CN1094965A - 抗人类b淋巴细胞限制分化抗原的嵌合及放射标记抗体 - Google Patents
抗人类b淋巴细胞限制分化抗原的嵌合及放射标记抗体 Download PDFInfo
- Publication number
- CN1094965A CN1094965A CN93121424A CN93121424A CN1094965A CN 1094965 A CN1094965 A CN 1094965A CN 93121424 A CN93121424 A CN 93121424A CN 93121424 A CN93121424 A CN 93121424A CN 1094965 A CN1094965 A CN 1094965A
- Authority
- CN
- China
- Prior art keywords
- antibody
- cell
- antibodies
- people
- chimeric
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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
- C07K16/2887—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
-
- 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
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- 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
- C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S424/00—Drug, bio-affecting and body treating compositions
- Y10S424/80—Antibody or fragment thereof whose amino acid sequence is disclosed in whole or in part
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S424/00—Drug, bio-affecting and body treating compositions
- Y10S424/801—Drug, bio-affecting and body treating compositions involving antibody or fragment thereof produced by recombinant dna technology
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
- Y10S530/867—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof involving immunoglobulin or antibody produced via recombinant dna technology
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Immunology (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Genetics & Genomics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Cell Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
本文公开了为治疗B细胞淋巴瘤设计的治疗学
处理方法。这些方法基于包括使用免疫活性鼠/人
嵌合抗-CD20抗体、放射性标记抗-CD20抗体给药
的治疗策略,以及包括使用嵌合抗-CD20抗体及放
射标记抗-CD20抗体的协作策略。
Description
所列的整个本文件准备讨论的参考文献,仅为本文描述本文件申请日以前的情报所用,本文不构成承认(或者表示,或者暗示)这些参考文献为“先有技术”,或这些发明人无权由于先发明的优势或根据较早递交申请的优先权把这些描述的日期说得早于实际日期。
本发明针对使用抗B细胞表面抗原Bp35(CD20)的嵌合及放射标记抗体治疗B细胞淋巴瘤。
脊椎动物(例如灵长目,包括人、猿、猴等)的免疫系统由许多器官和细胞类型组成,这些器官及细胞类型进化出以下功能:准确和特异性地识别侵入脊椎动物宿主的外来微生物(抗原);特异性地与这些外来微生物结合;并且清除/破坏这些外来微生物。在其它一些类型中,淋巴细胞对于免疫系统来说是关键性的。淋巴细胞在胸腺,脾脏及骨髓(成年的)中产生,并相当于人(成年人)循环系统中存在的总白血细胞的30%。有二种主要的淋巴细胞的亚群体:T细胞和B细胞。T细胞在细胞介导免疫中起作用,而B细胞在抗体产生(体液免疫)中起作用。然而T细胞和B细胞被认为在典型免疫反应中是相互依赖的,当T细胞受体结合于抗原片段(该片段结合于抗原呈递细胞表面上的主要组织相容性复合物(MHC)糖蛋白上)上时T细胞被激活;此种激活作用引起生物学介体(白细胞介素)释放,该介体实质上能刺激B细胞分化并产生抗该抗原的抗体(免疫球蛋白)。
在宿主中每种B细胞在其表面表达不同的抗体,因此,一种B细胞将表达以一种抗原特异性的抗体,而另一方面B细胞将表达对不同的抗原特异性的抗体。由此,B细胞是十分多样性的,此种多样性对免疫系统来说是至关重要的。在人体中,每种B细胞可产生巨大数量的抗体分子(即约10 7至108)。当外来抗原被中和时,一般停止这种抗体产生(或者大大降低)。然而偶然地特定B细胞的繁殖也传统继续不断进行;这种繁殖可产生称为“B 细胞瘤”的癌。
T细胞和B细胞二者均含表面蛋白,这些表面蛋白可被用作分化及鉴定的“标记”。一种这样的人B细胞标记是人B淋巴细胞限制分化抗原Bp35,称为“CD20”,“CD20”在B细胞发育前期的早期表达,并保持直至浆细胞分化。特别是该CD20分子可以调节激活过程中的步骤(该步骤为细胞周期启动及分化所要求的),并且通常在肿瘤B细胞中高水平表达。由定义可知CD20即存在于“正常”B细胞上,也存在于“恶性”B细胞上(即这些B细胞不停地繁殖可导致B细胞淋巴瘤)。因此,CD20表面抗原有可能作为对B细胞淋巴瘤“定靶”的候选物。
实质上,这样的定靶过程可归纳如下:将对CD20 B细胞表面抗原特异性的抗体(例如)注射入患者体内,这些抗-CD20抗体便特异性结合到(明显地)正常及恶性B细胞二者的CD20细胞表面抗原上;结合于CD20表面抗原的抗-CD20抗体可引起肿瘤B细胞破坏并消耗掉。此外能破坏肿瘤的化学试剂或放射性标记也可与该抗-CD20抗体相连,以便该试剂能特异地输送到(例如)肿瘤B细胞处。不管采用什么方法,基本目的是破坏肿瘤,具体方法可由所使用的具体抗-CD20抗体来决定,因此定靶CD20抗原的可使用的方法是十分不同的。
例如已有多种定靶CD20表面抗原的尝试被报道过。鼠(小鼠)单克隆抗体1F5(一种抗-CD20抗体)已报道过以连续静脉输注到B细胞淋巴瘤患者的方式给药。据报道要耗尽循环的肿瘤细胞,要求极高的1F5水平(>2g),而其结果据说是“暂时的”(Press等人“Monoclonal Antibody 1F5(Anti-CD20)Serotherapy of Human B-Cell Lymphomas”Blood 69/2:584-591(1987))。该方法的潜在问题是非人单克隆抗体(例如鼠单克隆抗体)一般缺乏人效应物功能,即它们不能介导补体依赖性溶解或通过抗体依赖性细胞毒性或Fc-受体介导的吞噬作用来溶解人靶细胞。而且非人单克隆抗体可由人宿主识别为外来蛋白,因此,反复注射此类外来抗体可产生导致有害过敏反应的免疫反应诱导作用。有关基于鼠的单克隆抗体,通常称为人抗-鼠抗体反应,或“HAMA”反应。此外,这些外来抗体可能受到宿主免疫系统的攻击,其结果使得它们在到达靶位之前被中和掉。
淋巴细胞和淋巴瘤对放射疗法的固有敏感性有如下几个原因:放射性标记抗体的离子化射线的局部发射,可以杀死带或不带与结合抗原的抗体靠得很近的靶抗原(例如CD20)的细胞;穿透的射线可以消除在巨大的或不良的血管化肿瘤中有限地接近抗体的问题;而且所需的抗体总数可减少。放射性核素发射放射性粒子,该粒子可损害细胞DNA到细胞修复机制不能使细胞继续存活的程度;因此,假如靶细胞是肿瘤,放射性标记物可有利地杀死肿瘤细胞。根据定义,放射性标记抗体包括使用放射性物质,患者(即可能的骨髓移植)以及保健医生(即在带有放射性的条件下工作时需高度警惕)可能都需要采取预防措施。
因此,一种改进鼠单克隆抗体使之在治疗B细胞紊乱中有效的方法是将放射性标记或毒素连接到抗体上,以使标记或毒素位于肿瘤部位。例如,上面提到的IF5抗体已以磺-131(131I)做标记,并据报道在两个患者中进行过生物学分布评价,见Eary,J.F.等人“Imaging and Treatment of B-Cell Lymphoma”J.Nuc.Med.31/8:1257-1268(1990);也参见Press,O.W.等人,“Treatment of Refractory Non-Hodgkin′s Lymphoma With Radiolabled MB-1(Anti-CD37)Antibody”J.Clin.Onc.7/8:1027-1038(1989)(表明一个经131I标记过的IF5治疗的患者达到部分反应);Goldenberg,D.M.等人,“Targeting,Dosimetry and Radioimmuno therapy of B-Cell Lymphomas With Iodine-131-Labeied LL2 Monoclonal antibody”J.Clin.Onc.9/4:548-564(1991)(接受多次注射的8个病人中的三个据报道产生了HAMA反应);Appelbaum,F.R.“Radiolabled Monoclonal Antibodies in the Treatment of Non-Hodgkin′s Lymphoma”Hem./Onc.Clinics of N.A.5/5:1013-1025(1991)(文献综述),Press,O.W.等人“Radiolabled-Antibody Therapy of B-Cell Lymphoma With Autologous Bone Marrow Support”New England Journal of Medicine 329/17:1219-12223(1993)(碘-131标记抗-CD20抗体IF5和B1);以及Kaminski,M.G.等人,“Radioimmunotherapy of B-Cell Lymphoma With[131I]Anti-B1(Anti-CD20)Antibody”NEJM 329/7(1993)(碘-131标记抗-CD20抗体B1;本文下面称之为“Kaminski”)。
也已将毒素(即羟柔毛霉素或丝裂霉素C之类的化疗剂)连接于抗体,参见例如PCT公开申请WO 92/07466(1992年5月14日公 开)。
“嵌合”抗体,即含有来自两种或多种不同物种(例如鼠和人)的各部分的抗体,已被开发为另一种连接抗体。例如Liu,A.Y.等人“Production of a Mouse-Human Chimeric Monoclonal Antibody to CD20 With Potent Fc-Dependent Biologic Activity”J.Immun.139/10:3521-3526(1987),介绍了一种抗CD20抗原的鼠一个嵌合抗体。也参见PCT公开申请WO 88/04936。然而在这篇参考文献中没有资料提供有关使用这类嵌合抗体治疗B细胞紊乱的能力、效力或实用性的内容。应注意,体外的功能性检测(例如补体依赖性溶胞(CDC);抗体依赖性细胞毒(ADCC)等)不可能当然地予料嵌合抗体破坏或消耗表达特异抗原的靶细胞的体内能力。参见例如Robinson,R.D.等人“Chimeric mouse-human anti-carcinoma antibodies that mediate different anti-tumor cell biological activities。”Hum.Antibod.Hybridomas 2:84-93(1991)(检测不出ADCC活性的嵌合鼠-人抗体)。因此只有通过体内实验才可真正评价嵌合抗体的可能的治疗效力。
本技术领域所需的,可成为重大进展的工作是定靶CD20抗原以治疗灵长类包括(但不限于)人的B细胞淋巴瘤的治疗方法。
本文所公开的是为治疗B细胞紊乱,特别是B细胞淋巴瘤所设计的治疗方法。这些方法是基于施用免疫学活性的嵌合抗-CD20抗体用以消耗掉外周血B细胞,包括与淋巴瘤相关的B细胞;施用放射性标记抗-CD20抗体,用以定靶与局部和外周B细胞相关的肿瘤;以及用合作治疗策略,施用嵌合抗-CD20抗体和放射标记抗-CD20抗体。
对附图的简要说明:
图1是适用于生产免疫活性嵌合抗-CD抗体(TCAE8)的串联嵌合抗体表达载体的图示。
图2A至2E是图1载体的核酸序列;
图3A至3F是图1载体的核酸序列,该序列进一步含鼠轻链和重链可变区(TCAE8中的抗-CD20);
图4是来自鼠抗-CD20单克隆抗体2B8的鼠可变区轻链的核酸及氨基酸序列(包括CDR和构架区);
图5是来自鼠抗-CD20单克隆抗体2B8的鼠可变区重链的核酸和氨基酸序列(包括CDR和构架区);
图6是证明萤光标记人C1q与嵌合抗-CD20抗体结合的流式细胞计数结果,包括作为对照的标记C1q,标记C1q与鼠抗-CD20单克隆抗体2B8,以及标记C1q与人IgG1,k;
图7表示嵌合抗-CD20抗体和鼠抗-CD20单克隆抗体2B8相比较的补体相关的溶胞结果。
图8表示嵌合抗-CD20抗体和2B8相比对体内人效应细胞的抗体介导的细胞毒性结果;
图9A,9B和9C给出分别输注免疫活性嵌合抗-CD20抗体0.4mg/kg(A),1.6mg/kg(B),及6.4mg/kg(C)之后,非人灵长类外周血B淋巴细胞消耗的结果。
图10给出输注0.01mg/kg免疫活性嵌合抗-CD20抗体后,非人灵长类外周血B淋巴细胞消耗的特别结果;
图11给出在使用B细胞成淋巴肿瘤的小鼠体异物物记录模式中Y2B8产生的杀肿瘤结果;
图12给出在使用B细胞成淋巴肿瘤的小鼠体异物记录模式中,C2B2产生的杀肿瘤结果;
图13给出在使用B细胞成淋巴肿瘤的鼠体异物记录模式中,Y2B8和C2B8相结合所产生的杀肿瘤结果;
图14A和14B给出得自C2B8的Ⅰ/Ⅱ期临床分析的结果,表明患者B细胞群体随时间的消耗,证明病患部分缓解(14A)及病患轻度缓解(14B)。
一般来说,抗体由两轻链和两重链分子组成,这些链形成一个普通的Y型,轻链和重链共同构成Y的两臂,重链构成Y的下部。轻链和重链被分成结构和功能同源区。轻链(VL)和重链(VH)二者的可变区决定了识别能力和特异性。轻链(CL)和重链(CH)的不变区赋于其重要的生物学性质,例如抗体链结合,分泌,经胎盘的流动性、Fc受体结合、补体结合等等。导致免疫球蛋白基因在产抗体细胞中表达的一系列活动是十分复杂的。可变区域基因序列位于不同种系基因片段(称之为“VH”、“D”和“JH”或“VL”和“JL”。这些基因片段由DNA重排被连接形成在重链和轻链分别表达的完全V区域。该经重排连接的V片段(VL-JL和VH-D-JH)然后编码完全可变区或者分别编码轻链和重链的抗原结合区域。
使用抗-CD20鼠单克隆抗体(IF5)进行的人B细胞淋巴瘤的血清免疫疗法已由Press等人介绍过(69 Blood 584,1987,见上面),但遗憾的是据载其治疗反应只是暂时的。此外,据报道有25%的经试验的患者显示出对血清疗法的人抗鼠抗体(HAMA)反应。Press等人指出,这些抗体与毒素或放射性同位素结合,比起未结合的抗体来说,可产生更持久的临床效果。
由于B细胞淋巴瘤的效果衰减效应,并确实需要对付该疾病的可行治疗方法,我们已着手研究带有一种特殊抗体2B8(作为各方法之间的共同纽带)的不同的方法。一个这样的方法有益地利用了哺乳动物体系容易和有效地恢复外周血B细胞的能力;使用该方法,我们试图实际上消除或消耗外周血和淋巴组织中的B细胞,以作为除去B细胞淋巴瘤的手段。我们利用特殊的免疫活性嵌合抗-CD20抗体达到了这一目的。在另一个方法中,我们探索以放射性标记定靶肿瘤细胞使之破坏。
本文所使用术语“抗-CD20抗体”是特异性识别35000道尔顿的细胞表面非糖基化磷酸蛋白的抗体,该蛋白一般叫作人B淋巴细胞限制分化抗原Bp35,通常称之为CD20。本文所用术语“嵌合”,当针对抗-CD20抗体使用时,包括最优选的利用重组脱氧核糖核酸技术得到,并含人(包括免疫学相关物种例如黑猩猩)和非人成份的抗体;嵌合抗体的不变区最优选地基本上等同于天然人抗体的不变区;该嵌合抗体的可变区最优选地来源于非人源,且具有所需的对CD20细胞表面抗原的致免疫性和特异性。非人来源可以是任何可用于产生抗人CD20细胞表面抗原的抗体的任何脊椎动物源,或含有人CD20细胞表面抗原的材料。此类非人来源包括(但不限于)啮齿动物(例如兔、大鼠、小鼠等等)和非人灵长类动物(例如Old World猴、猿等)。最优选的非人成分(可变区)来源于鼠类。当针对嵌合抗-CD20抗体时本文所用短语“免疫学活性”意指结合人C1q,介导人B淋巴样细胞系补体依赖性溶解(CDC),并且通过抗体依赖性细胞毒性(ADCC)溶解人靶细胞的嵌合抗体。本文中所用短语“间接标记”和“间接标记法”意指螯合剂共价连接到抗体上,并且至少有一个放射性核素插入该螯合剂中。优选的螯合剂和放射性核素列举在Srivagtava S.C.和Mease,S.C.的“Progress in Research on Ligands,Nuclides and Techniques for Laleling Monoclonal Antibodies”Nucl.Med.Bio.18/6:589-603(1991)(Srivagtava)一文中,该文引入本文作为参考。一种特别优选的螯合剂是1-异硫氰酸根合苯甲基-3-甲基二(1,2-亚乙基)三胺五乙酸(MX-DTPA);间接标记所用特别优选的放射性核素包括铟[111]和钇[90]。本文中所用短语“直接标记”和“直接标记法”意指放射性核素共价直接连接到抗体上(一般借助氨基酸残基)。优选的放射性核素在Srivagtava中提供;一种特别优选的用于直接标记的放射性核素是碘[131],借助酪氨酸残基共价连接。间接标记法特别优选。
本文所公开的治疗方法是基于灵长类动物免疫系统很快恢复或复原外周血B细胞的能力。此外,因为灵长类动物的基本免疫反应是由T细胞引起的,所以当免疫系统有外周血B细胞缺损时,不一定需要额外的预防措施(即隔离病人等)。由于灵长类动物免疫系统的以上这些及其它细微差别,我们的治疗B细胞紊乱的方法允许使用免疫活性嵌合抗-CD20抗体清除外周血B细胞。
根据定义,因为外周血B细胞紊乱可表明需要进入(access)血的治疗,所以免疫活性嵌合抗-CD20抗体和放射标记抗-CD20抗体的给药途径优选非肠道进行;本文使用的术语“非肠道”包括静脉、肌内、皮下、直肠、阴道或腹膜给药。这些给药方式中,最优选静脉给药。
免疫活性嵌合抗-CD20抗体及放射标记抗-CD20抗体一般由标准技术提供,将其加入药用可接受的缓冲剂,例如无菌盐水、无菌缓冲水、丙二醇,或上述缓冲液的混合物中给药。制备非肠道给药药剂的方法见Pharmaceutical Carriers & Formulations,Martin Remington′s Pharmaceutical Sciences,15th Ed.(Mack Pub.Co.,Easton,PA 1975)(引入本文作为参考)。
用于在任何给定患者中产生独特治疗效果的免疫学活性嵌合抗-CD20抗体的特定治疗有效量,可以由本领域普通技术人员熟知的标准技术来确定。
有效剂量(即治疗有效量)免疫活性嵌合抗-CD20抗体是约0.001-约30mg/kg体重,更优选约0.01-约25mg/kg体重,而最优选约0.4-约20.0mg/kg体重。其它剂量也可用;影响剂量的因素包括(但不限于)患病严重程度,以前用过的治疗方法,患者的总的健康状况,是否存在其它疾病等等。技术人员通过评估具体病人很容易确定落入上述范围内的适当剂量,假如需要,也可在该范围之外。
按这些剂量引入免疫活性嵌合抗-CD20抗体,可以以一次治疗完成,也可以以多次治疗完成。对于嵌合抗体来说,优选分多次治疗引入;优选方法由与该病相关的治疗方法来预测。虽然不希望受任何具体理论所束缚,但因为免疫活性嵌合抗-CD20抗体既具有免疫活性,又能与CD20结合,一旦开始引入该免疫活性嵌合抗-CD20抗体到个体中,则外周血B细胞消耗便开始了;我们观察到在治疗输注后24小时内几乎完全消耗掉。由此,该免疫活性嵌合抗-CD20抗体(或放射性标记抗-CD20抗体)随后引入(一次或多次)患者体内时,则可推定:a)消除保留的外周血B细胞;b)开始从淋巴节消耗B细胞;c)开始从其它组织源,例如骨髓、肿瘤等等消耗B细胞。当反复引入免疫活性嵌合抗-CD20抗体时再次表明,出现一系列现象,每种现象我们都认为对有效治疗疾病是很重要的。第一现象可以看作原则上针对基本上消耗患者的外周血B细胞;随后的各现象可认为是原则上针对同时或者分步从系统中清除剩余的B细胞,清除淋巴节B细胞,或清除其它组织B细胞。
实际上,虽然单剂量也提供效益,并能有效利用于病患治疗/控制,但优选的治疗过程可分几步进行;最优选将免疫活性嵌合抗-CD20抗体以约0.4-约20mg/kg体重,每周给患者施用一次,持续2-10个星期(最优选持续4星期左右)。
对于放射性标记抗-CD20抗体的使用来说,优选抗体是非嵌合的,该优选是根据与鼠抗体相比,嵌合抗体的循环半衰期明显要长些来预测出的(即由于循环半衰期较长时,放射性核素在患者体内存在时间增长)。但是,如果相对于鼠抗体来说,与嵌合抗体相结合使用时,采用较低毫居里(mCi)剂量,则放射性标记抗体可以有益地施用。该情况使得在保持治疗效益的同时,骨髓毒性可降至能接受的水平。
不同的放射性核素都可用于本发明,相信本领域技术人员能很容易地决定哪种放射性核素在不同情况下是最为适合的。例如,碘[131]是已知用于定靶免疫治疗的放射性核素,但由于下述原因碘[131]的临床应用可能受到限制:8天的物理半衰期;在血液中和肿瘤部位碘化抗体都发生脱卤素作用;以及发射特性(例如大量γ成分),它可使肿瘤中的局部剂量积累处于次优化状况。
随着优良螯合剂的出现,将金属螯合基团连于蛋白上的可能性,提高了使用其它放射性核素(例如铟[111]和钇[90])的机会。钇 [90]用于放射性免疫治疗有几个优点:它的64小时的半衰期足以使得抗体沉积于肿瘤周围,并且不像碘[131]之类,钇[90]是高能量的纯β发射源,其衰变时无γ射线相随,在组织中,它的作用范围为100-1000细胞直径。而且,它的射线穿透量极小,使得门诊病人可以施用钇[90]标记抗体。再有,标记抗体的内化对于杀死细胞来说并不需要,而离子化射线的局部发射对于无靶抗原的相邻肿瘤细胞来说应是致命的。
钇[90]的一种非治疗性限制是因为它缺乏明显的γ射线,使得以此造影很困难,为避免这一问题,在以钇[90]标记抗-CD20治疗给药之前,将诊断“造影”放射性核素(例如铟[111])用来测定肿瘤的位置和相对尺寸。铟[111]用作特别优选的诊断放射性核素,因为:在约1-约10mCi之间可安全给药无明显毒性;并且从其影像资料一般可预知随后的钇[90]标记抗体的分布。大部份造影研究采用5mCi铟[111]标记抗体,因为该剂量既安全又比起较低剂量来说提高了造影效果,在施用抗体之后3-6天出现最优影像。参见例如Murray,J.L.,26 J.Nuc.Med.3328(1985)and Carraguillo,J.A.等人26 J.Nuc.Med.67(1985)。
钇[90]标记抗-CD20的有效单治疗剂量(即治疗学上有效量)在约5-约75mCi之间,更优选约10-约40mCi之间。碘[131]标记抗-CD20抗体的有效单治疗非骨髓剥离剂量在约5-约70mCi之间,更优选约5-约40mCi之间。碘[131]标记抗-CD20抗体的有效单治疗剥离剂量(即可以要求自体骨髓移植)在约30-约600mCi之间,更优选约5-小于500mCi。在与嵌合抗-CD20抗体相结合时,由于比鼠抗体有较长的循环半衰期,碘[131]标记嵌合抗-CD20抗体的有效单治疗非骨髓剥离剂量在约5-约40mCi之间,更优选小于约30mCi。成像标准(例如对铟[111]标记物来说)一般小于约5mCi。
对于放射性标记抗-CD20抗体,其治疗可采用单次治疗法或多次治疗法。因为使用放射性核素成分,因此优选治疗之前,收集经受由放射性引起的潜在的致命骨髓毒性的病人的外周干细胞(PSC)或骨髓(BM),使用标准技术收集BM和/或PSC,为能够再输注将其净化和冷冻。此外,最优选治疗之前对病人进行使用诊断标记抗体(例如用铟[111]的诊断剂量测量法研究,其目的在于保证在任何正常器官或组织中,治疗标记抗体(例如使用钇[90])将不致于变得不必要的“过浓”。
已介绍过嵌合鼠-人抗体,例如见Morrison,S.L.et al.,PNAS 11:6851-6854(1984年11月);欧洲专利公开No.173494;Boulianne,G.L.at al.,Nature 312:643(1984年12月);Neuleiger,M.S.et al.,Nature 314:268(1985年3月);欧洲专利公开No.125023;Tan at al.,J.Immunol.135:8564(1985年11月);Sun,L.K.at al.,Hybridoma 5/1:517(1986);Sahagan et al.,J.Immunol.137:1066-1074(1986)。总的参见Muron,Nature 312:597(1984年12月);Dickson,Genetic Engineering News 5/3(1985年3月);Marx,Science 229:455(1985年8月);以及Morrison Science 229:1202-1209(1985年9月)。Robinson et al.在PCT公开号WO88/04936中介绍了一种带有人不变区及鼠可变区的嵌合抗体,对CD20的一个抗原决定基有特异性。Robinson参考文献的嵌合抗体的鼠部分来源于2H7小鼠单
克隆抗体(gamma 2b,kappa)。虽然该文献指出所述嵌合抗体是治疗B细胞紊乱的“首选候选物”,但可以认为该论点只不过是一种建议,对本领域研究人员来说要确定该建议是否对该特定抗体来说是正确的,特别因为该文献缺乏任何支持治疗效果的数据,更重要的是缺乏使用高等哺乳动物例如灵长目或人所得到的数据。
产生嵌合抗体的方法本领域技术人员是已知的。例如,在不同的质粒中使用免疫球蛋白轻链和免疫球蛋白重链,其轻链和重链可以分开表达。然后可以将其提纯并于体外组装成完全的抗体。完成此种组装的方法已有人介绍过,见例如Scharff,M.,Harvey Lectures 69:125(1974)。从还原分离的轻链和重链形成IgG抗体的体外反应参数也已有人介绍过,例如见Beychok,S.Cells of Immunoglobulin Synthesis,Academic Press,New Yorik,p.69,1979。将重链和轻链在同样细胞中区表达使达到细胞内协同并将重链和轻链连接成完全的H2L2IgG抗体也是可能的。该共表达在相同宿主细胞中使用相同质粒,或者使用不同质粒均可行。
另一方法,即我们为形成嵌合非人/人抗-CD20抗体的最优选方法是基于使用包括(从头开始)来自人源的编码重链和轻链不变区的D-NA的表达载体。该载体能插入编码非人可变区的DNA,以产生各种非人抗-CD20抗体,筛选并分析各种特性(例如结合特异性种类,抗原决定基结合区等等)。此后可将来自优选的或所需的抗-CD20抗体的编码轻链和重链可变区的cDNA掺入载体中。我们称这些类型的载体为串联嵌合抗体表达(TCAE)载体。一种最为优选的,被用于产生治疗淋巴瘤的免疫活性嵌合抗-CD20抗体的TCAE载体是TCAE8。TCAE 8是本专利文件受让人所拥有的称作TCAE 5.2的载体的衍生物,其区别在于TCAE 5.2中显性可选择标志(新霉素磷酸转移酶“NEO”)的转译起始位点是一个一致Kozak序列,而TCAE8中,该区域是一个部分损伤的一致Kozak序列。有关TCAE载体(也称为ANEX载体)的显性可选择标志的起始位点对蛋白质表达的影响的详细内容已详细公开在本申请的共同未决申请中。
TCAE8包含四个(4)转录盒,这些按序串联,即无可变区的人免疫球蛋白轻链;无可变区的人免疫球蛋白重链;DHFR;以及NEO。每一转录盒包含其本身的真核生物启动子及多聚腺苷化区(参考图1,该图以图形表示TCAE8载体),特别是:
1)免疫球蛋白重链前面的CMV启动子/增强子是轻链前面的启动子/增强子,从-350位的Nhe I位点到-16位的Sst I位点的截短部分(见41 Cell 521,1985);
2)通过PCR反应由cDNA扩增衍生出人免疫球蛋白轻链不变区。在TCAE8中,这是人免疫球蛋白轻链K不变区(Kabat编号,氨基酸108-214,异型Km8(见Kabat,E.A."Sequences of proteins of immunological interest"NIH Publication,Fifth Ed.No.91-3242,1991)),和人免疫球蛋白重链γ1不变区(Kabat编号氨基酸114-478,异型Gmla、Gmlz)。该轻链从正常人血中分离(IDEC Pharmaceuticals Corporation,La Jolla,CA);其RNA被用于合成cDNA,然后用PCR技术将其扩增(引物来自Kabat一致序列)。重链从以RNA制备的cDNA分离出(使用PCR技术),所述RNA则从以人IgG1载体(见,3 Prot.Eng.531,1990;vector pNr162)转染的细胞衍生的。在该分离人IgGl中有二个氨基酸被改变使之与来自Kabat的一致氨基酸序列相匹配,即氨基酸225由缬氨酸变为丙氨酸(GTT到GCA),而氨基酸287由蛋氨酸变为赖氨酸(ATG到AAG);
3)该人免疫球蛋白轻链和重链盒含有分泌免疫球蛋白链的合成信号序列;
4)该人免疫球蛋白轻链和重链盒含特异性DNA限制位点,该位点允许插入维持转换读码,并且不改变免疫球蛋白链中发现的正常氨基酸的轻链和重链免疫球蛋白可变区;
5)该DHFR盒包含其本身的真核生物启动子(小鼠β球蛋白主启动子,“BETA”)及多聚腺苷化区域(牛生长激素多聚腺苷化区,“BGH”);以及
6)该NEO盒含其本身的真核生物启动子及多聚腺苷化区域(SV40早期多聚腺苷化区“SV”)。
就TCAE8载体和NEO盒来说,该Kozak区是部份损伤的一致Kozak序列(它包括一上游ClaI位点):
ClaI -3 +1
GGGAGCTTGG ATCGAT ccTct ATG Gtt
(在TCAE 5.2载体中,该变化是在ClaI和ATG区之间,即ccAcc.)
TCAE8的完全序列表(包括四个转录盒的特异成分)列于图2中(SEQ.ID NO.1)。
正如将被本领域技术人员所认识的,TCAE载体在生产免疫活性嵌合抗-CD20抗体时有益于大大缩短时间。生产和分离非人轻链和重链可变区,接着将其掺入人轻链不变转录盒及人重链不变转录盒中,使其生产出免疫活性嵌合抗-CD20抗体。
使用鼠源及杂交瘤技术,我们衍生出最优选的,对CD20抗原具特异性的非人可变区。使用聚合酶链反应(PCR)技术,该鼠轻链和重链可变区被直接克隆进TCAE8载体-这是将非人可变区掺进TCAE载体的最优选途径。该优选方法主要是根据PCR反应的效力及插入的精确性来预测出的。但是其它完成该目的的等同方法也是可采用的。例如使用TCAE8(或等同载体)可获得非人抗-CD20抗体的可变区序列,接着合成序列各部分的寡核苷酸,如果适合合成整个序列,然后,将整个合成序列的各部分插入载体的适当位置。相信本领域技术人员能完成该工作。
我们的最优选免疫活性嵌合抗-CD20抗体,从使用包括来自单克隆抗-CD20抗体的鼠可变区的TCAE8载体衍生而来;该抗体(下面将详细讨论)称为“2B8”。在TCAE8从2B8(TCAE8中的抗-CD20)所获得的可变区完全序列列在图3中(SEQ.ID.NO.2)。
用于蛋白表达的宿主细胞系最优选哺乳动物源;相信本领域的技术人员有能力优选决定最适合于表达本文所需基因产物的具体宿主细胞系。典型的宿主细胞系包括(但不限于)DG44和DUXB11(中国仓鼠卵巢细胞系,DHFR-),HELA(人宫颈癌),CVI(猴肾细胞系),COS(带有SV40 T抗原的CVI衍生物),R1610(中国仓鼠成纤维细胞),BALBC/3T3(小鼠成纤维细胞),HAK(仓鼠肾细胞系),SP2/0(小鼠骨髓瘤),P3x63-Ag3.653(小鼠骨髓瘤),BFA-lclBPT(牛内皮细胞),RAJI(人淋巴细胞)以及293(人肾)。宿主细胞系一般可从市场购得,从美国组织培养收藏中心或从公开的文献索取。
优选的宿主细胞系是DG44(CHO)或SP2/0,分别参见Urland,G.et al.,"Effect of gamma rays and the dihydrofolate reductase locus:deletions and inversions"Som.Cell & Mol.Gen.12/6:555-566(1986)和Shulman,M.et al.,"A better cell line for making hybridomas secreting specific antibodies."Nature 276:269(1978)。最优选的细胞系是DG44。可利用本领域任何现有技术来将质粒转染进宿主细胞。这些方法包括(但不限于)转染(包括电泳及电穿孔)、与包膜DNA细胞融合、微注射及以完整病毒感染。参见Ridgway,A.A.G."Mammalian Expression vectors"Chapter 24.2,pp.470-472 Vectors,Rodriguez and Denhardt,Eds.(Butterworths,Boston,MA 1988)。最优选的质粒引入宿主中的方法是借助电穿孔。
实施例
下述实施例不试图(也不构成)对本发明的限制。这些实施例试图说明:使用放射性标记抗-CD20抗体(I2B8)剂量造影;放射性标记抗-CD20抗体(Y2B8);及利用特定载体(TCAE8)和来自鼠抗-CD20单克隆抗体(2B8)的可变区衍生的免疫活性嵌合抗-CD20抗体(C2B8)。
Ⅰ.放射性标记抗-CD20抗体2B8
A.抗-CD20单克隆抗体(鼠)的生产(2B8)
用人成淋巴细胞样细胞系SB给BALB/C小鼠反复接种(见Adams,R.A.et al.,“Direct implantation and serial transplantation of human acute lymphoblastic leukemia in hamsters,SB-2”Can.Res.28:1121-1125(1968);该细胞系可取自美国组织培养物收藏中心,Rockville,MD.其保藏号为ATCC CCL 120),于3-4个月内每周注射一次。正如由已知CD20-特异性抗体的抑制作用所测定的(所用抗-CD20抗体是Leu 16,Beckton Dickinson,San Jose,CA,Cat.NO.7670;和B1 Coulter Corp.,Hialeah.FL.Cat.NO.6602201),鉴定出表现出高抗-CD20抗体血清效价的小鼠。然后移除该鼠脾脏。按照Einfeld,D.A.et al(1988 EMBO 7:711)所述方法,将脾细胞与小鼠骨髓瘤SP2/0相融合(SP2/0在ATCC的保藏号为ATCC CRL 8006)。
用放射免疫测试法测试CD20的特异性,简要说来,使用Valentine,M.A.等人(1989)在J.Biol.Chem.264:11282所述的碘珠法以Ⅰ125放射标记经提纯的抗-CD20 B1(Ⅰ125碘化钠ICN.Irvine,CA.Cat No.28665H)。通过来自各融合孔的0.05ml培养基与1% BSA,PBS(pH7.4)中的0.05ml Ⅰ125标记抗-CD20 B1(10ng)和含100,000SB细胞的0.5ml相同缓冲液一起共保温来筛选杂交瘤。室温下保温1小时之后,将细胞转移到96孔滴定平板上(V & P Scientific,San Diego,CA)来收集细胞并彻底洗涤。含未标记抗-CD20 B1的平行孔和不含抑制抗体的孔分别作为阳性和阴性对照。将含大于50%抑制作用的孔放大并克隆。表现出最高抑制作用的抗体来自本文称作“2B8”的克隆细胞系。
B.2B8-MX-DTPA结合物的制备
ⅰ.MX-DTPA
碳-14-标记的1-异硫氰酸根合苯甲基-3-甲基二(1,2-亚乙基)三胺五乙酸(碳-14标记MX-DTPA)用作将放射性标记连接到2B8上的螯合剂。操作MX-DTPA要保持在无金属条件下进行,即要采用无金属试剂,若可能,同时采用Alconox洗涤,并用Milli-Q水漂洗的聚丙烯塑料容器(烧瓶、烧杯、量筒、移液管)。从Dr.Otto Gansow处获得干燥固态MX-DTPA(NationalInstitute of Health,Bethesda,MD)并于4℃干燥贮存(避光),按2-5mM浓度在Milli-Q水中配制原液,于-70℃贮存。也从Coulter Immunology(Hialeah Florida)获得MX-DTPA的二钠盐水溶液并于-70℃贮存。
ⅱ.制备2B8
采用以CENTRICON 30TM旋转过滤器(30000D,MWCO;Amicon)反复缓冲交换的方法,将抗体转移到无金属的含150mM NaCl的50mM二羟乙基甘氨酸-NaOff(pH8.6)中来制备供与MX-DTPA连接用的纯化2B8。一般是将50-200μl蛋白质(10mg/nl)加入到过滤元件中,接着加入2ml二羟乙基甘氨酸缓冲液。于4℃,在Sorval SS-34转子中上(6000 rpm,45min)将过滤器离心处理,保留液体积约50-100μl。使用同样过滤器将该过程重复二次,将保留液转移到聚丙烯1.5ml螺丝帽试管中检测蛋白质,稀释至10.0mg/ml并于4℃贮存直到使用。将蛋白质同样使用前述方法转移到含150mM NaCl和0.05%叠氮钠的50mM柠檬酸钠(pH5.5)中。
ⅲ.2B8与MX-DTPA的连接
于室温下在聚丙烯试管中将2B8与MX-DTPA连接。冷冻的MX-DTPA原液临使用前再解冻。按MX-DTPA对2B8的摩尔比为4∶1的比例,将10mg/ml的蛋白质50-200ml与MX-DTPA反应。加入MX-DTPA原液并慢慢搅拌混合物,反应便开始,该连接过程于室温下过夜进行(14-20小时)。通过渗析或反复超滤将未反应的MX-DTPA从连接物中移至(如实施例I.B.ⅱ所述)无金属含0.05%叠氮钠的生理盐水(0.9% w/v)中。将蛋白质浓度调节到10mg/ml并在聚丙烯试管中于4℃贮存直至放射标记。
ⅳ.测定MX-DTPA掺入量
用闪烁计数法测定MX-DTPA掺入量,将从纯化连接物所得结果与碳[14]标记的MX-DTPA的比活进行比较。对于某些使用非放射性MX-DTPA(Coulter Immunology)的研究,则将连接物与已知浓度和比活的过量钇[90]放射性载体溶液一起培养来测定MX-DTPA的掺入量。
已知浓度的氯化钇原液以加入无载体钇[90](氯化物盐)的无金属0.05 N HCl来配制。将该溶液的等分样以闪烁计数分析测定该试剂的精确比活性。将相当于预期将连接到抗体上的螯合物摩尔数的三倍量的氯化钇试剂(一般为2mcl/mcl抗体)加入到聚丙烯试管中,并用2M乙酸钠调节pH到4.0-4.5。然后将连接抗体加入并于室温下保温15-30分钟。加入20mM EDTA至终浓度为1mM来使反应骤冷,并将溶液pH值用2M乙酸钠调节到约6。
保温5分钟后,将整个内容物用高效排阻色谱(见下文)进行纯化,将洗脱出的含蛋白质级分合并,测定蛋白质浓度,并以等分样测定放射性。用氯化钇[90]制剂的比活性及蛋白质浓度来计算出螯合物的掺入量。
ⅴ.2B8-MX-DTPA的免疫活性
使用整细胞ELISA测定连接2B8的免疫活性。通过离心收集培养物中的对数中期的SB细胞,并用1X HBSS洗涤二次。将细胞在HBSS中稀释至1-2×106个细胞/ml,并按50,000-100,000个细胞/孔将其等分进96孔聚苯乙烯微滴平板上。将该板真空干燥2小时(40-50℃,使细胞固定于塑料上,这些板于-20℃贮存干燥直至使用,检测时,临使用才将板加热至室温,然后用含1% BSA pH7.2-7.4的1X PBS封闭(2小时)。将检测样品在1X PBS/1% BSA中稀释,施于板上并以同样缓冲液连续稀释(1∶2)。于室温下将板保温1小时。用1X PBS洗板三次。将第二抗体(山羊抗小鼠IgGl-特异性HRP结合物50μl)加入各孔中(在1X PBS/1% BSA中按1∶1500稀释)并于室温下保温1小时。用1X BPS洗板4次,接着加入ABTS底物溶液(50mM柠檬酸钠,含0.01% ATBS及0.001% H2O2,pH4.5)。保温15-30分钟后在405nm波长处测定该板,在检测试验中包括抗原阴性HSB细胞以检测非特异性结合。将吸收率值分别对稀释倍数作图,并将其与在同样板上使用天然抗体试验所获值(代表100%免疫活性)相比较计算出连接物的免疫活性,在滴定图的线性部分上取几个值进行比较并测出平均值(数据未显示出)。
ⅵ.制备铟[111]标记的2B8-MX-DTPA(I2B8)
将连接物用无载体铟[111]放射标记。将0.05 M HCl中的同位素(0.1-2 mCi/mg抗体)等分样移进聚丙烯管中并加入约十分之一体积的无金属2M HCl。保温5分钟后,加入无金属2M乙酸钠调节pH到4.0-4.4。加入从在生理盐水或含0.05%叠氮钠的50mM柠檬酸钠/150mM NaCl中的10.0mg/ml DTPA的原液来源的约0.5mg 2B8-MX-DTPA,立即将混合物轻轻搅拌。用pH试检查溶液的pH值,证实该值在4.0-4.5之间,并将混合物于室温保温15-30分钟。然后加入20mM EDTA至终浓度为1mM而使反应停止,再用2M乙酸钠将反应混合物调节到约为pH6.0。
保温5-10分钟后,将未结合的放射同位素用排阻色谱除去。HPLC单元由Waters Model 6000或TosoHaas Model TSK-6110溶剂传输体系分别配以Waters U6K或Rheodyne 700注射阀组成。使用凝胶渗透柱(BioRad SEC-250;7.5×300mm或相近的TosoHaas柱)和SEC-250防护柱(7.5×100mm)来进行色谱分离。该体系并装有级分收集器(Pharmacia Frac200)及配有280nm滤光器的UV检测器(Pharmacia Model UV-1)。将样品上样,并以1.0ml/min的流动速度,用1×PBS(pH7.4)匀速洗脱。收集半毫升各级分在玻璃试管中,并将这些等分样在γ计数器上计数。将低窗及高窗分别定于100和500KeV。
将相应于洗脱出的蛋白峰的放射活性物加,用从柱中洗脱出的总放射性来除该数,来计算出放射性掺入量,该值表达为百分数(未列出数据)。在某些情况下,可用瞬息薄层色谱(ITLC)来测定放射性掺入量。将放射性标记的连接物用1X PBS或1X PBS/1mM DTPA以1∶10或1∶20比例加以稀释,然后将其1μl点在距1×5cm ITLCSG纸条的一端1.5cm处,使用10%乙酸铵甲醇液∶水(1∶1 v/v)进行上行色谱使纸展开。将该纸条干燥,从中部横切开,用γ计数法测定相应各部分的放射活性。将与纸条下半部相对应的放射活性(与蛋白质结合放射活性)以总的放射性的百分数表示,该总放射活性系将上下两半的值相加而得(数据未列出)。
通过测量放射性标记连接物的适当等分样的放射性来测定比活性,该值对计数器效率(一般75%)进行校正,并与前面利用280nm波长处的吸收率所测的连接物蛋白质浓度相关,该结果值表达为mCi/mg蛋白。
在某些实验中,采用相似于上面所述方法但不用HPLC提纯来用铟[111]放射性标记2B8-MX-DTPA,该方法称之为“混合速标”法(mix-and-shoot)。
ⅶ.制备钇[90]标记的2B8-MX-DTPA(Y2B8)
遵循已介绍过的制备I2B8相同的方法用以制备钇[90]标记的2B8-MX-DTPA(Y2B8)连接物,不同的是未采用2ng HCl;如上所述,所用钇标记连接物制剂均用排阻色谱提纯。
C.非人动物研究
Ⅰ.放射性标记 2B8-MX-DTPA的生物学分布
以6-8周龄的BALB/C小鼠进行I2B8的组织生物学分布评定。按照上述“混合速标”法,使用临床级2B8-MX-DTPA制备放射性标记连接物。该连接物的比活是2.3mCi/mg,并将该连接物在含50mg/ml HSA的PBS(pH7.4)中配制。用100μl I2B8(约21μCi)给小鼠静脉注射,将三只一组的各组小鼠于0、24、48及72小时以颈离位的方式杀死。杀死之后将尾、心脏、肺、肝、肾、脾、肌肉及大腿取下,洗涤并称重;并将血液样品取出用于分析。由γ计数法测定相应各样品的放射性,并且随后测定出每克组织所注射剂量的百分比。未扣除各器官所带的血液所代表的活性量。
另一个不同的方法是,分别将于4℃和30℃保温10星期的2B8-MX-DTPA等分样用铟[111]标记,使二制剂中比活为2.1mCi/mg。然后按上述方法研究这些连接物在小鼠体内的生物学分布。
对于剂量测定法测定来说,是用铟[111]标记2B8-MX-DTPA,使其比活达2.3mCi/mg,以约1.1μCi量注射入20只BALB/C小鼠的各鼠体内。然后分别于1、24、48及72小时将5只一组的各组鼠杀死,将其器官取出准备用于分析。此外,也将皮肤,肌肉和骨各部分取出并处理以进行分析;也于24-72小时各时间点收集尿和粪便加以分析。
使用相似方法,用钇[90]放射标记2B8-MX-DTPA,并在BALB/C小鼠体内评估72小时期间其生物学分布。用HPLC排阻色谱提纯之后,用约1μCi的临床配制连接物(比活为12.2mCi/mg),给五只一组的四组鼠分别进行静脉注射。然后于1、24、48及72小时将各组分别杀死,按上面所述分析其器官及组织。通过用γ闪烁计数器测量其轫致放射能量,从而测量相应各组织样品的放射活性,然后将活性值表达为每克组织注射剂量的百分数或每器官注射剂量的百分数。因为各器官及其它组织经反复漂洗除去了表面血液,这样各器官不充盈血液,因此各器官活性值未减去内部所带的血液所代表的活性分布。
ⅱ.I2B8的肿瘤定位
在患Ramos B细胞肿瘤的无胸腺小鼠体内测定放射标记2B8-MX-DTPA的定位作用。用含有1.2×107Ramos肿瘤细胞的0.1ml RPMI-1640,经皮下注射(左后胁)给予6-8周龄的无胸腺小鼠,所说肿瘤细胞事先适应在无胸腺小鼠体内生长。两星期中肿瘤长出,其重从0.07至1.1g。然后用100μl铟[111]标记2B8-MX-DTPA(16.7μCi)给鼠静脉注射,并将三只一组的各组鼠分别于0、24、48及72小时以断颈方式杀死。杀死之后,取出尾、心、肺、肝、肾、脾、肌肉、大腿及肿瘤,洗涤并称重,也取出血液样品用于分析。用γ计数法测定相应各样品的放射活性,并算出每克组织所注射剂量的百分数。
ⅲ.用放射性标记2B8-MX-DTPA进行生物学分布和肿瘤定位研究
遵循上述(实施例I.B.Vⅲ.a)初步生物学分布实验,用铟[111]放射标记连接物2B8,使其比活性达2.3mCi/mg,将约1.1μCi注射入20只BALB/C小鼠的各只,测定放射性标记物的生物学分布。随后于1、24、48及72小时分别杀死五只一组的各组鼠,然后将其各器官及部分皮肤、肌内及骨取出并处理以进行分析。此外,在24-72小时各时间点也收集尿及粪便加以分析。血中的放射性水平从1小时时所占每克注射剂量的40.3%降至72小时时的18.9%(未列出数据)。而整个实验中,心、肾、肌肉和脾各值则保持在0.7-9.8%的范围内。肺中的放射性水平发现从1小时时的14.2%降至72小时时的7.6%。而相似的肝每克注射剂量值分别为10.3%和9.9%。这些数据如下述用于测定放射吸收剂量估算I2B8。
在BALB/C小鼠体内评估比活为12.2mCi/mg抗体的钇[90]标记连接物的生物学分布。放射性掺入达>90%,并用HPLC提纯该放射性标记的抗体。72小时内评估主要器官及皮肤、肌肉、骨、以及尿和粪便中的放射性的组织积沉,并表达为注射剂量/g组织的百分数。结果(未列出)表明,相应于血液的放射性水平从1小时时的每克注射剂量的约39.2%降至72小时时的约15.4%,而相应于尾、心、肾、肌肉及脾的放射性水平,在整个实验过程中却大致保持10.2%不变或稍小。重要的是相应于骨的放射性是在1小时时的每克注射剂量的4.4%至72小时时的3.2%范围内。总的来说,这些结果表明该连接物中很少有游离钇与之共存,在研究过程中很少有游离放射性金属释放出。这些数据将如下述用于测定放射吸收剂量估算Y2B8。
制备2B8-MX-DTPA并用铟[111]标记,使其比活达2.7mCi/mg,用于肿瘤定位研究。然后给12只患Ramos B细胞肿瘤的无胸腺小鼠每只注射100μl标记的连接物(约24μCi)。肿瘤重量为0.1-1.0g范围。注射后的第0、24、48及72小时各时间点,通过后眼窝穿刺抽取50μl血,断颈杀死鼠,将尾、心、肺、肝、肾、脾、大腿及肿瘤取出,将组织处理并称重,使用γ计数器测定相应于各组织样品的放射性,将其值表达为每克所注射剂量的百分数。
结果(未列出)证明铟[111]2B8-MX-DTPA在肿瘤中的浓度在整个实验过程中稳定增加。72小时之后注射剂量的13%沉积在肿瘤中。相反的在血液中的水平,在实验过程中由零小时时的超过30%降至72小时时的13%。实验结束时,所有其它组织(除肌肉外)含每克组织的注射剂量的1.3%至6.0%之间;肌肉组织含有每克的注射剂量的约13%。
D.人类研究
ⅰ.2B8和2B8-MX-DTPA:用人组织作免疫组织学研究
使用一组用丙酮固定的32种不同人组织来评价鼠单克隆抗体2B8的组织反应活性。抗体2B8与具高度限制性组织分布形式的抗-CD20抗原反应,该组织分布形式仅在淋巴样组织(包括造血源的组织)中的细胞亚群中观察到。
在淋巴节中,免疫活性在成熟外皮B-淋巴细胞群体以及胚层中心繁殖细胞中观察到。阳性反应也在外周血,扁桃体B细胞面、脾的白髓以及胸腺中发现的40-70%髓质淋巴细胞中观察到。阳性反应也在大肠的固有层的滤泡(Peyer氏斑)中看到。最后,聚集或散布于各种器官的基质中(这些器官包括膀胱、乳房、宫颈、食管、肺、肋腺、前列腺、小肠及胃)的淋巴样细胞与抗体2B8反应也是阳性的(数据未列出)。
发现所有简单的上皮细胞、以及分层的上皮及不同器官的上皮都不与之反应。同样,与神经外胚层细胞(包括脑,脊椎及外周神经的外胚层细胞)也不反应。间质元件,例如骨胳和平滑肌细胞、成纤维细胞、内皮细胞以及多形态核炎性细胞也发现是阴性的(未列出数据)。
使用用丙酮固定的一组16种不同人组织来评价2B8-MX-DTPA连接物组织反应活性。正如前面用天然抗体所证明的(未列出数据),该2B8-MX-DTPA连接物也识别表现出高度限制性分布形式的CD20抗原,该分布形式仅在淋巴样来源细胞亚群中发现。在淋巴节中,免疫活性在B细胞群体中观察到。在脾的白髓及胸腺髓质淋巴细胞中发现很强反应活性。在膀胱、心脏、大肠、肝、肺及子宫中散布的淋巴细胞中也观察到免疫活性,这归结于这些组织中存在炎性细胞所致。正如与天然抗体一样,神经外胚层细胞或间质元件也未发现反应活性(未列出数据)。
ⅱ.I2B8(造影)及Y2B8(治疗)的临床分析
a.Ⅰ/Ⅱ期临床试验单剂量治疗研究
现进行Ⅰ/Ⅱ期I2B8(造影)临床分析,接着进行Y2B8单剂量治疗临床分析。对单剂量研究,采用下述方案
1.收集外周干细胞(PSC)或骨髓(BM)并净化;
2.I2B8造影;
3.Y2B8治疗(三种剂量水平);及
4.PSC或自体BM移植(假如必要,则根据连续3天绝对中性白细胞计数低于500/mm3或血小板低于20000/mm3,同时骨髓检查时无骨髓复原迹象来决定)。
Y2B8的剂量水平如下:
剂量水平 剂量(mCi)
1 20
2 30
3 40
每个剂量水平用来治疗3个患者,以确定最大耐受剂量(MTD)。
造影(剂量测量法)研究进行如下:使用I2B8对每个患者进行二次体内生物学分布研究。第一次实验中,以1小时内静脉输注(ⅰ.ⅴ.)给药2mg I2B8(5mCi);一星期后由静脉给药2B8(即非连接抗体),其输入速率不超过250mg/hr,紧接着在1小时期间静脉给药2mg I2B8(5mCi)。在上述两次实验中I2B8输注之后立即给每个患者造影,在时间t=14-18小时(假如指明)、t=24小时、t=72小时及t=96小时(假如指明)重复造影。测定整个身体铟[111]标记的平均保留时间;也对可识别器官或肿瘤患部(有意义区域)作此种测定。
将这些有意义区域与整个身体的标记物浓度进行比较。根据该比较结果,使用标准方法可测定Y2B8的估计位置及浓度。假如Y2B8的估计累积剂量比估计的整个身体的剂量大8倍、或假如肝中的估计累积剂量超过1500cGy,那么不应以Y2B8来处理。
假如该造影研究可以接受,那么先按0.0或1.0mg/kg患者体重的2B8量,由静脉输注给药,其输入速率不超过250mg/小时。然后以20mCi/小时的速度静脉输注Y2B8(10、20或40mCi)给药。
b.Ⅰ/Ⅱ期临床试验:多剂量治疗研究
现进行Y2B8的Ⅰ/Ⅱ期临床分析,对于多剂量研究,按下述方案:
1.收集PSC或BM;
2.I2B8造影;
3.Y2B8治疗(三种剂量水平)采用4次剂量或者总累积剂量为80mCi;及
4.PSC或自体BM移植(根据医生的决定)
Y2B8的剂量水平如下:
剂量水平 剂量(mCi)
1 10
2 15
3 20
每个剂量水平治疗三个患者确定其MTD。
造影(剂量测量法)研究按如下进行:用头二个患者测定未标记抗体(即2B8)的优选造影剂量。四小时期间,这头两个患者将接受250CC生理盐水中的未标记2B8 100mg,接着给予0.5mCi I2B8。于时间t=0,t=10min,t=120min,t=24hr,t=48hr收集血样供生物学分布测定用。分别在t=2hr,t=24hr及t=48hr用多区域γ照相机摄取影象。在第48小时摄影后,给病人如上述输入250mg 2B8,接着给予4.5mCi I2B8,然后按上面所述取血及摄影。假如100mg 2B8产生优良影象,那么随后两个病人按上面所述给予50mg 2B8,接着给予0.5mCi I2B8,48小时后再给与100mg 2B8,然后再给4.5mCi I2B8。假如250mg 2B8产生优良影像,然后下两个病人将按上述给予250mg 2B8,接着给予0.5mCi I2B8,48小时之后再给予500mg 2B8并给予4.5mCi I2B8。后面的病人将以提供最优造影的最低量2B8处理。最优造影定义如下:(1)使抗体消失最慢的最有效造影;(2)在单一器官中分隔最小的最好分布状况;(3)患处的最佳主观分辨度(肿瘤/背景对比)。
对于前4个病人,Y2B8的第一次治疗剂量将在I2B8最后剂量后的第14天开始,而后面的病人Y2B8第一次治疗剂量将在I2B8后的2-7天开始。
用Y2B8治疗之前,除了前面的4个病人外其余的病人按上面所述给与2B8,接着静脉输注Y2B8(在5-10分钟期间输完)。在t=0分钟,t=10分钟,t=120分钟,t=24小时,t=48小时分别取血样用于生物学分布。约每6-8星期患者将收到重复Y2B8剂量(与第一次剂量相同的剂量给药)最多共4次,或总累计剂量80mCi。最优选患者的WBC大于或等于3000,且AGC大于或等于100,000之后再接受随后的Y2B8剂量。
三种剂量水平研究完成之后,将确定MTD值,然后其它的患者再进入研究,这些患者将接受MTD。
Ⅱ.嵌合抗-CD20抗体的生产(C2B8)
A.嵌合抗-CD20免疫球蛋白DNA表达载体的构建
从2B8小鼠杂交瘤细胞分离出RNA(如Chomczynki,P.等人在“Single step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.”Anal.Biochem.162:156-159(1987)中所述),并由此制备cDNA。通过聚合酶链反应,使用与小鼠轻链信号序列5′端和小鼠轻链J区3′端同源的一套DNA引物,从cDNA中分离小鼠免疫球蛋白轻链可变区DNA。引物序列如下:
1.VL有意义(SEQ.ID.NO.3)
5′ATC AC AGATCT CTC ACC ATG GAT TTT CAG GTG CAG ATT ATC AGC TTC 3′
(下面划线的部分是Bgl Ⅱ位点;上面划线的部分是起始密码子)
2.VL反义(SEQ.ID.NO.4)
5′TGC AGC ATC CGT ACG TTT GAT TTC CAG CTT 3′
(下面划线部分是Bsi WI位点)
TCAE8中的相应Bgl Ⅱ和Bsi WI位点见图1和2,TCAE8中抗-CD20中的相应位点见图3。
将这些得到的DNA片段直接克隆进TCAE8载体中人kappa轻链不变区的前面并测序。所测定的鼠可变区轻链的DNA序列绘于图4中(SEQ.ID.NO.5),也见图3核苷酸978至1362。图4也提供来自该鼠可变区的氨基酸序列以及CDR和构架区。来自2B8的小鼠轻链可变区是小鼠kappa Ⅵ家族,见前面所述Kabat的文献。
按相似方法分离出小鼠重链可变区并克隆到人IgGl不变区之前。
引物如下:
1.VL有意义(SEQ.ID.NO.6)
5′GCG GCT CCC ACGCGT GTC CTG TCC CAG 3′
(底下划线的部分是Mlu I位点)
2.VL反义(SEQ.ID.NO.7)
5′GG(G/C)TGT TGT GCTAGC TG(A/C)(A/G)GA GAC(G/A)GT GA 3′
(下面划线的部分是Nhe I位点)
TCAE8中的相应Mlu I和Nhe I位点见图1及图2,TCAE8中抗-CD20中的相应位点见图3。
该小鼠重链的序列绘于图5(SEQ.ID.NO.8),也参见图3,核苷酸2401至2820。图5也提供来自该鼠可变区的氨基酸序列以及CDR和构架区。来自2B8的小鼠重链可变区是小鼠VH2B家族,见前面所述Kabat的文献。
B.创建产生嵌合抗-CD20的CHO和SP2/0转染瘤
将中国仓鼠卵(CHO)细胞DG44于减次黄嘌呤和胸苷的SSFM Ⅱ培养基(Gibco,Grand Island,NY,Form No.910456PK)中培养;而将SP2/0小鼠骨髓瘤细胞在Dulbecco氏改良伊格尔培养基(DMEM)(Irvine Scientific,Santa Ana,Ca.,Cat.No.9024)并加有5%胎牛血清及20ml/l谷氨酰胺的培养基中培养。使用BTX600电穿孔体系(BTX.San Diego.CA)在0.4ml一次性电穿孔池中,以由Not Ⅰ所限制过的25μgCHO或50μgSP2/0质粒DNA将4百万细胞电穿孔,条件是CHO用210伏,SP2/0用180伏,400微法,13欧姆。各电穿孔物铺于6个96孔的平皿(约7000个细胞/孔)上。各平皿加以含G418(GENETICIN,Gibco,Cat.No.860-1811)的培养基,其加入方式是对于CHO来说,以400μg/ml活性化合物比例(培养基中还包括50μM次黄嘌呤和8μM胸苷)加入,或对SP2/0来说按800μg/ml加入,于电穿孔后两天加入,此后2或3天加一次直至菌落产生为止。将菌落的上清液用对人抗体特异性的ELISA来检测其嵌合免疫球蛋白的存在。将产生最高量免疫球蛋白的菌落展开,并铺于含加氨甲蝶呤(25nM为SP2/0,5nM为CHO)的培养基的96孔平板上,2-3天添加一次。按上面所述检测上清液并检查产生最大量免疫球蛋白的菌落。使用蛋白A亲和色谱将嵌合抗-CD20抗体从上清液中提纯。
采用聚丙烯酰胺电泳法分析提纯的嵌合抗-CD20,并估计纯度超过95%。根据2B8确定嵌合抗体的亲和性及特异性。以直接和竞争结合测试法试验嵌合抗-CD20抗体,与鼠抗-CD20单克隆抗体2B8相比,证明对许多CD20阳性B细胞系有差不多的亲合性及特异性(数据未列出)。通过I125放射标记嵌合抗-CD20直接结合来测定嵌合抗体的表观亲和常数(Kap)并且以Scatchard作图法来与放射性标记2B8相比较。估测出的CHO产生的嵌合抗-CD20的Kap是5.2×10-9M,而SP2/0产生的抗体为7.4×10-9M,2B8估测的Kap是3.5×10-9M。放射免疫测试的直接竞争用来通过比较其与2B8有效竞争的能力确认嵌合抗体的免疫活性的特异性及保留程度。产生对B细胞上CD20抗原结合作用50%抑制作用所需的嵌合抗-CD20和2B8抗体的量基本相等(数据未列出),即设想由于嵌合作用所引起的抗-CD20抗体的抑制活性损失极小。
实施例Ⅱ.B的结果特别表明,使用TCAE8载体从CHO和SP2/0转染瘤产生嵌合抗-CD20抗体,该嵌合抗体基本上与鼠抗-CD20单克隆抗体2B8有相同的特异性和结合能力。
C.嵌合抗-CD20抗体的免疫活性测试
ⅰ.人Clq分析
以流式细胞计数测试法,使用萤光素标记Clq(Clq从Quidel,Mira Mesa,CA.Prod.No.A400获得,而FITC标记从Sigma,St.Louis MO,Prod.No.F-7250获得,按照Selected Methods In Cellular Immunology,Michell & Shiigi,Ed.(W.H.Freeman & Co.San Francisco,CA,1980,p.292)一书所述方法进行Clq的FITC标记)来评价由CHO和SP2/0细胞系产生的嵌合抗-CD20抗体对人Clq的结合作用。使用Becton Dickinson FACScanTM流式细胞计数器(在515-545nm范围内测量萤光素)来得到分析结果。相等量的嵌合抗-CD20抗体,人IgGl,K骨髓瘤蛋白(Binding site,San Diego,Ca,Prod.No.BP078)和2B8与相当数量的CD20-阳性SB细胞共培养,接着用FACS缓冲液(.2% BSA于PSA中,pH7.4,.02%叠氮钠)洗涤,除去未连接的抗体,接着与FITC标记的Clq一起培养,保温30-60分钟之后,再次洗涤细胞。用FACScanTM,遵循厂商的说明对三种条件(包括FITC标记Clq作为对照)进行分析。结果绘于图6中。
正如图6所显示的,仅仅对于嵌合抗-CD20抗体条件才观察到显著的萤光增强,即仅仅与嵌合抗-CD20抗体结合的SB细胞才呈Clq阳性,而其它条件则得到与对照物相同的图形。
ⅱ.补体依赖性细胞溶解
在人血清存在下(补体源)分析嵌合抗-CD20抗体溶解淋巴瘤细胞系的能力。于37℃,将100μCi51Cr与1×106SB细胞混合1小时,由此以51Cr标记CD20阳性SB细胞。然后在相等量的人补体及相当量的(0-50μg/ml)嵌合抗-CD20抗体或2B8存在下,于37℃,将标记SB细胞培养4小时(见Brunner,K.T.et al.,"Quantitative assay of the lytic action of immune lymphoid cells on51Cr-labeled allogeneic target cells in vitro"Immunology 14:181-189(1968)),结果绘于图7。
图7的结果特别表明,在这些条件下,嵌合抗-CD20抗体产生显著溶胞作用(49%)。
ⅲ.抗体依赖性细胞毒性效应细胞检测
利用CD20阳性细胞(SB)和CD20阴性细胞(T细胞白血病系HSB,见Adams,Richard,"Formal Disussion"Can.Res.27:2479-2482(1967);ATCC保藏号ATCC CCL 120.1)进行该项研究,该两细胞用51Cr标记。分析按照Brunner,K.T.et al.,"Quantitative assay of the lytic action of immune lymphoid cells on51Cr-labeled allogeneic target cells in vitro;inhibition by isoantibody and drugs."Immunology 14:181-189(1968)所述方法进行。于37℃保温4小时后,观察到CD20阳性SB靶细胞(51Cr-标记)的嵌合抗-CD20抗体依赖性细胞介导的显著的溶胞作用,并且该效果也由CHO和SP2/0产生的抗体所观察到(效应细胞是人外周淋巴细胞,效应细胞:靶的比例是100∶1)。靶细胞的有效溶解于3.9μg/ml获得。相反的,在同样情况下,鼠抗-CD20单克隆抗体2B8从统计学上看无明显效果,而CD20阴性HSB细胞则不溶解。结果示于图8中。
实施例Ⅱ的结果特别表明,实施例Ⅰ的嵌合抗-CD20抗体具免疫学活性。
Ⅲ.使用嵌合抗-CD20抗体体内消耗B细胞
A.非人灵长类动物研究
分别进行三个非人灵长类动物研究。为方便起见,这三个研究分别称之为“嵌合抗-CD20:CHO & SP2/0”,“嵌合抗-CD20:CHO”及“高剂量嵌合抗-CD20”,其条件如下:
嵌合抗-CD20:CHO & SP2/0
将6只体重在4.5到7公斤范围内的猕猴(White Sands Research Center,Alamogordo,NM)按2只一组分成三组。每组中的两个动物均给予相同剂量的免疫活性嵌合抗-CD20抗体,而每组一个动物给予CHO转染瘤产生的纯化抗体,另一个给予SP2/0转染瘤产生的抗体。三个组接受的抗体剂量相应为每天0.1mg/kg,0.4mg/kg及1.6mg/kg持续连续4天。该嵌合免疫活性抗-CD20抗体与无菌盐水混合,通过静脉输注给药,每次输注前取血样。另外在最后一次注射后开始的24小时(T=0)及此后的第1、3、7、14和28天均抽取血样,并且此后按二星期的间隔再抽血样直至第90天研究完成为止。
于2000RPM将约5ml来自各动物的全血离心5分钟。取出血浆用于检测可溶的嵌合抗-CD20抗体水平。其沉淀(含外周血白细胞和红血细胞)再悬浮于胎牛血清中用于萤光标记抗体分析(见“Fluorescent Antibody Labeling of Lymphoid Cell Population”如后面所述)。
嵌合抗-CD20:CHO
将6只体重4-6公斤的猕猴(White Sands)按2只一组分成三组,所有的动物均给注射从CHO转染瘤产生的免疫活性嵌合抗-CD20抗体(于无菌盐水中)。该三组再按下法分开:第一组每日静脉注射0.01mg/kg抗体持续4天;第二组每日静脉注射0.4mg/kg抗体持续4天;第三组单次静脉注射6.4mg/kg抗体。三个组均在治疗开始前抽取血样,此后于最后注射之后的T=0、1、3、7、14和28天如上所述分别抽血样,这些血样均都加工用于萤光标记抗体分析(见后面“Fluorescent Antibody Labeling”)。除进行外周血B细胞定量分析外,还在最后一次注射之后的第7、14及28天取淋巴节活检,并且为用流式细胞计数器进行淋巴细胞总数定量分析而作单细胞制剂染色。
高剂量嵌合抗-CD20
给2只猕猴(White Sands)每周输注16.8mg/kg从CHO转染瘤得到的免疫活性嵌合抗-CD20抗体(于无菌盐水中)持续连续4周。治疗结束时,将两动物麻醉取出骨髓,并取淋巴节活检。用Leu16将两份组织染色用流式细胞计数器测定B淋巴细胞的存在,此测定遵从Ling,N.R.等人的“B-cell and plasma cell antigens”Leucocyte Typing Ⅲ White Cell Differentiations Antigens,A.J.McMichael,Ed.(Oxford University Press,Oxford UK 1987)p.302所述方法进行。
淋巴样细胞总体的萤光抗体标记
除去血浆之后,用Hanks平衡盐溶液(HBSS)洗白细胞二次,并再悬浮于与血浆等体积的胎牛血清(56℃热失活30分钟)中。将该细胞制剂0.1ml体积分配于6支15ml圆锥形离心管的每支中。将对人淋巴细胞表面标志CD2(AMAC,Westbrook,ME),CD20(Becton Dickinson)及人IgM(Binding Site,San Diego,CA)具特异性的萤光素标记单克隆抗体加入到这些管的3支中,用以鉴定T和B淋巴细胞总数。所有的试剂预先试验过对相应的猴淋巴细胞抗原呈阳性。嵌合抗-CD20抗体与猴B细胞表面CD20的结合作用,在第4个管中使用与藻红素偶联的多克隆山羊抗-人IgG(AMAC)来测量。该试剂被预先吸附在猴Ig-琼脂糖柱上以阻斥对猴Ig的交叉反应活性,由此可进行连接于细胞的嵌合抗-CD20抗体的特异性检测并定量分析。第5支管既包含抗-IgM又包含抗-人IgG试剂用于B细胞群双染色。第6支管中的样品未加试剂用于测定自体萤光。将细胞与萤光抗体保温30分钟,用0.5ml固定缓冲液(0.15M NaCl,1%多聚甲醛 pH7.4)洗涤和固定,并在Beton Dickinson FACScanTM仪上分析。淋巴细胞总数一开始由前右夹角光散射在点绘图上与未标记的白细胞一起鉴定出。然后排除所有其它的作用,分离出总淋巴细胞总数,随后的萤光测量值仅反映剩下的淋巴细胞特异性作用。
外周血B淋巴细胞的消耗
虽然用CHO转染瘤衍生的嵌合抗-CD20抗体,以1.6mg/kg及6.4mg/kg的剂量水平给猴注射后7天,而用SP2/0产生的抗体以0.4mg/kg剂量水平给猴注射后7天,B细胞恢复开始稍增,但CHO及SP2/0产生的抗体之间在效力上没有看出有明显差别。图9A、B及C提供源于嵌合抗-CD20:CHO及SP2/0研究的结果,其中图9A针对0.4mg/kg剂量水平,图9B针对1.6mg/kg剂量水平,而图9C针对6.4mg/kg剂量水平。
正如图9所证明的,在所有试验过的剂量范围内,治疗处理之后,外周血B细胞水平出现急剧下降(>95%),并且这些水平保持到输注后7天,经过这一期间后,B细胞开始恢复,而开始恢复的时间与剂量水平无关。
在嵌合抗-CD20:CHO研究中,每日4次注射(共0.04mg/kg)期间,采用10倍较低抗体剂量浓度(0.01mg/kg)。图10给出这一研究结果,该剂量消耗外周血B细胞总数至正常水平的约50%(以抗-表面IgM或Leu16抗体估测)。该结果也表明,对非人灵长类动物来说,以免疫活性嵌合抗-CD20抗体在该剂量浓度,在该时间内,便使得CD20抗原在B淋巴细胞群体上达到饱和的情况不会出现,治疗处理之后最初3天内,在血样中检出抗体包被的B淋巴细胞,然而在第7天时,便检不出抗体包被细胞了。
表Ⅰ归纳了单剂量或多剂量免疫活性嵌合抗-CD20抗体对外周血细胞总数影响的结果,单剂量条件是6.4mg/kg,多剂量条件是0.4mg/kg连续4天(这些结果来源于上面所述对猴的研究)。
表Ⅰ
C2B8灵长类动物研究得出的外周血总数
猴 剂量 天数 CD2 抗-Hu IgG
A 0.4mg/kg 预先抽血 81.5 -
(4剂) 0 86.5 0.2
7 85.5 0.0
21 93.3 -
28 85.5 -
B 0.4mg/kg 预先抽血 81.7 -
(4剂) 0 94.6 0.1
7 92.2 0.1
21 84.9 -
28 84.1 -
C 6.4mg/kg 预先抽血 77.7 0.0
(1剂) 7 85.7 0.1
21 86.7 -
28 76.7 -
D 6.4mg/kg 预先抽血 85.7 0.1
(1剂) 7 94.7 0.1
21 85.2 -
28 85.9 -
抗-Hu IgG+
猴 抗-Hu IgM*Leu-16 %B细胞消耗
A - 9.4 0
0.3 0.0 97
0.1 1.2 99
- 2.1 78
- 4.1 66
B - 14.8 0
0.2 0.1 99
0.1 0.1 99
- 6.9 53
- 8.7 41
C 0.2 17.0 0
0.1 0.0 99
- 14.7 15
- 8.1 62
D 0.1 14.4 0
0.2 0.0 99
- 9.2 46
- 6.7 53
*双染色总数,它表明嵌合抗-CD20包被B细胞的程度。
归纳于表Ⅰ中的数据表明,不管单剂量或多剂量水平,在抗体过剩的情况下外周血中B细胞的消耗都很快且效果很好。此外,至少最后一次注射后7天都能观察到消耗作用,到21天时观察到部分B细胞恢复。
表Ⅱ归纳采用表Ⅰ的治疗制式(0.4mg/kg4次日剂量或6.4mg/kg 1次)时,免疫活性嵌合抗-CD20对淋巴结中细胞总数的影响,也提供正常淋巴结(对照猴、腋下和腹股沟的)和正常骨髓(二只猴)的比较值。
表Ⅱ
淋巴节的细胞总数分析
猴 剂量 天数 CD2 抗-Hu IgM
A 0.4mg/kg 7 66.9 -
(4剂) 14 76.9 19.6
28 61.6 19.7
B 0.4mg/kg 7 59.4 -
(4剂) 14 83.2 9.9
28 84.1 15.7
C 6.4mg/kg 7 75.5 -
(1剂) 14 74.1 17.9
28 66.9 23.1
D 6.4mg/kg 7 83.8 -
(1剂) 14 74.1 17.9
28 84.1 12.8
表II(续)
抗-Hu IgG+
猴 抗-Hu IgM*Leu-16 %B淋巴细胞消耗
A 7.4 40.1 1
0.8 22.6 44
- 26.0 36
B 29.9 52.2 0
0.7 14.5 64
- 14.6 64
C 22.3 35.2 13
1.1 23.9 41
- 21.4 47
D 12.5 19.7 51
0.2 8.7 78
- 12.9 68
表II(续)
抗-Hu IgG+ %B淋巴细胞
CD2 抗-Hu IgM 抗-Hu IgM Leu16 消耗
正常淋巴节
对照1
腋下 55.4 25.0 - 41.4 NA
腹沟股 52.1 31.2 - 39.5 NA
正常骨髓
对照2 65.3 19.0 - 11.4 NA
对照3 29.8 28.0 - 16.6 NA
表Ⅱ的结果表明,两种治疗制式均有效地消耗掉B淋巴细胞。表Ⅱ还表明,对于非人灵长类动物来说,使用免疫活性嵌合抗-CD20抗体,则B细胞在淋巴组织中的完全饱和状态不会达到。此外在治疗后第7天观察到抗体包被细胞,接着在第14天明显地观察到消耗掉淋巴结B细胞。
根据这些数据,进行上述单次高剂量嵌合抗-CD20研究,主要是测定药理学/毒理学。该研究用以评价随着嵌合抗体的给药所引起的毒性,以及B细胞从外周血淋巴结和骨髓中消耗的效力。此外,因为表Ⅱ数据表明,在那些实验中淋巴结B细胞大部分在治疗后的7-14天消耗掉,因此可以证明采用周剂量制式会获更佳效果。表Ⅲ归纳出高剂量嵌合抗-CD20研究的结果。
表Ⅲ
淋巴结和骨髓的细胞总数分析淋巴细胞总数(%)
猴 CD2 CD20amIgM+抗-C2B8bC2B8c天数d
腹沟股淋巴节
E 90.0 5.3 4.8 6.5 22
F 91.0 6.3 5.6 6.3 22
G 89.9 5.0 3.7 5.8 36
H 85.4 12.3 1.7 1.8 36
骨髓
E 46.7 4.3 2.6 2.8 22
F 41.8 3.0 2.1 2.2 22
G 35.3 0.8 1.4 1.4 36
H 25.6 4.4 4.3 4.4 36
a表示以Leu 16染色的总数。
b表示双染色总数,对表面IgM细胞和嵌合抗体包被的细胞均为阳性。
c表示对嵌合抗体[包括双染色表面IgM阳性细胞及单染色(表面IgM阴性)细胞]染色的总计数量。
d最后一次16.8mg/kg剂量注射后的天数。
被评价的两动物在治疗停止后第22天含有的B细胞少于5%,而对照的淋巴结中为40%(见上表Ⅱ)。同样,在以嵌合抗-CD20抗体治疗的动物骨髓中,CD20阳性细胞水平小于3%,而正常动物为11-15%(见上表Ⅱ)。被评价的动物在治疗停止后第36天,其中1只(H)在淋巴结中有约12%B细胞,在骨髓中有4.4%B细胞,而另外1只(G)的淋巴结中有约5%细胞,骨髓中有0.8%,该数据表明了显著的B细胞消耗作用。
实施例ⅢA.的结果特别证明了低剂量免疫活性嵌合抗-CD20可产生长效灵长类动物体内的外周血B细胞消耗。这些数据也证明,当反复高剂量抗体给药时,在外周淋巴结和骨髓中也能引起B细胞总数的显著消耗。继续跟踪试验动物表明,即使在治疗的第一星期产生如此严重的外周B淋巴细胞消耗,也未观察到不利的健康影响。而且,还观察到B细胞总数的恢复,由此得出结论,通过治疗,这些灵长类动物的多能干细胞不会受到不利影响。
B.C2B8的临床分析
ⅰ.C2B8的Ⅰ/Ⅱ期临床试验:单剂量治疗研究
将组织学记载复发B细胞瘤的15个病人,在Ⅰ/Ⅱ期临床试验中以C2B8治疗。以剂量逐步升级实验方式给每个病人以单剂量C2B8,即以10mg/m2,50mg/m2,100mg/m2,250mg/m2及500mg/m2量,每种剂量分别给予3个病人,通过0.22微米孔衬里滤器经静脉输注进行治疗,输注用生理盐水稀释至最终体积250cc或最大浓度1mg/ml的C2B8。第1小时内初始输入速度为50cc/hr,若未发现毒性反应,则剂量输入速度可逐渐加大直至最大值200cc/hr。
毒性(由临床医生指明的)分级为从“无”,到“发热”,到“中度”(两个病人)直至“严重”(一个病人),所有病人均完成了此治疗处理过程。分析外周血淋巴细胞,特别测定C2B8对T细胞和B细胞的影响。所有的病人得到一致结果,用C2B8输注之后消耗外周血B淋巴细胞,此种消耗维持两星期以上。
一个病人(接受100mg/m2C2B8)表现出对C2B8治疗的部分反应(持续四周以上,所有可测量显示的患部两垂直直径之积相加,共降低了50%以上,在此期间无新患部出现且已有的患部无增大现象),至少另一个病人(接受500mg/m2)表现出对C2B8治疗的较差反应(所有可测量显示的患部两最大垂直直径之积相加,共降低不到50%,但至少有25%)。对于有代表性的效率,其PBL结果示于图14中,表现出PR的病人其数据在图14A中,表现出MR的病人其数据示于图14B。图14中,下述符号表示:
=淋巴细胞,
=CD3+细胞(T细胞),
=CD20+细胞,
=CD10+细胞,
=κ,
=λ及
=C2B8。正如所表明的,B细胞标志CD20和CD19,κ和λ,在两星期之上均被消耗,而T细胞数量只开始有稍许下降,并在相当快的时间内便回复到近似基线水平。
ⅱ.C2B8的Ⅰ/Ⅱ期临床试验:多剂量治疗研究
有明显进行性症状的,组织学上证实患B细胞淋巴瘤的病人适于作此项实验,将其分为二部分:在Ⅰ期,包括剂量递增至有限毒性特性剂量,并确定其生物学活性耐受剂量水平,每3个病人一组的各组,每周静脉输注C2B8共分为4次。三种水平的累积剂量如下:500mg/m2(125mg/m2/输注)、1000mg/m2(250mg/m2/输注)、1500mg/m2(375mg/m2/输注,定义生物学活性耐受剂量并确定之,其定义为既具有可耐受的毒性又具有足够的活性的最低剂量)。在Ⅱ期,其它病人将得到生物学活性可耐受剂量,但侧重测定C2B8四种剂量活性。
Ⅳ.结合治疗:C2B8和Y2B8
使用C2B8及Y2B8的结合治疗法在小鼠异记录模式(nu/nu小鼠,雌性,约10周龄)中使用B细胞成淋巴瘤(Ramos肿瘤细胞)进行研究。为进行比较,其它小鼠也用C2B8和Y2B8治疗。
在37℃和5% CO2条件下将Ramos肿瘤细胞(ATCC,CRL 1596)维持在使用补充有10%胎牛血清及谷氨酰胺的RPMI-1640的培养物中。给9只约7-10周龄的雌性裸鼠,使用装有25号针头的1cc注射器,经皮下注射1.7×106Ramos细胞(体积为0.10ml,HBSS),使其引发肿瘤。所有动物控制在层流通风厨中,并且所有的笼子,垫子,食物及水都经高压灭菌处理。通过割切肿瘤使肿瘤细能过筛,并将其通过40目筛,用IX HBSS(50ml)通过离心处理(1300 RPM)将细胞洗二次,再悬浮于IX HBSS至10×106细胞/ml,于-70℃冷冻直至使用。
为满足不同实验条件,将细胞分几批将其解冻,用离心法(1300 RPM)将其沉淀并用IX HBSS洗二次。然后再将细胞悬浮至约2.0×106细胞/ml。使用装有25号针头的1cc注射器给约9-12只小鼠皮下注射0.10ml细胞悬浮液,注射在动物的左边,接近中部区。在约两周后肿瘤扩展。将肿瘤切下并按上面所述处理,所试动物按前述注射1.67×106细胞的0.10ml HBSS悬浮液。
根据初步的剂量实验,确定采用200mg C2B8和100μCi Y2B8用于此项研究。给90只雌性nu/nu小鼠(约10周龄)注射肿瘤细胞。约10天后,将24只鼠分成四个实验组(六只一组)同时努力在各组中维持差不多的肿瘤大小分布(平均肿瘤大小,以肿瘤的长×宽之积表示,约为80mm2)。使用装有25号针头的100μl Hamilton注射器,按下述剂量,通过尾静脉注射法对下列各组进行处理:
A.生理盐水
B.Y2B8(100μCi)
C.C2B8(200μg)及
D.Y2B8(100μCi)+C2B8(200μg)
初次注射后,以C2B8治疗的组给予第二次C2B8注射(200μg/鼠),用测径器每2天或3天测量肿瘤一次。
按如下方法制备治疗材料:
A.制备Y2B8
将氯化钇[90](6mCi)移入聚丙烯试管,并用无金属2M乙酸钠调节pH值4.1-4.4。加入2B8-MX-DTPA(于生理盐水中0.3mg,见上面2B8-MX-DTPA的制备),并以涡旋方式轻轻混合。保温15分钟之后,加入0.05×体积20mM EDTA及0.05×体积2M乙酸钠使反应骤冷。将5.0μl该反应混合物在含75mg/ml HSA及1mM DTPA的2.5ml 1×PBS(配制缓冲液)中稀释,测定其放射活性浓度,通过加入10.0μl到20ml EcolumeTM闪烁混合液中进行计数。将剩余的反应混合物加到3.0ml配制缓冲液中,无菌过滤并于2-8℃贮存直至使用。比活性(注射时为14mCi/mg)根据加到反应混合物中的抗体量使用放射性浓度和计算出的蛋白质浓度来计算。使用瞬息薄层色谱来测定蛋白相关放射性。放射性掺入为95%。使用之前将Y2B8在配制缓冲液中稀释,并无菌过滤(最后的放射性浓度是1.0mCi/ml)。
B.制备C2B8
按上述方法制备C2B8。C2B8在生理盐水中以5.0mg/ml浓度作为无菌试剂提供。注射之前,该C2B8在生理盐水中稀释至2.0mg/ml并无菌过滤。
C.结果
治疗之后,肿瘤大小表达为长宽之积。按图11(Y2B8与盐水相比),图12(C2B8与盐水相比),图13(Y2B8+C2B8与盐水相比)所示日期测量,也测定标准误差。
正如图13所示,Y2B8和C2B8结合使用表现出与单独使用Y2B8或者C2B8所获差不多的杀肿瘤效果。
Ⅴ.其它治疗方案
以前述实施例的观点来找出其它治疗方案是显而易见的,一个这类方案是在约一星期内使用C2B8所用的治疗剂量,以2B8和放射性标记2B8(例如Y2B8)结合给药,或以2B8、C2B8及例如Y2B8一起给药,或者以C2B8和例如Y2B8一起给药。另一个方案是利用放射性标记的C2B8-该方案使得采用C2B8的免疫活性部分的优点加上了相应的放射性标记的优点。优选的放射性标记物包括钇[90],它可给出与C2B8与鼠抗体2B8相比较大的循环半衰期。由于C2B8消耗B细胞的能力及可从放射标记物得到的优点,因此一个优选的替代方案是用C2B8(以单剂量或多剂量)治疗病人,使得大部份(假如不是全部)外周B细胞消耗掉,然后再用放射性标记2B8,因为外周B细胞已消耗掉,那么放射性标记2B8便增加了定靶肿瘤细胞的机会。由于已在文献中报道过以碘[131]标记的各种结果(见Kaminski的文献),故优选碘[131]标记的2B8。一个其它优选方案是首先使用放射性标记2B8(或C2B8),努力增加肿瘤的通透性,接着以单剂量或多剂量C2B8治疗。该方案的意图是增加C2B8达到肿瘤块的外边和里边的机会。一个进一步的方案是包括使用化疗剂与C2B8结合使用。该方案包括所谓“交错”治疗法,即用化疗剂治疗,接着用C2B8治疗,然后再重复此法。此外,开始用单剂或多剂量C2B8治疗,此后用化疗治疗也是可行的。优选的化疗剂包括(但不限于)环磷酰胺,阿霉素,长春新碱,及强的松(见Armitage,J.O.et al.,Cancer 50:1695(1982)列入本文作为参考)。
前面列举的替代治疗方案并不作为一种限制范围,而应看作是有代表性的实例。
Ⅵ.有关保藏情况
抗-CD20于TCAE8中(为保藏起见在大肠杆菌中转化)保藏于美国典型培养物保藏中心(ATCC)(12301 Parklawn Drive,Rockville,Maryland,20852),该保藏是遵从国际承认用于专利程序的微生物保藏,布达佩斯条约(简称布达佩斯条约)的规定而履行的。该微生物由ATCC于1992年11月9日进行过试验证明其该日期仍存活。ATCC指定该微生物的ATCC保藏号为:ATCC 69119(抗-CD20于TCAE8中)。按布达佩斯条约规定,杂交瘤2B8于1993年6月22日[保藏于ATCC。该培养物的存活力于1993年6月25日测定过,ATCC指定该杂交瘤的ATCC保藏号为:HB11388。
序列目录
(1)总的情况
(ⅰ)申请人:Darrell Anderson,Nabil Hanna,John Leonard,Roland Newman,及Mitchell Reff和William H.Rastetter
(ⅱ)发明题目:抗人类B淋巴细胞限制分化抗原的嵌合及放射标记抗体在治疗B细胞淋巴瘤中的应用
(ⅲ)序列数:8
(ⅳ)通讯地址
(A)收信人:IDEC药物公司
(B)街道:11011 Torreyana Road
(C)城市:San Diego
(D)州:California
(E)国家:U.S.A
(F)邮编:92121
(Ⅴ)计算机可读类型
(A)媒介类型:Diskette,3.5 inch,1.44Mb
(B)计算机:Macintosh
(C)操作系统:MS.DOS
(D)软件:Microsoft Word 5.0
(ⅵ)现申请情况
(A)申请号:
(B)申请日:
(C)分类:
(ⅶ)代理人/代理机构情报
(A)姓名:Burgoon,Richard P.Jr.
(B)登记号:34,787
(C)案卷号:
(ⅷ)电讯情报
(A)电话号码:(619)550-8300
(B)传真:(619)550-8750
(2)SEQ ID NO:1情报
(ⅰ)序列特征
(A)长度:8540碱基
(B)类型:核酸
(C)链型:单链
(D)拓扑结构:环型
(ⅱ)分子类型:DNA(基因组的)
(ⅲ)假设的:是
(ⅳ)反意:否
(ⅸ)序列描述SEQ ID NO:1
(3)SEQ ID NO:2情报
(ⅰ)序列特征
(A)长度:9209碱基
(B)类型:核酸
(C)链型:单链
(D)拓扑结构:环型
(ⅱ)分子类型:DNA(基因组的)
(ⅲ)假设的:是
(ⅳ)反意:否
(ⅸ)序列描述SEQ ID NO:2
(4)SEQ ID NO:3情报
(ⅰ)序列特征
(A)长度:54碱基
(B)类型:核酸
(C)链型:单链
(D)拓扑结构:线型
(ⅱ)分子类型:DNA(基因组的)
(ⅲ)假设的:是
(ⅳ)反意:否
(ⅸ)序列描述SEQ ID NO:2
5′ATC ACA GAT CTC TCA CCA TGG ATT TTC AGG TBC AGA TTA TCA GCT TC3′
(5)SEQ ID NO:4情报
(ⅰ)序列特征
(A)长度:30碱基
(B)类型:核酸
(C)链型:单链
(D)拓扑结构:线型
(ⅱ)分子类型:DNA(基因组的)
(ⅲ)假设的:是
(ⅳ)反意:否
(ⅸ)序列描述SEQ ID NO:4
5′TGC AGC ATC CGT ACG TTT GAT TTC CAG CTT3′
(6)SEQ ID NO:5情报
(ⅰ)序列特征
(A)长度:384碱基
(B)类型:核酸
(C)链型:单链
(D)拓扑结构:线型
(ⅱ)分子类型:DNA(基因组的)
(ⅲ)假设的:是
(ⅳ)反意:否
(ⅸ)序列描述SEQ ID NO:5
(7)SEQ ID NO:6情报
(ⅰ)序列特征
(A)长度:27碱基
(B)类型:核酸
(C)链型:单链
(D)拓扑结构:线型
(ⅱ)分子类型:DNA(基因组的)
(ⅲ)假设的:是
(ⅳ)反意:否
(ⅸ)序列描述SEQ ID NO:6
5′GCG GCT CCC ACG CGT GTC CTG TCC CAG 3′
(8)SEQ ID NO:7情报
(ⅰ)序列特征
(A)长度:29碱基
(B)类型:核酸
(C)链型:单链
(D)拓扑结构:线型
(ⅱ)分子类型:DNA(基因组的)
(ⅲ)假设的:是
(ⅳ)反意:是
(ⅸ)序列描述SEQ ID NO:7
5′GGS TGT TGT GCT AGC TGM RGA GAC RGT GA 3′
(9)SEQ ID NO:8情报
(ⅰ)序列特征
(A)长度:420碱基
(B)类型:核酸
(C)链型:单链
(D)拓扑结构:线型
(ⅱ)分子类型:DNA(基因组的)
(ⅲ)假设的:是
(ⅳ)反意:否
(ⅸ)序列描述SEQ ID NO:8
Claims (20)
1、治疗B细胞淋巴瘤的方法,包括给人施用治疗有效量的至少一种免疫活性嵌合抗-CD20抗体。
2、权利要求1的方法,其中施用于所说人的所说抗体量是所说人的每公斤体重约0.001至约30mg抗体之间(mg/kg)。
3、权利要求1的方法,其中所说抗体衍生自TCAE8中含抗-CD20的转染瘤,该TCAE8中的抗-CD20贮存于美国典型培养物中心,是ATCC贮存号69119的微生物的一部分。
4、权利要求1的方法,进一步还包括施用第二种治疗学上有效量的至少一种免疫活性嵌合抗-CD20抗体。
5、权利要求4的方法,其中所说的抗体附加给药于所说人,是在所说抗体对所说人的所说第一次给药之后的约7天内进行。
6、治疗B细胞淋巴瘤的方法,包括下述步骤:
1)在第一次给药期间,第一次给人治疗有效量的免疫活性嵌合抗-CD20 抗体;
2)在第二次随后给药期间,给与第二次治疗有效量的所说抗体;
3)在第三次随后给药期间,给与第三次治疗有效量的所说抗体;
7、权利要求6的方法,其中所说的第1、第2和第3次所说抗体治疗有效量为约0.001mg/kg至约30mg/kg之间。
8、权利要求6的方法,其中所说第二次给药期是在所说第一次给药期的约7天内。
9、权利要求6的方法,其中所说第三次给药期是在所说第一次给药期的约14天内。
10、权利要求6的方法,其中所说的抗体衍生自TCAE8中含抗-CD20的转染瘤(ATCC贮存号69119)。
11、免疫活性嵌合抗-CD20,它从含有TCAE8中的抗-CD20(ATCC保藏号69119)的转染瘤产生。
12、分泌抗-CD20抗体的杂交瘤,所说杂交瘤是美国典型培养物保藏中心保藏号为HB11388的微生物。
13、从权利要求12的杂交瘤分泌的单克隆抗体。
14、根据权利要求12的放射性标记抗体。
15、根据权利要求14的放射性标记抗体,其中的放射性标记物选自钇[90],铟[111]及碘[131]所组成的一组之中。
16、治疗B细胞淋巴瘤的方法,包括给人施用治疗有效量的权利要求14的抗体。
17、权利要求16的方法,其中所说抗体的放射性标记物是钇[90]。
18、治疗B细胞淋巴瘤的方法,包括下述步骤:
1)在第一次给药期,给人施用免疫活性嵌合抗-CD20抗体;及
2)在第二次给药期,给人施用放射性标记抗-CD20抗体;
19、权利要求18的方法,其中嵌合抗-CD20,衍生自TCAE8中的抗-CD20的转染瘤,该抗-CD20贮存于美国典型培养物收藏中心,是ATCC贮存号69119的微生物的一部分。
20、权利要求8的方法,其中所说放射性标记抗体含由杂交瘤分泌的单克隆抗体,该杂交瘤是美国典型培养物收藏中心贮存号为HB 11388的微生物的等同物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US97889192A | 1992-11-13 | 1992-11-13 | |
US978,891 | 1992-11-13 |
Related Child Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2006100900848A Division CN101007851B (zh) | 1992-11-13 | 1993-11-12 | 抗人类b淋巴细胞限制分化抗原的嵌合及放射标记抗体 |
CN2004100488083A Division CN1607006B (zh) | 1992-11-13 | 1993-11-12 | 抗人类b淋巴细胞限制分化抗原的嵌合及放射标记抗体在治疗b细胞淋巴瘤中的应用 |
CN200610090080XA Division CN101007850B (zh) | 1992-11-13 | 1993-11-12 | 抗人类b淋巴细胞限制分化抗原的嵌合及放射标记抗体 |
CN2006100900829A Division CN1912111B (zh) | 1992-11-13 | 1993-11-12 | 抗人类b淋巴细胞限制分化抗原的嵌合及放射标记抗体 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1094965A true CN1094965A (zh) | 1994-11-16 |
CN1270774C CN1270774C (zh) | 2006-08-23 |
Family
ID=25526490
Family Applications (5)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2006100900829A Expired - Lifetime CN1912111B (zh) | 1992-11-13 | 1993-11-12 | 抗人类b淋巴细胞限制分化抗原的嵌合及放射标记抗体 |
CN200610090080XA Expired - Lifetime CN101007850B (zh) | 1992-11-13 | 1993-11-12 | 抗人类b淋巴细胞限制分化抗原的嵌合及放射标记抗体 |
CNB931214246A Expired - Lifetime CN1270774C (zh) | 1992-11-13 | 1993-11-12 | 抗人类b淋巴细胞限制分化抗原的嵌合及放射标记抗体 |
CN2006100900848A Expired - Lifetime CN101007851B (zh) | 1992-11-13 | 1993-11-12 | 抗人类b淋巴细胞限制分化抗原的嵌合及放射标记抗体 |
CN2004100488083A Expired - Lifetime CN1607006B (zh) | 1992-11-13 | 1993-11-12 | 抗人类b淋巴细胞限制分化抗原的嵌合及放射标记抗体在治疗b细胞淋巴瘤中的应用 |
Family Applications Before (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2006100900829A Expired - Lifetime CN1912111B (zh) | 1992-11-13 | 1993-11-12 | 抗人类b淋巴细胞限制分化抗原的嵌合及放射标记抗体 |
CN200610090080XA Expired - Lifetime CN101007850B (zh) | 1992-11-13 | 1993-11-12 | 抗人类b淋巴细胞限制分化抗原的嵌合及放射标记抗体 |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2006100900848A Expired - Lifetime CN101007851B (zh) | 1992-11-13 | 1993-11-12 | 抗人类b淋巴细胞限制分化抗原的嵌合及放射标记抗体 |
CN2004100488083A Expired - Lifetime CN1607006B (zh) | 1992-11-13 | 1993-11-12 | 抗人类b淋巴细胞限制分化抗原的嵌合及放射标记抗体在治疗b细胞淋巴瘤中的应用 |
Country Status (24)
Country | Link |
---|---|
US (2) | US5736137A (zh) |
EP (1) | EP2000149B1 (zh) |
KR (1) | KR100365632B1 (zh) |
CN (5) | CN1912111B (zh) |
AT (2) | ATE431158T1 (zh) |
BR (1) | BR1100622A (zh) |
CA (1) | CA2626445A1 (zh) |
DE (3) | DE69334259D1 (zh) |
DK (2) | DK1005870T3 (zh) |
ES (2) | ES2321567T3 (zh) |
FR (1) | FR04C0018I2 (zh) |
GE (3) | GEP20074162B (zh) |
HK (3) | HK1109634A1 (zh) |
HU (1) | HU219264B (zh) |
IL (1) | IL107591A (zh) |
LU (1) | LU91620I2 (zh) |
MY (1) | MY111196A (zh) |
NL (1) | NL300424I1 (zh) |
PL (1) | PL175557B1 (zh) |
PT (2) | PT2000149E (zh) |
SG (1) | SG45294A1 (zh) |
TW (1) | TW376320B (zh) |
UA (1) | UA27946C2 (zh) |
ZA (1) | ZA938466B (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1329524C (zh) * | 2001-10-19 | 2007-08-01 | 图尔地区及大学医疗中心 | 评估抗体治疗反应的方法和组合物 |
CN100409898C (zh) * | 1998-08-11 | 2008-08-13 | 拜奥根Idec公司 | 包括施用抗-cd20抗体的b-细胞淋巴瘤联合疗法 |
Families Citing this family (713)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
US7744877B2 (en) * | 1992-11-13 | 2010-06-29 | Biogen Idec Inc. | Expression and use of anti-CD20 Antibodies |
US5736137A (en) * | 1992-11-13 | 1998-04-07 | Idec Pharmaceuticals Corporation | Therapeutic application of chimeric and radiolabeled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma |
WO1994011026A2 (en) | 1992-11-13 | 1994-05-26 | Idec Pharmaceuticals Corporation | Therapeutic application of chimeric and radiolabeled antibodies to human b lymphocyte restricted differentiation antigen for treatment of b cell lymphoma |
US5595721A (en) * | 1993-09-16 | 1997-01-21 | Coulter Pharmaceutical, Inc. | Radioimmunotherapy of lymphoma using anti-CD20 |
US5885574A (en) * | 1994-07-26 | 1999-03-23 | Amgen Inc. | Antibodies which activate an erythropoietin receptor |
WO1996004925A1 (en) * | 1994-08-12 | 1996-02-22 | Immunomedics, Inc. | Immunoconjugates and humanized antibodies specific for b-cell lymphoma and leukemia cells |
US8771694B2 (en) * | 1994-08-12 | 2014-07-08 | Immunomedics, Inc. | Immunoconjugates and humanized antibodies specific for B-cell lymphoma and leukemia cells |
US20030180290A1 (en) * | 1995-06-07 | 2003-09-25 | Idec Pharmaceuticals Corporation | Anti-CD80 antibody having ADCC activity for ADCC mediated killing of B cell lymphoma cells alone or in combination with other therapies |
US6373497B1 (en) | 1999-05-14 | 2002-04-16 | Zight Corporation | Time sequential lookup table arrangement for a display |
US7033589B1 (en) * | 1997-02-20 | 2006-04-25 | Biogen Idec Ma Inc. | γ-1 anti-human CD23 monoclonal antibodies and use thereof as therapeutics |
US6893636B2 (en) * | 1997-02-20 | 2005-05-17 | Biogen Idec Ma Inc. | Gamma-1 and gamma-3 anti-human CD23 monoclonal antibodies and use thereof as therapeutics |
US6991790B1 (en) | 1997-06-13 | 2006-01-31 | Genentech, Inc. | Antibody formulation |
US6171586B1 (en) * | 1997-06-13 | 2001-01-09 | Genentech, Inc. | Antibody formulation |
US20020088019A1 (en) * | 1997-09-02 | 2002-07-04 | Oron Yacoby-Zeevi | Methods of and pharmaceutical compositions for improving implantation of embryos |
US6177545B1 (en) * | 1997-09-02 | 2001-01-23 | Insight Strategy & Marketing Ltd. | Heparanase specific molecular probes and their use in research and medical applications |
US20040213789A1 (en) * | 1997-09-02 | 2004-10-28 | Oron Yacoby-Zeevi | Heparanase activity neutralizing anti-heparanase monoclonal antibody and other anti-heparanase antibodies |
US6699672B1 (en) | 1997-09-02 | 2004-03-02 | Insight Biopharmaceuticals Ltd. | Heparanase specific molecular probes and their use research and medical applications |
US6562950B2 (en) * | 1997-09-02 | 2003-05-13 | Insight Strategy & Marketing Ltd. | Heparanase activity neutralizing anti-heparanase monoclonal antibody |
US20030161823A1 (en) * | 1998-08-31 | 2003-08-28 | Neta Ilan | Therapeutic and cosmetic uses of heparanases |
US20010006630A1 (en) * | 1997-09-02 | 2001-07-05 | Oron Yacoby-Zeevi | Introducing a biological material into a patient |
US6194551B1 (en) | 1998-04-02 | 2001-02-27 | Genentech, Inc. | Polypeptide variants |
US6242195B1 (en) | 1998-04-02 | 2001-06-05 | Genentech, Inc. | Methods for determining binding of an analyte to a receptor |
US6528624B1 (en) | 1998-04-02 | 2003-03-04 | Genentech, Inc. | Polypeptide variants |
DE69942021D1 (de) * | 1998-04-20 | 2010-04-01 | Glycart Biotechnology Ag | Glykosylierungs-engineering von antikörpern zur verbesserung der antikörperabhängigen zellvermittelten zytotoxizität |
US20030217375A1 (en) * | 1998-08-31 | 2003-11-20 | Eyal Zcharia | Transgenic animals expressing heparanase and uses thereof |
US6224866B1 (en) | 1998-10-07 | 2001-05-01 | Biocrystal Ltd. | Immunotherapy of B cell involvement in progression of solid, nonlymphoid tumors |
US20010033839A1 (en) * | 1999-10-04 | 2001-10-25 | Emilio Barbera-Guillem | Vaccine and immunotherapy for solid nonlymphoid tumor and related immune dysregulation |
MXPA01004649A (es) * | 1998-11-09 | 2002-05-06 | Idec Pharma Corp | Tratamiento con anticuerpo quimerico anti-cd20 para pacientes que reciben transplantes de medula osea o celulas madre de sangre periferica. |
MXPA01004648A (es) | 1998-11-09 | 2002-05-06 | Idec Pharma Corp | Tratamientro de enfermedades hematologicas malignas asociadas con celulas tumorales de la circulacion usando el anticuerpo quimerico anti-cd20. |
AU1727500A (en) * | 1998-11-17 | 2000-06-05 | Tanox, Inc. | Bispecific molecules cross-linking itim and itam for therapy |
US6737056B1 (en) | 1999-01-15 | 2004-05-18 | Genentech, Inc. | Polypeptide variants with altered effector function |
US7183387B1 (en) | 1999-01-15 | 2007-02-27 | Genentech, Inc. | Polypeptide variants with altered effector function |
PL209392B1 (pl) * | 1999-01-15 | 2011-08-31 | Genentech Inc | Przeciwciało, komórka gospodarza, sposób wytwarzania przeciwciała oraz zastosowanie przeciwciała |
MY133346A (en) * | 1999-03-01 | 2007-11-30 | Biogen Inc | Kit for radiolabeling ligands with yttrium-90 |
US20020102208A1 (en) | 1999-03-01 | 2002-08-01 | Paul Chinn | Radiolabeling kit and binding assay |
EP1157118A4 (en) * | 1999-03-01 | 2002-07-17 | Insight Strategy & Marketing | POLYNUCLEOTID ENCODING A POLYPEPTIDE WITH HEPARANASE ACTIVITY AND ITS EXPRESSION IN GENETICALLY MODIFIED CELLS |
EP1645291A1 (en) | 1999-05-07 | 2006-04-12 | Genentech, Inc. | Treatment of autoimmune diseases with antagonists which bind to B cell surface markers |
ATE311199T1 (de) * | 1999-05-07 | 2005-12-15 | Genentech Inc | Behandlung von autoimmunkrankheiten mit antagonisten die oberflächenmarker von b zellen binden |
WO2000074718A1 (en) * | 1999-06-09 | 2000-12-14 | Immunomedics, Inc. | Immunotherapy of autoimmune disorders using antibodies which target b-cells |
ITMI991299A1 (it) * | 1999-06-11 | 2000-12-11 | Consiglio Nazionale Ricerche | Uso di anticorpi contro antigeni di superficie per il trattamento della malattia trapianto contro ospite |
US6949245B1 (en) * | 1999-06-25 | 2005-09-27 | Genentech, Inc. | Humanized anti-ErbB2 antibodies and treatment with anti-ErbB2 antibodies |
US20030086924A1 (en) * | 1999-06-25 | 2003-05-08 | Genentech, Inc. | Treatment with anti-ErbB2 antibodies |
US20040013667A1 (en) * | 1999-06-25 | 2004-01-22 | Genentech, Inc. | Treatment with anti-ErbB2 antibodies |
KR100754049B1 (ko) * | 1999-06-25 | 2007-08-31 | 제넨테크, 인크. | 전립선암을 치료하기 위한 약제 제조에 사용되는 항-ErbB2 항체 및 조성물 |
US7041292B1 (en) | 1999-06-25 | 2006-05-09 | Genentech, Inc. | Treating prostate cancer with anti-ErbB2 antibodies |
HUP0202238A3 (en) * | 1999-07-12 | 2004-05-28 | Idec Pharmaceuticals Inc San D | Blocking immune response to a foreign antigen using an antagonist which binds to cd20 |
US6451284B1 (en) * | 1999-08-11 | 2002-09-17 | Idec Pharmaceuticals Corporation | Clinical parameters for determining hematologic toxicity prior to radioimmunotheraphy |
US8557244B1 (en) | 1999-08-11 | 2013-10-15 | Biogen Idec Inc. | Treatment of aggressive non-Hodgkins lymphoma with anti-CD20 antibody |
AU6929100A (en) * | 1999-08-23 | 2001-03-19 | Biocrystal Limited | Methods and compositions for immunotherapy of b cell involvement in promotion ofa disease condition comprising multiple sclerosis |
US20020028178A1 (en) * | 2000-07-12 | 2002-03-07 | Nabil Hanna | Treatment of B cell malignancies using combination of B cell depleting antibody and immune modulating antibody related applications |
CA2390412A1 (en) * | 1999-11-08 | 2001-05-17 | Idec Pharmaceuticals Corporation | Treatment of b cell malignancies using anti-cd40l antibodies in combination with anti-cd20 antibodies and/or chemotherapeutics and radiotherapy |
IL150755A0 (en) * | 2000-02-16 | 2003-02-12 | Genentech Inc | Uses of agonists and antagonists to modulate activity of tnf-related molecules |
US20030185796A1 (en) * | 2000-03-24 | 2003-10-02 | Chiron Corporation | Methods of therapy for non-hodgkin's lymphoma |
BR0109705A (pt) * | 2000-03-31 | 2005-01-11 | Idec Pharma Corp | Uso combinado de anticorpos ou antagonistas anti-citocina e anticd20 para o tratamento de linfoma de célula b |
AU4761601A (en) | 2000-04-11 | 2001-10-23 | Genentech Inc | Multivalent antibodies and uses therefor |
AU5345901A (en) | 2000-04-13 | 2001-10-30 | Univ Rockefeller | Enhancement of antibody-mediated immune responses |
BR0110364A (pt) * | 2000-04-25 | 2003-12-30 | Idec Pharma Corp | Administração intratecal de rituximab para tratamento de linfomas do sistema nervoso central |
WO2001083781A2 (en) * | 2000-04-28 | 2001-11-08 | Millennium Pharmaceuticals, Inc. | 14094, a novel human trypsin family member and uses thereof |
KR20030007640A (ko) * | 2000-05-19 | 2003-01-23 | 제넨테크, 인크. | ErbB 길항제에 의한 암 치료요법에 대한 효과적인반응의 가능성을 개선시키기 위한 유전자 검출 분석 |
JP2004512262A (ja) | 2000-06-20 | 2004-04-22 | アイデック ファーマスーティカルズ コーポレイション | 非放射性抗cd20抗体/放射標識抗cd22抗体の組合せ |
AU6541801A (en) * | 2000-06-22 | 2002-01-02 | Idec Pharma Corp | Bispecific fusion protein and method of use for enhancing effector cell killing of target cells |
US20060029604A1 (en) * | 2000-06-28 | 2006-02-09 | Gerngross Tillman U | Immunoglobulins comprising predominantly a GlcNAc2Man3GlcNAc2 glycoform |
US20060034828A1 (en) * | 2000-06-28 | 2006-02-16 | Gerngross Tillman U | Immunoglobulins comprising predominantly a GlcNAcMAN5GLCNAC2 glycoform |
US20060024304A1 (en) * | 2000-06-28 | 2006-02-02 | Gerngross Tillman U | Immunoglobulins comprising predominantly a Man5GlcNAc2 glycoform |
US20060034830A1 (en) * | 2000-06-28 | 2006-02-16 | Gerngross Tillman U | Immunoglobulins comprising predominantly a GalGlcNAcMan5GLcNAc2 glycoform |
CN1446104A (zh) * | 2000-07-12 | 2003-10-01 | Idec药物公司 | 利用b细胞排除抗体和免疫调制抗体联合治疗b细胞恶性肿瘤的相关应用 |
WO2002022212A2 (en) * | 2000-09-18 | 2002-03-21 | Idec Pharmaceuticals Corporation | Combination therapy for treatment of autoimmune diseases using b cell depleting/immunoregulatory antibody combination |
AU2002213357A1 (en) * | 2000-10-20 | 2002-05-06 | Idec Pharmaceuticals Corporation | Variant igg3 rituxan r and therapeutic use thereof |
US7906492B2 (en) * | 2001-01-16 | 2011-03-15 | Sloan-Kettering Institute For Cancer Research | Therapy-enhancing glucan |
US7507724B2 (en) | 2001-01-16 | 2009-03-24 | Sloan-Kettering Institute For Cancer Research | Therapy-enhancing glucan |
US7754208B2 (en) * | 2001-01-17 | 2010-07-13 | Trubion Pharmaceuticals, Inc. | Binding domain-immunoglobulin fusion proteins |
US7829084B2 (en) * | 2001-01-17 | 2010-11-09 | Trubion Pharmaceuticals, Inc. | Binding constructs and methods for use thereof |
US20030133939A1 (en) | 2001-01-17 | 2003-07-17 | Genecraft, Inc. | Binding domain-immunoglobulin fusion proteins |
AU2008200400B2 (en) * | 2001-01-17 | 2012-06-07 | Aptevo Research And Development Llc | Binding domain-immunoglobulin fusion proteins |
CN1911965B (zh) * | 2001-01-17 | 2013-05-29 | 新兴产品开发西雅图有限公司 | 结合域-免疫球蛋白融合蛋白 |
US20070065436A1 (en) * | 2001-01-31 | 2007-03-22 | Biogen Idec Inc. | Anti-cd80 antibody having adcc activity for adcc mediated killing of b cell lymphoma cells alone or in combination with other therapies |
CA2444661A1 (en) | 2001-01-31 | 2002-08-08 | Idec Pharmaceutical Corporation | Use of cd23 antagonists for the treatment of neoplastic disorders |
US20020159996A1 (en) | 2001-01-31 | 2002-10-31 | Kandasamy Hariharan | Use of CD23 antagonists for the treatment of neoplastic disorders |
WO2002060485A2 (en) | 2001-01-31 | 2002-08-08 | Idec Pharmaceuticals Corporation | Use of immunoregulatory antibodies in the treatment of neoplastic disorders |
US20030103971A1 (en) * | 2001-11-09 | 2003-06-05 | Kandasamy Hariharan | Immunoregulatory antibodies and uses thereof |
US20030211107A1 (en) * | 2002-01-31 | 2003-11-13 | Kandasamy Hariharan | Use of CD23 antagonists for the treatment of neoplastic disorders |
AU2002307037B2 (en) * | 2001-04-02 | 2008-08-07 | Biogen Idec Inc. | Recombinant antibodies coexpressed with GnTIII |
ATE507839T1 (de) | 2001-04-02 | 2011-05-15 | Genentech Inc | Kombinationstherapie |
CA2443694A1 (en) * | 2001-04-09 | 2002-10-17 | Progenics Pharmaceuticals, Inc. | Anti-cd19 immunotoxins |
US20020193569A1 (en) * | 2001-06-04 | 2002-12-19 | Idec Pharmaceuticals Corporation | Bispecific fusion protein and method of use for enhancing effector cell killing of target cells |
EP1404813A4 (en) * | 2001-06-13 | 2004-11-24 | Genentech Inc | METHOD FOR CULTIVATING ANIMAL CELLS AND POLYPEPTIDE PRODUCTION IN ANIMAL CELLS |
WO2003014294A2 (en) * | 2001-08-03 | 2003-02-20 | Genentech, Inc. | Tacis and br3 polypeptides and uses thereof |
JP2005524379A (ja) * | 2001-08-03 | 2005-08-18 | グリカート バイオテクノロジー アクチェンゲゼルシャフト | 抗体依存性細胞傷害性の増強を伴う抗体グリコシル化改変体 |
US7255858B2 (en) * | 2001-08-10 | 2007-08-14 | University Of Virginia Patent Foundation | Enhancing the efficacy of immunotherapies by supplementing with complement |
US7205048B2 (en) | 2001-09-17 | 2007-04-17 | Invitrogen Corporation | Functionalized fluorescent nanocrystal compositions and methods of making |
US7214428B2 (en) * | 2001-09-17 | 2007-05-08 | Invitrogen Corporation | Highly luminescent functionalized semiconductor nanocrystals for biological and physical applications |
US6955855B2 (en) * | 2001-09-17 | 2005-10-18 | Biocrystal, Ltd. | Nanocrystals |
EP1438583B1 (en) * | 2001-09-20 | 2009-09-16 | Board of Regents, The University of Texas System | Measuring circulating therapeutic antibody, antigen and antigen/antibody complexes using elisa assays |
ZA200700168B (en) | 2001-10-10 | 2010-02-24 | Novo Nordisk As | Remodeling and glycoconjugation of peptides |
US20050069962A1 (en) | 2001-10-12 | 2005-03-31 | Archer Robert M | Antibody complexes and methods for immunolabeling |
US8323903B2 (en) * | 2001-10-12 | 2012-12-04 | Life Technologies Corporation | Antibody complexes and methods for immunolabeling |
CN100423777C (zh) * | 2001-10-25 | 2008-10-08 | 杰南技术公司 | 糖蛋白组合物 |
US6671189B2 (en) * | 2001-11-09 | 2003-12-30 | Minebea Co., Ltd. | Power converter having primary and secondary side switches |
DE60230918D1 (de) | 2001-11-16 | 2009-03-05 | Biogen Idec Inc | Polycistronische expression von antikörpern in cho zellen |
US20060024292A1 (en) * | 2001-12-27 | 2006-02-02 | Gerngross Tillman U | Immunoglobulins comprising predominantly a Gal2GlcNAc2Man3GlcNAc2 glycoform |
DE60325334D1 (de) | 2002-02-05 | 2009-01-29 | Genentech Inc | Proteinaufreinigung |
JP2005517025A (ja) | 2002-02-08 | 2005-06-09 | エクサイト セラピーズ, インコーポレイテッド | 免疫学的欠損を有する患者において免疫応答性を回復するための、組成物および方法 |
US8287864B2 (en) * | 2002-02-14 | 2012-10-16 | Immunomedics, Inc. | Structural variants of antibodies for improved therapeutic characteristics |
RU2004127458A (ru) * | 2002-02-14 | 2005-10-27 | Иммуномедикс, Инк. (Us) | Анти-cd20 антитела, их гибридные белки и способы их использования |
US20040002587A1 (en) * | 2002-02-20 | 2004-01-01 | Watkins Jeffry D. | Fc region variants |
US20160279239A1 (en) | 2011-05-02 | 2016-09-29 | Immunomedics, Inc. | Subcutaneous administration of anti-cd74 antibody for systemic lupus erythematosus and autoimmune disease |
US8361464B2 (en) | 2002-03-01 | 2013-01-29 | Immunomedics, Inc. | Anthracycline-Antibody Conjugates for Cancer Therapy |
US7662925B2 (en) * | 2002-03-01 | 2010-02-16 | Xencor, Inc. | Optimized Fc variants and methods for their generation |
US20040132101A1 (en) | 2002-09-27 | 2004-07-08 | Xencor | Optimized Fc variants and methods for their generation |
US20090042291A1 (en) * | 2002-03-01 | 2009-02-12 | Xencor, Inc. | Optimized Fc variants |
DK1483294T3 (da) * | 2002-03-01 | 2010-11-08 | Immunomedics Inc | Internaliserende anti-CD74-antistoffer og fremgangsmåder til deres anvendelse |
US20030180292A1 (en) * | 2002-03-14 | 2003-09-25 | Idec Pharmaceuticals | Treatment of B cell malignancies using anti-CD40L antibodies in combination with anti-CD20 antibodies and/or chemotherapeutics and radiotherapy |
JP4319979B2 (ja) | 2002-04-26 | 2009-08-26 | ジェネンテック・インコーポレーテッド | タンパク質の非アフィニティ精製 |
MXPA05000940A (es) * | 2002-07-25 | 2005-05-16 | Genentech Inc | Anticuerpos taci y su uso. |
US8946387B2 (en) * | 2002-08-14 | 2015-02-03 | Macrogenics, Inc. | FcγRIIB specific antibodies and methods of use thereof |
US8187593B2 (en) * | 2002-08-14 | 2012-05-29 | Macrogenics, Inc. | FcγRIIB specific antibodies and methods of use thereof |
US8968730B2 (en) | 2002-08-14 | 2015-03-03 | Macrogenics Inc. | FcγRIIB specific antibodies and methods of use thereof |
US8044180B2 (en) * | 2002-08-14 | 2011-10-25 | Macrogenics, Inc. | FcγRIIB specific antibodies and methods of use thereof |
US8193318B2 (en) * | 2002-08-14 | 2012-06-05 | Macrogenics, Inc. | FcγRIIB specific antibodies and methods of use thereof |
CA2499816C (en) | 2002-09-27 | 2013-07-30 | Xencor, Inc. | Optimized fc variants and methods for their generation |
ATE540978T1 (de) * | 2002-10-17 | 2012-01-15 | Genmab As | Humane monoklonale antikörper gegen cd20 |
JP4033390B2 (ja) * | 2002-10-30 | 2008-01-16 | 独立行政法人科学技術振興機構 | 不死化ナチュラルキラー細胞株 |
US20040258685A1 (en) * | 2002-11-21 | 2004-12-23 | Genentech, Inc. | Therapy of non-malignant diseases or disorders with anti-ErbB2 antibodies |
SE0203731D0 (sv) * | 2002-12-13 | 2002-12-13 | Mitra Medical Technology Ab | Reagent |
ES2633311T3 (es) * | 2002-12-16 | 2017-09-20 | Genentech, Inc. | Variantes de inmunoglobulina y usos de las mismas |
EP2368578A1 (en) * | 2003-01-09 | 2011-09-28 | Macrogenics, Inc. | Identification and engineering of antibodies with variant Fc regions and methods of using same |
US7960512B2 (en) * | 2003-01-09 | 2011-06-14 | Macrogenics, Inc. | Identification and engineering of antibodies with variant Fc regions and methods of using same |
JP4177123B2 (ja) * | 2003-01-10 | 2008-11-05 | 富士通株式会社 | 配線図形検証方法、プログラム及び装置 |
US20040202666A1 (en) * | 2003-01-24 | 2004-10-14 | Immunomedics, Inc. | Anti-cancer anthracycline drug-antibody conjugates |
KR20050102627A (ko) * | 2003-01-27 | 2005-10-26 | 바이오겐 아이덱 엠에이 인코포레이티드 | Igsf9 및 liv-1을 사용한 암 치료용 조성물 및치료방법 |
US20090010920A1 (en) * | 2003-03-03 | 2009-01-08 | Xencor, Inc. | Fc Variants Having Decreased Affinity for FcyRIIb |
US8388955B2 (en) * | 2003-03-03 | 2013-03-05 | Xencor, Inc. | Fc variants |
JP2006522811A (ja) * | 2003-04-09 | 2006-10-05 | ジェネンテック・インコーポレーテッド | TNFαインヒビターに対して不十分な反応を示す患者の自己免疫疾患治療法 |
TWI353991B (en) | 2003-05-06 | 2011-12-11 | Syntonix Pharmaceuticals Inc | Immunoglobulin chimeric monomer-dimer hybrids |
JP5416338B2 (ja) * | 2003-05-09 | 2014-02-12 | デューク ユニバーシティ | Cd20特異的抗体およびその使用方法 |
EP1629001A2 (en) * | 2003-06-05 | 2006-03-01 | Genentech, Inc. | Blys antagonists and uses thereof |
US20050163775A1 (en) * | 2003-06-05 | 2005-07-28 | Genentech, Inc. | Combination therapy for B cell disorders |
WO2004108065A2 (en) * | 2003-06-09 | 2004-12-16 | Insight Biopharmaceuticals Ltd. | Heparanase activity neutralizing anti- heparanase monoclonal antibody and other anti-heparanase antibodies |
US7754209B2 (en) | 2003-07-26 | 2010-07-13 | Trubion Pharmaceuticals | Binding constructs and methods for use thereof |
EP3722309A1 (en) | 2003-07-28 | 2020-10-14 | Genentech, Inc. | Reducing protein a leaching during protein a affinity chromatography |
BRPI0412217A (pt) * | 2003-07-29 | 2006-08-22 | Genentech Inc | método de avaliação da eficácia de anticorpo, métodos de imunoterapia, método de detecção de anticorpos neutralizantes a anticorpo terapêutico e método de avaliação da eficácia de antagonista |
MXPA06002134A (es) * | 2003-08-29 | 2006-05-31 | Genentech Inc | Terapia de trastornos oculares. |
US20060134105A1 (en) * | 2004-10-21 | 2006-06-22 | Xencor, Inc. | IgG immunoglobulin variants with optimized effector function |
US9714282B2 (en) | 2003-09-26 | 2017-07-25 | Xencor, Inc. | Optimized Fc variants and methods for their generation |
US8883147B2 (en) | 2004-10-21 | 2014-11-11 | Xencor, Inc. | Immunoglobulins insertions, deletions, and substitutions |
US8399618B2 (en) | 2004-10-21 | 2013-03-19 | Xencor, Inc. | Immunoglobulin insertions, deletions, and substitutions |
US8101720B2 (en) * | 2004-10-21 | 2012-01-24 | Xencor, Inc. | Immunoglobulin insertions, deletions and substitutions |
SI1673398T1 (sl) | 2003-10-16 | 2011-05-31 | Micromet Ag | Multispecifiäśne deimunizirajoäśe cd3 povezovalne molekule |
EP1684869B1 (en) | 2003-11-04 | 2011-07-20 | Novartis Vaccines and Diagnostics, Inc. | Methods of therapy for b cell-related cancers |
US20050112130A1 (en) * | 2003-11-05 | 2005-05-26 | Bhat Neelima M. | Enhanced B cell cytotoxicity of CDIM binding antibody |
PL2380911T3 (pl) | 2003-11-05 | 2018-10-31 | Roche Glycart Ag | Cząsteczki wiążące antygen o zwiększonym powinowactwie wiązania z receptorem Fc oraz zwiększonej funkcji efektorowej |
JP2008504002A (ja) | 2003-11-12 | 2008-02-14 | バイオジェン・アイデック・エムエイ・インコーポレイテッド | 新生児Fcレセプター(FcRn)結合ポリペプチド改変体、ダイマーFc結合タンパク質、およびそれらに関連する方法 |
CN1914226B (zh) * | 2003-11-25 | 2012-02-01 | 达纳-法伯癌症研究院有限公司 | SARS-CoV抗体及其使用方法 |
US20050191297A1 (en) * | 2003-12-19 | 2005-09-01 | Genentech, Inc. | Detection of CD20 in transplant rejection |
AU2004305560A1 (en) * | 2003-12-19 | 2005-07-07 | Genentech, Inc. | Detection of CD20 in therapy of autoimmune diseases |
FR2867982B1 (fr) * | 2004-03-26 | 2007-07-20 | Jean Marie Andrieu | Procede pour amplifier l'activite de vaccins therapeutiques |
EP1745288A2 (en) * | 2004-04-16 | 2007-01-24 | Genentech, Inc. | Assay for antibodies |
EP1742660A2 (en) * | 2004-04-16 | 2007-01-17 | Genentech, Inc. | Treatment of disorders |
KR20070012408A (ko) * | 2004-04-16 | 2007-01-25 | 제넨테크, 인크. | B 세포 고갈을 증대시키는 방법 |
US7850962B2 (en) * | 2004-04-20 | 2010-12-14 | Genmab A/S | Human monoclonal antibodies against CD20 |
US20050271658A1 (en) * | 2004-05-05 | 2005-12-08 | Genentech, Inc. | Preventing autoimmune disease |
CN103127502A (zh) | 2004-05-20 | 2013-06-05 | 津莫吉尼蒂克斯公司 | 使用il-21和单克隆抗体疗法治疗癌症的方法 |
AR049200A1 (es) | 2004-06-04 | 2006-07-05 | Genentech Inc | Metodo para tratar esclerosis multiple con una composicion que contiene un anticuerpo cd20 |
MXPA06014067A (es) * | 2004-06-04 | 2007-02-15 | Genentech Inc | Metodo para tratar lupus. |
US9109255B2 (en) * | 2004-06-18 | 2015-08-18 | The Board Of Trustees Of The Leland Stanford Junior University | Methods and compositions for determining responsiveness to antibody therapy |
CN101014619B (zh) | 2004-07-15 | 2010-11-03 | 赞科股份有限公司 | 优化的Fc变体 |
AU2005267028A1 (en) * | 2004-07-22 | 2006-02-02 | Genentech, Inc. | Method of treating Sjogren's syndrome |
JP4994232B2 (ja) | 2004-07-23 | 2012-08-08 | ジェネンテック, インコーポレイテッド | 抗体又はその断片の結晶化 |
JP5055603B2 (ja) | 2004-08-04 | 2012-10-24 | メントリック・バイオテック・リミテッド・ライアビリティ・カンパニー | 変異Fc領域 |
WO2006033732A1 (en) * | 2004-08-17 | 2006-03-30 | Invitrogen Corporation | Synthesis of highly luminescent colloidal particles |
AU2005285347A1 (en) * | 2004-08-19 | 2006-03-23 | Genentech, Inc. | Polypeptide variants with altered effector function |
US7662926B2 (en) * | 2004-09-02 | 2010-02-16 | Genentech, Inc. | Anti-Fc-gamma receptor antibodies, bispecific variants and uses therefor |
ZA200701783B (en) * | 2004-09-02 | 2009-10-28 | Genentech Inc | Anti-Fc-gamma RIIB receptor antibody and uses therefor |
US7655229B2 (en) * | 2004-09-02 | 2010-02-02 | Chan Andrew C | Anti-FC-gamma RIIB receptor antibody and uses therefor |
MX2007002855A (es) * | 2004-09-08 | 2007-04-27 | Genentech Inc | Metodos para usar ligandos de receptor de muerte y anticuerpos cd20. |
US20090175854A1 (en) * | 2004-09-08 | 2009-07-09 | Genentech, Inc. | Methods of using death receptor ligands and CD20 antibodies |
RU2411956C2 (ru) * | 2004-10-05 | 2011-02-20 | Дженентек, Инк. | Способ лечения васкулита |
JO3000B1 (ar) | 2004-10-20 | 2016-09-05 | Genentech Inc | مركبات أجسام مضادة . |
ATE556126T1 (de) * | 2004-10-29 | 2012-05-15 | Life Technologies Corp | Funktionalisierte fluoreszierende nanokristalle und verfahren zu deren herstellung und verwendung |
EP1810035A4 (en) | 2004-11-10 | 2010-03-17 | Macrogenics Inc | EFFECTOR FUNCTION OBTAINED BY CREATION BY BIOLOGICAL GENE OF FC ANTIBODY REGIONS |
US8802820B2 (en) * | 2004-11-12 | 2014-08-12 | Xencor, Inc. | Fc variants with altered binding to FcRn |
US8367805B2 (en) * | 2004-11-12 | 2013-02-05 | Xencor, Inc. | Fc variants with altered binding to FcRn |
US8546543B2 (en) | 2004-11-12 | 2013-10-01 | Xencor, Inc. | Fc variants that extend antibody half-life |
US20070135620A1 (en) * | 2004-11-12 | 2007-06-14 | Xencor, Inc. | Fc variants with altered binding to FcRn |
KR101027427B1 (ko) | 2004-11-12 | 2011-04-11 | 젠코어 인코포레이티드 | FcRn에 대하여 증가된 결합력을 갖는 Fc 변이체 |
GB2420976B (en) * | 2004-11-19 | 2006-12-20 | Zvi Finkelstein | Therapeutic implant |
SG158089A1 (en) * | 2004-12-17 | 2010-01-29 | Genentech Inc | Antiangiogenesis therapy of autoimmune disease in patients who have failed prior therapy |
EP2290088A1 (en) | 2004-12-22 | 2011-03-02 | Genentech, Inc. | Methods for producing soluble multi-menbrane-spanning proteins |
EP1674479A1 (en) * | 2004-12-22 | 2006-06-28 | Memorial Sloan-Kettering Cancer Center | Modulation of Fc Gamma receptors for optimizing immunotherapy |
RU2393483C2 (ru) * | 2004-12-23 | 2010-06-27 | Ф.Хоффманн-Ля Рош Аг | Детекция терапевтического антитела у экспериментального животного |
DE602004021404D1 (de) | 2004-12-23 | 2009-07-16 | Gpc Biotech Ag | Quadratsäurederivate mit antiproliferativer Wirkung |
DK1838736T3 (da) | 2005-01-05 | 2013-06-03 | Biogen Idec Inc | Cripto-bindende molekyler |
MX2007008218A (es) * | 2005-01-13 | 2007-08-17 | Genentech Inc | Procedimiento de tratamiento. |
DOP2006000029A (es) * | 2005-02-07 | 2006-08-15 | Genentech Inc | Antibody variants and uses thereof. (variantes de un anticuerpo y usos de las mismas) |
TW200714289A (en) * | 2005-02-28 | 2007-04-16 | Genentech Inc | Treatment of bone disorders |
US20160355591A1 (en) | 2011-05-02 | 2016-12-08 | Immunomedics, Inc. | Subcutaneous anti-hla-dr monoclonal antibody for treatment of hematologic malignancies |
US8475794B2 (en) | 2005-04-06 | 2013-07-02 | Ibc Pharmaceuticals, Inc. | Combination therapy with anti-CD74 antibodies provides enhanced toxicity to malignancies, Autoimmune disease and other diseases |
US8349332B2 (en) | 2005-04-06 | 2013-01-08 | Ibc Pharmaceuticals, Inc. | Multiple signaling pathways induced by hexavalent, monospecific and bispecific antibodies for enhanced toxicity to B-cell lymphomas and other diseases |
US9284375B2 (en) | 2005-04-15 | 2016-03-15 | Macrogenics, Inc. | Covalent diabodies and uses thereof |
US9963510B2 (en) * | 2005-04-15 | 2018-05-08 | Macrogenics, Inc. | Covalent diabodies and uses thereof |
US11254748B2 (en) | 2005-04-15 | 2022-02-22 | Macrogenics, Inc. | Covalent diabodies and uses thereof |
AU2006236439B2 (en) * | 2005-04-15 | 2012-05-03 | Macrogenics, Inc. | Covalent diabodies and uses thereof |
AR053579A1 (es) * | 2005-04-15 | 2007-05-09 | Genentech Inc | Tratamiento de la enfermedad inflamatoria intestinal (eii) |
EP1874350A2 (en) * | 2005-04-22 | 2008-01-09 | Genentech, Inc. | Method for treating dementia or alzheimer's disease with a cd20 antibody |
US8034902B2 (en) * | 2005-05-04 | 2011-10-11 | Quark Pharmaceuticals, Inc. | Recombinant antibodies against CD55 and CD59 and uses thereof |
AU2006298519A1 (en) * | 2005-05-09 | 2007-04-12 | Glycart Biotechnology Ag | Antigen binding molecules having modified Fc regions and altered binding to Fc receptors |
WO2006127517A2 (en) * | 2005-05-20 | 2006-11-30 | Genentech, Inc. | Pretreatment of a biological sample from an autoimmune disease subject |
EP1885757A2 (en) * | 2005-05-24 | 2008-02-13 | Avestha Gengraine Technologies Pvt. Ltd. | A method for the production of a monoclonal antibody to cd20 for the treatment of b-cell lymphoma |
CN101495509B (zh) | 2005-07-08 | 2015-04-22 | 比奥根艾迪克Ma公司 | Sp35抗体及其用途 |
DK1912675T3 (en) | 2005-07-25 | 2014-03-24 | Emergent Product Dev Seattle | B-cell reduction using specific and cd37-cd20-specific binding molecules |
BRPI0614183A2 (pt) | 2005-07-25 | 2011-03-15 | Trubion Pharmaceuticals Inc | uso de dose única de moléculas de ligação especìficas para cd20 |
US20080279850A1 (en) * | 2005-07-25 | 2008-11-13 | Trubion Pharmaceuticals, Inc. | B-Cell Reduction Using CD37-Specific and CD20-Specific Binding Molecules |
LT2573114T (lt) * | 2005-08-10 | 2016-10-10 | Macrogenics, Inc. | Atpažinimas ir konstravimas antikūnų su variantinėmis fc sritimis ir jų panaudojimo būdai |
US20090215992A1 (en) * | 2005-08-19 | 2009-08-27 | Chengbin Wu | Dual variable domain immunoglobulin and uses thereof |
SG2014010029A (en) | 2005-08-19 | 2014-08-28 | Abbott Lab | Dual variable domain immunoglobin and uses thereof |
EP2500359A3 (en) | 2005-08-19 | 2012-10-17 | Abbott Laboratories | Dual variable domain immunoglobulin and uses thereof |
US7612181B2 (en) * | 2005-08-19 | 2009-11-03 | Abbott Laboratories | Dual variable domain immunoglobulin and uses thereof |
US20090136525A1 (en) * | 2005-09-02 | 2009-05-28 | Tillman Gerngross | Immunoglobulins Comprising Predominantly a Glcnacman3Glcnac2 Glycoform |
EP1931709B1 (en) | 2005-10-03 | 2016-12-07 | Xencor, Inc. | Fc variants with optimized fc receptor binding properties |
WO2007056411A2 (en) * | 2005-11-08 | 2007-05-18 | Genentech, Inc. | Method of producing pan-specific antibodies |
MY149159A (en) | 2005-11-15 | 2013-07-31 | Hoffmann La Roche | Method for treating joint damage |
US9726673B2 (en) * | 2005-11-23 | 2017-08-08 | Genentech, Inc. | Methods and compositions related to B cell assays |
WO2007064911A1 (en) * | 2005-12-02 | 2007-06-07 | Biogen Idec Inc. | Anti-mouse cd20 antibodies and uses thereof |
US8323644B2 (en) * | 2006-01-17 | 2012-12-04 | Sloan-Kettering Institute For Cancer Research | Therapy-enhancing glucan |
WO2007102200A1 (ja) | 2006-03-07 | 2007-09-13 | Osaka University | 抗cd20モノクローナル抗体 |
CA2644903A1 (en) * | 2006-03-10 | 2007-09-20 | Macrogenics, Inc. | Identification and engineering of antibodies with variant heavy chains and methods of using same |
EP2389948A1 (en) | 2006-03-23 | 2011-11-30 | Novartis AG | Anti-tumor cell antigen antibody therapeutics |
AU2007244683A1 (en) | 2006-04-27 | 2007-11-08 | Pikamab, Inc. | Methods and compositions for antibody therapy |
US20080118978A1 (en) | 2006-04-28 | 2008-05-22 | Takashi Sato | Anti-tumor agent |
US7727525B2 (en) * | 2006-05-11 | 2010-06-01 | City Of Hope | Engineered anti-CD20 antibody fragments for in vivo targeting and therapeutics |
ES2489646T3 (es) | 2006-05-26 | 2014-09-02 | Macrogenics, Inc. | Anticuerpos humanizados específicos a Fc gamma RIIB y sus métodos de uso |
CN105837690A (zh) * | 2006-06-12 | 2016-08-10 | 新兴产品开发西雅图有限公司 | 具有效应功能的单链多价结合蛋白 |
CA2656224C (en) * | 2006-06-26 | 2018-01-09 | Macrogenics, Inc. | Combination of fc.gamma.riib antibodies and cd20-specific antibodies and methods of use thereof |
HUE030269T2 (en) | 2006-06-26 | 2017-04-28 | Macrogenics Inc | FC RIIB-specific antibodies and methods for their use |
FR2902799B1 (fr) | 2006-06-27 | 2012-10-26 | Millipore Corp | Procede et unite de preparation d'un echantillon pour l'analyse microbiologique d'un liquide |
US8372399B2 (en) * | 2006-08-31 | 2013-02-12 | Cardiac Pacemakers, Inc. | Bispecific antibodies and agents to enhance stem cell homing |
US20080058922A1 (en) * | 2006-08-31 | 2008-03-06 | Cardiac Pacemakers, Inc. | Methods and devices employing vap-1 inhibitors |
US8636995B2 (en) * | 2006-08-31 | 2014-01-28 | Cardiac Pacemakers, Inc. | Methods and devices to regulate stem cell homing |
US20080112961A1 (en) * | 2006-10-09 | 2008-05-15 | Macrogenics, Inc. | Identification and Engineering of Antibodies with Variant Fc Regions and Methods of Using Same |
US9382327B2 (en) | 2006-10-10 | 2016-07-05 | Vaccinex, Inc. | Anti-CD20 antibodies and methods of use |
US8652466B2 (en) | 2006-12-08 | 2014-02-18 | Macrogenics, Inc. | Methods for the treatment of disease using immunoglobulins having Fc regions with altered affinities for FcγRactivating and FcγRinhibiting |
US8362217B2 (en) | 2006-12-21 | 2013-01-29 | Emd Millipore Corporation | Purification of proteins |
US8569464B2 (en) * | 2006-12-21 | 2013-10-29 | Emd Millipore Corporation | Purification of proteins |
US20100267933A1 (en) * | 2006-12-21 | 2010-10-21 | Moya Wilson | Purification of proteins |
DK2436696T3 (en) | 2007-01-05 | 2017-09-04 | Univ Zuerich | Anti-beta-amyloid antibody and uses thereof |
DE102007001370A1 (de) * | 2007-01-09 | 2008-07-10 | Curevac Gmbh | RNA-kodierte Antikörper |
LT2740744T (lt) | 2007-01-09 | 2018-05-10 | Biogen Ma Inc. | Sp35 antikūnai ir jų panaudojimas |
NZ577933A (en) | 2007-01-22 | 2011-12-22 | Genentech Inc | Polyelectrolyte precipitation and purification of antibodies |
US8450348B2 (en) * | 2007-02-21 | 2013-05-28 | Forma Tm, Llc | Derivatives of squaric acid with anti-proliferative activity |
US8280711B2 (en) * | 2007-03-12 | 2012-10-02 | ESBATech, an Alcon Biomedical Research Unit, LLC. | Sequence based engineering and optimization of single chain antibodies |
US7960139B2 (en) | 2007-03-23 | 2011-06-14 | Academia Sinica | Alkynyl sugar analogs for the labeling and visualization of glycoconjugates in cells |
WO2008122039A2 (en) * | 2007-04-02 | 2008-10-09 | The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Selenocysteine mediated hybrid antibody molecules |
FR2915398B1 (fr) * | 2007-04-25 | 2012-12-28 | Lab Francais Du Fractionnement | "ensemble de moyens pour le traitement d'une pathologie maligne, d'une maladie auto-immune ou d'une maladie infectieuse" |
EP1995309A1 (en) * | 2007-05-21 | 2008-11-26 | Vivalis | Recombinant protein production in avian EBx® cells |
EP2019101A1 (en) * | 2007-07-26 | 2009-01-28 | GPC Biotech AG | Pyrazol[3,4-d]pyrimidin-4-one useful as Kinase Inhibitor |
CA2689941C (en) | 2007-06-25 | 2019-10-29 | Esbatech Ag | Methods of modifying antibodies, and modified antibodies with improved functional properties |
WO2009000098A2 (en) * | 2007-06-25 | 2008-12-31 | Esbatech Ag | Sequence based engineering and optimization of single chain antibodies |
US20090324596A1 (en) | 2008-06-30 | 2009-12-31 | The Trustees Of Princeton University | Methods of identifying and treating poor-prognosis cancers |
US10745701B2 (en) | 2007-06-28 | 2020-08-18 | The Trustees Of Princeton University | Methods of identifying and treating poor-prognosis cancers |
EP4245766A3 (en) | 2007-07-09 | 2024-01-17 | Genentech, Inc. | Prevention of disulfide bond reduction during recombinant production of polypeptides |
ES2527297T3 (es) * | 2007-07-31 | 2015-01-22 | Regeneron Pharmaceuticals, Inc. | Anticuerpos humanos para CD20 humano y método para utilizar los mismos |
AU2008295140A1 (en) | 2007-09-05 | 2009-03-12 | F. Hoffmann-La Roche Ag | Combination therapy with type I and type II anti-CD20 antibodies |
NZ584848A (en) * | 2007-09-28 | 2012-09-28 | Intrexon Corp | Therapeutic gene-switch constructs and bioreactors for the expression of biotherapeutic molecules, and uses thereof |
US20090098118A1 (en) | 2007-10-15 | 2009-04-16 | Thomas Friess | Combination therapy of a type ii anti-cd20 antibody with an anti-bcl-2 active agent |
JP2011500715A (ja) | 2007-10-16 | 2011-01-06 | ザイモジェネティクス, インコーポレイテッド | 自己免疫疾患の治療のためのBLyS阻害剤および抗CD20剤の組合せ |
CN101820892A (zh) * | 2007-10-22 | 2010-09-01 | 昂科利蒂克斯生物科技公司 | 增殖性疾病的治疗方案 |
US20090110688A1 (en) * | 2007-10-24 | 2009-04-30 | Georg Fertig | Combination therapy of type ii anti-cd20 antibody with a proteasome inhibitor |
PE20091434A1 (es) | 2007-10-30 | 2009-10-17 | Genentech Inc | Purificacion de anticuerpos por cromatografia de intercambio cationico |
US8795667B2 (en) * | 2007-12-19 | 2014-08-05 | Macrogenics, Inc. | Compositions for the prevention and treatment of smallpox |
EP2231183A2 (en) * | 2007-12-21 | 2010-09-29 | Genentech, Inc. | Therapy of rituximab-refractory rheumatoid arthritis patients |
ES2532461T3 (es) | 2007-12-26 | 2015-03-27 | Xencor, Inc. | Variantes de FC con enlazamiento alterado a FCRN |
EP2077281A1 (en) | 2008-01-02 | 2009-07-08 | Bergen Teknologioverforing AS | Anti-CD20 antibodies or fragments thereof for the treatment of chronic fatigue syndrome |
US7914785B2 (en) | 2008-01-02 | 2011-03-29 | Bergen Teknologieverforing As | B-cell depleting agents, like anti-CD20 antibodies or fragments thereof for the treatment of chronic fatigue syndrome |
EP2085095B1 (en) | 2008-01-17 | 2012-03-07 | Philogen S.p.A. | Combination of an anti-EDb fibronectin antibody-IL-2 fusion protein, and a molecule binding to B cells, B cell progenitors and/or their cancerous counterpart |
CA2711736A1 (en) | 2008-01-18 | 2009-07-23 | Medimmune, Llc | Cysteine engineered antibodies for site-specific conjugation |
WO2009097095A2 (en) * | 2008-01-28 | 2009-08-06 | The Regents Of The University Of California | Methods for treating hematopoietic malignancies |
NZ587284A (en) * | 2008-03-25 | 2012-05-25 | Roche Glycart Ag | Use of a type ii anti-cd20 antibody with increased antibody dependent cellular cytotoxicity (adcc) in combination with cyclophosphamide, vincristine and doxorubicine for treating non-hodgkin' s lymphomas |
ES2589912T3 (es) | 2008-04-02 | 2016-11-17 | Macrogenics, Inc. | Anticuerpos específicos para el complejo BCR y procedimientos de uso de los mismos |
EP2247304B1 (en) | 2008-04-02 | 2016-05-25 | MacroGenics, Inc. | Her2/neu-specific antibodies and methods of using same |
JP6013733B2 (ja) | 2008-04-11 | 2016-10-25 | 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 | Cd37免疫治療薬および二機能性化学療法薬とのその組合せ |
EP2112150B1 (en) | 2008-04-22 | 2013-10-16 | Forma Therapeutics, Inc. | Improved raf inhibitors |
EP2112152A1 (en) | 2008-04-22 | 2009-10-28 | GPC Biotech AG | Dihydropteridinones as Plk Inhibitors |
WO2009134738A1 (en) * | 2008-04-29 | 2009-11-05 | Genentech, Inc. | Responses to immunizations in rheumatoid arthritis patients treated with a cd20 antibody |
EP2282769A4 (en) | 2008-04-29 | 2012-04-25 | Abbott Lab | DUAL VARIABLE DOMAIN IMMUNOGLOBULINS AND ITS USES |
US20100260668A1 (en) * | 2008-04-29 | 2010-10-14 | Abbott Laboratories | Dual Variable Domain Immunoglobulins and Uses Thereof |
NZ589436A (en) * | 2008-06-03 | 2012-12-21 | Abbott Lab | Dual variable domain immunoglobulins and uses thereof |
WO2009149189A2 (en) | 2008-06-03 | 2009-12-10 | Abbott Laboratories | Dual variable domain immunoglobulins and uses thereof |
ES2675730T3 (es) * | 2008-06-04 | 2018-07-12 | Macrogenics, Inc. | Anticuerpos con unión alterada a FcRn y métodos de uso de los mismos |
US8999702B2 (en) * | 2008-06-11 | 2015-04-07 | Emd Millipore Corporation | Stirred tank bioreactor |
BRPI0914666A2 (pt) | 2008-06-25 | 2015-10-20 | Esbatech Alcon Biomed Res Unit | otimização da solubilidade de ligantes imunológicos |
EP3266453A1 (en) | 2008-07-03 | 2018-01-10 | Mayo Foundation for Medical Education and Research | Treating cancer |
KR101054362B1 (ko) | 2008-07-03 | 2011-08-05 | 재단법인 목암생명공학연구소 | 재조합 단백질의 푸코스 함량을 감소시키는 방법 |
JP5674654B2 (ja) * | 2008-07-08 | 2015-02-25 | アッヴィ・インコーポレイテッド | プロスタグランジンe2二重可変ドメイン免疫グロブリンおよびその使用 |
JP2011527572A (ja) | 2008-07-09 | 2011-11-04 | バイオジェン・アイデック・エムエイ・インコーポレイテッド | Lingo抗体または断片を含む組成物 |
KR101030978B1 (ko) * | 2008-07-10 | 2011-04-28 | (주) 에이프로젠 | 동물세포용 재조합 발현벡터 |
US8680020B2 (en) | 2008-07-15 | 2014-03-25 | Academia Sinica | Glycan arrays on PTFE-like aluminum coated glass slides and related methods |
US20100021460A1 (en) * | 2008-07-15 | 2010-01-28 | Genentech, Inc. | Methods of Treating Autoimmune Diseases Using CD4 Antibodies |
UA108735C2 (uk) * | 2008-07-21 | 2015-06-10 | Структурні варіанти антитіл для покращення терапевтичних характеристик | |
US8900851B2 (en) * | 2008-07-22 | 2014-12-02 | The Research Foundation For The State University Of New York | Multi-well platform |
KR102196883B1 (ko) | 2008-08-14 | 2020-12-30 | 제넨테크, 인크. | 고유 단백질 대체 이온 교환 막 크로마토그래피를 이용한 오염물의 제거 방법 |
EP2684570A1 (en) | 2008-09-10 | 2014-01-15 | F. Hoffmann-La Roche AG | Compositions and methods for the prevention of oxidative degradation of proteins |
AR073295A1 (es) | 2008-09-16 | 2010-10-28 | Genentech Inc | Metodos para tratar la esclerosis multiple progresiva. articulo de fabricacion. |
AU2009309387A1 (en) * | 2008-10-28 | 2010-05-06 | Avesthagen Limited | An expression vector and processes thereof |
KR20110097913A (ko) * | 2008-12-04 | 2011-08-31 | 아보트 러보러터리즈 | 이원 가변 도메인 면역글로불린 및 이의 용도 |
GB2466025A (en) | 2008-12-08 | 2010-06-09 | Univ Francois Rabelais De Tour | C3/ITGAM polymorphisms and cancer prognosis |
EP2373689A1 (en) | 2008-12-12 | 2011-10-12 | MedImmune, LLC | Crystals and structure of a human igg fc variant with enhanced fcrn binding |
CN102257122B (zh) | 2008-12-16 | 2015-07-29 | Emd密理博公司 | 搅拌槽反应器及方法 |
SG171764A1 (en) | 2008-12-16 | 2011-07-28 | Millipore Corp | Purification of proteins |
EP2949666B1 (en) | 2008-12-19 | 2018-12-19 | Biogen International Neuroscience GmbH | Human anti-alpha-synuclein antibodies |
CA2747326C (en) | 2008-12-22 | 2017-05-16 | Millennium Pharmaceuticals, Inc. | Combination of aurora kinase inhibitors and anti-cd20 antibodies |
WO2010075249A2 (en) | 2008-12-22 | 2010-07-01 | Genentech, Inc. | A method for treating rheumatoid arthritis with b-cell antagonists |
EP2382238A1 (en) | 2008-12-31 | 2011-11-02 | Biogen Idec MA Inc. | Anti-lymphotoxin antibodies |
US20110142836A1 (en) * | 2009-01-02 | 2011-06-16 | Olav Mella | B-cell depleting agents for the treatment of chronic fatigue syndrome |
CA2744670C (en) | 2009-01-06 | 2018-05-15 | Ziad Mallat | A b cell depleting agent for the treatment of atherosclerosis |
EP2400992B1 (en) | 2009-02-27 | 2015-07-22 | Genentech, Inc. | Methods and compositions for protein labelling |
MX2011009362A (es) | 2009-03-05 | 2011-09-26 | Abbott Lab | Proteinas de union a il-17. |
PT2406284T (pt) | 2009-03-10 | 2016-09-29 | Biogen Ma Inc | Anticorpos anti-bcma |
KR101781654B1 (ko) | 2009-03-12 | 2017-09-25 | 제넨테크, 인크. | 조혈 악성종양의 치료를 위한 포스포이노시티드 3-키나제 억제제 화합물 및 화학요법제의 조합물 |
EP2233500A1 (en) | 2009-03-20 | 2010-09-29 | LFB Biotechnologies | Optimized Fc variants |
CN102428103B (zh) | 2009-03-24 | 2015-04-08 | 泰华生物制药美国公司 | 抗light的人源化抗体及其使用 |
US20100247484A1 (en) | 2009-03-31 | 2010-09-30 | Heinrich Barchet | Combination therapy of an afucosylated antibody and one or more of the cytokines gm csf, m csf and/or il3 |
EP2435476A4 (en) | 2009-05-27 | 2013-04-17 | Synageva Biopharma Corp | ANTIBODIES OBTAINED FROM BIRDS |
WO2010145846A1 (en) | 2009-06-15 | 2010-12-23 | Bayer Bioscience N.V. | Nicotiana benthamiana plants deficient in xylosyltransferase activity |
RU2012101999A (ru) | 2009-06-22 | 2013-07-27 | МЕДИММЬЮН, ЭлЭлСи | РЕКОМБИНАНТНЫЕ УЧАСТКИ Fc ДЛЯ САЙТ-СПЕЦИФИЧЕСКОЙ КОНЪЮГАЦИИ |
WO2011000543A1 (en) * | 2009-06-30 | 2011-01-06 | Philochem Ag | Murine antibody display library |
UY32808A (es) * | 2009-07-29 | 2011-02-28 | Abbott Lab | Inmunoglobulinas como dominio variable dual y usos de las mismas |
PT2464725T (pt) | 2009-08-11 | 2020-05-21 | Hoffmann La Roche | Produção de proteínas em meios de cultura celular isentos de glutamina |
CA2769595A1 (en) | 2009-08-14 | 2011-02-17 | Roche Glycart Ag | Combination therapy of an afucosylated cd20 antibody with fludarabine and/or mitoxantrone |
TWI409079B (zh) | 2009-08-14 | 2013-09-21 | Roche Glycart Ag | 非典型岩藻醣化cd20抗體與苯達莫斯汀(bendamustine)之組合療法 |
NZ598929A (en) | 2009-09-01 | 2014-05-30 | Abbvie Inc | Dual variable domain immunoglobulins and uses thereof |
EP3736338A1 (en) | 2009-09-01 | 2020-11-11 | F. Hoffmann-La Roche AG | Enhanced protein purification through a modified protein a elution |
US9493578B2 (en) | 2009-09-02 | 2016-11-15 | Xencor, Inc. | Compositions and methods for simultaneous bivalent and monovalent co-engagement of antigens |
KR20120104517A (ko) * | 2009-09-03 | 2012-09-21 | 제넨테크, 인크. | 류마티스 관절염의 치료, 진단 및 모니터링 방법 |
AR078161A1 (es) | 2009-09-11 | 2011-10-19 | Hoffmann La Roche | Formulaciones farmaceuticas muy concentradas de un anticuerpo anti cd20. uso de la formulacion. metodo de tratamiento. |
BR112012007760A2 (pt) | 2009-10-07 | 2015-08-25 | Macrogenics Inc | Método de atenuar fucosilação pós translacional de uma região fc de igc humana, anticorpo que se liga especificamente a um antigeno de câncer caracteristico de um cancêr polipeptideo |
AU2010306677B2 (en) | 2009-10-15 | 2013-05-23 | Abbvie Inc. | Dual variable domain immunoglobulins and uses thereof |
AU2010309931B2 (en) * | 2009-10-19 | 2015-08-20 | F. Hoffmann-La Roche Ag | Non-cross-reactive anti IgG antibodies |
UY32979A (es) * | 2009-10-28 | 2011-02-28 | Abbott Lab | Inmunoglobulinas con dominio variable dual y usos de las mismas |
EP2325185A1 (en) | 2009-10-28 | 2011-05-25 | GPC Biotech AG | Plk inhibitor |
US10087236B2 (en) | 2009-12-02 | 2018-10-02 | Academia Sinica | Methods for modifying human antibodies by glycan engineering |
US11377485B2 (en) | 2009-12-02 | 2022-07-05 | Academia Sinica | Methods for modifying human antibodies by glycan engineering |
US20120309056A1 (en) | 2010-02-04 | 2012-12-06 | Leon Arnaud | Fed-batch process using concentrated cell culture medium for the efficient production of biologics in eb66 cells |
WO2011097527A2 (en) | 2010-02-04 | 2011-08-11 | Xencor, Inc. | Immunoprotection of therapeutic moieties using enhanced fc regions |
US20110189178A1 (en) * | 2010-02-04 | 2011-08-04 | Xencor, Inc. | Immunoprotection of Therapeutic Moieties Using Enhanced Fc Regions |
US9173961B2 (en) | 2010-02-10 | 2015-11-03 | Immunogen, Inc. | CD20 antibodies and uses thereof |
TW201129383A (en) * | 2010-02-10 | 2011-09-01 | Immunogen Inc | CD20 antibodies and uses thereof |
CA2791652C (en) | 2010-03-02 | 2018-06-12 | Kyowa Hakko Kirin Co., Ltd. | Modified antibody composition |
AU2011223782B2 (en) | 2010-03-04 | 2014-09-18 | Macrogenics, Inc. | Antibodies reactive with B7-H3, immunologically active fragments thereof and uses thereof |
US8802091B2 (en) | 2010-03-04 | 2014-08-12 | Macrogenics, Inc. | Antibodies reactive with B7-H3 and uses thereof |
CN103124564B (zh) | 2010-03-22 | 2016-11-09 | 弗·哈夫曼-拉罗切有限公司 | 对于稳定含有蛋白质的制剂有用的组合物和方法 |
CA3002192C (en) | 2010-03-26 | 2023-03-07 | Memorial Sloan-Kettering Cancer Center | Antibodies to muc16 and methods of use thereof |
JP5767207B2 (ja) | 2010-03-26 | 2015-08-19 | 協和発酵キリン株式会社 | 新規修飾部位導入抗体および抗体フラグメント |
WO2011120135A1 (en) | 2010-03-29 | 2011-10-06 | Zymeworks, Inc. | Antibodies with enhanced or suppressed effector function |
EP3372617B1 (en) | 2010-04-02 | 2024-07-24 | Amunix Pharmaceuticals, Inc. | Binding fusion proteins, binding fusion protein-drug conjugates, xten-drug conjugates and methods of making and using same |
WO2011130332A1 (en) | 2010-04-12 | 2011-10-20 | Academia Sinica | Glycan arrays for high throughput screening of viruses |
CN102844049B (zh) | 2010-04-27 | 2016-06-01 | 罗切格利卡特公司 | 无岩藻糖基化CD20抗体与mTOR抑制剂的联合疗法 |
MX2012012743A (es) | 2010-05-03 | 2012-11-23 | Genentech Inc | Composiciones y metodos utiles para reducir la viscosidad de formulaciones que contienen proteina. |
EP2568976B1 (en) | 2010-05-10 | 2015-09-30 | Academia Sinica | Zanamivir phosphonate congeners with anti-influenza activity and determining oseltamivir susceptibility of influenza viruses |
NZ628792A (en) | 2010-05-14 | 2016-03-31 | Abbvie Inc | Il-1 binding proteins |
JP5612761B2 (ja) | 2010-05-17 | 2014-10-22 | イー・エム・デイー・ミリポア・コーポレイシヨン | 生体分子の精製のための刺激応答性ポリマー |
WO2011150110A1 (en) | 2010-05-25 | 2011-12-01 | Genentech, Inc. | Methods of purifying polypeptides |
PL2576580T3 (pl) | 2010-05-28 | 2017-03-31 | F.Hoffmann-La Roche Ag | Zmniejszenie poziomu mleczanu i zwiększenie wytwarzania polipeptydu przez obniżenie poziomu ekspresji dehydrogenazy mleczanowej i kinazy dehydrogenazy pirogronianowej |
BR112012033002B1 (pt) | 2010-06-24 | 2021-10-13 | Genentech, Inc | Composição aquosa de matéria, método de inibição de agregação induzida por agitação e método de prevenção de oxidação |
US20120009196A1 (en) | 2010-07-08 | 2012-01-12 | Abbott Laboratories | Monoclonal antibodies against hepatitis c virus core protein |
UY33492A (es) | 2010-07-09 | 2012-01-31 | Abbott Lab | Inmunoglobulinas con dominio variable dual y usos de las mismas |
NZ605400A (en) | 2010-07-09 | 2015-05-29 | Biogen Idec Hemophilia Inc | Chimeric clotting factors |
EP2409712A1 (en) | 2010-07-19 | 2012-01-25 | International-Drug-Development-Biotech | Anti-CD19 antibody having ADCC and CDC functions and improved glycosylation profile |
EP2409993A1 (en) | 2010-07-19 | 2012-01-25 | International-Drug-Development-Biotech | Anti-CD19 antibody having ADCC function with improved glycosylation profile |
AU2011283694B2 (en) | 2010-07-29 | 2017-04-13 | Xencor, Inc. | Antibodies with modified isoelectric points |
ES2667100T3 (es) | 2010-08-02 | 2018-05-09 | Macrogenics, Inc. | Diacuerpos covalentes y sus usos |
US20130130317A1 (en) | 2010-08-02 | 2013-05-23 | Kyowa Hakko Kirin Co., Ltd | Method for producing substance |
KR20130045914A (ko) | 2010-08-03 | 2013-05-06 | 에프. 호프만-라 로슈 아게 | 만성 림프구성 백혈병(cll) 생체지표 |
WO2012018790A2 (en) | 2010-08-03 | 2012-02-09 | Abbott Laboratories | Dual variable domain immunoglobulins and uses thereof |
EP3578205A1 (en) | 2010-08-06 | 2019-12-11 | ModernaTX, Inc. | A pharmaceutical formulation comprising engineered nucleic acids and medical use thereof |
BR112013003279A2 (pt) | 2010-08-13 | 2016-06-14 | Genentech In | “métodos para tratar uma doença, método para neutralizar ou bloquear a atividade de il-1ß e/ou il-18, anticorpo, usos de um anticorpo e usos de um anticorpo monoclonal” |
EP2606071B1 (en) * | 2010-08-17 | 2019-12-18 | F.Hoffmann-La Roche Ag | Anti-human igg1 antibody |
AR082693A1 (es) | 2010-08-17 | 2012-12-26 | Roche Glycart Ag | Terapia de combinacion de un anticuerpo anti-cd20 afucosilado con un anticuerpo anti-vegf |
MX2013002270A (es) | 2010-08-26 | 2013-05-14 | Abbvie Inc | Inmonoglubinas de dominio variable doble y usos de las mismas. |
WO2012030512A1 (en) | 2010-09-03 | 2012-03-08 | Percivia Llc. | Flow-through protein purification process |
AU2011308496A1 (en) | 2010-10-01 | 2013-05-02 | Moderna Therapeutics, Inc. | Engineered nucleic acids and methods of use thereof |
AU2011315181B2 (en) | 2010-10-11 | 2016-07-28 | Biogen International Neuroscience Gmbh | Human anti-tau antibodies |
CN103476793A (zh) | 2010-11-08 | 2013-12-25 | 基因技术公司 | 皮下施用的抗-il-6受体抗体 |
DK2653540T3 (en) | 2010-12-15 | 2018-02-05 | Inter Univ Research Institute Corporation Research Organization Of Information And Systems | PROCEDURE FOR PRODUCING PROTEIN |
CA2819436A1 (en) | 2010-12-16 | 2012-06-21 | Roche Glycart Ag | Combination therapy of an afucosylated cd20 antibody with a mdm2 inhibitor |
AU2011343161B2 (en) | 2010-12-17 | 2017-02-02 | Neurimmune Holding Ag | Human anti-SOD1 antibodies |
US8853365B2 (en) | 2010-12-21 | 2014-10-07 | Abbvie Inc. | Dual variable domain immunnoglobulins and uses thereof |
JP5882913B2 (ja) | 2010-12-27 | 2016-03-09 | 協和発酵キリン株式会社 | 培地およびキレート剤を含む水溶液の調製方法 |
WO2012095514A1 (en) | 2011-01-14 | 2012-07-19 | Vivalis | Recombinant protein production system |
US9433686B2 (en) | 2011-01-31 | 2016-09-06 | The Regents Of The University Of California | Methods for treating castration resistant prostate cancer and metastasis by reducing B-cell number and/or function |
KR20140022815A (ko) | 2011-02-28 | 2014-02-25 | 제넨테크, 인크. | B-세포 길항제에 대한 반응을 예측하기 위한 생물학적 마커 및 방법 |
TWI671315B (zh) | 2011-03-28 | 2019-09-11 | 法商賽諾菲公司 | 具有交叉結合區定向之雙重可變區類抗體結合蛋白 |
CA2828289C (en) | 2011-03-29 | 2020-07-21 | Roche Glycart Ag | Antibody fc variants |
JP2014511687A (ja) | 2011-03-31 | 2014-05-19 | モデルナ セラピューティクス インコーポレイテッド | 工学操作された核酸の送達および製剤 |
EP2506015A1 (en) | 2011-04-01 | 2012-10-03 | Universität Regensburg | A prognostic and therapeutic signature for malignant melanoma |
EP2699598B1 (en) | 2011-04-19 | 2019-03-06 | Pfizer Inc | Combinations of anti-4-1bb antibodies and adcc-inducing antibodies for the treatment of cancer |
AU2012253571A1 (en) | 2011-05-09 | 2014-01-09 | Mayo Foundation For Medical Education And Research | Cancer treatments |
EP2707723B1 (en) | 2011-05-12 | 2016-02-10 | Genentech, Inc. | Multiple reaction monitoring lc-ms/ms method to detect therapeutic antibodies in animal samples using framework signature pepides |
EP2710042A2 (en) | 2011-05-16 | 2014-03-26 | Fabion Pharmaceuticals, Inc. | Multi-specific fab fusion proteins and methods of use |
BR122016016837A2 (pt) | 2011-05-21 | 2019-08-27 | Macrogenics Inc | moléculas de ligação a cd3; anticorpos de ligação a cd3; composições farmacêuticas; e usos da molécula de ligação a cd3 |
AU2012259162C1 (en) | 2011-05-21 | 2020-05-21 | Macrogenics, Inc. | Deimmunized serum-binding domains and their use for extending serum half-life |
RU2011122942A (ru) | 2011-06-08 | 2012-12-20 | Общество С Ограниченной Ответственностью "Асинэкс Медхим" | Новые ингибиторы киназ |
TR201815563T4 (tr) | 2011-06-23 | 2018-11-21 | Biogen Int Neuroscience Gmbh | Anti-alfa sinüklein bağlayıcı moleküller. |
EP2537933A1 (en) | 2011-06-24 | 2012-12-26 | Institut National de la Santé et de la Recherche Médicale (INSERM) | An IL-15 and IL-15Ralpha sushi domain based immunocytokines |
AU2012280267B2 (en) | 2011-07-06 | 2016-04-21 | Morphosys Ag | Therapeutic combinations of anti-cd20 and anti-gm-csf antibodies and uses thereof |
ES2809211T3 (es) | 2011-07-08 | 2021-03-03 | Emd Millipore Corp | Filtros de profundidad mejorados para procesos biotecnológicos desechables |
WO2019071023A1 (en) | 2017-10-04 | 2019-04-11 | Yale University | COMPOSITIONS AND METHODS FOR MAKING POLYPEPTIDES CONTAINING SELENOCYSTEINE |
WO2013009868A1 (en) | 2011-07-11 | 2013-01-17 | Yale University | Compositions and methods for making selenocysteine containing polypeptides |
US9738707B2 (en) | 2011-07-15 | 2017-08-22 | Biogen Ma Inc. | Heterodimeric Fc regions, binding molecules comprising same, and methods relating thereto |
US9181532B2 (en) | 2011-07-29 | 2015-11-10 | Icon Genetics Gmbh | Production of galactosylated N-glycans in plants |
EP2550975A1 (en) | 2011-07-29 | 2013-01-30 | Sanofi | Combination therapy for the treatment of CD19+ B-cell malignancies symptoms comprising an anti-CD19 maytansinoid immunoconjugate and rituximab |
WO2013022855A1 (en) | 2011-08-05 | 2013-02-14 | Xencor, Inc. | Antibodies with modified isoelectric points and immunofiltering |
US9464124B2 (en) | 2011-09-12 | 2016-10-11 | Moderna Therapeutics, Inc. | Engineered nucleic acids and methods of use thereof |
US20140234307A1 (en) | 2011-09-27 | 2014-08-21 | The United States Of America,As Represented By The Secretary,Department Of Health And Human Services | Method of treating multiple sclerosis by intrathecal depletion of b cells and biomarkers to select patients with progressive multiple sclerosis |
PT3682905T (pt) | 2011-10-03 | 2022-04-07 | Modernatx Inc | Nucleósidos, nucleótidos e ácidos nucleicos modificados e respetivas utilizações |
WO2013050155A1 (en) | 2011-10-04 | 2013-04-11 | Icon Genetics Gmbh | Nicotiana benthamiana plants deficient in fucosyltransferase activity |
DK2766392T3 (da) | 2011-10-10 | 2019-10-07 | Xencor Inc | Fremgangsmåde til oprensning af antistoffer |
US10851178B2 (en) | 2011-10-10 | 2020-12-01 | Xencor, Inc. | Heterodimeric human IgG1 polypeptides with isoelectric point modifications |
TW201323440A (zh) | 2011-10-24 | 2013-06-16 | Abbvie Inc | 抗骨硬化素(sclerostin)之免疫結合物 |
JP6316195B2 (ja) | 2011-10-26 | 2018-04-25 | エランコ ティーアゲズンタイト アーゲー | モノクローナル抗体および使用の方法 |
US20130302274A1 (en) | 2011-11-25 | 2013-11-14 | Roche Glycart Ag | Combination therapy |
HRP20220717T1 (hr) | 2011-12-16 | 2022-07-22 | Modernatx, Inc. | Modificirani pripravci mrna |
ES2697676T3 (es) | 2011-12-22 | 2019-01-25 | Hoffmann La Roche | Cromatografía de membrana de intercambio iónico |
WO2013102042A2 (en) | 2011-12-30 | 2013-07-04 | Abbvie Inc. | Dual specific binding proteins directed against il-13 and/or il-17 |
TW201334789A (zh) | 2012-01-31 | 2013-09-01 | Genentech Inc | 抗ige抗體及其使用方法 |
EP2814514B1 (en) | 2012-02-16 | 2017-09-13 | Atyr Pharma, Inc. | Histidyl-trna synthetases for treating autoimmune and inflammatory diseases |
CN109880867A (zh) | 2012-03-27 | 2019-06-14 | 弗·哈夫曼-拉罗切有限公司 | 用于重组蛋白质的改进的收获操作 |
EP2834358A4 (en) | 2012-04-02 | 2016-03-09 | Moderna Therapeutics Inc | MODIFIED POLYNUCLEOTIDES FOR THE PRODUCTION OF NUCLEAR PROTEINS |
US9254311B2 (en) | 2012-04-02 | 2016-02-09 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of proteins |
US9283287B2 (en) | 2012-04-02 | 2016-03-15 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of nuclear proteins |
US9572897B2 (en) | 2012-04-02 | 2017-02-21 | Modernatx, Inc. | Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins |
US10130714B2 (en) | 2012-04-14 | 2018-11-20 | Academia Sinica | Enhanced anti-influenza agents conjugated with anti-inflammatory activity |
US9796780B2 (en) | 2012-05-14 | 2017-10-24 | Biogen Ma Inc. | LINGO-2 antagonists for treatment of conditions involving motor neurons |
AU2013270684B2 (en) | 2012-06-08 | 2018-04-19 | Sutro Biopharma, Inc. | Antibodies comprising site-specific non-natural amino acid residues, methods of their preparation and methods of their use |
JP2015525222A (ja) | 2012-06-08 | 2015-09-03 | バイオジェン・エムエイ・インコーポレイテッドBiogen MA Inc. | キメラ性凝固因子 |
UY34905A (es) | 2012-07-12 | 2014-01-31 | Abbvie Inc | Proteínas de unión a il-1 |
JP6154900B2 (ja) | 2012-07-13 | 2017-06-28 | ロシュ グリクアート アクチェンゲゼルシャフト | 二重特異性抗vegf/抗ang−2抗体及び眼血管疾患の処置におけるそれらの使用 |
JP6302909B2 (ja) | 2012-08-18 | 2018-03-28 | アカデミア シニカAcademia Sinica | シアリダーゼの同定および画像化のための細胞透過性プローブ |
US9547009B2 (en) | 2012-08-21 | 2017-01-17 | Academia Sinica | Benzocyclooctyne compounds and uses thereof |
EP2890402B1 (en) | 2012-08-31 | 2019-04-17 | Sutro Biopharma, Inc. | Modified amino acids comprising an azido group |
JOP20200236A1 (ar) | 2012-09-21 | 2017-06-16 | Regeneron Pharma | الأجسام المضادة لمضاد cd3 وجزيئات ربط الأنتيجين ثنائية التحديد التي تربط cd3 وcd20 واستخداماتها |
WO2014052713A2 (en) | 2012-09-27 | 2014-04-03 | Massachusetts Institute Of Technology | Her2-and vegf-a-binding proteins with enhanced stability |
EP3967306A1 (en) | 2012-10-01 | 2022-03-16 | Mayo Foundation for Medical Education and Research | Cancer treatments |
CN104870014A (zh) | 2012-10-09 | 2015-08-26 | 比奥根Ma公司 | 联合治疗及用于治疗脱髓鞘病症的用途 |
PL2839860T3 (pl) | 2012-10-12 | 2019-10-31 | Medimmune Ltd | Pirolobenzodiazepiny i ich koniugaty |
TWI601745B (zh) | 2012-11-01 | 2017-10-11 | 艾伯維有限公司 | 抗-vegf/dll4雙重可變區域免疫球蛋白及其用途 |
EP3466973A1 (en) | 2012-11-01 | 2019-04-10 | AbbVie Inc. | Stable dual variable domain immunoglobulin protein formulations |
DK3150256T3 (da) | 2012-11-02 | 2020-08-24 | Tg Therapeutics Inc | Kombination af anti-cd20-antistof og pi3-kinaseselektiv hæmmer |
EP4074834A1 (en) | 2012-11-26 | 2022-10-19 | ModernaTX, Inc. | Terminally modified rna |
CN104994885B (zh) | 2012-12-19 | 2017-09-29 | 基因泰克公司 | 用于放射性卤素蛋白质标记的方法和组合物 |
US9598484B2 (en) | 2012-12-21 | 2017-03-21 | Biogen Ma Inc. | Human anti-tau antibodies |
CN104936980B (zh) | 2012-12-31 | 2019-06-07 | 生物控股有限公司 | 用于治疗和预防多瘤病毒相关的疾病的重组人抗体 |
US10968276B2 (en) | 2013-03-12 | 2021-04-06 | Xencor, Inc. | Optimized anti-CD3 variable regions |
US11053316B2 (en) | 2013-01-14 | 2021-07-06 | Xencor, Inc. | Optimized antibody variable regions |
US10131710B2 (en) | 2013-01-14 | 2018-11-20 | Xencor, Inc. | Optimized antibody variable regions |
US10487155B2 (en) | 2013-01-14 | 2019-11-26 | Xencor, Inc. | Heterodimeric proteins |
US9701759B2 (en) | 2013-01-14 | 2017-07-11 | Xencor, Inc. | Heterodimeric proteins |
CN105051069B (zh) | 2013-01-14 | 2019-12-10 | Xencor股份有限公司 | 新型异二聚体蛋白 |
US9605084B2 (en) | 2013-03-15 | 2017-03-28 | Xencor, Inc. | Heterodimeric proteins |
AU2014207549B2 (en) | 2013-01-15 | 2018-12-06 | Xencor, Inc. | Rapid clearance of antigen complexes using novel antibodies |
BR112015017560A2 (pt) * | 2013-01-24 | 2018-05-15 | Scripps Korea Antibody Institute | biblioteca de fv à base de combinação de proteína e modo de preparação da mesma |
JP2016513098A (ja) | 2013-02-07 | 2016-05-12 | イミューノメディクス、インコーポレイテッドImmunomedics, Inc. | 癌の標的治療用抗体と抱合した極めて強力なプロドラック形態の2−ピロリノドキソルビシン(p2pdox) |
LT3889173T (lt) | 2013-02-15 | 2023-10-10 | Bioverativ Therapeutics Inc. | Optimizuotas viii faktoriaus genas |
US9487587B2 (en) | 2013-03-05 | 2016-11-08 | Macrogenics, Inc. | Bispecific molecules that are immunoreactive with immune effector cells of a companion animal that express an activating receptor and cells that express B7-H3 and uses thereof |
BR112015023333A8 (pt) | 2013-03-13 | 2018-04-17 | Medimmune Ltd | pirrolbenzodiazepinas e conjugados dos mesmos |
RU2694055C2 (ru) | 2013-03-13 | 2019-07-09 | Дженентек, Инк. | Составы антител |
SG10201705245TA (en) | 2013-03-14 | 2017-07-28 | Macrogenics Inc | Bispecific Molecules That Are Immunoreactive With Immune Effector Cells That Express An Activating Receptor And An Antigen Expressed By A Cell Infected By A Virus And Uses Thereof |
US8980864B2 (en) | 2013-03-15 | 2015-03-17 | Moderna Therapeutics, Inc. | Compositions and methods of altering cholesterol levels |
US10544187B2 (en) | 2013-03-15 | 2020-01-28 | Xencor, Inc. | Targeting regulatory T cells with heterodimeric proteins |
US9062108B2 (en) | 2013-03-15 | 2015-06-23 | Abbvie Inc. | Dual specific binding proteins directed against IL-1 and/or IL-17 |
WO2014144960A2 (en) | 2013-03-15 | 2014-09-18 | Abbvie Biotherapeutics Inc. | Fc variants |
EP2968498A4 (en) | 2013-03-15 | 2016-09-07 | Biogen Ma Inc | PREPARATIONS CONTAINING FACTOR IX POLYPEPTIDE |
US10858417B2 (en) | 2013-03-15 | 2020-12-08 | Xencor, Inc. | Heterodimeric proteins |
US10106624B2 (en) | 2013-03-15 | 2018-10-23 | Xencor, Inc. | Heterodimeric proteins |
US10519242B2 (en) | 2013-03-15 | 2019-12-31 | Xencor, Inc. | Targeting regulatory T cells with heterodimeric proteins |
RU2015147696A (ru) | 2013-04-09 | 2017-05-12 | Бостон Байомедикал, Инк. | Способы лечения злокачественной опухоли |
CN105324124A (zh) | 2013-04-19 | 2016-02-10 | 赛腾制药 | 降低的血管渗漏综合征的细胞因子衍生治疗 |
EP2805730A1 (en) | 2013-05-21 | 2014-11-26 | Bergen Teknologioverforing AS | Nitric oxide donor for the treatment of chronic fatigue syndrome |
BR112015029788B1 (pt) | 2013-05-31 | 2024-01-02 | Zymeworks Inc | HETERO-MULTÍMERO, USO E MÉTODO PARA PREPARAR DO MESMO, COMPOSIÇÃO FARMACÊUTICA E MÉTODO PARA REDUZIR FUNÇÃO EFETORA DE UM CONSTRUTO IgG FC |
WO2014210397A1 (en) | 2013-06-26 | 2014-12-31 | Academia Sinica | Rm2 antigens and use thereof |
US9981030B2 (en) | 2013-06-27 | 2018-05-29 | Academia Sinica | Glycan conjugates and use thereof |
EP3019522B1 (en) | 2013-07-10 | 2017-12-13 | Sutro Biopharma, Inc. | Antibodies comprising multiple site-specific non-natural amino acid residues, methods of their preparation and methods of their use |
UA116479C2 (uk) | 2013-08-09 | 2018-03-26 | Макродженікс, Інк. | БІСПЕЦИФІЧНЕ МОНОВАЛЕНТНЕ Fc-ДІАТІЛО, ЯКЕ ОДНОЧАСНО ЗВ'ЯЗУЄ CD32B I CD79b, ТА ЙОГО ЗАСТОСУВАННЯ |
US11384149B2 (en) | 2013-08-09 | 2022-07-12 | Macrogenics, Inc. | Bi-specific monovalent Fc diabodies that are capable of binding CD32B and CD79b and uses thereof |
EP2839842A1 (en) | 2013-08-23 | 2015-02-25 | MacroGenics, Inc. | Bi-specific monovalent diabodies that are capable of binding CD123 and CD3 and uses thereof |
EP2840091A1 (en) | 2013-08-23 | 2015-02-25 | MacroGenics, Inc. | Bi-specific diabodies that are capable of binding gpA33 and CD3 and uses thereof |
WO2015035044A2 (en) | 2013-09-04 | 2015-03-12 | Abbvie Biotherapeutics Inc. | Fc VARIANTS WITH IMPROVED ANTIBODY-DEPENDENT CELL-MEDIATED CYTOTOXICITY |
JP6486368B2 (ja) | 2013-09-06 | 2019-03-20 | アカデミア シニカAcademia Sinica | 改変されたグリコシル基を含む糖脂質を用いたヒトiNKT細胞の活性化 |
CN105722500B (zh) | 2013-09-11 | 2019-08-30 | 伊戈尔生物药品股份有限公司 | 包含离子性液体的液体蛋白质制剂 |
EP3052106A4 (en) | 2013-09-30 | 2017-07-19 | ModernaTX, Inc. | Polynucleotides encoding immune modulating polypeptides |
EP3052521A1 (en) | 2013-10-03 | 2016-08-10 | Moderna Therapeutics, Inc. | Polynucleotides encoding low density lipoprotein receptor |
US9840493B2 (en) | 2013-10-11 | 2017-12-12 | Sutro Biopharma, Inc. | Modified amino acids comprising tetrazine functional groups, methods of preparation, and methods of their use |
EP3062780A1 (en) | 2013-11-01 | 2016-09-07 | Bergen Teknologioverføring AS | Activators or stimulators of soluble guanylate cyclase for use in treating chronic fatigue syndrome |
ES2839087T3 (es) | 2013-11-12 | 2021-07-05 | Ogd2 Pharma | Anticuerpo derivado de IGG1 humana con actividad pro-apoptótica |
KR20160089532A (ko) | 2013-12-17 | 2016-07-27 | 제넨테크, 인크. | Pd-1 축 결합 길항제 및 항-cd20 항체를 사용하여 암을 치료하는 방법 |
CA2937123A1 (en) | 2014-01-16 | 2015-07-23 | Academia Sinica | Compositions and methods for treatment and detection of cancers |
US10150818B2 (en) | 2014-01-16 | 2018-12-11 | Academia Sinica | Compositions and methods for treatment and detection of cancers |
CA2935748A1 (en) | 2014-02-25 | 2015-09-03 | Immunomedics, Inc. | Humanized rfb4 anti-cd22 antibody |
EP2915569A1 (en) | 2014-03-03 | 2015-09-09 | Cytune Pharma | IL-15/IL-15Ralpha based conjugates purification method |
TWI754319B (zh) | 2014-03-19 | 2022-02-01 | 美商再生元醫藥公司 | 用於腫瘤治療之方法及抗體組成物 |
EP3129767B1 (en) | 2014-03-27 | 2021-09-01 | Academia Sinica | Reactive labelling compounds and uses thereof |
EA201691925A1 (ru) | 2014-03-28 | 2017-06-30 | Ксенкор, Инк. | Биспецифические антитела, которые связываются с cd38 и cd3 |
US20170049887A1 (en) | 2014-04-25 | 2017-02-23 | University Of Florida Research Foundation, Inc. | Methods of permitting a subject to receive multiple doses of recombinant adeno-associated virus |
US10118969B2 (en) | 2014-05-27 | 2018-11-06 | Academia Sinica | Compositions and methods relating to universal glycoforms for enhanced antibody efficacy |
WO2015184004A1 (en) | 2014-05-27 | 2015-12-03 | Academia Sinica | Anti-cd20 glycoantibodies and uses thereof |
WO2015184002A1 (en) | 2014-05-27 | 2015-12-03 | Academia Sinica | Anti-her2 glycoantibodies and uses thereof |
EP3149045B1 (en) | 2014-05-27 | 2023-01-18 | Academia Sinica | Compositions and methods relating to universal glycoforms for enhanced antibody efficacy |
CA2950433A1 (en) | 2014-05-28 | 2015-12-03 | Academia Sinica | Anti-tnf-alpha glycoantibodies and uses thereof |
JP6695286B2 (ja) | 2014-06-13 | 2020-05-20 | メイヨ・ファウンデーション・フォー・メディカル・エデュケーション・アンド・リサーチ | リンパ腫の処置 |
KR20170020371A (ko) | 2014-06-16 | 2017-02-22 | 메이오 파운데이션 포 메디칼 에쥬케이션 앤드 리써치 | 골수종의 치료 |
US11008561B2 (en) | 2014-06-30 | 2021-05-18 | Bioverativ Therapeutics Inc. | Optimized factor IX gene |
PL3166401T3 (pl) | 2014-07-09 | 2021-01-25 | F. Hoffmann-La Roche Ag | Dostosowanie pH w celu poprawy wyników regeneracji banków komórek po rozmrożeniu |
CN113651887A (zh) | 2014-07-29 | 2021-11-16 | 神经免疫控股公司 | 人源抗亨廷顿蛋白(htt)抗体及其用途 |
EP3191500A4 (en) | 2014-09-08 | 2018-04-11 | Academia Sinica | HUMAN iNKT CELL ACTIVATION USING GLYCOLIPIDS |
CN114181312A (zh) | 2014-09-10 | 2022-03-15 | 豪夫迈·罗氏有限公司 | 半乳糖改造的免疫球蛋白1抗体 |
JP6531166B2 (ja) | 2014-09-10 | 2019-06-12 | メドイミューン・リミテッドMedImmune Limited | ピロロベンゾジアゼピン及びそのコンジュゲート |
JP7072384B2 (ja) | 2014-09-15 | 2022-05-20 | ジェネンテック, インコーポレイテッド | 抗体製剤 |
PT3262071T (pt) | 2014-09-23 | 2020-06-16 | H Hoffnabb La Roche Ag | Métodos de utilização de imunoconjugados anti-cd79b |
MX2017004076A (es) | 2014-09-29 | 2017-07-04 | Univ Duke | Moleculas biespecificas que comprenden un brazo orientado a la envoltura vih-1. |
CN108064248B (zh) | 2014-09-30 | 2022-03-15 | 生物控股有限公司 | 人源抗二肽重复(dpr)抗体 |
EP3200804A4 (en) | 2014-10-01 | 2018-04-18 | Eagle Biologics, Inc. | Polysaccharide and nucleic acid formulations containing viscosity-lowering agents |
US9446148B2 (en) | 2014-10-06 | 2016-09-20 | Mayo Foundation For Medical Education And Research | Carrier-antibody compositions and methods of making and using the same |
MA40835A (fr) | 2014-10-23 | 2017-08-29 | Biogen Ma Inc | Anticorps anti-gpiib/iiia et leurs utilisations |
MA40861A (fr) | 2014-10-31 | 2017-09-05 | Biogen Ma Inc | Anticorps anti-glycoprotéines iib/iiia |
EP3221359B1 (en) | 2014-11-17 | 2020-05-27 | Regeneron Pharmaceuticals, Inc. | Methods for tumor treatment using cd3xcd20 bispecific antibody |
US10259887B2 (en) | 2014-11-26 | 2019-04-16 | Xencor, Inc. | Heterodimeric antibodies that bind CD3 and tumor antigens |
MX2017006918A (es) | 2014-11-26 | 2018-01-25 | Xencor Inc | Anticuerpos heterodimericos que se unen a cd3 y cd38. |
DK3223845T3 (da) | 2014-11-26 | 2021-08-16 | Xencor Inc | Heterodimere antistoffer, der binder cd3 og cd20 |
US10093733B2 (en) | 2014-12-11 | 2018-10-09 | Abbvie Inc. | LRP-8 binding dual variable domain immunoglobulin proteins |
WO2016105450A2 (en) | 2014-12-22 | 2016-06-30 | Xencor, Inc. | Trispecific antibodies |
WO2016112270A1 (en) | 2015-01-08 | 2016-07-14 | Biogen Ma Inc. | Lingo-1 antagonists and uses for treatment of demyelinating disorders |
US9975965B2 (en) | 2015-01-16 | 2018-05-22 | Academia Sinica | Compositions and methods for treatment and detection of cancers |
US10495645B2 (en) | 2015-01-16 | 2019-12-03 | Academia Sinica | Cancer markers and methods of use thereof |
CA2972072A1 (en) | 2015-01-24 | 2016-07-28 | Academia Sinica | Novel glycan conjugates and methods of use thereof |
WO2016141387A1 (en) | 2015-03-05 | 2016-09-09 | Xencor, Inc. | Modulation of t cells with bispecific antibodies and fc fusions |
RU2758113C2 (ru) | 2015-03-17 | 2021-10-26 | Мемориал Слоан-Кеттеринг Кэнсер Сентер | Антитела к muc16 и их применение |
US10722523B2 (en) | 2015-03-17 | 2020-07-28 | The Regents Of The University Of California | Chemoimmunotherapy for epithelial cancer |
EP3936524A3 (en) | 2015-05-11 | 2022-06-15 | F. Hoffmann-La Roche AG | Compositions and methods of treating lupus nephritis |
JP6771492B2 (ja) | 2015-05-30 | 2020-10-21 | モレキュラー テンプレーツ, インク.Molecular Templates, Inc. | 脱免疫化された志賀毒素aサブユニット足場及びそれを含む細胞標的化分子 |
KR20180015195A (ko) | 2015-06-03 | 2018-02-12 | 보스톤 바이오메디칼, 인크. | 암의 치료에 사용하기 위한 암 줄기능 저해제 및 면역치료제를 포함하는 조성물 |
TW201710286A (zh) | 2015-06-15 | 2017-03-16 | 艾伯維有限公司 | 抗vegf、pdgf及/或其受體之結合蛋白 |
EP3108897A1 (en) | 2015-06-24 | 2016-12-28 | F. Hoffmann-La Roche AG | Antibodies against human csf-1r for use in inducing lymphocytosis in lymphomas or leukemias |
BR112017024610A2 (pt) | 2015-06-24 | 2018-07-31 | F. Hoffmann-La Roche Ag | anticorpos para receptor antitransferrina com afinidade especificada |
MX2017016645A (es) | 2015-06-29 | 2018-11-09 | Genentech Inc | Anticuerpo anti-cd20 de tipo ii para su uso en el trasplante de órganos. |
TWI741992B (zh) | 2015-08-03 | 2021-10-11 | 美商百歐維拉提夫治療公司 | 因子ix融合蛋白以及其製備及使用方法 |
US11098079B2 (en) | 2015-08-13 | 2021-08-24 | Amgen Inc. | Charged depth filtration of antigen-binding proteins |
TW201707725A (zh) | 2015-08-18 | 2017-03-01 | 美國馬友醫藥教育研究基金會 | 載體-抗體組合物及其製造及使用方法 |
TWI835006B (zh) | 2015-08-28 | 2024-03-11 | 美商亞穆尼克斯製藥公司 | 嵌合多肽組合體以及其製備及使用方法 |
JP7002446B2 (ja) | 2015-09-21 | 2022-03-04 | アプティーボ リサーチ アンド デベロップメント エルエルシー | Cd3結合ポリペプチド |
AR106189A1 (es) | 2015-10-02 | 2017-12-20 | Hoffmann La Roche | ANTICUERPOS BIESPECÍFICOS CONTRA EL A-b HUMANO Y EL RECEPTOR DE TRANSFERRINA HUMANO Y MÉTODOS DE USO |
IL258317B1 (en) | 2015-10-02 | 2024-08-01 | Hoffmann La Roche | Human anti–CD20/human transferrin receptor bispecific antibodies and methods of use |
TW201713360A (en) | 2015-10-06 | 2017-04-16 | Mayo Foundation | Methods of treating cancer using compositions of antibodies and carrier proteins |
CN108473555B (zh) | 2015-11-02 | 2022-10-25 | 生物蛋白有限公司 | 条件活性多肽 |
EP3387013B1 (en) | 2015-12-07 | 2022-06-08 | Xencor, Inc. | Heterodimeric antibodies that bind cd3 and psma |
US10525137B2 (en) | 2015-12-30 | 2020-01-07 | Genentech, Inc. | Formulations with reduced degradation of polysorbate |
WO2017120501A1 (en) | 2016-01-07 | 2017-07-13 | Mayo Foundation For Medical Education And Research | Methods of treating cancer with interferon |
EP4137570A1 (en) | 2016-02-01 | 2023-02-22 | Bioverativ Therapeutics Inc. | Optimized factor viii genes |
CA3014531A1 (en) | 2016-02-12 | 2017-08-17 | Mayo Foundation For Medical Education And Research | Hematologic cancer treatments |
JP2019515874A (ja) | 2016-03-01 | 2019-06-13 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | 改変された細胞死誘導を有するオビヌツズマブ変異体 |
WO2017149018A1 (en) | 2016-03-02 | 2017-09-08 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and kits for predicting the risk of relapse in patients suffering from idiopathic nephrotic syndrome |
US10336784B2 (en) | 2016-03-08 | 2019-07-02 | Academia Sinica | Methods for modular synthesis of N-glycans and arrays thereof |
KR20180127320A (ko) | 2016-03-14 | 2018-11-28 | 유니버시티에트 이 오슬로 | 변경된 FcRn 결합을 갖는 조작된 면역글로불린 |
JP7034489B2 (ja) | 2016-03-15 | 2022-03-14 | アイタブメッド (エイチケイ) リミテッド | 多重特異性Fab融合タンパクおよびその使用 |
WO2017165439A1 (en) | 2016-03-21 | 2017-09-28 | Mayo Foundation For Medical Education And Research | Methods for improving the therapeutic index for a chemotherapeutic drug |
AU2017238119A1 (en) | 2016-03-21 | 2018-10-11 | Mayo Foundation For Medical Education And Research | Methods for reducing toxicity of a chemotherapeutic drug |
AU2017242031B2 (en) | 2016-03-29 | 2023-07-27 | Geltor, Inc. | Expression of proteins in gram-negative bacteria wherein the ratio of periplasmic volume to cytoplasmic volume is between 0.5:1 and 10:1 |
US10618969B2 (en) | 2016-04-06 | 2020-04-14 | Mayo Foundation For Medical Education And Research | Carrier-binding agent compositions and methods of making and using the same |
CR20180484A (es) | 2016-04-15 | 2019-03-05 | Macrogenics Inc | Moléculas de unón b7-h3 novedosas, conjugados anticuerpos-fármaco de los mismos y métodos de uso de los mismos |
JP2019514870A (ja) | 2016-04-22 | 2019-06-06 | 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 | B細胞悪性腫瘍の処置のための方法及びワクチン組成物 |
KR20190015351A (ko) | 2016-05-27 | 2019-02-13 | 티지 쎄라퓨틱스, 인코포레이티드 | B-세포 증식성 장애를 치료하기 위한 항-cd20 항체, p13 키나제-델타 선택적 억제제 및 btk 억제제의 조합 |
CN110352070B (zh) | 2016-06-14 | 2024-09-17 | Xencor股份有限公司 | 双特异性检查点抑制剂抗体 |
US11098107B2 (en) | 2016-06-15 | 2021-08-24 | Sutro Biopharma, Inc. | Antibodies with engineered CH2 domains, compositions thereof and methods of using the same |
CN109715663B (zh) | 2016-06-28 | 2022-11-25 | Xencor股份有限公司 | 结合生长抑素受体2的异源二聚抗体 |
BR112019000630A2 (pt) | 2016-07-13 | 2019-07-09 | Biogen Ma Inc | regimes de dosagem dos antagonistas de lingo-1 e usos para tratamento de distúrbios desmielinizante |
JP2018035137A (ja) | 2016-07-13 | 2018-03-08 | マブイミューン ダイアグノスティックス エイジーMabimmune Diagnostics Ag | 新規な抗線維芽細胞活性化タンパク質(fap)結合薬剤およびその使用 |
GB201613167D0 (en) | 2016-07-29 | 2016-09-14 | Univ Southampton | Cancer and b-cell related disease therapy |
WO2018039274A1 (en) | 2016-08-22 | 2018-03-01 | CHO Pharma Inc. | Antibodies, binding fragments, and methods of use |
US10793632B2 (en) | 2016-08-30 | 2020-10-06 | Xencor, Inc. | Bispecific immunomodulatory antibodies that bind costimulatory and checkpoint receptors |
CN107384932B (zh) | 2016-08-31 | 2020-10-20 | 北京天广实生物技术股份有限公司 | 抗人cd20人源化单克隆抗体mil62、其制备方法及用途 |
EP3506950A1 (en) | 2016-09-01 | 2019-07-10 | Mayo Foundation for Medical Education and Research | Methods and compositions for targeting t-cell cancers |
EP4177271A1 (en) | 2016-09-01 | 2023-05-10 | Mayo Foundation for Medical Education and Research | Carrier-pd-l1 binding agent compositions for treating cancers |
MX2019002564A (es) | 2016-09-06 | 2019-09-18 | Mayo Found Medical Education & Res | Composiciones de agente de unión de albúmina-paclitaxel y métodos de uso y elaboración de las mismas. |
WO2018048815A1 (en) | 2016-09-06 | 2018-03-15 | Nantibodyfc, Llc | Methods of treating triple-negative breast cancer using compositions of antibodies and carrier proteins |
JP2019526587A (ja) | 2016-09-06 | 2019-09-19 | マヨ ファウンデーション フォー メディカル エデュケーション アンド リサーチMayo Foundation For Medical Education And Research | Pd−l1を発現する癌を処置する方法 |
MX2019002728A (es) | 2016-09-09 | 2019-08-16 | Tg Therapeutics Inc | Combinacion de un anticuerpo anti-cd20, inhibidor de quinasa pi3-delta, y anticuerpo anti-pd-1 o anti-pd-l1 para el tratamiento hematologico de los canceres. |
CN108421048B (zh) * | 2016-09-28 | 2021-04-20 | 首都医科大学附属北京世纪坛医院 | 纳米活性碳靶向药物递送系统、制备方法及其用途 |
US20200023072A1 (en) | 2016-10-11 | 2020-01-23 | Medimmune Limited | Antibody-drug conjugates with immune-mediated therapy agents |
BR112019007288A2 (pt) | 2016-10-14 | 2019-07-09 | Xencor Inc | proteína heterodimérica biespecífica, composições de ácido nucleico e de vetor de expressão, vetor de expressão, célula hospedeira, e, métodos para produzir proteína heterodimérica biespecífica e para tratar câncer em um paciente |
WO2018102427A1 (en) | 2016-11-29 | 2018-06-07 | Boston Biomedical, Inc. | Naphthofuran derivatives, preparation, and methods of use thereof |
WO2018100096A1 (en) | 2016-12-01 | 2018-06-07 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Use of anti-uchl1 igg plasma concentration for diagnosing idiopathic steroid sensitive nephrotic syndrome |
MA46968A (fr) | 2016-12-02 | 2019-10-09 | Bioverativ Therapeutics Inc | Procédés d'induction de tolérance immunitaire à des facteurs de coagulation |
IL308416A (en) | 2016-12-02 | 2024-01-01 | Bioverativ Therapeutics Inc | Methods for the treatment of hemophilic arthritis with the help of chimeric blood coagulation factors |
BR112019015569A2 (pt) | 2017-01-31 | 2020-03-17 | Bioverativ Therapeutics Inc. | Proteínas de fusão do fator ix e métodos para a sua produção e uso |
GB201703876D0 (en) | 2017-03-10 | 2017-04-26 | Berlin-Chemie Ag | Pharmaceutical combinations |
EP3606964A4 (en) | 2017-04-03 | 2020-12-09 | Immunomedics, Inc. | SUBCUTANE ADMINISTRATION OF ANTIBODY DRUG CONJUGATES FOR CANCER THERAPY |
EP3624846B1 (en) | 2017-05-16 | 2024-08-07 | Bhami's Research Laboratory, Pvt. Ltd. | High concentration protein formulations with reduced viscosity including a combination of nicotinic acid and tryoptophan |
CA3062656A1 (en) | 2017-05-17 | 2018-11-22 | Boston Biomedical, Inc. | Methods for treating cancer |
CA3067603A1 (en) | 2017-06-30 | 2019-01-03 | Xencor, Inc. | Targeted heterodimeric fc fusion proteins containing il-15/il-15ra and antigen binding domains |
EP3652206A1 (en) | 2017-07-10 | 2020-05-20 | International-Drug-Development-Biotech | Treatment of b cell malignancies using afucosylated pro-apoptotic anti-cd19 antibodies in combination with anti cd20 antibodies or chemotherapeutics |
JP2020528061A (ja) | 2017-07-26 | 2020-09-17 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | BET阻害剤、Bcl−2阻害剤及び抗CD20抗体を用いた併用療法 |
US10759865B2 (en) | 2017-08-22 | 2020-09-01 | Eyal Levit | Treatment of diabetes mellitus |
US11180541B2 (en) | 2017-09-28 | 2021-11-23 | Geltor, Inc. | Recombinant collagen and elastin molecules and uses thereof |
WO2019077123A1 (en) | 2017-10-20 | 2019-04-25 | INSERM (Institut National de la Santé et de la Recherche Médicale) | METHODS AND KITS FOR IDENTIFYING WHETHER A SUBJECT IS REACHED OR RISK OF BEING WITH AUTOIMMUNE MYOPATHY |
AU2018366199A1 (en) | 2017-11-08 | 2020-05-28 | Xencor, Inc. | Bispecific and monospecific antibodies using novel anti-PD-1 sequences |
US10981992B2 (en) | 2017-11-08 | 2021-04-20 | Xencor, Inc. | Bispecific immunomodulatory antibodies that bind costimulatory and checkpoint receptors |
AU2018390418B2 (en) | 2017-12-19 | 2023-12-21 | Xencor, Inc. | Engineered IL-2 Fc fusion proteins |
WO2019175071A1 (en) | 2018-03-13 | 2019-09-19 | F. Hoffmann-La Roche Ag | Therapeutic combination of 4-1 bb agonists with anti-cd20 antibodies |
CN112154153A (zh) | 2018-03-28 | 2020-12-29 | 百时美施贵宝公司 | 白介素-2/白介素-2受体α融合蛋白以及使用方法 |
AU2019247415A1 (en) | 2018-04-04 | 2020-10-22 | Xencor, Inc. | Heterodimeric antibodies that bind fibroblast activation protein |
WO2019204655A1 (en) | 2018-04-18 | 2019-10-24 | Xencor, Inc. | Tim-3 targeted heterodimeric fusion proteins containing il-15/il-15ra fc-fusion proteins and tim-3 antigen binding domains |
JP7436383B2 (ja) | 2018-04-18 | 2024-02-21 | ユーシーエル ビジネス リミテッド | 操作された調節性t細胞 |
CA3097593A1 (en) | 2018-04-18 | 2019-10-24 | 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 |
CA3098103A1 (en) | 2018-05-23 | 2019-11-28 | Adc Therapeutics Sa | Molecular adjuvant |
EA202092904A1 (ru) | 2018-07-03 | 2021-04-22 | Бристол-Маерс Сквибб Компани | Способы получения рекомбинантных белков |
CN112384219A (zh) | 2018-07-09 | 2021-02-19 | 千禧制药公司 | Sumo-激活酶抑制剂和抗cd20抗体的施用 |
WO2020028909A1 (en) | 2018-08-03 | 2020-02-06 | Brown University | Oral formulations with increased uptake |
CN109273050B (zh) * | 2018-08-03 | 2021-07-13 | 五邑大学 | 一种用于解析复杂多聚体蛋白受体的脉冲电子顺磁共振数据的系统及方法与应用 |
MA53495A (fr) | 2018-08-31 | 2021-12-08 | Regeneron Pharma | Stratégie de dosage permettant d'atténuer le syndrome de libération de cytokines pour des anticorps bispécifiques cd3/c20 |
CN112955172A (zh) | 2018-09-17 | 2021-06-11 | 美国卫生和人力服务部 | 靶向cd19和cd20的双顺反子嵌合抗原受体及其用途 |
MA53822A (fr) | 2018-10-03 | 2021-08-11 | Xencor Inc | Protéines de fusion fc hétérodimères d'il -12 |
GB201816554D0 (en) | 2018-10-10 | 2018-11-28 | Centauri Therapeutics Ltd | Novel compounds and therapeutic uses thereof |
US20210380923A1 (en) | 2018-10-10 | 2021-12-09 | Boehringer Ingelheim International Gmbh | Method for membrane gas transfer in high density bioreactor culture |
GB201816553D0 (en) | 2018-10-10 | 2018-11-28 | Centauri Therapeutics Ltd | Novel compounds and therapeutic uses thereof |
US20210340277A1 (en) | 2018-10-11 | 2021-11-04 | The Scripps Research Institute | Antibody compounds with reactive arginine and related antibody drug conjugates |
EP3868784A4 (en) | 2018-10-15 | 2022-07-27 | Industry-Academic Cooperation Foundation, Yonsei University | ANTIBODIES WITH INCREASED PRODUCTIVITY AND METHODS FOR THEIR PRODUCTION |
RU2724469C2 (ru) | 2018-10-31 | 2020-06-23 | Закрытое Акционерное Общество "Биокад" | Моноклональное антитело, которое специфически связывается с cd20 |
JP7453151B2 (ja) | 2018-11-02 | 2024-03-19 | 協和キリン株式会社 | 液体培地の調製方法 |
JP2022507718A (ja) | 2018-11-20 | 2022-01-18 | コーネル ユニバーシティー | 放射線核種の大環状錯体およびがんの放射線療法におけるそれらの使用 |
KR20210100668A (ko) | 2018-12-06 | 2021-08-17 | 제넨테크, 인크. | 항-CD79b 면역접합체, 알킬화제 및 항-CD20 항체를 포함하는 미만성 큰 B-세포 림프종의 조합 요법 |
US20220018835A1 (en) | 2018-12-07 | 2022-01-20 | 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 |
JP2022523510A (ja) | 2019-01-31 | 2022-04-25 | エレクトロフィ,インコーポレイテッド | 粒子形成及び形態構造 |
EP3924386A4 (en) | 2019-02-13 | 2023-01-04 | The Brigham & Women's Hospital, Inc. | ANTI-PERIPHERAL LYMPH NODE RESPONSIBLE ANTIBODIES AND USES THEREOF |
JP7150999B2 (ja) | 2019-02-18 | 2022-10-11 | エーティービー セラピューティクス | 植物細胞または植物全体においてバインダー‐毒素融合タンパク質を産生する方法 |
CA3130695A1 (en) | 2019-02-27 | 2020-09-03 | Genentech, Inc. | Dosing for treatment with anti-tigit and anti-cd20 or anti-cd38 antibodies |
KR20210134725A (ko) | 2019-03-01 | 2021-11-10 | 젠코어 인코포레이티드 | Enpp3과 cd3에 결합하는 이종이량체 항체 |
CN113660953A (zh) | 2019-04-01 | 2021-11-16 | 豪夫迈·罗氏有限公司 | 用于稳定含蛋白质制剂的组合物和方法 |
CA3136691A1 (en) | 2019-04-12 | 2020-10-15 | Geltor, Inc. | Recombinant elastin and production thereof |
CA3138045C (en) | 2019-05-14 | 2024-02-20 | Genentech, Inc. | Methods of using anti-cd79b immunoconjugates to treat follicular lymphoma |
CN114269749B (zh) | 2019-06-10 | 2024-10-01 | 苏特罗生物制药公司 | 5H-吡咯并[3,2-d]嘧啶-2,4-二氨基化合物及其抗体偶联物 |
US20220259202A1 (en) | 2019-06-17 | 2022-08-18 | Sutro Biopharma, Inc. | 1-(4-(aminomethyl)benzyl)-2-butyl-2h-pyrazolo[3,4-c]quinolin-4-amine derivatives and related compounds as toll-like receptor (tlr) 7/8 agonists, as well as antibody drug conjugates thereof for use in cancer therapy and diagnosis |
WO2021021973A1 (en) | 2019-08-01 | 2021-02-04 | Bristol-Myers Squibb Company | Methods of improving protein productivity in fed-batch cell cultures |
AU2020339737A1 (en) | 2019-08-30 | 2022-03-17 | Vestlandets Innovasjonsselskap As | Method for the treatment of chronic fatigue syndrome using an inhibitory or cytotoxic agent against plasma cells |
TW202118512A (zh) | 2019-09-12 | 2021-05-16 | 美商建南德克公司 | 治療狼瘡性腎炎之組成物及方法 |
EP4027978A1 (en) | 2019-09-13 | 2022-07-20 | Elektrofi, Inc. | Compositions and methods for the delivery of therapeutic biologics for treatment of disease |
CN118557751A (zh) | 2019-10-18 | 2024-08-30 | 基因泰克公司 | 使用抗CD79b免疫缀合物治疗弥漫性大B细胞淋巴瘤的方法 |
AU2019474716A1 (en) | 2019-11-19 | 2022-07-07 | Protalix Ltd. | Removal of constructs from transformed cells |
AU2021212193A1 (en) | 2020-01-31 | 2022-09-08 | Celgene Corporation | Anti-CD30 antibody-drug conjugates and their use for the treatment of non-Hodgkin lymphoma |
US20230065628A1 (en) | 2020-02-19 | 2023-03-02 | Elektrofi, Inc. | Droplet Formation and Particle Morphology |
EP4114852A1 (en) | 2020-03-03 | 2023-01-11 | Sutro Biopharma, Inc. | Antibodies comprising site-specific glutamine tags, methods of their preparation and methods of their use |
JP2023522627A (ja) | 2020-04-17 | 2023-05-31 | エレクトロフィ,インコーポレイテッド | 連続的な液滴形成及び脱水によって粒子を形成する方法 |
EP4139359A1 (en) | 2020-04-24 | 2023-03-01 | Genentech, Inc. | Methods of using anti-cd79b immunoconjugates |
WO2021218862A1 (en) | 2020-04-26 | 2021-11-04 | Biocytogen Pharmaceuticals (Beijing) Co., Ltd | Modified immunoglobulins |
US20230293709A1 (en) | 2020-05-03 | 2023-09-21 | Shanghai Miracogen Inc. | Antibody-drug conjugate and preparation thereof |
US11919956B2 (en) | 2020-05-14 | 2024-03-05 | Xencor, Inc. | Heterodimeric antibodies that bind prostate specific membrane antigen (PSMA) and CD3 |
GB202007842D0 (en) | 2020-05-26 | 2020-07-08 | Quell Therapeutics Ltd | Polypeptide useful in adoptive cell therapy |
EP4189121A1 (en) | 2020-08-03 | 2023-06-07 | Genentech, Inc. | Diagnostic and therapeutic methods for lymphoma |
GB202012331D0 (en) | 2020-08-07 | 2020-09-23 | Petmedix Ltd | Therapeutic antibodies |
KR102607909B1 (ko) | 2020-08-19 | 2023-12-01 | 젠코어 인코포레이티드 | 항-cd28 조성물 |
CN112062855B (zh) | 2020-08-26 | 2024-08-30 | 北京天诺健成医药科技有限公司 | 一种含有衔接器的药物治疗剂的开发和应用 |
WO2022043415A1 (en) | 2020-08-27 | 2022-03-03 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for detecting the presence of pemphigus-specific autoantibodies in a sample |
GB202013477D0 (en) | 2020-08-27 | 2020-10-14 | Quell Therapeutics Ltd | Nucleic acid constructs for expressing polypeptides in cells |
JP2023542290A (ja) | 2020-09-10 | 2023-10-06 | ジェンマブ エー/エス | 濾胞性リンパ腫を治療するための併用療法におけるcd3及びcd20に対する二重特異性抗体 |
IL301086A (en) | 2020-09-10 | 2023-05-01 | Genmab As | Bispecific antibody against CD3 and CD20 in combination therapy for the treatment of follicular lymphoma |
KR20230066583A (ko) | 2020-09-10 | 2023-05-16 | 젠맵 에이/에스 | 미만성 대 b-세포 림프종을 치료하기 위한 조합 요법에서의 cd3 및 cd20에 대한 이중특이적 항체 |
CA3190349A1 (en) | 2020-09-10 | 2022-03-17 | Brian Elliott | Bispecific antibodies against cd3 and cd20 for treating chronic lymphocytic leukemia |
CN116782933A (zh) | 2020-09-10 | 2023-09-19 | 健玛保 | 用于治疗弥漫性大b细胞淋巴瘤的联合疗法中的针对cd3和cd20的双特异性抗体 |
WO2022066595A1 (en) | 2020-09-22 | 2022-03-31 | Bristol-Myers Squibb Company | Methods for producing therapeutic proteins |
IL301914A (en) | 2020-10-05 | 2023-06-01 | Protalix Ltd | Plant cells in which Dicer-like genes have been knocked out |
US20230372528A1 (en) | 2020-10-16 | 2023-11-23 | University Of Georgia Research Foundation, Inc. | Glycoconjugates |
WO2022103983A2 (en) | 2020-11-11 | 2022-05-19 | Sutro Biopharma, Inc. | Fluorenylmethyloxycarbonyl and fluorenylmethylaminocarbonyl compounds, protein conjugates thereof, and methods for their use |
US20220143026A1 (en) | 2020-11-12 | 2022-05-12 | Tg Therapeutics, Inc. | Triple combination to treat b-cell malignancies |
GB202102396D0 (en) | 2021-02-19 | 2021-04-07 | Adc Therapeutics Sa | Molecular adjuvant |
US11739144B2 (en) | 2021-03-09 | 2023-08-29 | Xencor, Inc. | Heterodimeric antibodies that bind CD3 and CLDN6 |
JP2024509274A (ja) | 2021-03-10 | 2024-02-29 | ゼンコア インコーポレイテッド | Cd3及びgpc3に結合するヘテロ二量体抗体 |
WO2022198192A1 (en) | 2021-03-15 | 2022-09-22 | Genentech, Inc. | Compositions and methods of treating lupus nephritis |
EP4314082A1 (en) | 2021-03-24 | 2024-02-07 | The United States of America, as represented by the Secretary, Department of Health and Human Services | Bicistronic chimeric antigen receptors designed to reduce retroviral recombination and uses thereof |
TW202306983A (zh) | 2021-04-20 | 2023-02-16 | 日商日本醫事物理股份有限公司 | 抗cd20抗體之放射性複合體,及放射性醫藥 |
EP4334354A1 (en) | 2021-05-06 | 2024-03-13 | Dana-Farber Cancer Institute, Inc. | Antibodies against alk and methods of use thereof |
CN117396232A (zh) | 2021-05-12 | 2024-01-12 | 基因泰克公司 | 使用抗cd79b免疫缀合物治疗弥漫性大b细胞淋巴瘤的方法 |
WO2022253756A1 (en) | 2021-06-01 | 2022-12-08 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of b cell depleting agents for the treatment of rheumatic heart disease |
IL307945A (en) | 2021-06-08 | 2023-12-01 | Xyphos Biosciences Inc | NKG2D antibody-ligand region fusion protein |
CN117412988A (zh) | 2021-06-08 | 2024-01-16 | 修普霍斯生物科学有限公司 | 抗体-nkg2d配体结构域融合蛋白 |
JP2024526122A (ja) | 2021-06-17 | 2024-07-17 | ペットメディックス・リミテッド | 抗イヌcd20抗体 |
CA3220318A1 (en) | 2021-06-17 | 2022-12-22 | Glaxosmithkline Intellectual Property Limited | Anti-baff antibodies for use in a method of treatment of long covid and/or post-acute sequelae sars-cov-2 infection (pasc) |
WO2023010060A2 (en) | 2021-07-27 | 2023-02-02 | Novab, Inc. | Engineered vlrb antibodies with immune effector functions |
WO2023015234A1 (en) | 2021-08-05 | 2023-02-09 | Bristol-Myers Squibb Company | Cell culture methods for producing therapeutic proteins |
CN117940455A (zh) | 2021-08-06 | 2024-04-26 | 佩特迈迪有限公司 | 抗体Fc变体 |
US20240336697A1 (en) | 2021-08-07 | 2024-10-10 | Genentech, Inc. | Methods of using anti-cd79b immunoconjugates to treat diffuse large b-cell lymphoma |
JP2024532262A (ja) | 2021-08-23 | 2024-09-05 | バイオベラティブ セラピューティクス インコーポレイテッド | 最適化第viii因子遺伝子 |
WO2023028455A1 (en) | 2021-08-23 | 2023-03-02 | Bioverativ Therapeutics Inc. | Closed-end dna production with inverted terminal repeat sequences |
WO2023049687A1 (en) | 2021-09-21 | 2023-03-30 | Bristol-Myers Squibb Company | Methods of controlling the level of dissolved oxygen (do) in a solution comprising a recombinant protein in a storage container |
TW202321308A (zh) | 2021-09-30 | 2023-06-01 | 美商建南德克公司 | 使用抗tigit抗體、抗cd38抗體及pd—1軸結合拮抗劑治療血液癌症的方法 |
AU2022355088A1 (en) | 2021-09-30 | 2024-05-16 | Bioverativ Therapeutics Inc. | Nucleic acids encoding factor viii polypeptides with reduced immunogenicity |
KR20240123846A (ko) | 2021-11-24 | 2024-08-14 | 다나-파버 캔서 인스티튜트 인크. | Ctla-4에 대한 항체 및 이의 사용 방법 |
CA3241395A1 (en) | 2021-12-17 | 2023-06-22 | Barbel SCHROFELBAUER | Antibodies and uses thereof |
CA3241407A1 (en) | 2021-12-17 | 2023-06-22 | Dana-Farber Cancer Institute, Inc. | Platform for antibody discovery |
WO2023144306A1 (en) | 2022-01-28 | 2023-08-03 | Genmab A/S | Bispecific antibody against cd3 and cd20 in combination therapy for treating diffuse large b-cell lymphoma |
WO2023150552A1 (en) | 2022-02-04 | 2023-08-10 | Dana-Farber Cancer Institute, Inc. | Compositions and methods for treatment of neurological disorders |
KR20240139085A (ko) | 2022-02-09 | 2024-09-20 | 펫메딕스 리미티드 | 치료 항체 |
WO2023164487A1 (en) | 2022-02-22 | 2023-08-31 | Brown University | Compositions and methods to achieve systemic uptake of particles following oral or mucosal administration |
WO2023198635A1 (en) | 2022-04-11 | 2023-10-19 | Astrazeneca Ab | T cell binding proteins |
WO2023212721A1 (en) | 2022-04-29 | 2023-11-02 | Elektrofi, Inc. | Injectable suspensions |
US11807689B1 (en) | 2022-06-01 | 2023-11-07 | Tg Therapeutics, Inc. | Anti-CD20 antibody compositions |
US11814439B1 (en) | 2022-06-01 | 2023-11-14 | Tg Therapeutics, Inc. | Anti-CD20 antibody compositions |
US11884740B1 (en) | 2022-06-01 | 2024-01-30 | Tg Therapeutics, Inc. | Anti-CD20 antibody compositions |
US11965032B1 (en) | 2022-06-01 | 2024-04-23 | Tg Therapeutics, Inc. | Anti-CD20 antibody compositions |
WO2024006272A1 (en) | 2022-06-27 | 2024-01-04 | Sutro Biopharma, Inc. | β-GLUCURONIDE LINKER-PAYLOADS, PROTEIN CONJUGATES THEREOF, AND METHODS THEREOF |
WO2024015229A1 (en) | 2022-07-15 | 2024-01-18 | Sutro Biopharma, Inc. | Protease/enzyme cleavable linker-payloads and protein conjugates |
WO2024039672A2 (en) | 2022-08-15 | 2024-02-22 | Dana-Farber Cancer Institute, Inc. | Antibodies against msln and methods of use thereof |
WO2024039670A1 (en) | 2022-08-15 | 2024-02-22 | Dana-Farber Cancer Institute, Inc. | Antibodies against cldn4 and methods of use thereof |
WO2024102734A1 (en) | 2022-11-08 | 2024-05-16 | Genentech, Inc. | Compositions and methods of treating childhood onset idiopathic nephrotic syndrome |
WO2024153636A1 (en) | 2023-01-17 | 2024-07-25 | Institut National de la Santé et de la Recherche Médicale | Vasorin as a biomarker and biotarget in nephrology |
US20240285762A1 (en) | 2023-02-28 | 2024-08-29 | Juno Therapeutics, Inc. | Cell therapy for treating systemic autoimmune diseases |
Family Cites Families (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US206903A (en) * | 1878-08-13 | Improvement in cultivators | ||
US213784A (en) * | 1879-04-01 | Improvement in inlaying metallic scroll-ornaments in hard rubber and allied gums | ||
US21781A (en) * | 1858-10-12 | Improved method o f lighting street-lamps by electricity | ||
US95963A (en) * | 1869-10-19 | Improvement in fence | ||
US186205A (en) * | 1877-01-16 | Improvement in buffing-rolls for thesoles of boots andshoes | ||
US26804A (en) * | 1860-01-10 | Bridle-bit | ||
US147885A (en) * | 1874-02-24 | Improvement in the manufacture of halters and bridles | ||
US9444A (en) * | 1852-12-07 | Hot-air furnace | ||
US197255A (en) * | 1877-11-20 | Improvement in receivers and stench-traps for street-sewers | ||
US163708A (en) * | 1875-05-25 | Improvement in harvester-rakes | ||
US4816567A (en) * | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
EP0173494A3 (en) * | 1984-08-27 | 1987-11-25 | The Board Of Trustees Of The Leland Stanford Junior University | Chimeric receptors by dna splicing and expression |
USRE38008E1 (en) * | 1986-10-09 | 2003-02-25 | Neorx Corporation | Methods for improved targeting of antibody, antibody fragments, hormones and other targeting agents, and conjugates thereof |
US6893625B1 (en) * | 1986-10-27 | 2005-05-17 | Royalty Pharma Finance Trust | Chimeric antibody with specificity to human B cell surface antigen |
IL85035A0 (en) * | 1987-01-08 | 1988-06-30 | Int Genetic Eng | Polynucleotide molecule,a chimeric antibody with specificity for human b cell surface antigen,a process for the preparation and methods utilizing the same |
US4975278A (en) * | 1988-02-26 | 1990-12-04 | Bristol-Myers Company | Antibody-enzyme conjugates in combination with prodrugs for the delivery of cytotoxic agents to tumor cells |
US5204244A (en) * | 1987-10-27 | 1993-04-20 | Oncogen | Production of chimeric antibodies by homologous recombination |
US5439665A (en) * | 1988-07-29 | 1995-08-08 | Immunomedics | Detection and treatment of infectious and inflammatory lesions |
IL162181A (en) * | 1988-12-28 | 2006-04-10 | Pdl Biopharma Inc | A method of producing humanized immunoglubulin, and polynucleotides encoding the same |
EP0556285A4 (en) * | 1990-11-05 | 1993-10-27 | Bristol-Myers Squibb Company | Synergistic therapy with combinations of anti-tumor antibodies and biologically active agents |
MX9204374A (es) * | 1991-07-25 | 1993-03-01 | Idec Pharma Corp | Anticuerpo recombinante y metodo para su produccion. |
US5686072A (en) * | 1992-06-17 | 1997-11-11 | Board Of Regents, The University Of Texas | Epitope-specific monoclonal antibodies and immunotoxins and uses thereof |
WO1994011026A2 (en) * | 1992-11-13 | 1994-05-26 | Idec Pharmaceuticals Corporation | Therapeutic application of chimeric and radiolabeled antibodies to human b lymphocyte restricted differentiation antigen for treatment of b cell lymphoma |
US5736137A (en) * | 1992-11-13 | 1998-04-07 | Idec Pharmaceuticals Corporation | Therapeutic application of chimeric and radiolabeled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma |
US5648267A (en) * | 1992-11-13 | 1997-07-15 | Idec Pharmaceuticals Corporation | Impaired dominant selectable marker sequence and intronic insertion strategies for enhancement of expression of gene product and expression vector systems comprising same |
US5595721A (en) * | 1993-09-16 | 1997-01-21 | Coulter Pharmaceutical, Inc. | Radioimmunotherapy of lymphoma using anti-CD20 |
US5678180A (en) * | 1995-06-07 | 1997-10-14 | Hughes Electronics | Communication system and method providing dispatch and cellular interconnect communications |
US6306393B1 (en) * | 1997-03-24 | 2001-10-23 | Immunomedics, Inc. | Immunotherapy of B-cell malignancies using anti-CD22 antibodies |
US6183744B1 (en) * | 1997-03-24 | 2001-02-06 | Immunomedics, Inc. | Immunotherapy of B-cell malignancies using anti-CD22 antibodies |
-
1993
- 1993-11-03 US US08/149,099 patent/US5736137A/en not_active Expired - Lifetime
- 1993-11-12 PL PL93320526A patent/PL175557B1/pl unknown
- 1993-11-12 DK DK99123967T patent/DK1005870T3/da active
- 1993-11-12 CN CN2006100900829A patent/CN1912111B/zh not_active Expired - Lifetime
- 1993-11-12 AT AT08013898T patent/ATE431158T1/de active
- 1993-11-12 IL IL10759193A patent/IL107591A/xx not_active IP Right Cessation
- 1993-11-12 DK DK08013898T patent/DK2000149T3/da active
- 1993-11-12 PT PT08013898T patent/PT2000149E/pt unknown
- 1993-11-12 SG SG1996002951A patent/SG45294A1/en unknown
- 1993-11-12 CN CN200610090080XA patent/CN101007850B/zh not_active Expired - Lifetime
- 1993-11-12 CN CNB931214246A patent/CN1270774C/zh not_active Expired - Lifetime
- 1993-11-12 CA CA002626445A patent/CA2626445A1/en not_active Withdrawn
- 1993-11-12 HU HU9501410A patent/HU219264B/hu active Protection Beyond IP Right Term
- 1993-11-12 UA UA95062664A patent/UA27946C2/uk unknown
- 1993-11-12 DE DE69334259T patent/DE69334259D1/de not_active Expired - Lifetime
- 1993-11-12 DE DE69334285T patent/DE69334285D1/de not_active Expired - Lifetime
- 1993-11-12 AT AT99123967T patent/ATE421335T1/de active
- 1993-11-12 DE DE122009000070C patent/DE122009000070I1/de active Pending
- 1993-11-12 PT PT99123967T patent/PT1005870E/pt unknown
- 1993-11-12 MY MYPI93002374A patent/MY111196A/en unknown
- 1993-11-12 ES ES99123967T patent/ES2321567T3/es not_active Expired - Lifetime
- 1993-11-12 CN CN2006100900848A patent/CN101007851B/zh not_active Expired - Lifetime
- 1993-11-12 ZA ZA938466A patent/ZA938466B/xx unknown
- 1993-11-12 ES ES08013898T patent/ES2326144T3/es not_active Expired - Lifetime
- 1993-11-12 KR KR1019950701928A patent/KR100365632B1/ko not_active IP Right Cessation
- 1993-11-12 EP EP08013898A patent/EP2000149B1/en not_active Expired - Lifetime
- 1993-11-12 CN CN2004100488083A patent/CN1607006B/zh not_active Expired - Lifetime
- 1993-12-14 TW TW082110578A patent/TW376320B/zh not_active IP Right Cessation
-
1997
- 1997-05-13 BR BR1100622-6A patent/BR1100622A/pt active IP Right Grant
-
2002
- 2002-03-14 US US10/096,964 patent/US20030082172A1/en not_active Abandoned
-
2004
- 2004-07-15 FR FR04C0018C patent/FR04C0018I2/fr active Active
-
2006
- 2006-07-07 GE GEAP20069498A patent/GEP20074162B/en unknown
-
2008
- 2008-01-11 HK HK08100410.4A patent/HK1109634A1/xx not_active IP Right Cessation
- 2008-01-11 HK HK08100409.7A patent/HK1109633A1/xx not_active IP Right Cessation
-
2009
- 2009-05-13 HK HK09104369.6A patent/HK1125574A1/xx not_active IP Right Cessation
- 2009-11-10 NL NL300424C patent/NL300424I1/nl unknown
- 2009-11-11 LU LU91620C patent/LU91620I2/fr unknown
-
2010
- 2010-01-06 GE GEAP200911620A patent/GEPI20105119B/en unknown
- 2010-01-06 GE GEAP201011620A patent/GEP20105119B/en unknown
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100409898C (zh) * | 1998-08-11 | 2008-08-13 | 拜奥根Idec公司 | 包括施用抗-cd20抗体的b-细胞淋巴瘤联合疗法 |
CN100531798C (zh) * | 1998-08-11 | 2009-08-26 | 拜奥根Idec公司 | 包括施用抗-cd20抗体的b-细胞淋巴瘤联合疗法 |
CN101695574A (zh) * | 1998-08-11 | 2010-04-21 | 拜奥根Idec公司 | 包括施用抗-cd20抗体的b-细胞淋巴瘤联合疗法 |
CN1329524C (zh) * | 2001-10-19 | 2007-08-01 | 图尔地区及大学医疗中心 | 评估抗体治疗反应的方法和组合物 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1094965A (zh) | 抗人类b淋巴细胞限制分化抗原的嵌合及放射标记抗体 | |
JP4203080B2 (ja) | B細胞リンパ腫の治療のためのヒトbリンパ球限定分化抗原に対するキメラ抗体と放射能標識抗体の療法利用 | |
US7744877B2 (en) | Expression and use of anti-CD20 Antibodies | |
CN1271205C (zh) | 重新构建的人抗hm1.24抗体 | |
CN1191855C (zh) | 淋巴细胞系肿瘤的治疗剂 | |
CN101028519A (zh) | 治疗免疫性疾病的药用组合物 | |
CN1373672A (zh) | 应用结合cd20的拮抗剂阻断对外来抗原的免疫应答 | |
CN1446104A (zh) | 利用b细胞排除抗体和免疫调制抗体联合治疗b细胞恶性肿瘤的相关应用 | |
CN1378459A (zh) | 使用与b细胞表面标志结合的拮抗剂治疗自身免疫病 | |
CN1192779A (zh) | 人b7.1和/或b7.2特异的猴源单克隆抗体灵长动物化形式,药用组合物 | |
CN1571797A (zh) | 抗hla-dr抗体 | |
CN1452636A (zh) | 抗树突细胞的人单克隆抗体 | |
CN1585822A (zh) | 抗体的多顺反子表达 | |
CN1454215A (zh) | 树突状细胞特异的抗原结合片段、组合物及其使用方法、被其识别的抗原及由其获得的细胞 | |
CN1747969A (zh) | 免疫球蛋白变体及其用途 | |
CN1272345C (zh) | 沉默型抗cd-28抗体及其应用 | |
CN101073667A (zh) | 淋巴细胞肿瘤抗体的增强剂 | |
CN1835972A (zh) | B细胞疾病的联合治疗 | |
CN1993142A (zh) | 用于治疗狼疮的方法 | |
CN1244772A (zh) | 靶向性细胞毒性细胞 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C17 | Cessation of patent right | ||
CX01 | Expiry of patent term |
Expiration termination date: 20131112 Granted publication date: 20060823 |