CN1030611A - 对一种吞噬细胞表面蛋白的粘附功能域有特异性的单克隆抗体 - Google Patents
对一种吞噬细胞表面蛋白的粘附功能域有特异性的单克隆抗体 Download PDFInfo
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Abstract
研制出一种杂交细胞系,其产生一种能与表达在
吞噬细胞表面的独特的抗原区域结合的单克隆抗
体。该单克隆抗体结合于CD11b糖蛋白的特定区
域,并激活该区域,以便抑制吞噬细胞的由于粘附所
产生的功能,但并不影响吞噬细胞的其它功能。此单
克隆抗体可在体外诊断免疫检测中作为反应物,以检
测正常人类嗜中性白细胞表面的独特的抗原区域。
Description
本发明涉及一种产生单克隆抗体的杂交瘤细胞系,该单克隆抗体与在吞噬细胞表面表达的特异抗原区相结合。尤其是,此单克隆抗体与CD11b糖蛋白的一个特定区域结合,并使该区域失活,从而阻止该吞噬细胞的由于粘附所产生的功能,但并不影响其它吞噬功能,
人的循环系统中的外周血液主要含有红血细胞,血小板,白血细胞。白血细胞族包括淋巴细胞,嗜中性白细胞,单核白细胞,嗜曙红细胞和嗜碱细胞。淋巴细胞主要有T细胞和B细胞两种亚型;淋巴细胞的其它亚型也是已知的。科学界对于白细胞的多种功能及其临床相关性已产生很大兴趣。
嗜中性白细胞,嗜曙红细胞和嗜碱细胞统称为“粒细胞”,因为它们含有细胞质的颗粒。粒细胞和单核白细胞统称为“吞噬细胞”,因为它们能够吞噬或消化细菌,其它微生物,及称之为“抗原”的其它类型的外源物质。这种吞噬作用对于宿主防御多种感染及各类发炎病症是很重要的。吞噬细胞是从骨髓中的普通先祖细胞产生的,它们在外周血液中循环,最后作为控制感染或反抗发炎反应的必需物进入组织。这种应答功能是在人类和动物(即灵长类动物和犬齿类动物)的吞噬细胞中发现的。
嗜中性白细胞在人类和动物外周血液中是最普通的白细胞。每微升正常人的全血平均含有5×103个白细胞,其中3,975个嗜中性白细胞,150个嗜曙红细胞,25个嗜碱细胞,250个单核白细胞,1,500个淋巴细胞。
在粒细胞或单核细胞对任一类感染或发炎的免疫应答中,这些出于对“化学引诱剂因子”,例如某些细菌产物,补体成伤等的响应,首先被激活,迁移至适当的区域。这种吸引过程称为“趋化性”。一旦位于发炎或感染的区域,粒细胞和单核白细胞就与它们的靶物紧紧结合。为此目的,这些细胞具有大量特定的细胞表面受体糖蛋白例如补体,Fc,及粘连蛋白(fibronectin)受体,用以促进这些相互作用。
在吞噬粘附中的一类最重要的细胞表面受体糖蛋白是白细胞粘附分子族,被称为“CAM”或CD11/CD18。这种糖蛋白至少含有3种细胞表面蛋白,其各具有2个亚基,它们具有共同的β亚基CD18,分子量是94,000道尔顿,并具有不同的α亚基。此类糖蛋白的已知成员被命名为:LFA-1(CD11a/CD18),Mol(CD11b/CD18),和P150,94(CD11c/CD18)。这些糖蛋白具有的α亚基分子量分别为180,000,155,000和150,000道尔顿。每一种这类细胞表面蛋白都已应用单克隆抗体进行了特异性鉴定。通过鉴定一种人类疾病,其中白细胞从遗传上缺少这类抗原,人们认识到这类表面糖蛋白的生物学重要性。该疾病特征为:复发的严重细菌感染和缺乏由于粘附所产生的功能,例如,吞噬作用,趋化性,白细胞凝集作用,以及嗜中性白细胞在塑料制品上的扩散作用。
Mol是一种细胞表面糖蛋白,出现于粒细胞,单核吞噬细胞和表面无标志细胞(Todd,R.F.Ⅲ,Nadler,L.M.,&Schlossman,S.F.,Antigens on human monocytes,Journal of Immunology,126:1435-1442,1981)。人当中的这种分子含有两个非共价连接的蛋白质,分子量分别为155,000和94,000道尔顿(Todd,R.F.Ⅲ,Van Agthoven,A.,Schlossman,S.F.,and Terhorst,D.,Structure analysis of different iation antigens Mo1 and Mo2 on human monocytes,Hybridoma 1:329-337,1982)。已证明这个复合物能将细胞粘附到多种表面,包括其它的粒细胞,内皮细胞及惰性底物。这些分子的遗传缺乏,将由于粒细胞不能介异抗微生物炎症应答而引起复发细菌感染。缺乏这些分子的病人表现出白细胞数目升高(称之为“白细胞增多”),及吞噬细胞活力出现功能性缺陷,这些特征是在体外测量对底物凝集粘附,趋向性,和调理粒子吞噬作用的降低或消失而得到证实的。可溶性发炎介质对于粒细胞和单核细胞的激活作用增加了这些分子的表达(Todd,R.F.Ⅲ,Arnaout,M.A.,Rosin.R.E.,Crowley,C.A.,Peters,W,A.,and Babior,B.M.,The subcellular localization of Mol(Mol alpha;formerly gP110),a surface of glycoprotein asso ciated with neutrophil adhesion,J.Clin,Invest.,74:1280-1290,1984;Arnaout,M.A.,Hakim.R.M.Todd,R.F.,Dana,N.and Colten,H.R.Increased expression of an adhes sion-promotion surface glycoprotein in the granulocytopenia of hemodialysis.New Egnl.J.Med.,312:457-462,1985)。抗Mo1糖蛋白的单克隆抗体能在体外有效地阻止嗜中性白细胞的凝集作用和吞噬作用。
Mo1糖蛋白特别令人感兴趣,因为这个特殊的分子结构能结合一称之为“ic3b”的成份,其为补体的第三成份的一个片段(Arnaout,M.A.,Todd,R.F.Ⅲ,Dana N.,Melamed,J.,Schlossman,S.F.,and Colten,H.R.Inhibition of Phagocytosis of complement C3 or Ig G-coated Particles and of ic3b binding by monoclonal antibodies to a monocyte-granulocyte membrane glycoprotein(Mo1),J.Clin.Invest.,72:171-179,1983),此外,Mo1糖蛋白在所有由于粘附所产生的吞噬细胞功能中是极其重要的。已证明不同的单克隆抗体能够阻碍Mo1糖蛋白起作用。
从本发明例举的新杂交细胞系中得到的单克隆抗体能抑制嗜中性白细胞的由于粘附所产生的功能,但不与补体第三组份的ic3b片段结合。此单克隆抗体用“MY904”来表示。它专门与嗜中性白细胞结合,即结合于CD11b/CD吞噬细胞表面蛋白质的抗原区,而此表面蛋白特异性地参与粒细胞粘附。吞噬细胞加进MY904单克隆抗体后会抑制吞噬细胞的由于粘附所产生的功能,但并不抑制CD11b/CD18分子的其它功能,例如与补体成份ic3b结合;也不抑制其它类型的嗜中性白细胞或单核细胞的功能,例如Fc受体激活,用趋化性肽段或佛波醇二酯激活呼吸释放,及其它功能。
此种特异的单克隆抗体得到广泛应用。MY904单克隆抗体结合嗜中性白细胞后可特异性地阻止嗜中性白细胞迁移至感染或发炎的区域。这种与嗜中性白细胞的结合可抑制已经位于发炎或感染区域的激活的嗜中性白细胞的粘附和扩散,然后阻断嗜中性白细胞释放毒素物质。单克隆抗体MY904可以用合适的标志物标记,以对CD11b/CD18分子进行免疫检测,或与适当底物相结合,用荧光激活细胞分类方法或磁珠分离方法排除结合细胞。MY904单克隆抗体阻止某些吞噬细胞功能的能力,对深入研究吞噬细胞功能,尤其是当有过量的或有害的吞噬细胞功能存在于临床病症时特别有用。此外,此单克隆抗体在CD11b/CD18表面表达的定量中极为有用,因此可用来诊断这里提到的Mo1缺乏症。
简而言之,本文将叙述一种杂交细胞系,其产生一种对Mo1抗原的由于粘附所产生的区域有特异性的单克隆抗体,该抗原表达于人类和动物吞噬细胞表面。该单克隆抗体对参与与嗜中性白细胞和单核细胞粘附的那部分
CD11b/CD18吞噬细胞表面蛋白质是特异的,因此,该单克隆抗体阻断由于粘附所产生的吞噬细胞功能,例如对于发炎或感染区域的趋化性和吞噬细胞作用,而不影响某些其它的吞噬细胞作用。此单克隆抗体由一杂交细胞系产生,其中一个融合参与者是用人的慢性粒细胞白血病细胞免疫的。
本发明所述单克隆抗体称为MY904。它是由用纯化的慢性粒细胞白血病(CGL)免疫的小鼠脾细胞与小鼠骨髓瘤细胞按照Kohler和的。
用于免疫的CGL细胞很独特,是专门制备的。从患有慢性粒细胞白血病(其CGL细胞处于胚细胞状态)的一位病人身上,用静脉穿刺方法取血进行例行诊断研究。单核细胞用Ficoll-Hypaque梯度密度沉淀方法制备,1.077g/cc。使用前将单核细胞在液氮汽化相低温保存于10%二甲亚砜中。免疫时,将CGL细胞试样融化,悬浮于磷酸盐缓冲盐水(PBS)中,将10×106细胞注射入Balb/c小鼠的腹腔和皮下。每周注射一次,共一个月。再过一个月,该小鼠用从同一患者体内得到的10×106细胞静脉注射入尾静脉进行加强。3天后,杀鼠取脾,用常规技术收集脾细胞。
接下来进行融合,以形成杂交瘤。冲洗脾细胞,将脾细胞与NS-1浆细胞瘤细胞系以8比1的比例在无血清培养基中混合。将这些细胞离心成小球状,悬浮于0.5ml30%聚乙二醇(PEG)溶液中,8分钟,25℃。倾析PEG,用次黄嘌呤-氨基嘌呤-胸苷培养基稀释细胞,分散于微滴板中。用间接免疫荧光和流动细胞计数检测该单克隆抗体MY904与取自病人的CGL细胞的反应性。MY904单克隆抗体是根据下述特性筛选的:其与用于免疫的CGL细胞反应而不与正常人的T淋巴细胞及B淋巴细胞反应。
MY904单克隆抗体表现出下列反应性:与所测10/10正常供体的纯化的单核细胞,10/10正常粒细胞,10/10正常骨髓单细胞样品反应。它不与纯化的B淋巴细胞反应。在外周血液大粒淋巴细胞的一个亚型上检测到低抗原密度,这个亚型已证明包括天然杀伤细胞。检测供养于组织培养物中的细胞系KG-1,其对MY904抗原决定基显示阳性。检测HL-60和U937髓细胞系,结果显示阴性,但如果在体外加入沸波醇二酯使之分化,则这两个细胞系都表达MY904抗原决定基。检测下述细胞系,结果显示阴性:K562,Daudi,Nalm-1,Nalm-6,JB,Raji,CEM,HSB及5个Epstein-Barr转化的B淋巴细胞系(Laz-221,-388,-156,-471,-509)。正常红细胞和血小板缺乏MY904表达,植物血凝素激活的T淋巴细胞即是如此。
曾研究过MY904抗原决定基在人类白血病细胞上的表达。该抗体与来自患有稳定状态的慢性粒细胞白血病(CGL)的患者的粒细胞都起反应。研究过患有处于胚细胞期的慢性粒细胞白血病的30位病人。其中9位患者的胚细胞为阳性。还研究过193例急性骨髓细胞白血病病例;其中56%患者的白细胞与MY904单克隆抗体反应。
该单克隆抗体属于IgG1亚类,免疫沉淀物属于糖蛋白,其含有来自表面标记的正常人类粒细胞中的分子量为155,000道尔顿和94,000道尔顿的2个亚基(Dana,N.,et al.Twofunctional domains in the phagocyte membrane glycoprotein Mo1 identified with monoclonal antibodies.J.Immunol.137:3259-3263,1986).单克隆抗体MY904的反应性分布并不抑制ic3b的结合,但却是由于粘附所产生的过程,粒细胞在塑料表面的扩散,以及趋化性的潜在抑制剂。(Dana et al.,出处同上)。与其它抗-Mo1单克隆抗体相比较,MY904单克隆抗体的独特性在于它只抑制由于粘附所产生的功能而不抑制ic3b的结合。所测其它抗体包括单克隆抗体44,903,94,17,OKM10,Leu15.(Dana et al.,出处同上)
因此,单克隆抗体MY904可鉴定Mo1粒细胞单核细胞表面糖蛋白,进而特异地与该糖蛋白上的一抗原决定基相结合,该抗原决定基参与粒细胞/单核细胞活性的由于粘附所产生的过程。
一种能产生MY904单克隆抗体的杂交细胞系样品于1987年8月19日贮存在美国典型培养物保藏中心(A.T.C.C.)(12301 Parklawn Drive,Rockville,Maryland 20852),登录号为A.T.C.C.No.H B9510。
体外研究表明,人类,犬齿类和亚人类灵长类白细胞具有相同的Mo1糖蛋白(Letvin,N.L.,Todd,R.F.Ⅲ,Palley.L.S.,and Griffin,J.D.灵长类和犬齿类动物粒细胞上的MY904骨髓表面抗原的保守性已被证实(Blood 61:408-410,1983)。此外,MY904单克隆抗体与正常狗的嗜中性白细胞的结合已表明可在用佛波醇酯PMA刺激后有效地抑制嗜中性白细胞体外凝集。(Giger,U.,Boxer,L.A.,Simpson,P.A.,Lucchesi,B.R.,and Todd,R.F.Ⅲ.Defficiency of leukocyte surface glycoproteins Mo1,LFA-1 and Leu-M5 in a dog with recurrent bacterial infection:an animal model,Blood 69:1622-1630,1987)。
MY904单克隆抗体的独特性是因为其对CD11b/CD18吞噬细胞表面蛋白质粘附区域特别地有效。此外,此抗体具有完全阻止吞噬细胞功能的能力,这些功能需要关键的细胞表面结构的表达才能实现。
Claims (21)
1、一种用杂交瘤技术生产的细胞系,其产生一种单克隆抗体,此抗体特异地与吞噬细胞膜糖蛋白Mol结合,以便只抑制粒细胞和单核细胞由于粘附所产生的功能,而不与补体成份ic3b相结合。
2、权利要求1所述细胞系,其中所述产生单克隆抗体的细胞是从用人类慢性粒细胞白血病(CGL)细胞免疫的小鼠得到的。
3、权利要求1所述细胞系,其中所述产生单克隆抗体的细胞是用人类慢性粒细胞白血病(CGL)细胞免疫的小鼠的脾细胞。
4、权利要求1所述细胞系,其中所述单克隆抗体的进一步的特征为,与人类T淋巴细胞和B淋巴细胞显示无反应性。
5、权利要求1所述细胞系,其中所述单克隆抗体表现出对来自慢性粒细胞白血病患者的外周血样的粒细胞的反应性。
6、权利要求1所述细胞系,其中单克隆抗体表现出对正常单核细胞,正常粒细胞和正常骨髓单核细胞的反应性。
7、权利要求1所述细胞系,其中单克隆抗体对正常红细胞和血小板无反应性。
8、用一种杂交瘤技术生产的细胞系,其具有贮存在ATCC的样品HB9510的基本特征,其产生对CD11b/CD18吞噬细胞表面蛋白质的粘附区域有特异性的MY904抗体。
9、一种单克隆抗体,其特异地结合于CD11b/CD18吞噬细胞表面蛋白的粘附区域,而并不表现出对补体成份ic3b的结合。
10、权利要求9所述单克隆抗体,其与人类T或B淋巴细胞显示无反应性。
11、权利要求9所述单克隆抗体,其显示与来自慢性粒细胞白血病患者外周血样的粒细胞的反应性。
12、权利要求9所述单克隆抗体,其显示对正常单核细胞,正常粒细胞和正常骨髓单核细胞的反应性。
13、权利要求9所述单克隆抗体,其与正常红细胞和血小板无反应性。
14、权利要求9所述单克隆抗体,其与人类和犬齿类动物的正常嗜中性细胞具有反应性。
15、权利要求9所述单克隆抗体,其由一具有A.T.C.C.贮存号为HB9510样品的基本特征的杂交细胞系所产生。
16、一种单克隆抗体,其特异地结合于Mol粒细胞和单核细胞表面蛋白的抗原决定基,以抑制正常粒细胞和单核细胞由于粘附所产生的功能的激活,且不与补体成份ic3b结合。
17、权利要求16所述单克隆抗体,其与人类正常嗜中性白细胞特异地结合。
18、权利要求16所述单克隆抗体,其与正常人类嗜中性细胞的一种表面糖蛋白结合,该糖蛋白具有2个亚基,分子量分别为155,000道尔顿和94,000道尔顿。
19、一种单克隆抗体,用作实验室体外诊断免疫检测中的一种反应物,在此检测中,该单克隆抗体主要结合于正常人类嗜中性白细胞表面的抗原区,该抗原区的特征是:是CD11/CD18吞噬细胞表面蛋白的粘附区域,其进一步的特征是不与补体成份ic3b结合。
20、权利要求19所述单克隆抗体,其中该表面蛋白质特征为:具有2个分子量分别为155,000道尔顿和94,000道尔顿的亚基,并与人类T淋巴细胞和B淋巴细胞无反应性。
21、权利要求19所述单克隆抗体,其通过杂交瘤技术从用人类慢性粒细胞白血病细胞免疫的小鼠获得,并对正常单核细胞,正常粒细胞和正常骨髓单核细胞显示反应性。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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US7025787A | 1987-07-06 | 1987-07-06 | |
US070,257 | 1987-07-06 | ||
US165,024 | 1988-03-07 | ||
US07/165,024 US5019648A (en) | 1987-07-06 | 1988-03-07 | Monoclonal antibody specific for the adhesion function domain of a phagocyte cell surface protein |
Publications (2)
Publication Number | Publication Date |
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CN1030611A true CN1030611A (zh) | 1989-01-25 |
CN1028114C CN1028114C (zh) | 1995-04-05 |
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CN88104150A Expired - Fee Related CN1028114C (zh) | 1987-07-06 | 1988-07-04 | 对一种吞噬细胞表面蛋白的粘附功能区域有特异性的单克隆抗体 |
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US (1) | US5019648A (zh) |
EP (1) | EP0357672B1 (zh) |
JP (1) | JPH03501560A (zh) |
KR (1) | KR960009013B1 (zh) |
CN (1) | CN1028114C (zh) |
AT (1) | ATE121130T1 (zh) |
AU (1) | AU616182B2 (zh) |
CA (1) | CA1340015C (zh) |
DE (1) | DE3853588T2 (zh) |
DK (1) | DK3390A (zh) |
ES (1) | ES2013338A6 (zh) |
IE (1) | IE61392B1 (zh) |
IL (1) | IL86676A (zh) |
MX (1) | MX9203245A (zh) |
WO (1) | WO1989000190A1 (zh) |
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US5019648A (en) * | 1987-07-06 | 1991-05-28 | Dana-Farber Cancer Institute | Monoclonal antibody specific for the adhesion function domain of a phagocyte cell surface protein |
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JPH03503600A (ja) * | 1988-03-31 | 1991-08-15 | バイオメディカル・システムズ・リミテッド | 治療用ネズミモノクローナル抗体 |
US5217870A (en) * | 1989-04-28 | 1993-06-08 | Biogen, Inc. | Monoclonal antibodies against CDX |
US5272263A (en) * | 1989-04-28 | 1993-12-21 | Biogen, Inc. | DNA sequences encoding vascular cell adhesion molecules (VCAMS) |
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US4935234A (en) * | 1987-06-11 | 1990-06-19 | Dana-Farber Cancer Institute | Method of reducing tissue damage at an inflammatory site using a monoclonal antibody |
US4840793A (en) * | 1987-06-11 | 1989-06-20 | Dana-Farber Cancer Institute | Method of reducing tissue damage at an inflammatory site using a monoclonal antibody |
US5019648A (en) * | 1987-07-06 | 1991-05-28 | Dana-Farber Cancer Institute | Monoclonal antibody specific for the adhesion function domain of a phagocyte cell surface protein |
-
1988
- 1988-03-07 US US07/165,024 patent/US5019648A/en not_active Expired - Lifetime
- 1988-05-02 DE DE3853588T patent/DE3853588T2/de not_active Expired - Fee Related
- 1988-05-02 AU AU17218/88A patent/AU616182B2/en not_active Ceased
- 1988-05-02 AT AT88904354T patent/ATE121130T1/de not_active IP Right Cessation
- 1988-05-02 EP EP88904354A patent/EP0357672B1/en not_active Expired - Lifetime
- 1988-05-02 KR KR1019890700406A patent/KR960009013B1/ko not_active IP Right Cessation
- 1988-05-02 WO PCT/US1988/001414 patent/WO1989000190A1/en active IP Right Grant
- 1988-05-02 JP JP63504165A patent/JPH03501560A/ja active Pending
- 1988-05-05 IE IE135788A patent/IE61392B1/en not_active IP Right Cessation
- 1988-06-09 IL IL86676A patent/IL86676A/xx not_active IP Right Cessation
- 1988-07-04 CN CN88104150A patent/CN1028114C/zh not_active Expired - Fee Related
- 1988-07-05 ES ES8802114A patent/ES2013338A6/es not_active Expired - Lifetime
- 1988-08-25 CA CA000566852A patent/CA1340015C/en not_active Expired - Fee Related
-
1990
- 1990-01-05 DK DK003390A patent/DK3390A/da not_active Application Discontinuation
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1992
- 1992-06-24 MX MX9203245A patent/MX9203245A/es unknown
Also Published As
Publication number | Publication date |
---|---|
EP0357672B1 (en) | 1995-04-12 |
US5019648A (en) | 1991-05-28 |
IE61392B1 (en) | 1994-11-02 |
DK3390D0 (da) | 1990-01-05 |
ES2013338A6 (es) | 1990-05-01 |
ATE121130T1 (de) | 1995-04-15 |
DE3853588T2 (de) | 1995-11-23 |
IL86676A0 (en) | 1988-11-30 |
MX9203245A (es) | 1992-07-01 |
CA1340015C (en) | 1998-08-25 |
EP0357672A1 (en) | 1990-03-14 |
AU1721888A (en) | 1989-01-30 |
AU616182B2 (en) | 1991-10-24 |
IE881357L (en) | 1989-01-06 |
KR960009013B1 (ko) | 1996-07-10 |
JPH03501560A (ja) | 1991-04-11 |
DK3390A (da) | 1990-03-05 |
WO1989000190A1 (en) | 1989-01-12 |
KR890701734A (ko) | 1989-12-21 |
CN1028114C (zh) | 1995-04-05 |
EP0357672A4 (en) | 1990-06-05 |
IL86676A (en) | 1992-06-21 |
DE3853588D1 (de) | 1995-05-18 |
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