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CN107001459B - 用于治疗炎症和自身免疫紊乱的抗age抗体 - Google Patents

用于治疗炎症和自身免疫紊乱的抗age抗体 Download PDF

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CN107001459B
CN107001459B CN201580056616.3A CN201580056616A CN107001459B CN 107001459 B CN107001459 B CN 107001459B CN 201580056616 A CN201580056616 A CN 201580056616A CN 107001459 B CN107001459 B CN 107001459B
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刘易斯·S·格鲁伯
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Abstract

一种用于治疗炎症或自身免疫紊乱的药物组合物，该药物组合物包含：(1)结合至细胞上的经AGE修饰的蛋白的抗体，以及(2)抗炎抗体。此外，结合至细胞上的经AGE修饰的蛋白的抗体也能单独有效地治疗炎症或自身免疫紊乱。

Description

用于治疗炎症和自身免疫紊乱的抗AGE抗体
背景技术
慢性炎症与多种疾病相关，包括阿尔茨海默氏病、糖尿病、动脉粥样硬化和癌症。自身免疫性疾病、例如骨关节炎和克罗恩病也与慢性炎症相关。慢性炎症的特征可能为促炎因子在病理部位附近以高于基线的水平存在，但比在急性炎症中发现的促炎因子低许多倍。这些促炎因子的实例包括TNF、IL-1α、ΙL-1β、IL-5、IL-6、IL-8、IL-12、IL-23、CD2、CD3、CD20、CD22、CD52、CD80、CD86、C5补体蛋白、BAFF、APRIL、IgE、α4β1整合蛋白以及α4β7整合蛋白。慢性炎症相关的疾病的治疗包括干扰促炎因子的作用的治疗，例如通过结合促炎因子或结合促炎因子的受体。
用于治疗慢性炎症和与慢性炎症相关的疾病的重要类别的药物包括抗炎抗体。此类药物不仅包括抗体，而且包括结合至促炎因子或促炎因子受体的其它蛋白质，并且包括抗体的恒定区。抗炎抗体的实例包括阿巴西普、阿法赛特、阿仑单抗、阿赛西普、贝利木单抗、卡那单抗、艾库组单抗、依帕珠单抗、那他珠单抗、奥瑞珠单抗(ocrelizumab)、奥法木单抗、奥马珠单抗、otelixizumab、利妥昔单抗、teplizumab、维多珠单抗、阿达木单抗、briakinumab、赛妥珠单抗、依那西普、戈利木单抗、英夫利昔单抗、美泊利单抗、瑞利珠单抗、托珠单抗和优特克单抗。
衰老细胞是处于不可逆的增殖停止状态的细胞。衰老是细胞的独特状态，并且与生物标志物相关，例如p16lnk4a的激活和β-半乳糖苷酶的表达。衰老细胞还与参与细胞间信号传导的许多因子(包括促炎因子)的分泌相关。这些因子的分泌被称为衰老相关的分泌表型或SASP。
晚期糖基化终末产物(AGEs，也称为经AGE修饰的蛋白或糖基化终末产物)来源于老化细胞中的蛋白质侧链与糖的非酶促反应(Ando,K.等,Membrane Proteins of HumanErythrocytes Are Modified by Advanced Glycation End Products during Aging inthe Circulation,Biochem Biophys Res Commun.,Vol.258,123,125(1999))。该反应起始于还原糖和氨基基团之间的可逆反应以形成席夫氏碱，进而形成共价键合的阿马多尔(Amadori)重排产物。一旦形成，阿马多尔产物进一步重排以生成AGEs。由糖尿病(DM)引起的高血糖和氧化应激促进膜蛋白的这种翻译后修饰(Lindsey JB,et al.,“Receptor ForAdvanced Glycation End-Products(RAGE)and soluble RAGE(sRAGE):CardiovascularImplications,”Diabetes Vascular Disease Research,Vol.6(1),7-14,(2009))。AGEs与多种病理病症相关，包括糖尿病并发症、炎症、视网膜病、肾病、动脉粥样硬化、中风、内皮细胞功能障碍和神经退行性紊乱(Bierhaus A,“AGEs and their interaction with AGE-receptors in vascular disease and diabetes mellitus.I.The AGE concept,”Cardiovasc Res,Vol.37(3),586-600(1998))。
经AGE修饰的蛋白也是衰老细胞的标志物。糖基化终末产物与衰老之间的这种关联是本领域公知的。参见例如Gruber,L.(WO 2009/143411,26Nov.2009)、Ando,K.等(Membrane Proteins of Human Erythrocytes Are Modified by Advanced GlycationEnd Products during Aging in the Circulation,Biochem Biophys Res Commun.,Vol.258,123,125(1999))、Ahmed,E.K.等(“Protein Modification and ReplicativeSenescence of Wl-38 Human Embryonic Fibroblasts”Aging Cells,vol.9,252,260(2010))、Vlassara,H.等(Advanced Glycosylation Endproducts on Erythrocyte CellSurface Induce Receptor-Mediated Phagocytosis by Macrophages,J.Exp.Med.,Vol.166,539,545(1987))和Vlassara等(“High-affinity-receptor-mediated Uptakeand Degradation of Glucose-modified Proteins:A Potential Mechanism for theRemoval of Senescent Macromolecules”Proc.Natl.Acad.Sci.USAI,Vol.82,5588,5591(1985))。此外，Ahmed,E.K.等表明糖基化终末产物是“细胞和细胞外蛋白质自发损伤的主要原因之一”(Ahmed,E.K.等，参见上文，第353页)。因此，糖基化终末产物的积累与衰老和功能缺失相关。
发明内容
在第一方面，本发明为用于治疗炎症或自身免疫紊乱的组合物，所述组合物包含：(i)结合至细胞上的经AGE修饰的蛋白的抗体，以及(ii)抗炎抗体。
在第二方面，本发明为治疗炎症或自身免疫紊乱的方法，所述方法包括给予结合至细胞上的经AGE修饰的蛋白的抗体。
在第三方面，本发明为治疗炎症或自身免疫紊乱的方法，所述方法包括干扰促炎因子的活性和杀死衰老细胞。
定义
术语“晚期糖基化终末产物”或“经AGE修饰的蛋白”(也称为“糖基化终末产物”)是指作为的结果而形成的经修饰的蛋白：糖与蛋白质侧链反应，进一步重排并形成不可逆的交联。该过程起始于还原糖和氨基基团之间的可逆反应以形成席夫氏碱，进而形成共价键合的阿马多尔重排产物。一旦形成，阿马多尔产物经历进一步的重排以生成AGEs。经AGE修饰的蛋白和针对经AGE修饰的蛋白的抗体在U.S.5,702,704(Bucala)和U.S.6,380,165(Al-Abed等)中描述。在糖化蛋白上发现的表位(例如在糖化白蛋白上发现的N-脱氧果糖基赖氨酸)不是AGEs。AGEs的实例包括2-(2-呋喃甲酰)-4(5)-(2-呋喃基)-1H-咪唑(“FFI”)；5-羟甲基-1-烷基吡咯-2-甲醛(“吡咯素(Pyrraline)”)；1-烷基-2-甲酰基-3,4-二糖基吡咯(“AFGP”)；非荧光模型AGE；羧甲基赖氨酸；以及戊糖素(pentosidine)。另一种AGE，ALI在Al-Abed等中描述。
“结合至细胞上的经AGE修饰的蛋白的抗体”意味着结合至经AGE修饰的蛋白并且包含抗体的恒定区的抗体或其它蛋白质，其中，所述蛋白质(被AGE修饰的)为通常发现结合在细胞表面上的蛋白质，所述细胞优选哺乳动物细胞，更优选人细胞、猫细胞、狗细胞、马细胞、骆驼科动物(例如，骆驼或羊驼)细胞、牛细胞、绵羊细胞或山羊细胞。经AGE修饰的白蛋白不是细胞上的经AGE修饰的蛋白，因为白蛋白并不是通常发现结合在细胞表面上的蛋白质。“结合至细胞上的经AGE修饰的蛋白的抗体”仅包括导致细胞移除、破坏或死亡的那些抗体。还包括例如缀合至毒素、药物或其它化学品或颗粒的抗体。优选地，抗体是单克隆抗体，但是多克隆抗体也是可以的。
“促炎因子”意味着促进炎症的因子。促炎因子的实例包括TNF或TNFα、IL-1α、IL-1β、IL-5、IL-6、IL-8、IL-12、IL-23、CD2、CD3、CD20、CD22、CD52、CD80、CD86、C5补体蛋白、BAFF、APRIL、IgE、α4β1整联蛋白和α4β7整联蛋白。许多这些因子和/或它们的受体在不同动物中可能具有不同的结构。名称前面的小写字母将用来指定源自不同动物或人类的因子，如下：人类＝h，猫＝f，狗＝d，马＝e，骆驼(或羊驼)＝c，牛＝b，绵羊＝o，以及山羊＝g；例如hTNF意味着人TNF。此外，在因子名称后的“R”表示该因子的受体，例如TNF-R是TNF的人受体，或IL-6R是IL-6的受体。这些指定可以组合使用，例如hIL-6R是IL-6的人受体。
在本发明中，“抗炎抗体”意味着结合至促炎因子或促炎因子受体降低促炎因子或其受体的活性并包含抗体恒定区的抗体或其它蛋白质。抗炎抗体的实例包括阿巴西普、阿法赛特、阿仑单抗、阿赛西普、贝利木单抗、卡那单抗、艾库组单抗、依帕珠单抗、那他珠单抗、奥瑞珠单抗(ocrelizumab)、奥法木单抗、奥马珠单抗、otelixizumab、利妥昔单抗、teplizumab、维多珠单抗、阿达木单抗、briakinumab、赛妥珠单抗、依那西普、戈利木单抗、英夫利昔单抗、美泊利单抗、瑞利珠单抗、托珠单抗和优特克单抗。优选地，抗体是单克隆抗体，但多克隆抗体也是可以的。
“衰老细胞”意味着处于不可逆的增殖停止状态并且表达衰老的一种或多种生物标志物(例如p16lnk4a的激活或β-半乳糖苷酶的表达)的细胞。此外，还包括表达衰老的一种或多种生物标志物、不在体内增殖但于特定条件下可在体外增殖的细胞，例如在ALS患者的肌肉中发现的一些卫星细胞。
具体实施方式
虽然已经研究衰老细胞一段时间了，但是仅最近才开始研究衰老细胞的体内效应。在一个的研究中，Baker,D.J.等(“Clearance of p16lnk4a-positive senescentcells delays ageing-associated disorders”,Nature,vol.479,pp.232-236,(2011))检测了小鼠中的衰老细胞的清除效果。然而，其中并未注意到对炎症和促炎因子的影响。在本申请之前，移除或杀死衰老细胞对炎症和促炎因子的作用是未知的。
本发明基于以下认识：许多与炎症相关的细胞网络具有正反馈元件。因为衰老细胞产生促炎因子，所以单独移除这些细胞引起炎症以及促炎因子的量和浓度的显著减少。这可以通过给予结合至细胞上的经AGE修饰的蛋白的抗体来完成。
此外，通过将降低促炎因子的活性和减少衰老细胞的数量联结在一起，产生协同效应：炎症的减少将大于基于任何一种组分的影响所预期到的。例如，这可以通过给予抗炎抗体和结合至细胞上的经AGE修饰的蛋白的抗体两者来完成。
结合至细胞上的经AGE修饰的蛋白的抗体(或“抗AGE抗体”)是本领域已知的。实例包括在U.S.5,702,704(Bucala)和U.S.6,380,165(Al-Abed等)中所描述的。实例包括结合至一种或多种AGEs的抗体，例如FFI、吡咯素、AFGP、ALI、羧甲基赖氨酸和戊糖素。优选地，抗体结合羧甲基赖氨酸。优选地，抗体对将在其中使用该抗体的动物是非免疫原性的，例如对如下是非免疫原性的：人；伴侣动物包括猫、狗和马；以及商业上重要的动物，例如骆驼(或羊驼)、牛(牛类)、绵羊和山羊。更优选地，抗体具有与动物的抗体相同的物种恒定区，以降低针对抗体的免疫应答，所述抗体例如为人源化抗体(用于人类)、猫源化抗体(用于猫)、犬源化抗体(用于狗)、马源化抗体(用于马)、骆驼源化抗体(用于骆驼或羊驼)、牛源化抗体(用于牛)、绵羊源化抗体(用于绵羊)或山羊源化抗体(用于山羊)。最优选地，抗体与将在其中使用该抗体的动物的抗体相同(除了可变区)，例如人抗体、猫抗体、狗抗体、马抗体、骆驼抗体、牛抗体、绵羊抗体或山羊抗体。这些动物抗体的恒定区和其它部分的细节在下文描述。
抗AGE抗体具有低的从抗体-抗原复合物解离的速率或kd(也称为kback或解离速率)，优选地至多9×10-3、8×10-3、7×10-3或6×10-3(sec-1)。抗AGE抗体对细胞的经AGE修饰的蛋白具有高亲和力，其可表达为至多9×10-6、8×10-6、7×10-6、6×10-6、5×10-6、4×10-6或3×10-6(M)的低的解离常数KD。
抗AGE抗体可被缀合至引起经AGE修饰的细胞破坏的试剂。此类试剂可以是毒素、细胞毒性试剂、磁性纳米颗粒和磁性旋涡盘(magnetic spin-vortex discs)。
缀合至抗AGE抗体的毒素可被注射到患者中以选择性地靶向并移除经AGE修饰的细胞，所述毒素例如成孔毒素(PFT)(Aroian R.等,“Pore-Forming Toxins and CellularNon-Immune Defenses(CNIDs),”Current Opinion in Microbiology,10:57-61(2007))。抗AGE抗体识别并结合至经AGE修饰的细胞。然后，毒素在细胞表面处引起孔形成并随后通过渗透裂解而引起细胞移除。
缀合至抗AGE抗体的磁性纳米颗粒可被注射到患者中以靶向并移除经AGE修饰的细胞。可以通过施加磁场来加热磁性纳米颗粒，以便选择性地移除经AGE修饰的细胞。
作为替代方案，磁性旋涡盘仅在施加磁场时磁化，以避免自聚集，自聚集可阻塞血管；当施加磁场时其开始旋转，导致靶细胞的膜破裂。缀合至抗AGE抗体的磁性旋涡盘特异性地靶向经AGE修饰的细胞类型，而不移除其它细胞。
抗体通常包含连接以形成“Y”形分子的多肽的两条轻链和两条重链。恒定区决定用于靶向抗原的机制。“Y”末端中的氨基酸序列(可变区)在不同抗体之间变化。该变化给予抗体结合抗原的特异性。包含轻链和重链的末端的可变区被进一步细分为高变区(HV-有时也称为互补决定区，或CDR)和框架(FR)区。当重组制备抗体时，也可能具有结合至两种不同的抗原的拥有可变区(或互补决定区)的单一抗体，“Y”的每个末端对各抗原而言是特异性的；这些抗体被称为双特异性抗体。
根据本发明的人源化抗AGE抗体具有以下的人恒定区的氨基酸序列：
Figure BDA0001272717840000071
抗AGE抗体可以具有一个或多个以下的互补决定区：
CDR1H(重链)：SYTMGVS
CDR2H(重链)：TISSGGGSTYYPDSVKG
CDR3H(重链)：QGGWLPPFAX
CDR1L(轻链)：RASKSVSTSSRGYSYMH
CDR2L(轻链)：LVSNLES
CDR3L(轻链)：QHIRELTRS
抗炎抗体是公知的，并且许多已经被批准用于人类使用。抗炎抗体的实例包括阿巴西普、阿法赛特、阿仑单抗、阿赛西普、贝利木单抗、卡那单抗、艾库组单抗、依帕珠单抗、那他珠单抗、奥瑞珠单抗(ocrelizumab)、奥法木单抗、奥马珠单抗、otelixizumab、利妥昔单抗、teplizumab、维多珠单抗、阿达木单抗、briakinumab、赛妥珠单抗、依那西普、戈利木单抗、英夫利昔单抗、美泊利单抗、瑞利珠单抗、托珠单抗和优特克单抗。优选地，抗炎抗体是结合至TNF或TNF-R的抗体。任何上述抗体均可以通过替换不结合促炎因子或促炎因子受体的部分进行修饰，以减少除了人以外的动物中的任何可能的免疫反应，上述部分是抗体的恒定区，该恒定区来自动物，例如猫、狗、马、骆驼(或羊驼)、牛、绵羊或山羊的抗体恒定区。这些恒定区以及这些动物的抗体的其它部分是公知的，并且其中的一些可以在如下中找到：Yaofeng Zhao等，“The bovine antibody repertoire”Developmental&ComparativeImmunology,Vol.30,Issues 1-2,2006,Pages 175-186；Wagner B等，“the complete mapof the Ig heavy chain constant gene region reveals evidence for seven IgGisotypes and for IgD in the horse”J Immunol.2004Sep 1；173(5):3230-42；Strietzel CJ等，“In Vitro functional characterization of feline IgGs”VetImmunol Immunopathol.2014Apr 15；158(3-4):214-23；Mayuri Patel等，“Sequence ofthe dog immunoglobulin alpha and epsilon constant region genes”Immunogenetics,March 1995,Volume 41,Issue 5,pp 282-286；以及David R.Maass等，“Alpaca(Lama pacos)as a convenient source of recombinant camelid heavy chainantibodies(VHHs)”J Immunol Methods.Jul 31,2007；324(1-2):13-25。
抗炎抗体具有低的从抗体-抗原复合物解离的速率或kd(也称为kback或解离速率)，优选地至多9×10-3、8×10-3、7×10-3、6×10-3、5×10-3、4×10-3、3×10-3、2×10-3或1×10-3(sec-1)。抗炎抗体具有对其相关的抗原的亲和力，其可表达为低的解离常数KD，至多为9×10-6、8×10-6、7×10-6、6×10-6、5×10-6、4×10-6、3×10-6、2×10-6、1×10-6、1×10-7或1×10-8(M)。
此类抗体的实例包括来自描述了抗TNF抗体的U.S.Pat.No.6,090,382的抗体。此类抗体可具有以下的一种或多种：
CDR3L(轻链)：Gln Arg Tyr Asn Arg Ala Pro Tyr Xaa，其中，Xaa是Thr或者Ala。
CDR3H(重链)：Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Xaa，其中，Xaa是Tyr或者Asn。
轻链可变区：Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala SerVal Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Tyr LeuAla Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala SerThr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp PheThr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Gln ArgTyr Asn Arg Ala Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys。
重链可变区：Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln ProGly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr AlaMet His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala Ile ThrTrp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val Glu Gly Arg Phe Thr Ile SerArg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu AspThr Ala Val Tyr Tyr Cys Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu AspTyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser。
同时为抗AGE抗体和抗炎抗体的双特异性抗体也可被使用。此类抗体具有来自抗AGE抗体的可变区(或互补决定区)和来自抗炎抗体的可变区(或互补决定区)。
如果期望另外的抗体，可以使用公知的方法制备。例如，多克隆抗体(pAbs)可以通过一次或多次注射免疫原(并且如果期望的话，也可以注射佐剂)在哺乳动物宿主中产生。通常，通过皮下或腹膜内注射将免疫原(以及佐剂)注射到哺乳动物中。免疫原可以是细胞的经AGE修饰的蛋白、促炎因子、促炎因子受体或它们的片段。佐剂的实例包括弗氏完全佐剂，单磷酰脂质A合成海藻糖二霉菌酸酯(trehalose dicorynomycolate)，氢氧化铝(alum)，热休克蛋白HSP70或HSP96，含有单磷酰脂质A的角鲨烯乳液，α2-巨球蛋白和表面活性物质，例如油乳剂、pleuronic polyols、聚阴离子和二硝基苯酚。为了改善免疫应答，免疫原可被缀合至在宿主中具有免疫原性的多肽，例如匙孔血蓝蛋白(KLH)、血清白蛋白、牛甲状腺球蛋白、霍乱毒素、不稳定性肠毒素、二氧化硅颗粒或大豆胰蛋白酶抑制剂。或者，pAbs也可以在鸡中制备，产生IgY分子。
单克隆抗体(mAbs)也可以通过如下制造：免疫宿主或宿主的淋巴细胞，收集分泌(或潜在分泌)mAb的淋巴细胞，将这些淋巴细胞融合至无限繁殖的细胞(例如骨髓瘤细胞)，以及筛选分泌期望的mAb的那些细胞。也可以使用其它技术，例如EBV杂交瘤技术。通过将编码抗体可变结构域的基因剪接到人(或其它动物)免疫球蛋白的恒定结构域的基因来生成嵌合抗体的技术产生“嵌合抗体”，所述嵌合抗体在氨基酸水平上基本上人类的(人源化的)或基本上为另一动物(如猫、狗、马、骆驼或羊驼、牛、绵羊或山羊)“源化”的。如果期望的话，mAbs可以通过常规方法(例如蛋白质A-琼脂糖凝胶、羟基磷灰石层析、凝胶电泳、透析、硫酸铵沉淀或亲和层析)从培养基或腹水中纯化。此外，人单克隆抗体可以通过免疫包含第三拷贝IgG人转基因座(trans-loci)和沉默的内源小鼠Ig基因座的转基因小鼠或者使用人转基因小鼠来生成。人源化单克隆抗体及其片段的生产还可以通过噬菌体展示技术来生成。
“药学上可接受的载体”包括与药物给予相容的任何和所有溶剂、分散介质、包衣剂、抗细菌和抗真菌剂、等渗剂和吸收延迟剂等。此类载体或稀释剂的优选实例包括水、盐水、林格氏溶液和右旋糖溶液。补充的活性化合物也可以被并入这些组合物中。用于肠胃外给予的溶液和悬浮液可以包括无菌稀释剂，例如注射用水、盐水溶液、聚乙二醇、甘油、丙二醇或其它合成溶剂；抗细菌剂，如对羟基苯甲酸苄酯或对羟基苯甲酸甲酯；抗氧化剂，如抗坏血酸或亚硫酸氢钠；缓冲剂，如乙酸盐、柠檬酸盐或磷酸盐；以及用于调节张力的药剂，如氯化钠或葡萄糖。pH可以用酸或碱调节，如盐酸或氢氧化钠。肠胃外制剂可以被包封在由玻璃或塑料制成的安瓿、一次性注射器或多剂量小瓶中。
适合注射的药物组合物包含无菌水溶液或分散体，用于临时制备无菌可注射溶液或分散体。对于静脉内给予，合适的载体包括生理盐水、抑菌水、CREMOPHOR
Figure BDA0001272717840000101
(BASF；Parsippany，NJ)或磷酸盐缓冲盐水(PBS)。在所有情况下，组合物必须是无菌的并且应该是液体的，以便使用注射器来给予。此类组合物在制造和储存期间应该是稳定的，并且必须防止微生物例如细菌和真菌的污染。各种抗细菌和抗真菌剂(例如对羟基苯甲酸酯、氯丁醇、苯酚、抗坏血酸和硫柳汞)可控制微生物污染。组合物中可以包含等渗剂如糖、多元醇如(甘露糖醇、山梨糖醇)和氯化钠。可延迟吸收的组合物中包含试剂诸如单硬脂酸铝和明胶。无菌可注射溶液可以通过如下制备：以所需的量将抗体和任选的其它治疗组分掺入所需的具有一种成分或成分的组合的合适的溶剂中，然后进行灭菌。制备无菌可注射溶液的无菌固体的制备方法包括通过真空干燥和冷冻干燥来产生固体。
为了通过吸入给予，抗体被作为从喷雾器或含有合适推进剂(例如二氧化碳等气体)的加压容器喷射的气溶胶递送。抗体也可以作为干粉通过吸入递送，例如使用iSPERSETM吸入药物递送平台(PULMATRIX，Lexington，Mass.)。当通过吸入给予时，在各种动物(包括人)中，鸡抗体(IgY)的使用可能是非免疫原性的。
各类型的抗体的合适的剂量水平通常为约0.01至500毫克每千克患者体重。优选地，剂量水平为约0.1至约250mg/kg；更优选地为约0.5至约100mg/kg。合适的剂量水平可以是约0.01至250mg/kg、约0.05至100mg/kg或约0.1至50mg/kg。在该范围内，剂量可以为0.05至0.5mg/kg、0.5至5mg/kg或5至50mg/kg。虽然各类型的抗体能够以每天1至4次(例如每天一次或两次)的方案给予，但抗体通常在体内具有长的半衰期。因此，各类型的抗体能够以每天一次、每周一次、每两周或三周一次、每月一次或每60天-90天一次给予。
为了确定结合到细胞上的经AGE修饰的蛋白的抗体单独或与抗炎抗体组合、或与多种抗炎抗体组合、或与其它抗炎剂(例如NSAIDS和/或类固醇)组合进行治疗的有效性，可对患者进行观察或采用各种测试。例如，在患者中可观察到自身免疫性紊乱或炎症的症状改善(例如皮肤发红减轻)；与治疗前的水平相比，各种促炎因子(如TNF)的血液检测显示出水平降低；以及与治疗前的水平相比，在炎症部位或其附近取得的组织活检中的各种促炎因子(如TNF)的检测显示出水平降低。
可以制备单位剂型以便于给予和剂量均一性。单位剂型是指作为单一剂量适合于待治疗对象的物理上离散的单位，其含有与所需的药物载体相关的治疗有效量的一种或多种类型的抗体。优选地，单位剂型在密封容器中并且是无菌的。
实施例
实施例1：给予抗糖基化终末产物抗体的体内研究
为了检测抗糖基化终末产物抗体的作用，将抗体以一日两次通过静脉内注射给予老龄CD1(ICR)小鼠(Charles River实验室)，每周一回，持续三周(第1天、第8天和第15天)，之后是10周的无治疗期。测试抗体是针对羧甲基赖氨酸(常见的AGE表位)产生的与匙孔血蓝蛋白缀合的可商购的小鼠抗糖基化终末产物抗体。在对照动物中使用生理盐水作为对照参考物。
称为“年轻”的小鼠为8周龄，称为“老年”的小鼠为88周龄(±2天)。从抗体的给予中未观察到不良事件。研究中使用的不同动物组在表1中示出。
表1
Figure BDA0001272717840000121
-＝未施用，Pre＝在开始用于收集脂肪组织的治疗前安乐死的动物子集。
通过实时qPCR在各组的脂肪组织中定量衰老细胞的标记物P16INK4a mRNA。结果在表2中示出。在该表中，ΔΔCt＝ΔCt对照组(2)均值-ΔCt实验组(1或3或5)均值；倍数表达式＝2-ΔΔCt。
表2
Figure BDA0001272717840000122
上表显示出，如同所预期的，比起未经治疗的年轻小鼠(对照组1)，未经治疗的老年小鼠(对照组2)表达高2.55倍的p16Ink4a mRNA。当将在恢复的第85天结束时安乐死的组2的未经治疗的老年小鼠和在治疗的第22天结束时安乐死的组1的未经治疗的年轻小鼠进行比较时，观察到该结果。当将来自组2的未经治疗的老年小鼠的结果与来自在第85天安乐死的组3的经治疗的老年小鼠的结果进行比较，观察到组2中的p16Ink4a mRNA比起在组3中高1.23倍。因此，当用2.5μg/g/BID/周的抗体对老年小鼠进行治疗时，p16Ink4a mRNA表达水平较低。
当将来自组2(对照)的未经治疗的老年小鼠的结果与来自在第22天安乐死的组5(5μg/g)的经治疗的老年小鼠的结果进行比较时，观察到组2(对照)中的p16Ink4a mRNA比组5(5μg/g)中的高3.03倍。该比较表明当以5.0μg/g/BID/周处理时，组5动物的p16Ink4amRNA表达的水平较低，提供了与未经治疗的年轻小鼠(即，组1)相当的p16Ink4a mRNA表达水平。不同于在恢复的第85天结束时安乐死的组3(2.5μg/g)的小鼠，组5的小鼠在治疗的第22天进行安乐死。
这些结果表明给予抗体导致杀死了衰老细胞。
实施例2：测试抗体的亲和力和动力学
使用Na,Na-双(羧甲基)-L-赖氨酸三氟乙酸盐(Sigma-Aldrich，St.Louis，MO)作为用于细胞的经AGE修饰的蛋白的模型底物来分析实施例1中使用的测试抗体的亲和力和动力学。在BIACORETM T200(GE Healthcare，Pittsburgh，PA)上进行无标记的相互作用分析，采用S系列传感器芯片CM5(GE Healthcare，Pittsburgh，PA)，用Fc1设置为空白，以及将Fc2用测试抗体(分子量150,000Da)固定。运行缓冲液是在25℃的温度下的HBS-EP缓冲液(10mM HEPES、150mM NaCl、3mM EDTA和0.05％P-20，pH 7.4)。软件是BIACORETMT200评估软件2.0版。在分析中使用双重对照(Fc2-1和仅注射缓冲液)，并将数据拟合为Langmuir 1：1结合模型。
表3：亲和力和动力学分析的实验设置
Figure BDA0001272717840000131
图1中展示出了相对于时间的应答的曲线图。可从分析确定以下值：
ka(1/Ms)＝1.857×103；kd(1/s)＝6.781×10-3；KD(M)＝3.651×10-6；Rmax(RU)＝19.52；并且Chi2＝0.114。由于拟合的Chi2值小于Rmax的10％，因此拟合是可靠的。
实施例3(预见的)：在类风湿性关节炎的抗原诱导关节炎(AIA)小鼠模型中给予抗糖基化终末产物抗体和小鼠抗小鼠TNF抗体的体内研究
为了检测抗糖基化终末产物抗体和小鼠抗小鼠TNF抗体对类风湿性关节炎(典型的炎性疾病，也是自身免疫性紊乱)的作用，将两种抗体同时给予至CD1(ICR)小鼠，该CD1(ICR)小鼠此前已用甲基化牛血清白蛋白处理，首先通过全身注射，然后注射到关节中，以产生AIA小鼠。通过静脉内注射一日两次给予抗糖基化终末产物抗体和抗TNF抗体的组合，每周一回，持续三周(第1天、第8天和第15天)。抗糖基化终末产物抗体是针对羧甲基赖氨酸(常见的AGE表位)产生的与匙孔血蓝蛋白缀合的可商购的小鼠抗糖基化终末产物抗体。在第一对照动物中使用生理盐水作为对照参考物，第二实验组仅给予抗糖基化终末产物抗体，并且在第二对照动物中仅使用抗TNF抗体作为第二对照参考物。各抗体的使用剂量水平为5μg/gm/BID/周。
在研究过程中观察动物，并采集血液以确定TNF的水平。在研究结束时，动物被安乐死并且关节组织被用于检测与类风湿性关节炎相关的损伤迹象。结果表明，第二实验组和第二对照组比起第一对照组显示出更少的关节损伤和较低的TNF水平。此外，第一实验组不仅显示出所有研究组中最少的关节损伤和最低水平的TNF，但是关节损伤和TNF水平方面的降低都大于仅基于第二实验组和第二对照组所预期的。结果表明抗糖基化终末产物抗体的抗炎作用以及使用抗糖基化终末产物抗体和抗炎抗体的协同效应。
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Claims (7)

1.结合至细胞上的经AGE修饰的蛋白的抗体在制备用于杀死患有炎症或自身免疫性紊乱的受试者中的衰老细胞的药物中的用途，
其中，所述结合至细胞上的经AGE修饰的蛋白的抗体为结合至羧甲基赖氨酸的抗体。
2.如权利要求1所述的用途，其中，所述结合至细胞上的经AGE修饰的蛋白的抗体是人抗体。
3.如权利要求1或2所述的用途，其中，所述结合至细胞上的经AGE修饰的蛋白的抗体是经缀合的抗体。
4.如权利要求3所述的用途，其中，所述经缀合的抗体是与选自于由如下所组成的组中的成员缀合的结合至细胞上的经AGE修饰的蛋白的抗体：毒素、细胞毒性试剂、磁性纳米颗粒和磁性旋涡盘。
5.如权利要求1或2所述的用途，其中，所述结合至细胞上的经AGE修饰的蛋白的抗体是单克隆抗体。
6.如权利要求1或2所述的用途，其中，所述结合至细胞上的经AGE修饰的蛋白的抗体是对选自于由如下所组成的组中的物种而言非免疫原性的抗体：人、猫、狗、马、骆驼、羊驼、牛、绵羊和山羊。
7.如权利要求1或2所述的用途，其中，所述结合至细胞上的经AGE修饰的蛋白的抗体被作为包含药物载体的无菌组合物使用。
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