CN112805032A - 与治疗性肿瘤学药剂组合使用抗ssea-4抗体的组合疗法 - Google Patents
与治疗性肿瘤学药剂组合使用抗ssea-4抗体的组合疗法 Download PDFInfo
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Abstract
本公开一般而言涉及治疗方法及组合物,其包括施用抗SSEA‑4抗体;单独或加成性和/或协同性结合其他肿瘤治疗性药剂以增进治疗功效,从而该相互作用改变Siglec‑9蛋白的表位结合,包括人类Siglec‑9或哺乳动物Siglec‑9;其中此类抗SSEA‑4组合物的用途有效预防癌症、降低癌症风险、或治疗癌症受试者。
Description
本申请要求2018年10月2日提交的美国专利申请号62/740,373的权益,其公开内容通过引用完整并入本文。
发明领域
本公开一般而言涉及治疗方法及组合物,其包含抗SSEA-4抗体,如单克隆抗体、嵌合抗体、人源化抗体、抗体片段等;单独或组合其他治疗性肿瘤学药剂。所述方法及组合物可以协同方式调控Siglec-9蛋白,如人类Siglec-9或哺乳动物Siglec-9的结合,且所述治疗方法及组合物的用途可用于预防癌症、降低癌症风险、或治疗癌症个体。
发明背景
SSEA-4(阶段特异性胚胎抗原4)为六糖(Neu5Acα2-3Galβ1-3GalNAcβ1-3Galα1-4Galβ1-4Glcβ),通常作为多能人类胚胎干细胞的细胞表面标记;其亦用于分离间充质干细胞并且富集神经祖细胞(Kannagi et al.(1983)EMBO J.2:2355–236)。最近的研究显示,SSEA-4与癌症的恶性有关,如癌细胞的侵袭与转移(Kavitha et al.(2015Glycobiology25:902–917;Lou et al.(2014)Proc Natl Acad Sci USA.111:2482–2487)。
SSEA-4的表达与肺癌、肾癌、乳癌、及口腔癌的转移潜力增加及预后不佳相关联(Kataguri et al.(2001)Glycoconj J.18:347–353;Gottschling et al.(2013)EurRespir J.41:656-663;Hung et al.(2013)J Am Chem Soc.135:5934–5937)。然而,在正常组织中,据报导SSEA-4在红血球及数个腺体组织的上皮细胞中以少量GSL表达(Kannagi etal.(1983)EMBO J.2:2355–236)。由于其性质,SSEA-4可作为癌症免疫疗法的有利独特标靶。
Siglecs(唾液酸结合免疫球蛋白型凝集素)为结合唾液酸的细胞表面蛋白家族,且主要在免疫细胞上发现。有14种不同的哺乳动物Siglecs,依据细胞表面受体-配体的相互作用,提供一系列的不同功能(Pillai et al.(2012)Annual Review ofImmunology.30:357–92)。多数Siglecs由于含有ITIM的细胞质区域,可抑制免疫细胞活化。Siglecs在结合至其配体时,经由其ITIM域招募抑制性蛋白质(如SHP磷酸酶)(Avril etal.(2004)Journal of Immunology.173(11):6841–9),其导致免疫细胞失活。因此,破坏Siglecs与其配体间的相互作用,可促进抗肿瘤免疫性。
唾液酸结合类免疫球蛋白(Ig)凝集素或SIGLEC(如CD33)为第一型跨膜蛋白家族,各具有独特的表达模式,大部分位于造血细胞中。位于19q13.3-q13.4的SIGLEC的类CD33亚组具有2个保守性细胞质酪氨酸为主的基序:免疫受体酪氨酸为主的抑制性基序(或ITIM)及在信号传导淋巴细胞活化分子(SLAM)中鉴定出的基序同源的基序,所述分子介导与SLAM关联蛋白(SAP)的结合。
唾液酸结合类Ig凝集素-9(Siglec-9)为表达在免疫与造血细胞,包括未成熟与成熟骨髓细胞(如单核细胞、巨噬细胞、树突细胞、嗜中性粒细胞、及微胶质细胞),以及类淋巴细胞(lymphoid cells)(如自然杀手细胞、B细胞、及CD8+T细胞的子集)上的第一型类免疫球蛋白跨膜蛋白(Crocker et al.(2007)Nat Rev Immunol.7:255-266;O'Reilly andPaulson(2009)Trends in Pharm.Sci.30:5:240-248;及Macauley et al.(2014)Nat.Rev.Imm.14:653-666)。Siglec-9为凝集素的Siglec家族成员,其结合糖蛋白与糖脂质的唾液酸残基。Siglec蛋白的一个潜在结合标靶为神经节苷脂(gangliosides);亦即,由神经酰胺连接唾液酸化聚糖所构成的糖脂质。大多数神经节苷脂享有共同的乳酸神经酰胺核心及一个或多个唾液酸残基。Siglec配体多样性的产生,藉由在不同的连接中(不论是支链或末端)添加其他中性糖类与唾液酸,以及修饰唾液酸本身。
在人体中,已鉴定出14种Siglec蛋白,且在小鼠中有9种,其由2-17个细胞外Ig域组成,包括氨基端V组域,其含有唾液酸结合位点。唾液酸结合区位于V组类Ig域,其在所有Siglecs中含有高度保守的2个芳香性残基与1个精氨酸的基序(Crocker et al.(2007)NatRev Immunol.7:255-266;McMillan and Crocker(2008)Carbohydr Res.343:2050-2056;Von Gunten and Bochner(2008)Ann NY Acad Sci.1143:61-82;May et al.(1998)MolCell.1:719-728;Crocker et al.(1999)Biochem J.341:355-361;以及Crocker andVarki(2001)Trends Immunol.2:337-342)。利用有与无结合配体的晶体结构,描绘出唾液酸化配体的结合位点(Attrill et al.(2006)J.Biol.Chem.28132774-32783;Alphey etal.(2003)J.Biol.Chem.278:5 3372-3377;Varki et al.,Glycobiology,16pp.1R-27R;以及May et al.(1998)Mol.Cell 1:5:719-728)。由于细胞膜富含唾液酸,因此Siglecs的配体结合可以顺式与反式的形式发生,两者皆影响其功能性质。各Siglec在结合哺乳动物细胞表面上发现的多样类型的唾液酸化聚糖上具有不同的偏好(Crocker et al.(2007)NatRev Immunol.7:255-266;以及Crocker et al.(2007)Nat Rev Immunol.7:255-266)。多数Siglec蛋白(包括Siglec-9)在其细胞质尾端含有一个或多个免疫受体酪氨酸为主的抑制性基序(ITIM)序列,使其能通过招募酪氨酸磷酸酶SHP1与SHP2,作为免疫功能的抑制受体及负调节剂(Crocker et al.(2007)Nat Rev Immunol.7:255-266;McMillan and Crocker(2008)Carbohydr Res.343:2050-2056;以及Von Gunten and Bochner(2008)Ann NY AcadSci.1143:61-82)。特定Siglecs的细胞质尾端含有免疫受体酪氨酸为主的活化基序(immunoreceptor tyrosine-based activating motif;ITAM)序列,使其能通过预测的招募脾酪氨酸激酶(spleen tyrosine kinase;Syk),作为免疫功能的活化受体及正调节剂(Macauley SM.et al.(2014)Nature Reviews Immunology 14,653-666)。Siglec蛋白家族与多种人类疾病有关,该疾病包括自体免疫性、感染易感性、多种类型癌症(包括淋巴瘤、白血病、及急性髓样白血病)、系统性红斑狼疮、类风湿性关节炎、神经变性性疾病、哮喘、变态反应、败血症、慢性阻塞性肺疾、移植物抗宿主病、嗜酸粒细胞增多、及骨质疏松症(Macauley SM.et al.(2014)Nature Reviews Immunology 14,653-666)。
Siglec-9在2000年从外周血单个核细胞中克隆出来(Angata and Varki(2000)J.Biol.Chem.275:29:22127-22135),并在颗粒细胞与单核细胞上检测到选择性表达。一独立团队从HL-60(人类前髓细胞白血病)细胞中分离出Siglec-9,并证实其在单核细胞、嗜中性粒细胞、NK细胞、B细胞、及CD8+T细胞的小型子集合上表达(Zhang et al.(2000)J.Biol.Chem.275:2922121-22126)。
Siglec-9在其细胞质域中含有1个细胞外N端类Ig(类免疫球蛋白)V型域,2个类IgC2组域,以及2个共有的ITIM基序。在COS细胞中表达Siglec-9时,证实以唾液酸依赖性方式结合红血球,其由末端a2-3或a2-6唾液酸连接介导(Angata and Varki(2000)J.Biol.Chem.275:22127-22135;Zhang et al.(2000)J.Biol.Chem.275:29 22121-22126)。进一步证实,Siglec-9由内源性细胞唾液酸屏蔽(masked),且仅在以唾液酸酶(sialidase)处理细胞时,结合至外源性末端a2-3或a2-6唾液酸探针(Yamaji(2002)J.Biol.Chem.277:8 6324-6332)。藉由交换Siglec-7与Siglec-9的区域(反之亦然),将Siglec-9 N端V组类Ig域内的的配体特异性映射至一小型区域Asn70-Lys75。在这些氨基酸残基内所取得个别Siglec配体特异性,支持一观点,即配体特异性由可变C-C'环的相互作用决定(Yamaji(2002)J.Biol.Chem.277:8 6324-6332)。病源体显然将唾液酸视为“自我”系统,因据报导,B群组链球菌可结合人类嗜中性粒细胞上的Siglec-9,从而降低对细菌(其可为致病性或常见的)的免疫反应(Carlin et al(2009)Blood 113:3333-3336)。体内Siglec-9唾液酸配体的其他来源为肿瘤分泌性粘蛋白,如MUC1、MUC2、MUC16;Siglec-9显示与癌症患者血清中的粘蛋白结合(Ohta et al.(2010)Biochem.andBiophys.Res.Comm.402:663-669;Belisle et al.(2010)Mol.Cancer 9:118)。
Siglec-9藉由酪氨酸激酶(可能是c-Src或Lck)磷酸化Tyr-433与Tyr-456,且功能为抑制性受体(Avril et al.(2004)J.Imm.173:6841-6849)。在ITIM域的近端Tyr-433的磷酸化后,Siglec-9结合SHP-2/PTPN11与SHP-1/PTPN6。由于突变并未排除酪氨酸磷酸化或Siglec-9的抑制性功能,因此膜远端ITIM基序似乎无显著贡献。Siglec-9显示可抑制FcERI介导的大鼠嗜碱性白血病细胞活性,该活性先前用于表征表达在NK细胞上的抑制性受体类别,称作KIRs(杀手类Ig受体)(Avril et al.(2004)J.Imm.173:6841-6849)。
磷酸酶活性另外与细胞内钙运动下降及多种蛋白质上酪氨酸磷酸化降低(Ulyanova,T.,et al.(1999)Eur J lmmunol 29,3440-3449;Paul,S.P.,et al.(2000)Blood 96,483-490)以及阻断信号转导与免疫反应(部分通过相邻的活化受体(包括含有ITAM基序的受体、模式识别受体(pattern recognition receptors)、Toll样受体(Toll-like receptors)、及损伤相关联的分子模式(DAMP)受体)上信号传导分子的去磷酸化)相关联。现已提出,含ITIM的Siglec受体与活化受体间的关联可由细胞外配体介导,其结合及桥接这些受体(Macauley SM.et al.(2014)Nature Reviews Immunology 14,653-666)。一些但并非全部的Siglec配体可诱导受体向下调节(Macauley SM.et al.(2014)NatureReviews Immunology 14,653-666)。酪氨酸激酶受体(Monsonego-Oran et al.(2002)Febsletters 528,83-89;以及Fasen et al.(2008)Cell&Molecular Biology 9.251-266)以及类固醇受体(Callige et al.(2005)Mol.Cell.Biol.25.4349-4358;以及Pollenz et al.(2006)Chemico-Biological Interactions.164.49-59)据报导出现配体诱导性受体降解。现认为,Siglec-9在急性髓样白血病(AML)细胞中经组成性回收,并显示可在这些细胞上介导抗Siglec-9单克隆抗体的快速胞饮作用(Biedermann et al.(2007)Leuk.Res.31:2:211-220)。然而,在AML或正常原代免疫细胞中,未有Siglec-9细胞浓度降低的报导。同样地,在任何类型的原代细胞中,未有受体再循环或抗体依赖性受体向下调节的报导。依据过表达系统进行的突变分析,Siglec-9在细胞表面上的表达部分取决于膜近端ITIM基序,而非远端基序(Biedermann et al.(2007)Leuk.Res.31:2:211-220)。
发明概述
本发明基于令人惊讶的发现,即阶段特异性胚胎抗原4(SSEA-4)可选择性结合Siglec-9,从而调控肿瘤对免疫细胞呈现。具体而言,本发明提供含有SSEA-4抗体的方法与组合物,以调控SSEA-4-Siglec-9的相互作用,从而增进肿瘤免疫呈现及改进NK细胞介导的细胞毒性。
在一方面,本发明的特征在于,对SSEA-4具有特异性的抗体或其结合片段,其可调控SSEA-4与Siglec-9的结合。抗SSEA-4抗体结合至Neu5Acα2→3Galβ1→3GalNAcβ1→3Galα1→4Galβ1→4Glcβ1。
在一方面,本发明提供一种治疗具有表达SSEA-4抗原的肿瘤细胞的受试者的方法,本方法包含施用受试者有效量的含有抗SSEA-4抗体或其片段的药物组合物。
在一实施方案中,抗SSEA-4抗体结合至肿瘤细胞可降低SSEA-4与Siglec-9间的结合相互作用。
在一实施方案中,SSEA-4与Siglec-9间的结合相互作用降低可导致Siglec-9与肿瘤细胞的结合下降。在一实施方案中,Siglec-9与肿瘤细胞的结合下降可诱发由Siglec-9/SSEA-4的接合所维持的免疫抑制(免疫屏蔽)的释出。
在一实施方案中,施用抗SSEA-4抗体可增加细胞毒性免疫细胞的活性。在一实施方案中,细胞毒性免疫细胞为NK细胞。
在一特定实施方案中,抗体或其抗原结合片段系选自于:
完整免疫球蛋白分子;
scFv;
Fab片段;
F(ab')2;或
双硫键连接的Fv。
在特定实施方案中,抗体为人源化抗体。
在特定实施方案中,抗体为IgG或IgM。
在特定实施方案中,药物组合物进一步包含至少一额外的治疗性药剂。
在一方面,本发明提供一种用于抑制癌细胞增殖的方法,包含施用有需求的受试者有效量的示例性药物组合物,其中癌细胞的增殖受抑制。表达SSEA-4的癌症包括但不局限于,肉瘤、白血病、淋巴瘤、胶质母细胞瘤、肺癌、乳癌、肺癌、食道癌、直肠癌、胆道癌、肝癌、口腔癌、胃癌、结肠癌、鼻咽癌、口咽癌、喉癌、食道癌、胃癌、肝癌、胆管癌、胆囊癌、膀胱癌、肠癌、肾癌、前列腺癌、卵巢癌、宫颈癌、子宫内膜癌、胰腺癌、睾丸癌、膀胱癌、头颈癌、口腔癌、神经内分泌癌、肾上腺癌、甲状腺癌、骨癌、皮肤癌、基底细胞癌、鳞状细胞癌、黑色素瘤、或脑肿瘤。
在特定实施方案中,本发明提供一种用于治疗受试者的癌症的方法。本方法包含施用有需求的受试者有效量的本文所述的示例性抗体。
本发明的一或多个实施方案将详述如下。本发明的其他特征和/或优势将显见于附图、数个实施方案的详述、及所附权利要求书。
附图简述
当参考附图且接合后续详尽说明考量时,可获取本发明的更完整理解。附图所示的实施方案仅旨在示例本发明,且不应理解为局限于本发明所述的实施方案。
图1.Siglec-9与SSEA-4神经酰胺的ELISA结合试验。
图2.利用外源性SSEA-4神经酰胺增加Siglec-9对肺癌细胞系(A549)的结合。
图3.利用添加示例性抗SSEA-4 Fab(OBI-898)降低Siglec-9与乳癌细胞系(MDA-MB 231)的结合。
图4.利用抗SSEA-4 Fab(OBI-898)与乳癌细胞系(MDA-MB 231)上SSEA-4的结合增进人类PBMC的细胞毒性。
图5.利用抗SSEA-4 Fab(OBI-898)与卵巢癌细胞系(SKOV-3)上SSEA-4的结合增进人类PBMC的细胞毒性。
图6.利用抗SSEA-4 Fab(OBI-898)与卵巢癌细胞系(SKOV-3)上SSEA-4的结合增进癌自御(Tecentriq)的细胞毒性。
图7.抗SSEA-4抗体(OBI-898)结合Siglec-9以释出免疫抑制的作用机制示意图。
图8.阶段特异性胚胎抗原4(SSEA-4)的结构。
图9.人类唾液酸结合免疫球蛋白型凝集素(Siglecs)的聚糖结合特异性。
图10.唾液酸结合的类Ig凝集素-9(Siglec-9)的示例性配体。
发明详述
本公开基于令人惊讶的发现,即阶段特异性胚胎抗原4(SSEA-4)可选择性结合Siglec-9,从而调控肿瘤对免疫细胞呈现。具体而言,本公开提供含有SSEA-4抗体的方法与组合物,以调控SSEA-4-Siglec-9的相互作用,从而增进肿瘤免疫呈现及改进NK细胞介导的细胞毒性。
本公开描述抗SSEA-4抗体的用途,作为癌症免疫疗法的一种新颖免疫检查点阻断疗法。SSEA-4首先经证实为Siglec-9的一种新颖肿瘤相关联的碳水化合物配体。抗SSEA-4抗体经发现可阻断Siglec-9与SSEA-4间的相互作用。体外试验显示,抗SSEA-4抗体强力逆转Siglec-9在NK细胞上的抑制功能,导致随后杀死肿瘤细胞。本文的揭示证实,靶向肿瘤细胞上的SSEA-4,可藉由阻断SSEA-4与Siglec-9间的接合,释出免疫细胞活性。因此,SSEA-4抗体可作为免疫检查点阻断剂(immune checkpoint blocker),可单独或结合其他用于肿瘤学的药剂。
在一方面,本公开涉及抗SSEA-4抗体与治疗性肿瘤学药剂的组合的用途,用以治疗癌症患者。在特定实施方案中,抗体为OBI-898(抗SSEA-4单克隆抗体)。示例性OBI-898如PCT专利公开号(WO2017172990A1)、美国专利公开号(US2018339061A1)专利申请案所述,其各自内容在此全部并入本案以作为参考资料。在一方面,本公开基于一项发现,即癌症上的SSEA-4可与免疫细胞上的Siglecs相互作用,造成免疫细胞失活。添加抗SSEA-4抗体以阻断SSEA-4与Siglecs间的接合,可释出免疫细胞的细胞毒性。治疗性肿瘤学药剂可与抗SSEA-4抗体组合,以增加对肿瘤的免疫细胞的毒性。
在一方面,本公开涉及与用于肿瘤学的治疗性药剂(如治疗性抗体和/或化学治疗性药剂)组合的抗SSEA-4抗体。本公开提供基于施用抗SSEA-4抗体的理念的实例,以挽救由SSEA-4与Siglecs的接合所诱导的免疫细胞失活,以改进抗癌功效。
已有描述,Siglec-9对细胞因子的产生具有免疫调控效果。在巨噬细胞的细胞系中,过表达Siglec-9且伴随TLR刺激,显示与促炎性细胞因子TNF-α与IL-6的产量下降及IL-10的上调相关联(Ando et al.(2008)Biochem.And Biophys.Res.Comm.369:878-883)。亦有显示,肿瘤产生的粘蛋白(mucins)结合至Siglec-9及未成熟的DC(Ohta et al.(2010)Biochem.and Biophys.Res.Comm.402:663-669)。在LPS与粘蛋白存在下,未成熟的DC产生较少的IL-12,但IL-10产量维持不变。此显示,Siglec-9使细胞因子的产生从促发炎性转向抗发炎性,从而相对于有害病原体、癌症、或其他病理学的清除,可维持耐受性的免疫状态。
Siglec-9的抑制性角色的进一步特征在于,自然杀手细胞(natural killercells)的功能及类淋巴细胞(如T细胞与嗜中性粒细胞)的调节(Crocker et al.(2012)Ann.N Y Acad.Sci.1253,102-111;Pillai et al.(2012)Annu.Rev.Immunol.30,357-392;von Gunten and Bochner(2008)Ann.N Y Acad.Sci.1143,61-82;Jandus et al.(2014)J.Clin.Invest.124(4)1810-1820;Ikehara et al.(2004)J.Biol.Chem.279:41 43117-43125;以及von Gunten et al.(2005)Blood106(4)1423-1431)。自然杀手细胞的功能性研究证实,表达Siglec-9结合唾液酸配体的肿瘤细胞可抑制NK细胞活化及杀死肿瘤细胞。许多人类肿瘤会强烈上调结合Siglec-9的唾液酸配体,其促使免疫脱逃(immune evasion)及癌症进展(Jandus et al.(2014)J.Clinic.Invest.124:4:1810-1820)。一般认为,唾液酸对肿瘤的上调,可促进“超级自我(super self)”的状态,其强烈抑制自然杀手细胞的免疫监视(immunosurveillance)(Macauley and Paulson(2014)Nat.Chem.Biol.10:1:7-8)。在类淋巴谱系细胞中,Siglec-9显示可经由ITIM酪氨酸磷酸化与SHP-1结合而负向调节T细胞受体信号传导。下游TCR信号传导分子ZAP-70显示Tyr319磷酸化下降及NFAT转录活性降低。当唾液酸配体结合域的保守性精氨酸残基突变时,Siglec-9对TCR信号传导的抑制效果下降(Ikehara et al.(2004)J.Biol.Chem.279:41 43117-43125)。在嗜中性粒细胞中,Siglec-9的接合可经由凋亡与非凋亡机制介导细胞死亡。嗜中性粒细胞源自非疾病性或类风湿性关节炎,且急性败血性休克患者历经Siglec-9依赖性死亡,其由抗体交联反应证实。败血性或RA患者衍生的嗜中性粒细胞证实,在Siglec-9连接时,有明显更多的细胞死亡;此增加可由与促发炎性细胞因子的短期预先培养而仿效,证实发炎导致引发Siglec-9死亡途径(Belisle et al.(2010)Mol.Cancer 9:118)。
Siglec-9的鼠科同源物为Siglec-E,其具有53%类似性。Siglec-E显示以唾液酸依赖性方式结合人类红血球,且在功能上类似Siglec-9,经由ITIMs招募SHP-1与SHP-2,在免疫细胞中介导抑制性信号传导(Yu et al Biochem.J.(2001)353,483-492)。在小鼠中,Siglec-E的基因失活,不会导致明显发育、组织学、或行为异常;且Siglec-E缺陷小鼠正常繁殖,代表Siglec-E并非必需的基因,且其功能可能局限在先天免疫(McMillan et al.(2013)Blood 121:11:2084-2094)。在以气溶胶LPS攻击Siglec-E缺陷小鼠时,证实增加肺脏中的嗜中性粒细胞招募,可藉由阻断132-整合素CD11b而逆转。Siglec-E缺陷型嗜中性粒细胞显示,以CD11b依赖性方式增加Syk与p38 MAPK的磷酸化。此证实,Siglec-E在急性肺脏发炎模型中的功能为抑制嗜中性粒细胞招募(McMillan et al.(2013)Blood 121:11:2084-2094)。在同基因(syngeneic)的癌症模型中,Siglec-E缺陷小鼠的嗜中性粒细胞可增进离体肿瘤细胞杀伤能力,并证实增加ROS产生与细胞凋亡诱导性配体(如TRAIL与FasL)(Laubli et al.(2014)PNAS 111(39)14211-14216)。
在肿瘤学上,经证实Siglec-9可作为急性髓样白血病的治疗标靶,因其在原代AML细胞上表达,但在许多患者骨髓样本的祖细胞中却不存在(Biedermann et al.(2007)Leuk.Res.31:2:211-220)。在实体癌中,上皮肿瘤细胞产生大量糖基化粘蛋白,其与Siglec-9结合,显示阻断增加的配体相互作用在治疗上有益(Ohta et al.(2010)Biochem.and Biophys.Res.Comm.402:663-669;Belisle et al.(2010)Mol.Cancer 9:118)。此外,在结直肠癌、乳癌、卵巢癌、非小细胞肺癌、及前列腺癌的组织切片中,发现Siglec-9配体的强力表达及肿瘤浸润Sig1ec-9+免疫细胞(Laubli et al.(2014)PNAS 111(39)14211-14216)。天然存在的降低唾液酸基配体结合的Siglec-9K131Q(A391C)多态性(rs16988910)发现,在非小细胞肺癌患者中,可明显改进早期存活率(<2年),尽管该效果在2年后消失(Laubli et al.(2014)PNAS 111(39)14211-14216)。
近来提出,表达在癌细胞上的唾液酸基-糖蛋白可经由Siglec-9结合,传导“活化”信息至肿瘤细胞,造成局部粘着激酶(Focal adhesion kinase;FAK)降解及细胞运动与侵袭增加(Sabit et al.(2013)J.Biol.Chem.288(49):35417-35427)。这些结果显示,Siglec-9-唾液酸基配体相互作用不仅对免疫系统的多种细胞类型具有抑制效果,还能经由直接对癌细胞作用以增进肿瘤转移。
据此,需要治疗性抗体,其特异性调控Siglec-9与一或多个Siglec-9配体间的Siglec-9相互作用,和/或降低一或多个Siglec-9活性,以治疗一或多个与Siglec-9活性不良相关联的疾病、病症、及病况。
定义
除非另有指明,本发明的实施采用分子生物学、微生物学、重组型DNA、及免疫学等常规技术,其皆落于本领域技术范围内。此类技术于文献中完整解释。参见,例如,Molecular Cloning A Laboratory Manual,2nd Ed.,ed.by Sambrook,Fritsch andManiatis(Cold Spring Harbor Laboratory Press,1989);DNA Cloning,Volumes I andII(D.N.Glover ed.,1985);Culture Of Animal Cells(R.I.Freshney,Alan R.Liss,Inc.,1987);Immobilized Cells And Enzymes(IRL Press,1986);B.Perbal,A PracticalGuide To Molecular Cloning(1984);the treatise,Methods In Enzymology(AcademicPress,Inc.,N.Y.);Gene Transfer Vectors For Mammalian Cells(J.H.Miller andM.P.Calos eds.,1987,Cold Spring Harbor Laboratory);Methods In Enzymology,Vols.154and 155(Wu et al.eds.),Immunochemical Methods In Cell And MolecularBiology(Mayer and Walker,eds.,Academic Press,London,1987);Antibodies:ALaboratory Manual,by Harlow and Lane s(Cold Spring Harbor Laboratory Press,1988);以及Handbook Of Experimental Immunology,Volumes I-IV(D.M.Weir andC.C.Blackwell,eds.,1986)。
如本文中使用的,术语“聚糖”意指多糖或寡糖。本文中使用的聚糖亦指糖缀合物(glycoconjugate),如糖蛋白、糖脂质、糖肽、糖蛋白体、肽聚糖、脂多糖、或蛋白聚糖的碳水化合物部分。聚糖通常仅由单糖类间的O-糖苷键联组成。举例而言,纤维素为由β-1,4-键结的D-葡萄糖组成的聚糖(或更特别地葡聚糖),且几丁质为由β-1,4-键结的N-乙酰基-D-葡萄糖胺组成的聚糖。聚糖可为单糖残基的均聚物或杂聚物,且可为直链或支链。可发现与糖蛋白和蛋白聚糖中蛋白质相连的聚糖。其通常于细胞外表面上发现。O-与N-键结的聚糖类很常见于真核生物,但亦可于原核生物中发现,尽管较不常见。N-键结的聚糖发现附着于序列子(sequon)的天冬酰胺的R基团氮(N)。序列子为Asn-X-Ser或Asn-X-Thr序列,其中X为除了脯氨酸以外的任何氨基酸。
如本文中使用的,“抗原”术语定义为任何能引发免疫反应的物质。
如本文中使用的,“免疫原性”术语意指免疫原、抗原、或疫苗引发免疫反应的能力。
如本文中使用的,“表位”术语定义为抗原分子接触抗体或T细胞受体的抗原结合位点的部分。
如本文中使用的,“疫苗”术语意指含有抗原的制备物,其由完整致病生物体(非活性或弱化)或此类生物体的组分(如蛋白质、肽、或多糖)所组成,用于赋予免疫性以对抗生物体导致的疾病。疫苗制备物可包括或排除天然、合成、或重组所衍生制备物的任一者。重组衍生的制备物可利用如重组型DNA技术取得。
如本文中使用的,“抗原特异性”术语意指细胞群的性质,使得特定抗原或抗原片段的供应造成特异性细胞增殖。
如本文中使用的,“特异性结合”术语意指结合对(如抗体与抗原)间的相互作用。在各种情况下,特异性结合可通过亲和性常数约10-6摩尔/升、约10-7摩尔/升、或约10-8摩尔/升或以下而实施。
如本文中使用的,短语“实质上类似”、“实质上相同”、“等同”、或“实质上等同”表示两个数值间足够高的相似程度(例如,一者与分子相关联,且其他者与参考/比较分子相关联),使得本领域技术人员在由所述值(如Kd值、抗病毒功效等)测量的生物特征背景中,将考虑到两个值间的差异为微小或无生物上和/或统计上显著性。举例而言,所述两个值间的差异为,作为参考/比较分子的值的函数,小于约50%、小于约40%、小于约30%、小于约20%、和/或小于约10%。
如本文中使用的,短语“实质上减少”或“实质上不同”表示两个数值间足够高的差异程度(一般而言一者与分子相关联,且其他者与参考/比较分子相关联),使得本领域技术人员在由所述值(如Kd值)测量的生物特征背景中,将考虑到两个值间的差异为统计上显著性。举例而言,所述两个值间的差异为,作为参考/比较分子的值的函数,大于约10%、大于约20%、大于约30%、大于约40%、和/或大于约50%。
如本文中使用的,“结合亲和性”一般而言意指分子(如抗体)的单一结合位点与其结合配对体(如抗原)间全部非共价相互作用总和的强度。除非另有指明,如本文中使用的“结合亲和性”意指固有结合亲和性,其反映了结合配对(如抗体与抗原)成员间的1:1相互作用。分子X与其配对体Y的亲和性一般而言可以解离常数(Kd)表示。亲和性可利用本领域习知的常见方法测定,包括本文所述者。低亲和性抗体一般而言结合抗原缓慢,且倾向容易解离,而高亲和性抗体一般而言结合抗原较快,且倾向保持更长结合时间。各测定结合亲和性的方法是本领域习知的,其任一者可用于本发明的目的。以下描述特定说明性实施方案。
于特定实施方案中,根据本发明的“Kd”或“Kd值”利用放射性标记抗原结合试验(RIA)测定,其以感兴趣抗体的Fab版本及其抗原进行,如下列试验所述。如下测定Fab对抗原的溶液结合亲和性:在存在滴定系列的未经标记的抗原下,以最小浓度(125I)标记的抗原平衡Fab,之后以抗Fab抗体涂布的板捕捉结合的抗原(Chen,et al.,(1999)J.Mol Biol293:865-881)。欲建立试验条件,将溶于50mM碳酸钠(pH 9.6)的5μg/mL捕捉抗Fab抗体(Cappel Labs)隔夜涂布于微量滴定板(Dynex),接着于室温下(约23℃)以溶于PBS的2%(w/v)牛血清白蛋白阻断二至五小时。于非吸附板中(Nunc,Cat#269620),将100pM或26pM[125I]抗原混合一系列稀释的感兴趣的Fab(例如,与抗VEGF抗体Fab-12的评估一致,参见Presta et al.,(1997)Cancer Res.57:4593-4599)。感兴趣的Fab随后隔夜培养;不过,可持续培养更长时间(如65小时)以确保达到平衡。之后将混合物移至捕捉板以室温培养(如一小时)。接着移除溶液,并以含0.1%Tween-20的PBS清洗板八次。当板干燥时,每孔加入150μL闪烁剂(MicroScint-20;Packard),且板于Topcount伽玛计数器(Packard)上计数十分钟。选择各Fab浓度产生小于或等于最大结合的20%,用于竞争结合试验。依据另一实施方案,于25℃下,利用表面等离振子共振试验(surface plasmon resonance assays)测定Kd或Kd值,其系使用BIAcoreTM-2000或BIAcoreTM-3000(BIAcore,Inc.,Piscataway,N.J.),其中使用固定化抗原CM5芯片,其响应单位(RU)为约10。简言之,依据供应商说明,以N-乙基-N′-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDC)与N-羟基琥珀酰亚胺(NHS)活化羧甲基化葡聚糖生物感应器芯片(CM5,BIAcore Inc.)。抗原事先以10mM乙酸钠(pH 4.8)稀释至5μg/mL(~0.2μM),再以流速5μL/分钟注射,达到约10响应单位(RU)的偶联蛋白。于抗原注射后,注射1M乙醇胺以阻断未反应基团。于各实验中,墨点(spot)经活化及乙醇胺阻断,而不固定蛋白,以用于参考减法(reference subtraction)。在动力学测定方面,于25℃下,将二倍系列稀释的Fab(0.78nM至500nM)注入含0.05%Tween 20的PBS(PBST),其流速约25μL/min。利用简单一对一朗缪尔结合模型(Langmuir binding model)(BIAcore EvaluationSoftware version 3.2)计算结合速率(kon)与解离速率(koff),其通过同时拟合(fitting)结合与解离传感图进行。计算平衡解离常数(Kd)为koff/kon比率。参见,如Chen,Y.,et al.,(1999)J.Mol Biol293:865-881。若前述表面等离振子共振试验所得的结合速率超过106M-1s-1,则可利用荧光淬火技术(fluorescent quenching technique)测定结合速率,所述荧光淬火技术于25℃下测定溶于PBS(pH 7.2)的20nM抗原抗体(Fab形式)的荧光发射强度(激发=295nm;发射=340nm,16nm带通)的增加或减少,其中存在浓度渐增的抗原,并以分光光度计测定,如停止流量分光光度计(Aviv Instruments)或配备搅拌型比色管的8000系列SLM-Aminco分光光度计(ThermoSpectronic)。
根据本发明的“结合速率(on-rate或rate of association或association rate或kon)”皆可于25℃下以前述的相同表面等离振子共振试验测定,并使用BIAcoreTM-2000或BIAcoreTM-3000(BIAcore,Inc.,Piscataway,N.J.),伴随固定化抗原CM5芯片,或者,根据本发明的“结合速率(association rate或kon)”亦可依据供应商说明,以相同表面等离振子N-乙基-N′-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDC)与N-羟基琥珀酰亚胺(NHS)测定。抗原事先以10mM乙酸钠(pH 4.8)稀释至5μg/mL(约0.2μM),再以流速5μL/分钟注射,达到约10响应单位(RU)的偶联蛋白。于抗原注射后,注射1M乙醇胺以阻断未反应基团。在动力学测定方面,于25℃下,将二倍系列稀释的Fab(0.78nM至500nM)注入含0.05%Tween 20的PBS(PBST),其流速约25μL/min。利用简单一对一朗缪尔结合模型(BIAcore EvaluationSoftware version 3.2)计算结合速率(kon)与解离速率(koff),其通过同时拟合结合与解离传感图进行。计算平衡解离常数(Kd)为koff/kon比率。参见,如Chen,Y.,et al.,(1999)J.Mol Biol293:865-881。然而,若前述表面等离振子共振试验所得的结合速率超过106M- 1s-1,则可利用荧光淬火技术测定结合速率,所述荧光淬火技术于25℃下测定溶于PBS(pH7.2)的20nM抗抗原抗体(Fab形式)的荧光发射强度(激发=295nm;发射=340nm,16nm带通)的增加或减少,其中存在浓度渐增的抗原,并以分光光度计测定,如停止流量分光光度计(Aviv Instruments)或配备搅拌型比色管的8000系列SLM-Aminco分光光度计(ThermoSpectronic)。
如本文中使用的“抗体(Ab)”及“免疫球蛋白(Igs)”是具有相同结构特征的糖蛋白。尽管抗体对特定抗原呈现结合特异性,但免疫球蛋白包括抗体与其他类抗体分子,其一般而言缺乏抗原特异性。举例而言,后一类多肽由淋巴系统于低量时及骨髓瘤于增量时产生。
如本文中使用的“抗体”与“免疫球蛋白”术语于最广泛的意义上互换使用,且包括单克隆抗体(如全长或完整单克隆抗体)、多克隆抗体、单价、多价抗体、多特异性抗体(如双特异性抗体,只要其具有所需的生物活性),且亦可包括特定抗体片段,如本文的更详尽说明。抗体可为嵌合、人类、人源化、和/或亲和性成熟抗体。
如本文中使用的抗体“可变区域(variable region)”或“可变域(variabledomain)”意指抗体重链或轻链的氨基端区。这些域一般而言是抗体的最可变部位,且含有抗原结合位点。
如本文中使用的“可变”术语意指事实上于抗体中可变区的特定部分序列差异极大,且用于各特定抗体对其特定抗原的结合及特异性。然而,于整个抗体可变域中,可变性并未均匀分布。其集中于三片段,称作互补决定区(CDRs)或高变区域,皆位于轻链与重链可变域。可变域中更高度保守的部分称作主链(framework;FR)。原始重链与轻链的可变区各包含四个FR区,大量具备β片层构型,利用三CDR相连接,其形成环连接,且在一些情况下,形成β片层结构的一部分。各链的CDR利用FR区与其他链的CDR紧贴在一起,导致形成抗体的抗原结合位点(参见,Kabat et al.,Sequences of Proteins of Immunological Interest,Fifth Edition,National Institute of Health,Bethesda,Md.(1991))。恒定域未直接涉及抗体与抗原的结合,但呈现多种效应子功能,如抗体参与抗体依赖性细胞毒性。
“Fv”为最小抗体片段,其含有完整的抗原识别与结合位点。于二链Fv种类,此区由一个重链与一个轻链可变区的二聚体以紧密、非共价结合组成。于单链Fv种类中,一个重链与一个轻链可变域可利用柔性肽连接子共价连接,如此轻链与重链可结合成“二聚体”结构,其类似于双链Fv种类。于此构型中,各可变域的三个CDR相互作用,以在VH-VL二聚体表面上界定出抗原结合位点。总的来说,该六个CDR赋予抗原与抗体结合特异性。然而,即使单一可变域(或Fv之一半,其仅含有三个对抗原特异性的CDR)仍具有识别及结合抗原的能力,尽管其亲和性低于整体结合位点。
“Fab”片段亦含有轻链恒定域与重链第一恒定域(CH1)。Fab′片段不同于Fab片段之处在于重链CH1域羧基端增加数个残基,包括一或多个半胱氨酸位于抗体铰链区。Fab′-SH于此表示Fab′恒定域的半胱氨酸残基含有游离硫醇基。产生的F(ab′)2抗体片段起初为Fab′片段配对,其间具有铰链半胱氨酸。抗体片段的其他化学偶联亦为习知。
任何脊椎动物物种的抗体(免疫球蛋白)的“轻链”可指定为两个明显不同类型之一,称作卡帕(κ)与拉目达(λ),其以其恒定域的氨基酸序列为基准。
术语“全长抗体”、“完整抗体”、及“全部抗体”于此可互换使用,意指抗体实质上为完整形式,而非以下定义的抗体片段。该术语特别指抗体重链含有Fc区。
如本文中使用的“抗体片段”仅包含完整抗体的一部分,其中该部分保留至少一个,且多达大多数或全部的通常与完整抗体中存在时该部分相关联的功能。于一个实施方案中,抗体片段包含完整抗体的抗原结合位点,因此保留结合抗原的能力。于另一个实施方案中,抗体片段,如包含Fc区的抗体片段,保留至少一种通常与完整抗体中存在时的Fc区相关联的生物功能,如FcRn结合、抗体半衰期调控、ADCC功能、及补体结合。于一个实施方案中,抗体片段为单价抗体,其具有实质上类似于完整抗体的体内半衰期。举例而言,此抗体片段可具有连接至Fc序列的抗原结合臂(arm),所述Fc序列能赋予该片段体内稳定性。
如本文中使用的“单克隆抗体”术语意指抗体取自一群实质上均质化抗体,亦即构成该群的个别抗体皆相同,除了可能的天然存在的突变以外,其以少量存在。因此,修饰语“单克隆”代表抗体的特征并非个别抗体的混合物。此单克隆抗体通常包括含有结合标靶的多肽序列的抗体,其中该标靶结合多肽序列由过程取得,该过程包括由复数个多肽序列中挑选单一标靶结合多肽序列。于特定实施方案中,单克隆抗体可排除天然序列。于一些方面,挑选过程可以是由复数个克隆中挑选独特克隆,如融合瘤克隆库、噬菌体克隆库、或重组型DNA克隆库。应理解到,所挑选的标靶结合序列可进一步改变,例如改进标靶亲和性、人源化标靶结合序列、改进其于细胞培养中的产量、减少其体内免疫原性、创建多特异性抗体等,且含有改变的标靶结合序列的抗体亦为本发明的单克隆抗体。相对于通常包括针对不同决定区(如表位)的不同抗体的多克隆抗体制备物,单克隆抗体制备物的各单克隆抗体针对抗原上单一决定区。除了其特异性以外,单克隆抗体制备物的优势在于,其通常不受其他免疫球蛋白污染。修饰语“单克隆”代表抗体的特征为取自实质上均质化群体的抗体,且不应理解为需要以任何特定方法产生抗体。举例而言,根据本发明使用的单克隆抗体可利用各种技术制成,包括例如融合瘤方法(如Kohler et al.,Nature,256:495(1975);Harlowet al.,Antibodies:ALaboratory Manual,(Cold Spring Harbor Laboratory Press,2nded.1988);Hammerling et al.所著:Monoclonal Antibodies and T-Cell hybridomas563-681(Elsevier,N.Y.,1981))、重组型DNA方法(参见,如美国专利号4,816,567)、噬菌体显示技术(参见,如Clackson et al.,Nature,352:624-628(1991);Marks et al.,J.Mol.Biol.222:581-597(1992);Sidhu et al.,J.Mol.Biol.338(2):299-310(2004);Leeet al.,J.Mol.Biol.340(5):1073-1093(2004);Fellouse,Proc.Natl.Acad.Sci.USA 101(34):12467-12472(2004);以及Lee et al.,J.Immunol.Methods 284(1-2):119-132(2004)、及用于以动物产生人类或类人类抗体的技术,其具有部分或全部的人类免疫球蛋白基因座或编码人类免疫球蛋白序列的基因(参见,如WO98/24893;WO96/34096;WO96/33735;WO91/10741;Jakobovits et al.,Proc.Natl.Acad.Sci.USA 90:2551(1993);Jakobovits et al.,Nature 362:255-258(1993);Bruggemann et al.,Year inImmunol.7:33(1993);美国专利号5,545,807;5,545,806;5,569,825;5,625,126;5,633,425;5,661,016;Marks et al.,Bio.Technology 10:779-783(1992);Lonberg et al.,Nature 368:856-859(1994);Morrison,Nature 368:812-813(1994);Fishwild et al.,Nature Biotechnol.14:845-851(1996);Neuberger,Nature Biotechnol.14:826(1996)与Lonberg and Huszar,Intern.Rev.Immunol.13:65-93(1995)。
本文中单克隆抗体特别包括“嵌合”抗体,其中一部分的重链和/或轻链相同或同源于源自特定物种抗体或属于特定抗体类别或子类的序列,而链的其余部分则相同或同源于源自另一物种抗体或属于另一抗体类别或子类的相对应序列以及此类抗体的片段,只要其呈现所需的生物活性(美国专利号4,816,567;以及Morrison et al.,Proc.Natl.Acad.Sci.USA 81:6851-6855(1984))。
本发明的抗体亦包括由本发明抗体产生的嵌合化或人源化单克隆抗体。
抗体可为全长或可包含抗体的片段(或数个片段),其具有抗原结合部位,包括但不局限于,Fab、F(ab')2、Fab',F(ab)'、Fv、单链Fv(scFv)、二价scFv(bi-scFv)、三价scFv(tri-scFv)、Fd、dAb片段(如Ward et al,Nature,341:544-546(1989))、CDR、双抗体、三抗体、四抗体、线型抗体、单链抗体分子、及由抗体片段形成的多特异性抗体。单链抗体由连接抗体片段制成,其使用重组型方法或合成的连接子进行,亦涵盖于本发明之中。Bird etal.Science,1988,242:423-426;Huston et al,Proc.Natl.Acad.Sci.USA,1988,85:5879-5883。
本发明的抗体或其抗原结合部位可为单特异性、双特异性、或多特异性。
所有抗体同型皆涵盖于本发明之中,包括IgG(如IgGl、IgG2、IgG3、IgG4)、IgM、IgA(IgAl、IgA2)、IgD、或IgE(所有类别与子类皆涵盖于本发明之中)。抗体或其抗原结合部位可为哺乳动物(如小鼠、人类)抗体或其抗原结合部位。抗体的轻链可为κ或λ类型。
因此,本发明的抗癌症抗体包括结合非鼠源,较佳为人源的重链或轻链可变区、重链或轻链恒定区、框架区、或其任何部位,其可并入本发明的抗体。
“人源化”形式的非人类(如鼠科)抗体为嵌合抗体,其含有衍生自非人类免疫球蛋白的最小序列。于一个实施方案中,人源化抗体为人类免疫球蛋白(受体抗体),其中受体高变区的残基以非人类物种(供应体抗体)高变区的残基替代,该非人类物种如小鼠、大鼠、兔、或非人类灵长类,其具有所需的特异性、亲和性、和/或能力。于一些情况下,人类免疫球蛋白的框架区(FR)残基以相对应的非人类残基替代。此外,人源化抗体可包含未在受体抗体或供应体抗体中发现的残基。这些修饰的进行旨在进一步精化抗体表达。一般而言,人源化抗体将包含至少一个,及通常两个基本上整个可变域,其中所有或实质上所有高变环对应于那些非人类免疫球蛋白的,且所有或实质上所有FR是那些人类免疫球蛋白序列的。人源化抗体亦将可选择地包含通常人类免疫球蛋白的至少一部分免疫球蛋白恒定区(Fc)。详情请参见Jones et al.,Nature 321:522-525(1986);Riechmann et al.,Nature 332:323-329(1988);以及Presta,Curr.Op.Struct.Biol.2:593-596(1992)。亦请参见下列引用的回顾文献及其中引用的参考资料:Vaswani and Hamilton,Ann.Allergy,Asthma&Immunol.1:105-115(1998);Harris,Biochem.Soc.Transactions 23:1035-1038(1995);Hurle and Gross,Curr.Op.Biotech.5:428-433(1994)。
本文中使用时的术语“高变区”、“HVR”、或“HV”意指抗体可变域的区域,其序列高变和/或形成结构上可定义环。一般而言,抗体包含六个高变区;三者位于VH(H1、H2、H3),且三者位于VL(L1、L2、L3)。许多高变区轮廓被使用,且涵盖于本文中。卡贝特(Kabat)互补决定区(CDRs)依据序列可变性,且最常被使用(Kabat et al.,Sequences of Proteins ofImmunological Interest,5th Ed.Public Health Service,National Institutes ofHealth,Bethesda,Md.(1991))。丘夏(Chothia)则提出结构环的位置(Chothia and LeskJ.Mol.Biol.196:901-917(1987))。
如本文中使用的“框架”或“FW”残基是本文定义的高变区残基以外的那些可变域残基。
术语“如卡贝特(Kabat)中的可变域残基的编号方式”或“如卡贝特(Kabat)中的氨基酸位置的编号方式”及其变化,意指卡贝特(Kabat)等人在Sequences of Proteins ofImmunological Interest,5th Ed.Public Health Service,National Institutes ofHealth,Bethesda,Md.(1991)中,用于汇编抗体的重链可变域或轻链可变域的编号系统。使用此编号系统,实际的线型氨基酸序列可含有较少或额外的对应于缩短或插入可变域的FR或HVR的氨基酸。举例而言,重链可变域可包括位于H2的残基52之后的单一氨基酸插入子(如卡贝特的残基52a),以及位于重链FR残基82之后的插入残基(如卡贝特的残基82a、82b、及82c等)。卡贝特的残基编号方式可针对给定的抗体进行确定,其利用“标准”卡贝特编号序列比对抗体序列的同源区域进行。
如本文中使用的“单链Fv”或“scFv”抗体片段包含抗体的VH与VL域,其中这些域以单一多肽链呈现。一般而言,scFv多肽进一步包含介于VH与VL域之间的多肽连接子,其使得scFv形成所需结构以进行抗原结合。针对scFv之评述,参见Pluckthun的The Pharmacologyof Monoclonal Antibodies,vol.113,Rosenburg and Moore eds.,Springer-Verlag,NewYork,pp.269-315(1994)。
如本文中使用的术语“双抗体”意指具有两个抗原结合位点的小型抗体片段,该片段包含连接至相同多肽链(即VH-VL)的轻链可变结构域(VL)的重链可变域(VH)。利用过短而无法在相同链的两个域间进行配对的连接子,各域被迫与另一链的互补域配对并创建两个抗原结合位点。双抗体更充分描述于例如EP 404,097;WO93/1161;以及Hollinger etal.,Proc.Natl.Acad.Sci.USA 90:6444-6448(1993)中。
如本文中使用的“人类抗体”指如下的抗体,其拥有的氨基酸序列相应于人类产生的抗体和/或利用任一制备人类抗体的技术制备,如本发明揭示的。此人类抗体的定义特别排除含有非人类抗原结合残基的人源化抗体。
如本文中使用的“亲和性成熟抗体”为抗体之一或多个HVR具有一或多个改变,其造成改进抗体与抗原的亲和性,并与母体抗体相比较,其不产生那些改变。于一个实施方案中,亲和性成熟抗体具有纳摩尔或甚至皮摩尔的亲和性以靶向抗原。亲和性成熟抗体利用本领域习知的程序产生。Marks et al.Bio/Technology 10:779-783(1992)描述亲和性的成熟利用VH与VL区改组。CDR和/或框架残基的随机突变描述于:Barbas et al.ProcNat.Acad.Sci.USA91:3809-3813(1994);Schier et al.Gene 169:147-155(1995);Yeltonet al.J.Immunol.155:1994-2004(1995);Jackson et al.,J.Immunol.154(7):3310-9(1995);以及Hawkins et al,J.Mol.Biol.226:889-896(1992)。
如本文中使用的“阻断抗体”或“拮抗抗体”是抗体能抑制或减少所结合抗原的生物活性。特定阻断抗体或拮抗抗体实质上或完全地抑制抗原的生物活性。
如本文中使用的“激动抗体”是抗体模拟感兴趣的多肽功能活性的至少一者。
如本文中使用的“病症”是可受益于本发明抗体治疗的任何病况。其包括慢性与急性病症或疾病,包括那些使哺乳动物易患所讨论的病症的病理状况。欲治疗之病症的非局限实例包括癌症。
如本文中使用的术语“细胞增殖性病症”与“增殖性病症”意指与一定程度的异常细胞增殖相关联的病症。于一个实施方案中,细胞增殖性病症为癌症。
如本文中使用的“肿瘤”意指所有肿瘤细胞生长与增殖,不论恶性或良性,以及所有癌前与癌性细胞与组织。如本文中使用的术语“癌症”、“癌性”、“细胞增殖性病症”、“增殖性病症”、及“肿瘤”是非互斥的。
如本文中使用的“癌症”与“癌性”意指或说明哺乳动物生理条件,特征通常为未调节的细胞生长/增殖。癌症的实例包括但不局限于,癌、淋巴瘤(如霍奇金氏与非霍奇金氏淋巴瘤)、母细胞瘤、肉瘤、及白血病。此类癌症的更特定实例包括鳞状细胞癌、小细胞肺癌、非小细胞肺癌、肺腺癌、鳞状肺癌、腹膜癌、肝细胞癌、胃肠癌、胰腺癌、神经胶质母细胞瘤、宫颈癌、卵巢癌、肝癌、膀胱癌、肝瘤、乳癌、结肠癌、结肠直肠癌、子宫内膜或子宫癌、唾腺癌、肾癌、肝癌、前列腺癌、外阴癌、甲状腺癌、肝癌、白血病与其他淋巴增殖性病症及各种头颈癌。
如本文中使用的“治疗”意指临床上的介入,其旨在改变经治疗的个体或细胞的自然过程,且可以在预防(prophylaxis)或在临床病理过程中进行。期望的治疗效果包括预防疾病发生或复发、缓解症状、减轻疾病的任何直接或间接病理后果、预防或减少发炎和/或组织/器官损伤、降低疾病进展速度、改善或减轻疾病状态、及缓解或改进预后。于特定实施方案中,本发明抗体系用于延缓疾病或病症的发展。
如本文中使用的“抗体-药物缀合物(ADC)”意指抗体缀合至细胞毒性剂,如化学治疗剂、药物、生长抑制剂、毒素(如细菌、真菌、植物或动物源的酶促活性毒素或其片段)、或放射性同位素(亦即,放射性缀合物)。
如本文中使用的“T细胞表面抗原”意指抗原可包括本领域习知的代表性T细胞表面标记,包括T细胞抗原受体(TcR),其为所有T细胞的主要定义标记,其中T细胞以其用于特异性识别MHC相关联的肽抗原。TcR相关联实例为称为CD3的蛋白复合体,其参与TcR结合至其关联MHC/抗原复合体后细胞内信号传导。T细胞表面抗原的其他实例可包括(或排除)CD2、CD4、CD5、CD6、CD8、CD28、CD40L、和/或CD44。
如本文中使用的“个体”或“受试者”是脊椎动物。于特定实施方案中,脊椎动物为哺乳动物。哺乳动物包括但不局限于,农场动物(如牛)、运动动物、宠物(如猫、狗、及马)、灵长类动物、小鼠、及大鼠。于特定实施方案中,脊椎动物是人类。
如本文中使用的因应治疗目的的“哺乳动物”意指任何分类为哺乳动物的动物,包括人类、家畜、及农场动物,以及动物园、运动场、或宠物动物,如狗、马、猫、牛等。于特定实施方案中,哺乳动物是人类。
如本文中使用的“有效量”意指在所需剂量与时间期内,能有效达到所需的治疗或预防结果的量。
本发明物质/分子的“治疗上有效量”可依因素,诸如个体的疾病状态、年龄、性别、及体重,以及该物质/分子于受试者内引发所需的反应的能力而变。治疗上有效量亦为,治疗上有益效果超越物质/分子之任何有毒或有害影响的量。“预防上有效量”意指在所需剂量与时间期内,能有效达到所需之预防结果的量。通常但非必需,因受试者在疾病之前或疾病早期阶段使用预防剂量,该预防上有效量将小于治疗上有效量。
如本文中使用的“细胞毒性剂”术语意指抑制或预防细胞功能和/或导致细胞破坏的物质。该术语旨在包括放射性同位素(如At211、I131、I125、Y90、Re186、Re188、Sm153、Bi212、P32、Pb212、及Lu的放射性同位素)、化学治疗剂(如甲氨蝶呤、亚德里亚霉素、长春花生物碱类、长春新碱、长春碱、依托泊苷、多柔比星、美法仑、丝裂霉素C、苯丁酸氮芥、柔红霉素、或其他嵌入剂)、酶及其片段,如核苷酸分解酶(nucleolyticenzymes)、抗生素、及毒素,如细菌、真菌、植物或动物源的小分子毒素或酶活性毒素,包括其片段和/或变体、及以下揭示的各种抗肿瘤剂或抗癌剂。其他细胞毒性剂说明如下。肿瘤毒杀剂(tumoricidal agent)导致肿瘤细胞破坏。
如本文中使用的,示例性治疗性肿瘤学药剂包括但不限于化学治疗剂和抗体。如本文中使用的“化学治疗剂”为用于治疗癌症的化学化合物。化学治疗剂的实例包括烷化剂,如噻替派(thiotepa)与环磷酰胺;烷基磺酸盐诸如白消安(busulfan)、英丙舒凡(improsulfan)和呱泊舒凡(piposulfan);氮丙啶类诸如苯并多巴(benzodopa)、碳酮(carboquone)、美杜多巴(meturedopa)和欧罗巴(uredopa);乙烯亚胺和甲基蜜胺类诸如六甲蜜胺(altretamine)、三亚乙基蜜胺(triethylenemelamine)、三亚乙基磷酰胺(trietylenephosphoramide)、三亚乙基硫代磷酰胺(triethiylenethiophosphoramide)和三甲基三聚氰胺(trimethylolomelamine);乙酰青霉素(acetogenins)(特别是牛油菌素(bullatacin)和黄曲坦酮(bullatacinone)));delta-9-四氢大麻酚(屈大麻酚(dronabinol),);β-拉巴醌;拉帕醇(lapachol);秋水仙碱(colchicines);桦木酸(betulinic acid);喜树碱(camptothecin)(包括其合成类似物拓朴替康(topotecan)CPT-11(伊立替康(irinotecan),)、乙酰喜树碱、东莨菪素(scopolectin)和9-氨基喜树碱);比欧抑素(bryostatin);卡利抑素(callystatin);CC-1065(包括其青蒿素、卡折来新(carzelesin)和比折来新(bizelesin)合成类似物);鬼臼毒素(podophyllotoxin);鬼臼酸(podophyllinic acid);替尼泊苷(teniposide);隐球菌素(cryptophycins)(特定地,隐球菌素1与隐球菌素8);多拉抑素(dolastatin);多卡米(duocarmycin)(包括合成类似物KW-2189与CB1-TM1);丝氨酸蛋白酶(eleutherobin);胰抑素(pancratistatin);沙卡地丁(sarcodictyin);海绵抑素(spongistatin);氮芥如苯丁酸氮芥、氯罗沙芬(chlomaphazine)、氯膦酰胺、雌莫司汀(estramustine)、异环磷酰胺(ifosfamide)、类二甲基二乙酸(mechlorethamine)、类二甲基二乙酸氧化物氯化氢、美法仑、诺维菌素(novembichin)、酚酯(phenesterine)、泼尼昔维汀(prednimustine)、曲伐酰胺(trofosfamide)、尿嘧啶芥(uracil mustard);亚硝脲类,如卡莫司汀(carmustine),氯佐他星(chlorozotocin),氟托他汀(fotemustine),洛莫司汀(lomustine),尼莫司汀(nimustine)和雷尼司他汀(ranimnustine);抗体如恩二烯(enediyne)抗生素(如卡奇霉素(calicheamicin),特别地,卡奇霉素(calicheamicin)伽马1I和卡奇霉素(calicheamicin)欧米加I1(参见,如Agnew,Chem.Intl.Ed.Engl.,33:183-186(1994));达内霉素(dynemicin),包括达内霉素A (dynemicin A);埃斯波(esperamicin);以及新抑癌素发色团(neocarzinostatin chromophore)与相关发色蛋白恩二烯抗体发色团)、阿什曲莫敏(aclacinomysins)、放线菌素(actinomycin)、奥沙拉霉素(authramycin)、西西他滨(azaserine)、博来霉素(bleomycins)、仙人掌霉素(cactinomycin)、卡那霉素(carabicin)、卡霉素(caminomycin)、卡齐霉素(carzinophilin)、染色质霉菌(chromomycinis)、更生霉素(dactinomycin)、柔红霉素、阿霉素(detorubicin)、6-重氮-5-氧代-L-正亮氨酸、多柔比星(包括吗啉-多柔比星、氰吗啉-多柔比星、2-吡咯啉-多柔比星和去氧多柔比星)、表柔比星(epirubicin)、表柔比星(esorubicin)、伊达比星(idarubicin)、马塞罗霉素(marcellomycin)、丝裂霉素(mitomycins)如丝裂霉素C、霉酚酸(mycophenolic acid)、诺卡霉素(nogalamycin)、奥利莫霉素(olivomycins)、培洛霉素(peplomycin)、普莫霉素(potfimromycin)、嘌呤霉素(puromycin)、三铁阿霉素(quelamycin)、罗霉素(rodorubicin)、链霉菌素(streptonigrin)、链球菌素(streptozocin)、结核菌素(tubercidin)、乌苯达霉素(ubenimex)、净诺抑素(zinostatin)、左柔比星(zorubicin);抗代谢物如甲氨蝶呤和5-氟基脲嘧啶(5-FU);叶酸类似物,如去蝶呤(denopterin)、甲氨蝶呤、蝶呤素(pteropterin)、三甲氧嘧啶(trimetrexate);嘌呤类似物如氟达拉滨(fludarabine)、6-巯基嘌呤(6-mercaptopurine)、噻虫胺(thiamiprine)、硫鸟嘌呤(thioguanine);嘧啶类似物如阿维菌素(ancitabine)、阿扎胞苷(azacitidine)、6-氮尿苷(6-azauridine)、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、二脱氧尿苷(dideoxyuridine)、多西菌定(doxifluridine)、依诺沙星(enocitabine)、氟尿苷(floxuridine);雄性激素例如咳嗽酮(calusterone)、屈他雄酮丙酸酯(dromostanolone propionate)、环硫雄醇(epitiostanol)、睪内酯(testolactone)、美雄酮(mepitiostane);抗肾上腺素如胺鲁米特(aminoglutethimide)、米托坦(mitotane)、三环烷(trilostane);叶酸补充剂如克罗酸(frolinic acid);乙酰丙酮胺(aceglatone);二磷酰胺糖苷(aldophosphamide glycoside);氨基乙酰丙酸(aminolevulinic acid);恩尿嘧啶(eniluracil);安吖啶(amsacrine);贝司布新(bestrabucil);比生群(bisantrene);依达曲沙(edatraxate);地灵酰胺(defofamine);地美可辛(demecolcine);地吖醌(diaziquone);依氟鸟氨酸(elfornithine);依利醋铵(Elliptinium Acetate);埃博霉素(epothilone);依托格鲁(etoglucid);硝酸镓;羟基尿素;香菇多糖(lentinan);氯尼达明(lonidamine);类美登素(maytansinoids)如美登素(maytansine)与安丝菌素(ansamitocine);米托胍腙(mitoguazone);米托蒽醌;美德眠(mopidanmol);钠硝石(nitraerine);喷脱抑素(pentostatin);蛋氨氮芥(phenamet);批柔比星(pirarubicin);洛索蒽醌(losoxantrone);2-乙基酰肼;甲节肼(procarbazine);多糖螯合物(JHS Natural Products,Eugene,Oreg.);雷佐生(razoxane);根瘤菌素(rhizoxin);西佐喃(sizofuran);错螺胺(spirogermanium);细交链孢菌酮酸(tenuazonicacid);三乙撑亚胺苯醌(triaziquone);2,2′,2″-三氯三乙基胺;单端孢霉烯毒素(trichothecenes)(特别是T-2毒素、抚孢菌素(verracurin)A、杆孢菌素(roridin)A和蛇行菌素(anguidine));氨基甲酸乙酯(urethane);长春地辛(vindesine) 达卡巴嗪(dacarbazine);甘露醇氮芥(mannomustine);二溴甘露醇(mitobronitol);二溴卫矛醇(mitolactol);哌血生(pipobroman);卡胞嘧啶(gacytosine);阿糖孢苷(arabinoside)(“Ara-C”);噻替哌(thiotepa);紫杉烷,如紫杉醇(Bristol-Myers Squibb Oncology,Princeton,N.J.);不含Cremophor的ABRAXANETM;紫杉醇的白蛋白工程化改造纳米颗粒配方(American PharmaceuticalPartners,Schaumberg,Ill.),以及欧洲紫杉醇(doxetaxel)(-PoulencRorer,Antony,France);苯丁酸氮芥(chloranbucil);吉西他滨(gemcitabine)6-硫鸟嘌呤;巯嘌呤;甲氨蝶呤;铂类似物如顺铂与卡铂;长春碱铂;依托泊苷(VP-16);衣弗酰胺(ifosfamide);米托蒽醌(mitoxantrone);长春新碱奥沙利铂(oxaliplatin);亚叶酸钙(leucovovin);长春瑞滨(vinorelbine)诺消灵(novantrone);依那普利(edatrexate);柔红霉素(daunomycin);氨基蝶呤(aminopterin);伊班膦酸盐(ibandronate);拓扑异构酶抑制剂RFS 2000;二氟基甲基鸟氨酸(DMFO);类维生素A如视黄酸;卡培他滨(capecitabine)上述任一者之医药上可接受盐类、酸或衍生物;以及上述二或多者之组合如CHOP,此为环磷酸酰胺、多柔比星、长春新碱与普赖苏农(prednisolone)之合并治疗缩写,以及FOLFOX,此为奥沙利铂(oxaliplatin)(ELOXATINTM)与5-FU及亚叶酸钙(leucovovin)合并治疗方案之缩写。
靶向SSEA-4的抗体
本发明的一方面为靶向SSEA-4相关抗原的新颖抗体。
示例性抗体包括抗体片段,抗体变体,单克隆抗体,多克隆抗体和重组抗体等。抗体可以在小鼠,兔子或人类中产生。
mAb 1J1s为单克隆抗体,其利用融合瘤细胞系(ATCC保藏号PTA-122679)产生。本文所述抗体可含有与抗体1J1s相同的VH与VL链。与1J1s结合至相同表位的抗体亦落入本发明的范畴。
以下提供实例及其氨基酸与核酸结构/序列:
表1.抗体1J1s的氨基酸与核苷酸序列
mAb 1G1s为小鼠单克隆抗体,其利用融合瘤细胞系(ATCC保藏号PTA-122678)产生。本文所述抗体可含有与抗体1G1s相同的VH与VL链。与1G1s结合至相同表位的抗体亦落入本发明的范畴。
以下提供实例及其氨基酸与核酸结构/序列:
表2.抗体1G1s的氨基酸与核苷酸序列
mAb 2F20s为单克隆抗体,其利用融合瘤细胞系(ATCC保藏号PTA-122676)产生。本文所述抗体可含有与抗体2F20s相同的VH与VL链。与2F20s结合至相同表位的抗体亦落入本发明的范畴。
以下提供实例及其氨基酸与核酸结构/序列:
表3.抗体2F20s的氨基酸与核苷酸序列
以下提供人源化抗SSEA4抗体(OBI-898)序列。
表4.抗SSEA4抗体(OBI-898)人源化克隆序列
本发明的一方面是特异于SSEA-4的新颖抗体。抗SSEA-4抗体结合至Neu5Acα2→3Galβ1→3GalNAcβ1→3Galα1→4Galβ1→4Glcβ1(SSEA-4六糖)。
本文所述抗体之任一者可为全长抗体或其抗原结合片段。于一些实例中,抗原结合片段为Fab片段、F(ab')2片段、或单链Fv片段。于一些实例中,抗原结合片段为Fab片段、F(ab')2片段、或单链Fv片段。于一些实例中,抗体为人类抗体、人源化抗体、嵌合抗体、或单链抗体。
本文所述抗体之任一者具有一或多个特征:(a)为重组型抗体、单克隆抗体、嵌合抗体、人源化抗体、人类抗体、抗体片段、双特异性抗体、单特异性抗体、单价抗体、IgG1抗体、IgG2抗体或抗体衍生物;(b)为人类、鼠科、人源化、或嵌合抗体、抗原结合片段、或抗体的衍生物;(c)为单链抗体片段、多体、Fab片段、和/或IgG、IgM、IgA、IgE、IgD同种型和/或其子类的免疫球蛋白;(d)具有一或多个下列特征:(i)介导癌细胞的ADCC和/或CDC;(ii)诱发和/或促进癌细胞的细胞凋亡;(iii)抑制癌细胞的标靶细胞增殖;(iv)诱发和/或促进癌细胞的吞噬作用;和/或(v)诱发和/或促进细胞毒性剂释放;(e)特异性结合肿瘤相关联的糖类抗原,其为肿瘤特异性碳水化合物抗原;(f)不结合表达于非癌细胞、非肿瘤细胞、良性癌细胞和/或良性肿瘤细胞上的抗原;和/或(g)特异性结合表达于癌症干细胞及正常癌细胞上的肿瘤相关联的碳水化合物抗原。
优选的是,抗体与其个别抗原的结合具特异性。“特异性”术语一般而言用于意指结合配对之一成员除了其特异性结合配对体以外,不会显示与分子有任何显著结合的情况,且除了本文指定之那些以外,其与任何其他分子具有小于约30%,优选为20%、10%、或1%的交叉反应性。
抗体适于以高亲和性(低KD值)结合标靶表位,且优选地KD为纳摩尔范围或更低。亲和性可利用本领域习知的方法测定,如表面等离振子共振法。
本发明抗SSEA-4抗体能敏感地与特异地直接检测表位,且用于常规生物分子试验,如免疫沉淀、ELISAs、或免疫显微镜,而无需质谱或基因操作。反而,其提供明显优势于观察与阐明这些途径的正常功能,及检测途径的功能失常。
于另一方面,本发明抗SSEA-4抗体可作为试剂,以检测各细胞类型与组织的癌症状态。
于又另一方面,本发明抗SSEA-4抗体适于发展为SSEA-4拮抗剂,其中阻断活性情况类似于本发明的这些主题抗体。举例而言,本发明的抗SSEA-4抗体可用于测定与鉴定其他具有相同SSEA-4结合特征和/或能阻断SSEA-4途径的抗体。
作为进一步实例,本发明抗SSEA-4抗体可用于鉴定其他抗SSEA-4抗体,其实质上结合同于本文示例性抗体的SSEA-4抗原决定区,包括线型与构象表位。
本发明的抗SSEA-4抗体可用于基于生理途径的试验,其中SSEA-4涉及筛选SSEA-4的小分子拮抗剂,其呈现类似于抗体阻断一或多个结合配对体与SSEA-4的结合的药理效用。
医药配方
于一个实施方案中,本发明提供包含本文所述的抗体或其抗原结合部位,及医药上可接受载体的药物组合物。于另一实施方案中,药物组合物包含编码本发明抗体或其抗原结合部位的核酸,及医药上可接受载体。医药上可接受载体包括生理上相容的任何及所有溶剂、分散介质、等张与吸收延迟剂、及其类似物。于一个实施方案中,组合物有效抑制受试者的癌细胞。
本发明药物组合物的给药途径包括但不局限于,静脉内、肌内、鼻内、皮下、口服、局部、皮下、皮内、经皮、表皮下、胃肠外、直肠、脊髓、或表皮施用。
本发明的药物组合物可制成注射剂,不论液体溶液或悬液,或制成固体形式,其于注射前适用于液体载体中的溶液或悬液。药物组合物亦可制成固体形式、乳化、或将活性成分包入微脂体载剂或其他颗粒载体中,以用于持续输送。举例而言,药物组合物可为油乳剂、油包水乳剂、水包油包水乳剂、特定位点乳剂、长驻留乳剂、粘性乳剂、微乳剂、纳米乳剂、脂质体、微粒、微球、纳米球、纳米颗粒、及各种天然或合成聚合物,如不可再吸收性不可渗透聚合物,如乙烯乙酸乙烯酯共聚物与共聚物、可溶胀聚合物如水凝胶、或可再吸收性聚合物,如胶原蛋白与特定多元酸或聚酯,如那些用于制造可再吸收性缝线者,其能持续释放药物组合物。
本发明的抗体或其抗原结合部位配制成药物组合物,用以输送至哺乳动物受试者。药物组合物单独施用,和/或与医药上可接受载剂、赋形剂、或载体混合。适用的载剂为,例如,水、盐液、葡萄糖、甘油、乙醇、或其类似物,及其缀合物。此外,载剂可含有少量辅助物质,如润湿剂或乳化剂、pH值缓冲剂、或佐剂。医药上可接受载体可包含生理上可接受化合物,其作为如稳定、或增加或减少本发明药物组合物的吸收率或清除率。生理上可接受化合物可包括,如碳水化合物,如葡萄糖、蔗糖、或葡聚糖、抗氧化剂,如抗坏血酸或谷胱甘肽、螯合剂、低分子量蛋白、清洁剂、微脂体载体、或赋形剂或其他稳定剂、和/或缓冲液。其他生理上可接受化合物包括润湿剂、乳化剂、分散剂、或防腐剂。参见,例如,21st edition ofRemington's Pharmaceutical Science,Mack Publishing Company,Easton,Pa.("Remington's")。本发明之药物组合物亦可包括辅助性物质,如药理学试剂、细胞因子、或其他生物反应调节剂。
此外,药物组合物可配制成中性或盐类形式的药物组合物。医药上可接受盐类包括酸加成盐(其伴随活性多肽的游离氨基形成),且其伴随无机酸,如盐酸或磷酸,或有机酸如乙酸、草酸、酒石酸、杏仁酸、及其类似物形成。由游离羧基形成的盐类亦可衍生自无机碱,如氢氧化钠、氢氧化钾、氢氧化铵、氢氧化钙、或氢氧化铁,以及有机碱诸如异丙基胺、三甲基胺、2-乙基氨基乙醇、组氨酸、普鲁卡因、及其类似物。
制备此类剂型的实际方法是习知的,或对本领域之技术人员而言将是显而易见。参见,例如,Remington's Pharmaceutical Sciences,Mack Publishing Company,Easton,Pennsylvania,21st edition。
药物组合物可于单一剂量治疗或多剂量治疗中按照时间表及适合于受试者年龄、体重及病况、使用之特定组合物、及施用途径、药物组合物是否用于预防或治疗目的等条件下施用一段时间。举例而言,于一个实施方案中,本发明的药物组合物的施用是每月一次、每月两次、每月三次、每隔一周(qow)、每周一次(qw)、每周两次(biw)、每周三次(tiw)、每周四次、每周五次、每周六次,每隔一天(qod)、每天(qd)、每天两次(qid)、或每天三次(tid)。
本发明抗体的施用时间,亦即,施用药物组合物的时间段可变,取决于多种因素之一者,如受试者反应等。举例而言,药物组合物可施用的时间范围为约一或多秒至一或多个小时、一天至约一周、约两周至约四周、约一个月至约两个月、约两个月至约四个月、约四个月至约六个月、约六个月至约八个月、约八个月至约一年、约一年至约二年、或约二年至约四年、或以上。
为便于施用及剂量均匀性,可使用剂量单位形式的口服或胃肠外药物组合物。本文中使用的剂量单位形式意指适于作为欲治疗受试者的单位剂量的物理离散单位;各单位含有预定量的活性化合物,其经计算以产生所需治疗效果,其与所需的医药载体相关联。
细胞培养试验与动物研究取得的数据可用于配制用于人体的一系列剂量。于一个实施方案中,此类化合物的剂量落于循环浓度范围内,包括具有些微或无毒性的ED50。剂量可于此范围内改变,取决于所用的剂型及所用的施用途径。于另一实施方案中,治疗上有效剂量可初步从细胞培养试验估计。于动物模式中可配制剂量,以达到循环血浆浓度范围,其包括细胞培养物时测定的IC50(亦即,受测化合物的浓度达到症状的半最大抑制)。Sonderstrup,Springer,Sem.Immunopathol.25:35-45,2003。Nikula et al.,Inhal.Toxicol.4(12):123-53,2000。
本发明抗体或抗原结合部位的治疗上或预防上有效量的示例性、非局限范围为约0.001至约60mg/kg的体重、约0.01至约30mg/kg的体重、约0.01至约25mg/kg的体重、约0.5至约25mg/kg的体重、约0.1至约20mg/kg的体重、约10至约20mg/kg的体重、约0.75至约10mg/kg的体重、约1至约10mg/kg的体重、约2至约9mg/kg的体重、约1至约2mg/kg的体重、约3至约8mg/kg的体重、约4至约7mg/kg的体重、约5至约6mg/kg的体重、约8至约13mg/kg的体重、约8.3至约12.5mg/kg的体重、约4至约6mg/kg的体重、约4.2至约6.3mg/kg的体重、约1.6至约2.5mg/kg的体重、约2至约3mg/kg的体重、或约10mg/kg的体重。
药物组合物经配制以含有有效量的本发明抗体或其抗原结合部位,其中该量取决于欲处理的动物及欲治疗的病况。于一个实施方案中,本发明抗体或其抗原结合部位的施用剂量范围为约0.01mg至约10g、约0.1mg至约9g、约1mg至约8g、约2mg至约7g、约3mg至约6g、约10mg至约5g、约20mg至约1g、约50mg至约800mg、约100mg至约500mg、约0.01μg至约lOg、约0.05μg至约1.5mg、约10μg至约1mg蛋白、约30μg至约500μg、约40μg至约300μg、约0.1μg至约200μg、约0.1μg至约5μg、约5μg至约10μg、约10μg至约25μg、约25μg至约50μg、约50μg至约100μg、约100μg至约500μg、约500μg至约1mg、约1mg至约2mg。任何特定受试者的具体剂量程度取决于多个因素,包括特定肽的活性、年龄、体重、整体健康状况、性别、饮食、施用时间、施用途径、及排泄速率,药物组合及特定疾病于治疗时的严重程度,并且可由本领域普通技术人员确定,而无需过度实验。
制备含有本发明抗体的治疗配方并保存,其藉由混合具所需纯度的抗体与任意的生理上可接受载体、赋形剂、或稳定剂(Remington's Pharmaceutical Sciences 16thedition,Osol,A.Ed.(1980)),使成水溶液、冻干、或其他干燥配方形式。可接受的载体、赋形剂、或稳定剂于使用的剂量与浓度下对受体无毒,且包括缓冲液如磷酸盐、柠檬酸盐、组氨酸、及其他有机酸;抗氧化剂包括抗坏血酸与甲硫氨酸;防腐剂(如十八烷基二甲基苄基氯化铵;六甲基氯化铵;苯扎氯铵、苄索氯铵;酚、丁基醇或苯甲醇;对羟基苯甲酸烷酯,如对羟基苯甲酸甲酯或丙酯;儿茶酚;间苯二酚;环己醇;3-戊醇;以及间甲酚);低分子量(小于约10个残基)多肽;蛋白质,如血清白蛋白、明胶、或免疫球蛋白;亲水性聚合物如聚乙烯吡咯烷酮;氨基酸如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸、或赖氨酸;单糖类、双糖类、及其他碳水化合物,包括葡萄糖、甘露糖、或糊精;螫合剂如EDTA;糖类如蔗糖、甘露糖醇、海藻糖、或山梨糖醇;盐形成反荷离子如钠;金属螯合物(如Zn-蛋白质螯合物);和/或非离子性表面活性剂如TWEENTM、PLURONICSTM、或聚乙二醇(PEG)。
本文的制剂亦可在必要时含有大于一者的活性化合物,以针对所需治疗的特定适应症,其包括但不限于,那些具有互补活性且不相互有不良影响者。此类分子合适地存在于组合中,其量对预期目的有效。
活性成分亦可包入微胶囊中,其制自例如凝聚技术或界面聚合作用,如分别为羟甲基纤维素或明胶微胶囊与聚(甲基丙烯酸甲酯)微胶囊;包入胶体药物输送系统(如微脂体、白蛋白微球、微乳剂、纳米颗粒、及纳米胶囊)或包入巨乳剂。此类技术揭示于Remington's Pharmaceutical Sciences 16th edition,Osol,A.Ed.(1980)。
用于体内施用的制剂必须无菌。此通过无菌过滤膜过滤而易于实现。
可制备持续释放制备物。持续释放制备物的适用实例包括含有本发明免疫球蛋白的固体疏水性聚合物的半透性基质,该基质为成形制品形式,如薄膜或微胶囊。持续释放基质的实例包括聚酯类、水凝胶(如聚(2-羟乙基甲基丙烯酸酯)或聚(乙烯醇))、聚交酯(美国专利号3,773,919)、L-谷氨酸与γ乙基-L-谷氨酸的共聚物、非降解性乙烯-乙酸乙烯酯、降解性乳酸-乙醇酸共聚物,如LUPRON DEPOTTM(由乳酸-乙醇酸共聚物与醋酸亮丙瑞林组成的可注射微球)、及聚-D-(-)-3-羟基丁酸。尽管聚合物,如乙烯-乙酸乙烯酯与乳酸-乙醇酸,能释放分子超过100天,但特定水凝胶的蛋白质释放时间则较短。当包入的免疫球蛋白长时间保留于体内时,其可因暴露于37℃水分而变性或聚集,造成丧失生物活性且可能改变免疫原性。依据涉及的机制,可规划用于稳定化的合理化策略。举例而言,若发现聚集机制为通过硫基-二硫化物交换而形成分子间S-S键,则可利用改良巯氢基残基、从酸性溶液冻干、控制含水量、使用合适添加剂、及开发特定聚合物基质组合物以达到稳定化。
用途
本发明抗体可用于如体外、离体、及体内治疗方法。本发明抗体可作为拮抗剂,以部分或全部阻断体外、离体、和/或体内的特异性抗原活性。此外,本发明的至少一些抗体可中和其他物种的抗原活性。据此,本发明抗体可用于抑制特异性抗原活性,如在含有抗原的细胞培养物中、在人类受试者中、或在其他哺乳动物受试者中(如黑猩猩、狒狒、绒猿、食蟹猴与恒河猴、猪、或小鼠),其具有本发明抗体可交叉反应的抗原。于一个实施方案中,本发明抗体可用于抑制抗原活性,其藉由使抗体与抗原接触以抑制抗原活性。于一个实施方案中,抗原为人类蛋白质分子。
于一个实施方案中,本发明抗体可用于抑制患有病症的受试者的抗原的方法,其中抗原活性是有害的,包含对受试者施用本发明的抗体,使得受试者的抗原活性受抑制。于一个实施方案中,抗原为人类蛋白质分子且受试者为人类受试者。或者,受试者可为表达抗原的哺乳动物,且本发明抗体可与之结合。此外,受试者可为抗原经导入的哺乳动物(如藉由施用抗原或藉由表达抗原转基因)。针对治疗目的,本发明抗体可施用人类受试者。此外,本发明抗体可施用表达抗原的非人类哺乳动物,其中抗体可与之交叉反应(如灵长类动物、猪、或小鼠),用于兽医目的或作为人类疾病的动物模式。关于后者,此类动物模式可用于评估本发明抗体的治疗功效(如剂量测试及施用时程)。本发明抗体可用于治疗、抑制与SSEA-4和SSEA-4化蛋白的异常表达和/或活性相关联的疾病、病症、或病况、延缓该疾病、病症、或病况进展、预防/延迟该疾病、病症、或病况复发、改善、或预防疾病、病症、或病况,包括但不局限于,癌症、肌肉病症、泛素途径相关的遗传病症、免疫/发炎性病症、神经障碍、及其他泛素途径相关的病症。
本发明抗体于治疗中可单独使用或结合其他组合物使用。举例而言,本发明抗体可与另一抗体和/或佐剂/治疗剂(如类固醇)共同施用。举例而言,本发明抗体于治疗方案中可结合抗发炎剂和/或抗菌剂,例如,治疗本文所述疾病之任一者,包括癌症、肌肉病症、泛素途径相关的遗传病症、免疫/发炎性病症、神经障碍、及其他泛素途径相关的病症。上述的此类结合治疗包括组合给药(其中两个或多个药物包括于同一或分开的配方中)与分开给药,于此情况下,可在施用辅助治疗之前和/或之后施用本发明的抗体。
本发明的抗体(与辅助治疗剂)可利用任何合适的方式施用,包括胃肠外、皮下、腹腔内、肺内、及鼻内,且视需求,用于局部治疗、病灶内施用。胃肠外输注包括肌肉内、静脉内、动脉内、腹腔内、或皮下施用。此外,抗体适于藉由脉冲输注施用,特别是针对抗体剂量渐降。给药可利用任何合适途径,如利用注射(如静脉内或皮下注射),其部分取决于施用是否为短暂或慢性。
于制备与施用抗体时,可考量本发明抗体的结合标靶的位置。当结合标靶为细胞内分子时,本发明的特定实施方案提供将抗体或其抗原结合片段导入含有结合标靶的细胞。于一个实施方案中,本发明抗体可于细胞内表达,成为内抗体。如本文中使用的“内抗体”术语意指抗体或其抗原结合部位于细胞内表达,且其能选择性结合标靶分子,其描述于Marasco,Gene Therapy 4:11-15(1997);Kontermann,Methods 34:163-170(2004);美国专利号6,004,940与6,329,173;美国专利申请公开号2003/0104402;及PCT公开号WO2003/077945。内抗体于细胞内表达受到将编码所需抗体或其抗原结合部位的核酸导入标靶细胞的影响(缺乏野生型前导序列与分泌信号,其通常与编码抗体或抗原结合片段的基因相关联)。可使用任何将核酸导入细胞的标准方法,包括但不局限于,显微注射、弹道注射、电穿孔、磷酸钙沉淀、微脂体、及以携带感兴趣核酸的逆转录病毒、腺病毒、腺相关病毒、及痘苗载体转染。编码本发明抗SSEA-4抗体的全部或部分的一或多个核酸可输送至标靶细胞,使得表达一或多个内抗体,其能于细胞内结合SSEA-4,并调控一或多个SSEA-4介导的细胞途径。
本发明抗体组合物将以符合良好医学实践的方式配制、给药、及施用。于此情况下的考虑因素包括,欲治疗的特定病症、欲治疗的特定哺乳动物、受试者患者的临床状况、病症成因、药剂递送部位、施用方法、施用方案、及医师习知的其他因素。抗体不需要而是任选地与目前用于预防或治疗有问题病症之一或多个药剂一同配制。此类其他药剂的有效量取决于配方中存在的本发明抗体的量、病症或治疗类型、及上述的其他因素。这些一般而言以与本文所述相同剂量与施用途径使用,或本文所述剂量的约1至99%,或以经验上/临床上确定为适当的任何剂量及任何途径使用。
针对疾病的预防或治疗,本发明抗体的适当剂量(当单独使用或与其他试剂结合使用时,如化学治疗剂)将取决于欲治疗疾病的类型、抗体类型、疾病严重性与过程、抗体是否用于预防或治疗目的、先前治疗、患者临床病史及对抗体的反应、及主治医师判断。抗体适合以一次性或一系列治疗之方式施用患者。取决于疾病类型与严重性,施用患者的起始候选剂量可为约1μg/kg至15mg/kg(如0.1mg/kg至10mg/kg)抗体,例如,不论是藉由一或多次分开施用,或连续输注。一通常每日剂量范围可从约1μg开始,以预防或治疗疾病,本发明抗体的适当剂量(数天或更长时间)取决于病况,治疗一般而言将持续到疾病症状出现抑制。抗体的一个示例性剂量范围为约0.05mg/kg至约10mg/kg。因此,可施用患者一或多剂的约0.5mg/kg、2.0mg/kg、4.0mg/kg、或10mg/kg(或其任何组合)。此类剂量可间歇施用,如每周或每三周(诸如使患者接受约2至约20剂,或诸如约6剂抗体)。一开始可施用较高负荷剂量,接着为一或多个较低剂量。示例性给药方案包含施用约4mg/kg的初始负荷剂量,接着每周维持约2mg/kg的抗体剂量。然而,可使用其他剂量方案。此治疗的进展易于以常规技术与试验监测。
治疗应用
本文描述治疗方法,包括对有需求的受试者施用治疗上有效量的组合物治疗,该组合物包括本文所述的一或多个抗体。
于特定实施方案中,有治疗需求的受试者(如人类患者)诊断出癌症、疑似患有癌症、或有癌症风险。癌症的实例包括但不局限于,肉瘤、皮肤癌、白血病、淋巴瘤、脑癌、肺癌、乳癌、口腔癌、食道癌、胃癌、肝癌、胆管癌、胰脏癌、结肠癌、肾癌、宫颈癌、卵巢癌、及前列腺癌。于特定实施方案中,癌症为肉瘤、皮肤癌、白血病、淋巴瘤、脑癌、肺癌、乳癌、卵巢癌、前列腺癌、结肠癌、或胰脏癌。于一些优选的实施方案中,癌症为脑癌或多形性胶质母细胞瘤(GBM)癌。在一个方面,受试者具有表达SSEA-4抗原的肿瘤。
在部分实施方案中,抗体能够通过与癌细胞或肿瘤细胞上的SSEA-4结合而靶向表达SSEA-4的癌细胞。在某些实施方案中,该抗体能够破坏或抑制癌细胞/肿瘤细胞上的SSEA-4与免疫掩蔽检查点抑制剂的结合,其在一些实施方案中可以是在细胞毒性或细胞抑制性免疫细胞上表达的Siglec-9。在某些实施方案中,破坏或抑制癌症/肿瘤细胞上的SSEA-4与细胞毒性免疫细胞上的免疫掩蔽检查点抑制剂的结合可激活先天的细胞毒性反应,其杀死癌症/肿瘤细胞和/或抑制癌症/肿瘤细胞的生长或分裂。在一些实施方案中,免疫掩蔽检查点抑制剂不包括Siglec 7。
该治疗导致减少肿瘤大小、消除恶性细胞、预防转移、预防复发、减少或毒杀弥漫性癌症、延长存活时间、和/或延长肿瘤癌症进展前时间。
于特定实施方案中,该治疗进一步包含在施用该抗体之前、期间、或之后,对受试者施用额外治疗。于特定实施方案中,额外治疗是以化学治疗剂治疗。于特定实施方案中,额外治疗是辐射治疗。
本发明方法在治疗与预防早期肿瘤方面特别有利,藉以防止进展到更晚期的阶段,使得晚期癌症相关的发病率与死亡率下降。本发明方法亦有利于预防肿瘤复发或肿瘤再生长,如于移除原发性肿瘤后仍存在的休眠肿瘤(dormant tumor),或减少或预防肿瘤发生。
于特定实施方案中,本文揭示的方法适用于癌症的治疗或预防,例如,该癌症的特征为Globo H、SSEA-3、和/或SSEA-4表达增加。于特定实施方案中,癌症包含癌症干细胞。于特定实施方案中,癌症为前期癌症(pre-cancer)和/或恶性癌症和/或抗药性癌症。于特定实施方案中,癌症为脑癌。
针对本发明的方法,癌症可为液体肿瘤,如白血病与淋巴瘤、实体瘤,如乳癌、结肠直肠癌、直肠癌、肺癌、肾细胞癌、神经胶质瘤(如退行性星形细胞瘤(anaplasticastrocytoma)、退行性少星形细胞瘤、退行性少突胶质细胞瘤、多形性胶质母细胞瘤(GBM))、肾癌、前列腺癌、肝癌、胰腺癌、软组织肉瘤、类癌、头颈癌、黑色素瘤、及卵巢癌。于一个实施方案中,癌症为脑癌或GBM。欲实施本文揭示的方法,可将有效量的上述含有至少一个本文所述抗体的药物组合物/配方施用于有治疗需求的受试者(如人类),其经由合适途径进行,例如,静脉内施用,如推注或连续输注一段时间、肌内、腹腔内、脑脊髓内、皮下、关节内、滑膜内、鞘内、口服、吸入、或局部途径。市售的液体配方喷雾器适于施用,包括喷射式喷雾器与超音波喷雾器。液体配方可直接雾化,且冻干粉末可于回溶后雾化。或者,可以氟碳配方与计量吸入器将抗体雾化,或制成冻干与粉碎之粉末吸入。
以本文所述方法治疗的受试者可为哺乳动物,优选人类。哺乳动物包括但不局限于,农场动物、竞技动物、宠物、灵长类动物、马、犬、猫、小鼠、及大鼠。需要治疗的人类受试者可以是、存在风险、或疑似患有癌症的人类患者,该癌症包括但不局限于,乳癌、肺癌、食道癌、直肠癌、胆道癌、肝癌、颊癌、胃癌、结肠癌、鼻咽癌、肾癌、前列腺癌、卵巢癌、宫颈癌、子宫内膜癌、胰腺癌、睾丸癌、膀胱癌、头颈癌、口腔癌、神经内分泌癌、肾上腺癌、甲状腺癌、骨癌、皮肤癌、基底细胞癌、鳞状细胞癌、黑色素瘤、或脑肿瘤。患有癌症的受试者可藉由常规医学检查而判定。
如本文中使用的“有效量”意指不论单独使用或结合一或多个其他活性剂使用,对受试者产生治疗效果所需的各活性剂的量。有效量可变,如本领域那些技术人员之理解,取决于欲治疗的特定病况、病况严重程度、个别患者参数,包括年龄、身体状况、尺寸、性别、及体重、治疗时间、并行治疗的性质,视需求,特定施用途径、及健康从业者之知识与专长范畴内的类似因素。这些因素是本领域技术人员习知,且仅能采取常规实验方式解决。一般而言优选的是,使用个别组分或其组合的最大剂量,亦即,依据健康医学判断的最高安全剂量。然而,本领域技术人员应理解到,基于疗法原因、心理原因、或实质上任何其他原因,患者可能坚持使用较低剂量或耐受剂量。
经验上考量,如半衰期,通常有助于确定投剂量。举例而言,可使用与人类免疫系统相容的抗体(如人源化抗体或完整人抗体)延长抗体半衰期,并防止抗体受宿主免疫系统攻击。于治疗过程中可确定与调整施用频率,且一般而言但不一定是,基于癌症的治疗和/或抑制和/或改善和/或延缓。或者,本文所述抗体的持续连续释放配方可能适用。用于达成持续释放的各配方与装置是本领域习知。
于一实例中,针对一或多次施用抗体的受试者,可凭经验决定本文所述抗体的剂量。对受试者给予递增剂量的抗体。欲评估抗体功效,可按照常规实践遵循疾病指示(如癌症)。
一般而言,针对施用本文所述抗体的任一者,起始候选剂量可为约2mg/kg。针对本发明的目的,通常每日剂量范围可为约0.1μg/kg至3μg/kg至30μg/kg至300μg/kg至3mg/kg至30mg/kg至100mg/kg或以上之任一者,其取决于上述参数。针对数天或更长时间的重复施用,根据病况,治疗持续到发生所需的症状抑制或直到达到足够的治疗程度以缓解癌症或其症状为止。示例性给药方案包括施用约2mg/kg的初始剂量,随后每周维持约1mg/kg抗体之剂量,或随后每隔一周施用约1mg/kg的维持剂量。然而,可使用其他剂量方案,其取决于从业人员预期达成的药代物动力学衰变模式。举例而言,考量每周给药一至四次。于特定实施方案中,可使用的给药范围为约3μg/mg至约2mg/kg(如约3μg/mg、约10μg/mg、约30μg/mg、约100μg/mg、约300μg/mg、约1mg/kg、及约2mg/kg)。于特定实施方案中,给药频率为每周一次、每2周一次、每4周一次、每5周一次、每6周一次、每7周一次、每8周一次、每9周一次、或每10周一次;或每月一次、每2个月一次、或每3个月一次,或更长时间。此治疗的进展易于利用常规技术与试验监测。所使用的给药方案,包括抗体,可随时间改变。
针对本发明的目的,本文所述抗体的适当剂量将取决于所使用的特异性抗体(或其组合物)、癌症的类型与严重程度、抗体是否用于预防或治疗目的、先前的治疗、患者临床病史与对抗体的反应、及主治医师的判断。本文所述抗体的施用可基本上持续一段预选时间,或可为一系列间隔剂量,如于癌症发展之前、期间、或之后进行。
如本文中使用的“治疗”术语意指施加或施用包括一或多个活性剂的组合物至受试者,其患有癌症、癌症症状、或癌症倾向,目的在于治愈、疗愈、减轻、缓解、改变、补救、改善、改进、或影响癌症、癌症症状、或癌症倾向。
缓解癌症包括延缓癌症的发展或进展,或降低癌症的严重程度。缓解癌症不一定需要治疗结果。如本文中使用的“延缓”癌症发展意指推迟、阻止、缓慢、延缓、稳定、和/或推迟癌症进展。取决于癌症和/或欲治疗的受试者之病史,此延迟可为不同时间长度。当相较于未使用方法时,“延迟”或减轻癌症发展或延缓癌症发病的方法,为在给定之时间范围内降低发生癌症之一或多个症状可能性(风险)和/或在给定之时间范围内减少症状程度的方法。此类比较通常基于临床研究,其使用足以给出统计学上显著结果的一些受试者。
癌症的“发展”或“进展”意指癌症的初步表达和/或后续发展。利用本领域习知的标准临床技术,可检测与评估癌症的发展。然而,发展亦指无法检测的进展。针对本发明之目的,发展或进展意指症状的生物过程。“发展”包括发生、复发、及发病。如本文中使用的癌症的“发病”或“复发”包括初始发病和/或复发。
医药领域那些普通技术人员习知的常规方法可用于施用药物组合物至受试者,其取决于欲治疗的疾病类型或疾病的部位。此组合物亦可经由其他常规途径施用,如利用口服、胃肠外、吸入喷雾、局部、直肠、鼻腔、口腔、阴道、或经由植入贮液等方式施用。本文中使用的“胃肠外”术语包括皮下、皮内、静脉内、肌肉内、关节内、动脉内、滑膜内、胸骨内、鞘内、脑内、及颅内注射或输注技术。此外,可经由可注射储库施用途径施用受试者,例如,使用1、3、或6个月的可注射储库或生物可降解性材料及方法。
可注射组合物可含有各载体,如植物油、二甲基乳酰胺、二甲基甲酰胺、乳酸乙酯、碳酸乙酯、肉豆蔻酸异丙酯、乙醇、及多元醇(甘油、丙二醇、液体聚乙二醇、及其类似物)。针对静脉内注射,可利用滴注法施用水溶性抗体,从而输注含有抗体与生理上可接受赋形剂的医药配方。生理上可接受赋形剂可包括例如,5%葡萄糖、0.9%盐液、林格氏液、或其他适用的赋形剂。肌肉内注射制备物,如抗体的适用可溶性盐形式无菌配方,可溶解于医药赋形剂(如注射用水、0.9%盐液、或5%葡萄糖溶液)并施用。
实施例
实施例1.Siglec-9与SSEA-4神经酰胺的ELISA结合试验
将溶于乙醇的SSEA-4神经酰胺(0.2μg)涂布在置于冰上的96孔板各孔中,且经涂布的板在室温下培养整夜。板各孔以100μL阻断缓冲液阻断,并在室温下(25℃)培养1小时。在阻断步骤之后,抽吸移除阻断缓冲液,且各孔以200μL清洗缓冲液(1X TBS,内含0.05%Tween20)清洗3次。利用样本稀释剂(1%BSA溶于1X TBS,内含0.05%tween20)从30μg/mL进行稀释,并将50μL Siglec-9 2X系列稀释移至板的指定孔中,随后板在室温下培养2小时。在培养之后,抽吸移除未结合的Siglec-9,且孔以200μL的清洗缓冲液清洗3次。将50μL二抗(抗人类IgG Fc-AP)(其以样本稀释剂进行1:200稀释)加入板各孔中,并在室温下培养1小时。在培养完成之后抽吸二抗;所有培养孔以200μL的清洗缓冲液清洗4次。将100μL底物溶液加入各孔中,并在37℃下显现20分钟。加入50μL终止溶液以终止反应。于板中短暂混合,并以ELISA读板仪在405nm下读取。图1显示人类Siglec-9在ELISA结合试验中可结合至SSEA-4神经酰胺。
实施例2.利用外源性SSEA-4神经酰胺增加肿瘤细胞上的Siglec-9结合
在24孔培养板中,以20μM SSEA-4神经酰胺(SSEA4Cer)预先温育人类A549肺癌细胞18–24小时。收集细胞并离心,随后在4℃下以Siglec-9染色30分钟。将样本清洗及离心,随后在4℃下以FITC标记的抗人类IgG染色30分钟。随后清洗并收集细胞。利用FACS CANTOII分析A549上的Siglec-9结合。图2显示外源性SSEA4Cer轻微增加Siglec-9与A549肺癌细胞的结合。
实施例3.藉由加入抗SSEA-4 Fab降低肿瘤细胞上的Siglec-9结合
在4℃的染色缓冲液中,将人类MDA-MB-231乳癌细胞与OBI-898Fab(抗SSEA-4抗体)一起温育30分钟。将样本清洗及离心,随后在4℃下以Siglec-9染色30分钟。将样本清洗及离心,随后在4℃下以FITC标记的抗人类IgG染色30分钟。随后清洗并收集细胞。利用FACSCANTO II分析MDA-MB-231上的Siglec-9结合。图3显示OBI-898Fab可降低Siglec-9与MDA-MB-231乳癌细胞之结合。
实施例4.利用抗SSEA-4 Fab结合乳癌细胞上的SSEA-4以增进人类PBMC的细胞毒性
依据PerkinElmer提供的技术手册,以DELFIA(Cat#PK-AD0116)标记标靶人类乳癌细胞系MDA-MB-231。在标记之后,在37℃下将5x103个细胞与有或无20μg/mL OBI-898Fab温育1小时。随后加入5x105个人PBMC,并在37℃下共同温育2小时。将试验板离心,随后将20μL上清液移至平底96孔板。添加200μL Eu溶液,并在室温下在振荡器上温育15分钟。以时间分辨荧光仪(time-resolved fluorometer)测定荧光。利用[(实验释出值-自发释出值)/(最大释出值-自发释出值)]x 100的公式计算特异性释出百分比(specific releasingpercentage)。图4显示抗SSEA-4 Fab阻断肿瘤上的SSEA-4以有效挽救免疫细胞杀死乳癌的细胞毒性。
实施例5.利用抗SSEA-4 Fab结合卵巢癌细胞系上的SSEA-4以增进人类PBMC的细胞毒性
依据PerkinElmer提供的技术手册,以DELFIA(Cat#PK-AD0116)标记标靶人类卵巢癌细胞系SKOV-3。在标记之后,在37℃下将5x103个细胞与有或无20μg/mL抗SSEA-4(OBI-898)Fab温育1小时。随后加入5x105个人PBMC,并在37℃下共同温育4小时。将试验板离心,随后将20μL上清液移至平底96孔板。添加200μL Eu溶液,并在室温下在振荡器上培养15分钟。以时间分辨荧光仪测定荧光。利用[(实验释出值-自发释出值)/(最大释出值-自发释出值)]x 100的公式计算特异性释出百分比。图5显示抗SSEA-4 Fab阻断肿瘤上的SSEA-4以有效挽救免疫细胞杀死卵巢癌的细胞毒性。
实施例6.利用抗SSEA-4 Fab结合卵巢癌细胞系上的SSEA-4以增进癌自御的细胞毒性
依据PerkinElmer提供的技术手册,以DELFIA(Cat#PK-AD0116)标记标靶人类卵巢癌细胞系SKOV-3。在标记之后,在37℃下将5x103个细胞与有或无20μg/mL抗SSEA-4(OBI-898)Fab温育1小时。随后加入5x105个人PBMC及20μg/mL的癌自御,并在37℃下共同温育4小时。将试验板离心,随后将20μL的上清液移至平底96孔板。添加200μL Eu溶液,并在室温下在振荡器上温育15分钟。以时间分辨荧光仪测定荧光。利用[(实验释出值-自发释出值)/(最大释出值-自发释出值)]x 100之公式计算特异性释出百分比。图6显示抗SSEA-4 Fab阻断肿瘤上的SSEA-4以增进癌自御杀死癌症的细胞毒性。
图7的结果显示,OBI-898(抗SSEA-4抗体)可阻断Siglec-9与肿瘤的接合,并释出免疫细胞的细胞毒性。
除非另有定义,否则本文中使用的所有技术性与科学性术语以及任何缩写字具有与本发明领域普通技术人员通常能理解的相同含义。尽管可使用传达与本文所述者类似或等同的信息的任何组合物、方法、套组、及工具以实践本发明,但用于传达信息的优选组合物、方法、套组、及工具如本文所述。
本文引用的所有参考文献皆在法律允许范围内并入本案以作为参考资料。这些参考文献的讨论仅旨在总结其作者提出的主张。不承认任何参考文献(或任何参考文献之一部分)与先前技术相关。申请人保留质疑任何所引用参考文献之准确性与相关性的权利。
Claims (20)
1.一种治疗具有表达SSEA-4抗原的癌细胞的受试者的方法,所述方法包含对所述受试者施用有效量的药物组合物,其包含抗SSEA-4抗体或其片段。
2.权利要求1的方法,其中抗SSEA-4抗体与所述癌细胞的结合降低SSEA-4与Siglec-9间的结合相互作用。
3.权利要求2的方法,其中所述SSEA-4与Siglec-9间的结合相互作用降低导致Siglec-9与癌细胞的降低结合。
4.权利要求3的方法,其中所述Siglec-9与癌细胞的降低结合诱导释出由Siglec-9/SSEA-4接合(engagement)所维持的免疫抑制(免疫屏蔽)。
5.权利要求1的方法,其中施用所述抗SSEA-4抗体增加细胞毒性免疫细胞的活性。
6.权利要求5的方法,其中所述细胞毒性免疫细胞为单核细胞、嗜中性粒细胞、NK细胞、B细胞、或CD8+T细胞。
7.权利要求5的方法,其中所述抗SSEA-4抗体为OBI-898。
8.权利要求1的方法,其中所述癌症选自于肉瘤、皮肤癌、白血病、淋巴瘤、脑癌、肺癌、乳癌、口腔癌、食道癌、胃癌、肝癌、胆管癌、胰腺癌、结肠癌、肾癌、宫颈癌、卵巢癌及前列腺癌;在特定实施方案中,所述癌症为肉瘤、皮肤癌、白血病、淋巴瘤、脑癌、肺癌、乳癌、卵巢癌、前列腺癌、结肠癌、或胰腺癌;在一些优选的实施方案中,所述癌症为脑癌或多态性胶质母细胞瘤(GBM)癌症。
9.一种通过抑制表达Siglec-9的细胞毒性免疫细胞与癌细胞上SSEA-4抗原的结合而活化先天细胞毒性免疫反应的方法,所述方法包含用SSEA-4的拮抗剂接触所述细胞毒性免疫细胞-癌细胞复合体;并且破坏或抑制Siglec-9与SSEA-4的结合。
10.权利要求9的方法,其中所述拮抗剂为SSEA-4抗体。
11.权利要求10的方法,其中所述抗SSEA-4抗体为OBI-898。
12.权利要求9的方法,其中所述细胞毒性免疫细胞为单核细胞、嗜中性粒细胞、NK细胞、B细胞、或CD8+T细胞。
13.权利要求9的方法,其中所述癌症选自于肉瘤、皮肤癌、白血病、淋巴瘤、脑癌、肺癌、乳癌、口腔癌、食道癌、胃癌、肝癌、胆管癌、胰腺癌、结肠癌、肾癌、宫颈癌、卵巢癌及前列腺癌;在特定实施方案中,所述癌症为肉瘤、皮肤癌、白血病、淋巴瘤、脑癌、肺癌、乳癌、卵巢癌、前列腺癌、结肠癌、或胰腺癌;在一些优选的实施方案中,所述癌症为脑癌或多态性胶质母细胞瘤(GBM)癌症。
14.一种治疗具有表达SSEA-4抗原的癌细胞的受试者的方法,所述方法包含对所述受试者施用有效量的包含抗SSEA-4抗体或其片段的药物组合物,从而抑制Siglec-9与癌细胞的结合。
15.一种降低Siglec-9与癌细胞的结合的方法,所述方法包含对受试者施用有效量的药物组合物,其包含抗SSEA-4抗体或其片段。
16.一种治疗具有表达SSEA-4抗原的癌细胞的受试者的方法,所述方法包含对所述受试者施用有效量的包含抗SSEA-4抗体或其片段的药物组合物,从而活化所述细胞毒性免疫细胞的活性。
17.一种增加具有癌症的受试者中的细胞毒性免疫细胞活性的方法,所述方法包含对所述受试者施用有效量的药物组合物,其包含抗SSEA-4抗体或其片段。
18.权利要求14-17的方法,其中所述抗SSEA-4抗体为OBI-898。
19.权利要求16-17的方法,其中所述细胞毒性细胞为单核细胞、嗜中性粒细胞、NK细胞、B细胞、或CD8+T细胞。
20.权利要求14-17的方法,其中所述癌症选自于肉瘤、皮肤癌、白血病、淋巴瘤、脑癌、肺癌、乳癌、口腔癌、食道癌、胃癌、肝癌、胆管癌、胰腺癌、结肠癌、肾癌、宫颈癌、卵巢癌及前列腺癌;在特定实施方案中,所述癌症为肉瘤、皮肤癌、白血病、淋巴瘤、脑癌、肺癌、乳癌、卵巢癌、前列腺癌、结肠癌、或胰腺癌;在一些优选的实施方案中,所述癌症为脑癌或多态性胶质母细胞瘤(GBM)癌症。
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