc. | Cytokine associated tumor infiltrating lymphocytes compositions and methods |
WO2023154799A1 (en) | 2022-02-14 | 2023-08-17 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Combination immunotherapy for treating cancer |
TW202342474A (zh) | 2022-02-14 | 2023-11-01 | 美商基利科學股份有限公司 | 抗病毒吡唑并吡啶酮化合物 |
WO2023159102A1 (en) | 2022-02-17 | 2023-08-24 | Regeneron Pharmaceuticals, Inc. | Combinations of checkpoint inhibitors and oncolytic virus for treating cancer |
WO2023161453A1 (en) | 2022-02-24 | 2023-08-31 | Amazentis Sa | Uses of urolithins |
WO2023164638A1 (en) | 2022-02-25 | 2023-08-31 | Bristol-Myers Squibb Company | Combination therapy for colorectal carcinoma |
WO2023168363A1 (en) | 2022-03-02 | 2023-09-07 | HCW Biologics, Inc. | Method of treating pancreatic cancer |
WO2023168404A1 (en) | 2022-03-04 | 2023-09-07 | Bristol-Myers Squibb Company | Methods of treating a tumor |
WO2023172921A1 (en) | 2022-03-07 | 2023-09-14 | Incyte Corporation | Solid forms, salts, and processes of preparation of a cdk2 inhibitor |
WO2023170606A1 (en) | 2022-03-08 | 2023-09-14 | Alentis Therapeutics Ag | Use of anti-claudin-1 antibodies to increase t cell availability |
WO2023177772A1 (en) | 2022-03-17 | 2023-09-21 | Regeneron Pharmaceuticals, Inc. | Methods of treating recurrent epithelioid sarcoma with bispecific anti-muc16 x anti-cd3 antibodies alone or in combination with anti-pd-1 antibodies |
WO2023178329A1 (en) | 2022-03-18 | 2023-09-21 | Bristol-Myers Squibb Company | Methods of isolating polypeptides |
WO2023180552A1 (en) | 2022-03-24 | 2023-09-28 | Institut Curie | Immunotherapy targeting tumor transposable element derived neoantigenic peptides in glioblastoma |
WO2023187024A1 (en) | 2022-03-31 | 2023-10-05 | Institut Curie | Modified rela protein for inducing interferon expression and engineered immune cells with improved interferon expression |
WO2023192478A1 (en) | 2022-04-01 | 2023-10-05 | Bristol-Myers Squibb Company | Combination therapy with anti-il-8 antibodies and anti-pd-1 antibodies for treating cancer |
WO2023196987A1 (en) | 2022-04-07 | 2023-10-12 | Bristol-Myers Squibb Company | Methods of treating tumor |
WO2023194607A1 (en) | 2022-04-07 | 2023-10-12 | Institut Curie | Myeloid cells modified by chimeric antigen receptor with cd40 and uses thereof for anti-cancer therapy |
WO2023194608A1 (en) | 2022-04-07 | 2023-10-12 | Institut Curie | Myeloid cells modified by chimeric antigen receptor and uses thereof for anti-cancer therapy |
US20230326022A1 (en) | 2022-04-08 | 2023-10-12 | Bristol-Myers Squibb Company | Machine Learning Identification, Classification, and Quantification of Tertiary Lymphoid Structures |
WO2023213764A1 (en) | 2022-05-02 | 2023-11-09 | Transgene | Fusion polypeptide comprising an anti-pd-l1 sdab and a member of the tnfsf |
WO2023213763A1 (en) | 2022-05-02 | 2023-11-09 | Transgene | Poxvirus encoding a binding agent comprising an anti- pd-l1 sdab |
WO2023214325A1 (en) | 2022-05-05 | 2023-11-09 | Novartis Ag | Pyrazolopyrimidine derivatives and uses thereof as tet2 inhibitors |
WO2023218046A1 (en) | 2022-05-12 | 2023-11-16 | Genmab A/S | Binding agents capable of binding to cd27 in combination therapy |
WO2023224912A1 (en) | 2022-05-16 | 2023-11-23 | Regeneron Pharmaceuticals, Inc. | Methods of treating metastatic castration-resistant prostate cancer with bispecific anti-psma x anti-cd3 antibodies alone or in combination with anti-pd-1 antibodies |
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 |
WO2023227949A1 (en) | 2022-05-27 | 2023-11-30 | Takeda Pharmaceutical Company Limited | Dosing of cd38-binding fusion protein |
WO2023230541A1 (en) | 2022-05-27 | 2023-11-30 | Viiv Healthcare Company | Piperazine derivatives useful in hiv therapy |
WO2023235847A1 (en) | 2022-06-02 | 2023-12-07 | Bristol-Myers Squibb Company | Antibody compositions and methods of use thereof |
US20230399342A1 (en) | 2022-06-08 | 2023-12-14 | Incyte Corporation | Tricyclic triazolo compounds as dgk inhibitors |
WO2023240156A1 (en) | 2022-06-08 | 2023-12-14 | Tidal Therapeutics, Inc. | Ionizable cationic lipids and lipid nanoparticles, and methods of synthesis and use thereof |
WO2023242351A1 (en) | 2022-06-16 | 2023-12-21 | Lamkap Bio Beta Ag | Combination therapy of bispecific antibodies against ceacam5 and cd47 and bispecific antibodies against ceacam5 and cd3 |
WO2023250400A1 (en) | 2022-06-22 | 2023-12-28 | Juno Therapeutics, Inc. | Treatment methods for second line therapy of cd19-targeted car t cells |
WO2023250430A1 (en) | 2022-06-22 | 2023-12-28 | Incyte Corporation | Bicyclic amine cdk12 inhibitors |
WO2024003353A1 (en) | 2022-07-01 | 2024-01-04 | Transgene | Fusion protein comprising a surfactant-protein-d and a member of the tnfsf |
US20240101557A1 (en) | 2022-07-11 | 2024-03-28 | Incyte Corporation | Fused tricyclic compounds as inhibitors of kras g12v mutants |
WO2024015372A1 (en) | 2022-07-14 | 2024-01-18 | Teon Therapeutics, Inc. | Adenosine receptor antagonists and uses thereof |
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 |
US20240043560A1 (en) | 2022-08-02 | 2024-02-08 | Regeneron Pharmaceuticals, Inc. | Methods of Treating Metastatic Castration-Resistant Prostate Cancer with Bispecific Anti-PSMA x Anti-CD28 Antibodies in Combination with Anti-PD-1 Antibodies |
US20240041929A1 (en) | 2022-08-05 | 2024-02-08 | Juno Therapeutics, Inc. | Chimeric antigen receptors specific for gprc5d and bcma |
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 |
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 |
WO2024040175A1 (en) | 2022-08-18 | 2024-02-22 | Pulmatrix Operating Company, Inc. | Methods for treating cancer using inhaled angiogenesis inhibitor |
WO2024040264A1 (en) | 2022-08-19 | 2024-02-22 | Massachusetts Institute Of Technology | Compositions and methods for targeting dendritic cell lectins |
WO2024052356A1 (en) | 2022-09-06 | 2024-03-14 | Institut National de la Santé et de la Recherche Médicale | Inhibitors of the ceramide metabolic pathway for overcoming immunotherapy resistance in 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 |
WO2024068617A1 (en) | 2022-09-26 | 2024-04-04 | Institut Curie | Myeloid cells expressing il-2 and uses thereof for quick anticancer therapy |
WO2024069009A1 (en) | 2022-09-30 | 2024-04-04 | Alentis Therapeutics Ag | Treatment of drug-resistant hepatocellular carcinoma |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5859205A (en) * | 1989-12-21 | 1999-01-12 | Celltech Limited | Humanised antibodies |
US6641809B1 (en) * | 1990-03-26 | 2003-11-04 | Bristol-Myers Squibb Company | Method of regulating cellular processes mediated by B7 and CD28 |
CA2072249C (en) * | 1991-06-28 | 2003-06-17 | Saiko Hosokawa | Human monoclonal antibody specifically binding to surface antigen of cancer cell membrane |
EP0711345A1 (en) | 1993-07-26 | 1996-05-15 | Dana Farber Cancer Institute | B7-2: ctl a4/cd 28 counter receptor |
JPH07291996A (ja) * | 1994-03-01 | 1995-11-07 | Yuu Honshiyo | ヒトにおけるプログラムされた細胞死に関連したポリペプチド、それをコードするdna、そのdnaからなるベクター、そのベクターで形質転換された宿主細胞、そのポリペプチドの抗体、およびそのポリペプチドまたはその抗体を含有する薬学的組成物 |
GB9601081D0 (en) | 1995-10-06 | 1996-03-20 | Cambridge Antibody Tech | Specific binding members for human transforming growth factor beta;materials and methods |
AU784062B2 (en) | 1999-08-23 | 2006-01-19 | Dana-Farber Cancer Institute, Inc. | Novel B7-4 molecules and uses therefor |
WO2001014557A1 (en) * | 1999-08-23 | 2001-03-01 | Dana-Farber Cancer Institute, Inc. | Pd-1, a receptor for b7-4, and uses therefor |
AU6422799A (en) | 1999-10-08 | 2001-04-23 | Toshihiko Matsuo | Oculomedin and glaucoma |
AU7676300A (en) | 1999-10-12 | 2001-04-23 | Cambridge Antibody Technology Limited | Human anti-adipocyte monoclonal antibodies and their use |
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 |
EP1445264B1 (en) | 2001-07-31 | 2011-09-14 | Ono Pharmaceutical Co., Ltd. | Substance specific to pd-1 |
IL149820A0 (en) * | 2002-05-23 | 2002-11-10 | Curetech Ltd | Humanized immunomodulatory monoclonal antibodies for the treatment of neoplastic disease or immunodeficiency |
US7488802B2 (en) * | 2002-12-23 | 2009-02-10 | Wyeth | Antibodies against PD-1 |
-
2003
- 2003-12-22 US US10/741,481 patent/US7488802B2/en not_active Expired - Fee Related
- 2003-12-22 ES ES03780521T patent/ES2367430T3/es not_active Expired - Lifetime
- 2003-12-22 AT AT03780521T patent/ATE514713T1/de not_active IP Right Cessation
- 2003-12-22 CA CA2508660A patent/CA2508660C/en not_active Expired - Fee Related
- 2003-12-22 CN CN2003801099298A patent/CN1753912B/zh not_active Expired - Fee Related
- 2003-12-22 MX MXPA05006828A patent/MXPA05006828A/es active IP Right Grant
- 2003-12-22 JP JP2004561922A patent/JP4511943B2/ja not_active Expired - Fee Related
- 2003-12-22 EP EP03780521A patent/EP1576014B1/en not_active Expired - Lifetime
- 2003-12-22 US US10/540,084 patent/US7521051B2/en not_active Expired - Fee Related
- 2003-12-22 BR BR0316880-8A patent/BR0316880A/pt not_active IP Right Cessation
- 2003-12-22 CN CN2010101700224A patent/CN101899114A/zh active Pending
- 2003-12-22 AU AU2003288675A patent/AU2003288675B2/en not_active Ceased
- 2003-12-22 WO PCT/IB2003/006304 patent/WO2004056875A1/en active Application Filing
-
2005
- 2005-06-14 IL IL169152A patent/IL169152A/en not_active IP Right Cessation
- 2005-07-12 NO NO20053389A patent/NO336442B1/no not_active IP Right Cessation
-
2006
- 2006-03-17 HK HK06103433.3A patent/HK1083510A1/xx not_active IP Right Cessation
-
2007
- 2007-08-17 US US11/893,989 patent/US20080311117A1/en not_active Abandoned
-
2009
- 2009-03-16 US US12/405,058 patent/US8088905B2/en not_active Expired - Fee Related
-
2010
- 2010-03-16 JP JP2010059987A patent/JP2010189395A/ja active Pending
- 2010-10-22 AU AU2010235966A patent/AU2010235966A1/en not_active Abandoned
Cited By (36)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113444165A (zh) * | 2011-10-17 | 2021-09-28 | Io生物技术公司 | 基于pd-l1的免疫疗法 |
US10519235B2 (en) | 2013-09-13 | 2019-12-31 | 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 |
US9834606B2 (en) | 2013-09-13 | 2017-12-05 | Beigene, Ltd | Anti-PD1 antibodies and their use as therapeutics and diagnostics |
US11186637B2 (en) | 2013-09-13 | 2021-11-30 | Beigene Switzerland Gmbh | Anti-PD1 antibodies and their use as therapeutics and diagnostics |
US9988450B2 (en) | 2013-09-13 | 2018-06-05 | Beigene Switzerland Gmbh | Anti-PD1 antibodies and their use as therapeutics and diagnostics |
WO2015035606A1 (en) * | 2013-09-13 | 2015-03-19 | Beigene, Ltd. | Anti-pd1 antibodies and their use as therapeutics and diagnostics |
EA034666B1 (ru) * | 2013-09-13 | 2020-03-04 | Бейджин Свитзерланд Гмбх | Антитело против pd-1 и его применение для лечения рака или вирусной инфекции и фрагмент антитела |
CN104558177A (zh) * | 2013-10-25 | 2015-04-29 | 苏州思坦维生物技术有限责任公司 | 拮抗抑制程序性死亡受体pd-1与其配体结合的单克隆抗体及其编码序列与用途 |
CN104558177B (zh) * | 2013-10-25 | 2020-02-18 | 苏州思坦维生物技术股份有限公司 | 拮抗抑制程序性死亡受体pd-1与其配体结合的单克隆抗体及其编码序列与用途 |
US11512132B2 (en) | 2014-07-03 | 2022-11-29 | Beigene, Ltd. | Anti-PD-L1 antibodies and their use as therapeutics and diagnostics |
US10544225B2 (en) | 2014-07-03 | 2020-01-28 | Beigene, Ltd. | Anti-PD-L1 antibodies and their use as therapeutics and diagnostics |
US10981994B2 (en) | 2014-07-22 | 2021-04-20 | Apollomics Inc. | Anti PD-1 antibodies |
US11560429B2 (en) | 2014-07-22 | 2023-01-24 | Apollomics Inc. | Anti PD-1 antibodies |
US10428146B2 (en) | 2014-07-22 | 2019-10-01 | Cb Therapeutics, Inc. | Anti PD-1 antibodies |
WO2016015685A1 (zh) * | 2014-07-30 | 2016-02-04 | 珠海市丽珠单抗生物技术有限公司 | 抗pd-1抗体及其应用 |
US11111300B2 (en) | 2014-08-05 | 2021-09-07 | Apollomics Inc. | Anti PD-L1 antibodies |
CN107074947B (zh) * | 2014-08-05 | 2021-04-09 | 马布奎斯特公司 | 结合至pd-1的免疫试剂 |
US11827707B2 (en) | 2014-08-05 | 2023-11-28 | Apollomics Inc. | Anti PD-L1 antibodies |
CN107074947A (zh) * | 2014-08-05 | 2017-08-18 | 马布奎斯特公司 | 结合至pd‑1的免疫试剂 |
US10435470B2 (en) | 2014-08-05 | 2019-10-08 | Cb Therapeutics, Inc. | Anti-PD-L1 antibodies |
CN113929782A (zh) * | 2014-09-16 | 2022-01-14 | 依奈特制药公司 | 对淋巴细胞中抑制途径的中和 |
CN107438621A (zh) * | 2014-10-27 | 2017-12-05 | 新加坡科技研究局 | 抗pd‑1抗体 |
CN114380909A (zh) * | 2015-03-30 | 2022-04-22 | 斯特库比股份有限公司 | 特异性针对糖基化的pd-l1的抗体及其使用方法 |
CN109152798A (zh) * | 2015-12-02 | 2019-01-04 | 斯特库比股份有限公司 | 特异于糖基化的pd-1的抗体及其使用方法 |
CN109152798B (zh) * | 2015-12-02 | 2022-10-21 | 斯特库比股份有限公司 | 特异于糖基化的pd-1的抗体及其使用方法 |
CN109311981A (zh) * | 2016-01-22 | 2019-02-05 | 马布奎斯特公司 | Pd1特异性抗体 |
US11534431B2 (en) | 2016-07-05 | 2022-12-27 | Beigene Switzerland Gmbh | Combination of a PD-1 antagonist and a RAF inhibitor for treating cancer |
US10864203B2 (en) | 2016-07-05 | 2020-12-15 | Beigene, Ltd. | Combination of a PD-1 antagonist and a RAF inhibitor for treating cancer |
US11701357B2 (en) | 2016-08-19 | 2023-07-18 | Beigene Switzerland Gmbh | Treatment of B cell cancers using a combination comprising Btk inhibitors |
CN110382536A (zh) * | 2017-01-20 | 2019-10-25 | 大有华夏生物医药集团有限公司 | 抗pd-1抗体及其用途 |
CN110382536B (zh) * | 2017-01-20 | 2023-12-19 | 大有华夏生物医药集团有限公司 | 抗pd-1抗体及其用途 |
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 |
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 |
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 |
Also Published As
Publication number | Publication date |
---|---|
BR0316880A (pt) | 2005-10-25 |
US20100028330A1 (en) | 2010-02-04 |
NO20053389D0 (no) | 2005-07-12 |
AU2010235966A1 (en) | 2010-11-11 |
CN1753912B (zh) | 2011-11-02 |
US8088905B2 (en) | 2012-01-03 |
IL169152A (en) | 2010-11-30 |
AU2003288675A1 (en) | 2004-07-14 |
JP2006521783A (ja) | 2006-09-28 |
JP2010189395A (ja) | 2010-09-02 |
ATE514713T1 (de) | 2011-07-15 |
US7521051B2 (en) | 2009-04-21 |
AU2003288675A8 (en) | 2004-07-14 |
MXPA05006828A (es) | 2005-09-08 |
CN1753912A (zh) | 2006-03-29 |
ES2367430T3 (es) | 2011-11-03 |
NO20053389L (no) | 2005-07-12 |
EP1576014B1 (en) | 2011-06-29 |
EP1576014A1 (en) | 2005-09-21 |
US20040213795A1 (en) | 2004-10-28 |
IL169152A0 (en) | 2007-07-04 |
US20080311117A1 (en) | 2008-12-18 |
US20060210567A1 (en) | 2006-09-21 |
CA2508660C (en) | 2013-08-20 |
NO336442B1 (no) | 2015-08-17 |
AU2003288675B2 (en) | 2010-07-22 |
US7488802B2 (en) | 2009-02-10 |
CA2508660A1 (en) | 2004-07-08 |
JP4511943B2 (ja) | 2010-07-28 |
HK1083510A1 (en) | 2006-07-07 |
WO2004056875A1 (en) | 2004-07-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101899114A (zh) | 抗pd-1抗体及其用途 | |
US10077305B2 (en) | Antibodies against PD-1 and uses thereof | |
TWI773647B (zh) | 新穎pd-1免疫調控劑 | |
CN100374465C (zh) | 抗gdf-8的中和抗体及其用途 | |
US9845356B2 (en) | Single agent anti-PD-L1 and PD-L2 dual binding antibodies and methods of use | |
CN103687945B (zh) | 抗-b7-h3抗体 | |
US11208483B2 (en) | CTLA-4 antibodies and uses thereof | |
US20040265960A1 (en) | Antibodies against human IL-21 receptor and uses therefor | |
KR20210084587A (ko) | 다가 조절 t 세포 조정제 | |
JP2018500384A (ja) | 腫瘍形成を治療するための治療の組合せ | |
CN104822704A (zh) | 针对分化簇3(cd3)的人源化的抗体 | |
SG189456A1 (en) | Novel anti-dr5 antibody | |
JP6786722B2 (ja) | プログラム化された細胞死蛋白質(pd−1)に対する新規抗体及びその用途 | |
AU2004236263A1 (en) | Compositions and methods for treatment of cryptococcosis | |
CN117396511A (zh) | 靶向cd47和pd-l1的双特异性抗体及其使用方法 | |
TW202304989A (zh) | 與gd2(神經節苷脂gd2)特異性結合的單克隆抗體或其抗原結合片段及其用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C12 | Rejection of a patent application after its publication | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20101201 |