CN111406072A - 新缀合物及其用途 - Google Patents
新缀合物及其用途 Download PDFInfo
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- CN111406072A CN111406072A CN201880063017.8A CN201880063017A CN111406072A CN 111406072 A CN111406072 A CN 111406072A CN 201880063017 A CN201880063017 A CN 201880063017A CN 111406072 A CN111406072 A CN 111406072A
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- csf
- conjugate
- growth factor
- ligand
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Abstract
本发明提供了新缀合物和包含本文所述新缀合物的药物组合物。还提供了所述新缀合物在使用或不使用抗癌剂的情况下在需要癌症治疗的受试者中抑制癌细胞生长并诱导抗体产生的用途。
Description
相关申请的交叉引用
本申请要求2017年9月29日提交的美国临时申请号62/565,509的优先权的权益,其全部内容通过引用并入本文。
发明背景
表皮生长因子受体(EGFR)是酪氨酸激酶受体ErbB家族的成员,其将生长诱导信号传递至已被表皮生长因子(EGF)配体刺激的细胞。它是上皮恶性肿瘤的关键因素,占所有癌细胞死亡的50%以上。由于在肿瘤微环境中持续产生EGF或者由于EGFR自身的突变(将受体锁定在持续激活状态)的结果,EGFR活性增强了肿瘤生长、侵袭和转移。
EGFR拮抗剂和酪氨酸激酶抑制剂已被美国食品和药品管理局批准用于治疗上皮癌。尽管EGFR拮抗剂在商业上取得了成功,但其用于治疗癌症的特征是通过酪氨酸激酶结构域的突变或其他癌蛋白的上调而产生的发育抗性。
为了有效地治疗癌症,如果身体开始针对这些癌症的正免疫应答,则将是优选的。粒细胞巨噬细胞集落刺激因子(GM-CSF)是一种细胞因子,其激活树突细胞进行抗原呈递并增强T淋巴细胞和B淋巴细胞的抗肿瘤功能。然而,由于临床证据表明GM-CSF可能诱导负调节免疫反应,因此关于GM-CSF作为免疫增强剂或治疗剂的作用的研究存在冲突。例如,与热休克蛋白疫苗一起施用的GM-CSF与黑色素瘤患者中骨髓来源的抑制细胞的诱导有关(Filipazzi P等,Identification of a new subset of myeloid suppressor cells inperipheral blood of melanoma patients with modulation by a granulocyte-macrophage colony-stimulation factor-based antitumor vaccine J Clin Oncol2007;25:2546–53)。在鼠模型中,高剂量的GM-CSF可能会增加骨髓来源的抑制细胞(Serafini等,High dose granulocyte-macrophage colony-stimulating factor-producing vaccines impair the immune response through the recruitment ofmyeloid suppressor cells.Cancer Res 2004;64:6337–43)。一项针对局部施用的GM-CSF作为疫苗佐剂的作用的随机多中心研究表明,在疫苗中包括GM-CSF的患者中,循环T细胞对多肽疫苗的应答显著更低。其原因尚待确定,但发现导致对GM-CSF蛋白作为局部佐剂的益处产生怀疑。(CL Slingluff Jr等,Effect of granulocyte/macrophage colony-stimulating factor on circulating CD8+and CD4+T-cell responses to amultipeptide melanoma vaccine:outcome of a multicenter randomized trial.ClinCancer Res.2009;15(22):7036-7044)
因此,需要更有效的基于免疫的癌症治疗。本发明解决了该需求和其他需求。
发明简述
本发明的实施方案提供了包含粒细胞巨噬细胞集落刺激因子(GM-CSF)多肽和配体的缀合物。
本发明还提供了药物组合物,其包含本文所述的缀合物和药学上可接受的赋形剂。
根据本发明的一个实施方案,提供了用于在受试者中抑制癌细胞生长的方法。该方法包括施用有效量的本文所述的缀合物,其中所述有效量的缀合物抑制所述受试者中的癌细胞生长。
根据本发明的另一个实施方案,提供了在受试者中诱导抗EGF抗体的方法。该方法包括在需要癌症治疗的受试者中施用有效量的包含GM-CSF多肽和EGF的缀合物的步骤,其中在所述受试者中诱导了有效量的抗EGF抗体。
根据本发明的又一个实施方案,提供了在受试者中诱导抗血管内皮生长因子(VEGF)抗体的方法。该方法包括以下步骤:向需要癌症治疗的受试者施用有效量的包含GM-CSF多肽和VEGF的缀合物,其中在所述受试者中诱导了有效量的抗VEGF抗体。
还提供了本文所述的缀合物在制备用于癌症的治疗性和/或预防性治疗的药物中的用途。
还提供了用于抑制癌细胞的治疗剂,其包含治疗有效量的本文所述的缀合物。
在本专利中使用的术语“发明”,“该发明”,“这个发明”和“本发明”旨在广泛地指代本专利和以下专利权利要求的所有主题。含有这些术语的陈述应理解为不是限制本文所述主题或不是限制以下专利权利要求的含义或范围。本专利所涵盖的发明的实施方案由以下权利要求书而非本发明简述所限定。本简述是本发明各个方面的高级概述,并介绍了一些概念,这些概念将在下面的详细描述部分中进一步描述。本简述并不旨在鉴别所要求保护的主题的关键或必要特征,也不旨在单独用于确定所要求保护的主题的范围。应当参考整个说明书,任何或所有附图以及每个权利要求的适当部分来理解所述主题。
通过参考说明书的其余部分和附图,可以进一步理解本发明的本质和优点。
附图简述
本专利或专利申请含有至少一个彩色附图。根据要求并支付必要费用,专利局将提供带有彩色附图的本专利或专利申请的副本。
图1A显示了本发明的缀合物mGM-CSF-hEGF的一个实施方案的氨基酸序列(SEQ IDNO:1)。图1B显示了本发明的缀合物mGM-CSF-mVEGFa的另一个实施方案的氨基酸序列(SEQID NO:2)。图1C显示了本发明的缀合物mGM-CSF-mPDGFA的第三实施方案的氨基酸序列(SEQID NO:3)。图1D显示了本发明的缀合物mGM-CSF-mbFGF的第四实施方案的氨基酸序列(SEQID NO:4)。
图2A与图2B示意性地示出了本发明的缀合物的作用机制。
图3是说明使用镍离子柱纯化mGM-CSF-hEGF的色谱图。
图4是在不同纯化步骤的纯化蛋白的SDS-PAGE和考马斯亮蓝染色。
图5是线图,示出了注射有如下的小鼠中的肿瘤大小:(a)仅鼠肾细胞癌(RENCA)细胞(亲代),(b)与表达mGM-CSF的细胞(mGM-CSF)混合的RENCA细胞,(c)与表达mGM-CSF-hEGF的细胞(mGM-CSF-hEGF)混合的RENCA细胞或(d)与表达mGM-CSF-mVEGF的细胞(mGM-CSF-mVEGF)混合的RENCA细胞。
图6A是示出了用PBS缓冲液或GM-CSF-EGF缀合物处理的小鼠中的肿瘤负荷的照片图像。图6B是柱状图,说明了用PBS缓冲液或GM-CSF-EGF缀合物处理的小鼠中来自荧光素酶的生物发光强度。
图7A和图7B是荧光激活细胞分选(FACS)图像,分别示出了实施例1的GM-CSF-EGF缀合物、EGF和PBS与乳腺癌细胞(MDA468)和肾细胞癌(RENCA)上的EGF受体的结合。
图8显示了mGM-CSF-EGF对GM-CSF依赖性NFS60白血病细胞增殖的作用。
图9是说明实施例1的hEGF和GM-CSF-hEGF缀合物对EGF受体的结合亲和力的线图。
图10A是显示在注射有实施例1的GM-CSF-EGF缀合物和PBS的小鼠中抗EGF抗体效价的线图。图10B是显示经mGM-CSF-EGF免疫的小鼠的血清抑制EGF与EGF受体结合的线图。
图11是显示用表达mGM-CSF或mGM-CSF-hEGF的B16-F10细胞接种的4组小鼠(具有或不具有抗CTLA-4抗体)中肿瘤大小的线图。
图12是示出分别用表达mGM-CSF、mGM-CSF-mPDGFA和mGM-CSF-mbFGF的B16-F10细胞注射的小鼠中的肿瘤大小的线图。
发明详述
如本文所用,冠词“一”和“一个”是指冠词的语法对象的一个或对于一个(即至少一个)。举例来说,“一个元件”是指一个元件或一个以上的元件。
如本文所用,“有效量”是指缀合物的剂量,其抑制癌细胞或足以减轻癌症的可检测的症状和迹象,例如体重减轻、疼痛和可触及的肿块(无论是临床上可触及的肿块,还是放射学上通过各种成像手段检查的肿块)。术语“有效量”和“治疗有效量”可互换使用。
术语“受试者”可以指患有癌症的脊椎动物或被认为需要癌症治疗的脊椎动物。受试者包括所有温血动物,例如哺乳动物,例如灵长类动物,并且更优选地,是人类。非人类的灵长类动物也是对象。术语受试者包括家养动物,例如猫、狗等,家畜(例如牛、马、猪、绵羊、山羊等)和实验动物(例如小鼠、兔子、大鼠、沙鼠、豚鼠等)。因此,本文考虑了兽医用途和药物制剂。
本文中的所有数字可被理解为由“约”修饰。如本文所用,术语“约”在指代可测量值时,意指涵盖与指定值±10%的变化,因为这种变化是适当的。
缀合物
本发明提供了缀合物或融合蛋白,其包含粒细胞巨噬细胞集落刺激因子(GM-CSF)多肽;和一个配体。在一些实施方案中,所述缀合物或融合蛋白进一步包含将所述GM-CSF多肽连接至所述配体形成所述缀合物的接头。
GM-CSF多肽是指糖蛋白生长因子家族,其控制粒细胞和单核细胞-巨噬细胞的产生、分化和功能。响应于细胞因子、免疫和炎性刺激,GM-CSF多肽由许多不同的细胞产生,例如活化的T细胞、B细胞、巨噬细胞和肥大细胞。重组GM-CSF是各种氨基酸的糖蛋白并且根据糖基化程度,其可以具有多种分子量。这种分子的示例性但绝非唯一的形式可见于美国专利号5,602,007和5,891,429,通过参考并入本文。在一个实施方案中,所述GM-CSF与SEQ IDNO:5(重组GM-CSF)至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%同源。在另一个实施方案中,所述GM-CSF与SEQ ID NO:6(GM-CSF的信号传导序列)至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%同源。
在一个实施方案中,所述配体是多肽。在另一个实施方案中,所述配体是肿瘤相关配体,其刺激癌细胞生长。在另一个实施方案中,所述配体是非抗体配体,即所述配体不是抗体。在另一个实施方案中,所述配体是非白介素配体,即所述配体不是白介素。在另一个实施方案中,所述配体不是癌细胞表达的受体。
在某些实施方案中,所述肿瘤相关配体与肿瘤细胞、巨噬细胞或内皮细胞的表面直接或间接相互作用。在某些实施方案中,所述肿瘤相关配体与肿瘤细胞受体、巨噬细胞受体或内皮细胞受体具有亲和力。
与肿瘤细胞表面直接相互作用或与肿瘤细胞受体具有亲和力的肿瘤相关配体的非限制性例子是表皮生长因子(EGF)多肽(例如SEQ ID NO:7)、CXC基序趋化因子12(CXCL12)多肽、肝细胞生长因子-1(HGF)多肽、胰岛素样生长因子(IGF)多肽、转化生长因子-α(TGF-α)或它们的活性片段或变体。直接与内皮细胞表面相互作用或与内皮细胞受体具有亲和力的肿瘤相关配体的非限制性例子是血管内皮生长因子(VEGF)多肽(例如SEQ IDNO:8)、血小板衍生生长因子(PDGF)多肽(例如SEQ ID NO:9)、成纤维细胞生长因子(FGF)多肽(例如SEQ ID NO:10)或它们的活性片段或变体。直接与巨噬细胞表面相互作用或与巨噬细胞受体具有亲和力的肿瘤相关配体的非限制性例子是集落刺激因子(CSF-1)多肽、巨噬细胞趋化蛋白-I(MCP-1)多肽、巨噬细胞炎性蛋白-1α(MIP-1α)多肽或它们的活性片段或变体。
在示例性的实施方案中,所述缀合物是融合蛋白。在某些实施方案中,所述缀合物或融合蛋白包含与SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3或SEQ ID NO:4至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%同源的氨基酸序列。
可以使用本领域技术人员已知的标准方法确定氨基酸之间的百分比同源性。例如,为了确定两个氨基酸序列之间的同源性百分比,将序列进行比对以达到最佳比较目的。然后比较在相应氨基酸位置的氨基酸残基。当第一序列中的一个位置被与第二序列中相应位置的相同氨基酸残基占据时,则序列在该位置是同源或相同的。考虑到为了最佳比对需要引入的缺口数和每个缺口的长度,两个序列之间的百分比同源性是序列共有的相同或同源位置数的函数。比较序列和确定两个序列之间的百分比同源性是本领域熟知的。NCBIBasic Local Alignment Search Tool(BLAST(Altschul等,J.Mol.Biol.215:403,1990))可从多种来源获得,包括国家生物技术信息中心(NCBI,Bethesda,Md.)和因特网,与序列分析程序如blastn结合使用。有关如何使用此程序确定序列相同性的说明可得自NCBI网站。
在一些实施方案中,所述缀合物与SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3或SEQID NO:4的区别在于少量的功能上无关紧要的氨基酸取代(例如保守取代)、缺失或插入并保留SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3或SEQ ID NO:4的功能性质,即所述缀合物在至少一个、优选所有的本文所述的体外或体内测定中抑制癌细胞生长。为了将氨基酸取代分类为保守或非保守,可以将氨基酸分类如下:第I组(疏水侧链):正亮氨酸,甲硫氨酸,丙氨酸,缬氨酸,亮氨酸,异亮氨酸;第II组(中性亲水侧链):半胱氨酸,丝氨酸,苏氨酸;第III组(酸性侧链):天冬氨酸,谷氨酸;第IV组(碱性侧链):天冬酰胺,谷氨酰胺,组氨酸,赖氨酸,精氨酸;第V组(影响链取向的残基):甘氨酸,脯氨酸;和第VI组(芳香族侧链):色氨酸,酪氨酸,苯丙氨酸。保守取代涉及相同类别氨基酸之间的取代。非保守取代构成将这些类别之一的成员交换为另一类别的成员。保守氨基酸取代是本领域已知的。例如,P Ng等(Annu.Rev.Genomics Hum.Genet.2006.7:61-80)提供了关于保守氨基酸修饰同时保留蛋白质稳定性和功能的指导:如果酪氨酸和色氨酸存在于特定位点,人们会预期另一个芳香族氨基酸苯丙氨酸在该位点也可以是耐受的。
在一个实施方案中,所述缀合物与SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3或SEQID NO:4的区别在于最多5个氨基酸改变,例如1、2、3、4或5个氨基酸改变。
在某些实施方案中,由于GM-CSF与配体的共价、非共价附着或连接而形成所述缀合物。缀合物的一个实例是“融合蛋白”或“融合多肽”,即通过连接两个或更多个编码序列而产生的多肽,所述两个或更多个编码序列最初编码为单独的多肽;连接的编码序列的翻译产生单个融合多肽。所述缀合物可以重组产生。在一些实施方案中,GM-CSF通过接头可操作地连接至配体以形成所述融合蛋白。所述接头肽的非限制性实例包括(VPGVG)n(SEQ IDNO:11),任何富含甘氨酸的接头如(GGGGS)n(SEQ ID NO:12)(PAPAP)n(SEQ ID NO:13)和(EAAAK)n(SEQ ID NO:14),其中n是2-4之间的整数。本领域技术人员可以使用本领域已知方法确定最合适的接头肽。
可选地,GM-CSF和配体可以独立地重组产生并通过化学手段连接形成本文所述的缀合物。
在一些实施方案中,本发明的缀合物与抗癌剂一起施用。抗癌剂的非限制性实例可见于Cancer Principles and Practice of Oncology,V.T.Devita,T.Lawrence andS.Rosenberg(editors),9th edition(2011),Lippincott Williams&WilkinsPublishers。这种抗癌剂的非限制性实例包括:化学疗法(例如烷化剂,铂类似物,抗代谢物),通过干扰致癌和癌症生长所需的特定靶向分子来抑制癌细胞生长的靶向疗法,而不是简单地干扰快速分裂的细胞(例如用常规化学治疗剂)。在一些实施方案中,所述靶癌症疗法包括激酶抑制剂、血管生成抑制剂、表皮生长因子受体(EGFR)抑制剂、HER2/neu受体或其组合、手术、放射疗法、生物疗法(例如白介素疗法、基因疗法、癌症疫苗、抗体疗法、免疫疗法)或其组合。
在一个实施方案中,所述抗癌剂是细胞毒性T淋巴细胞相关抗原4(CTLA-4)抗体。在另一实施方案中,所述抗癌剂是EGFR抗体。在另一个实施方案中,所述抗癌剂是酪氨酸激酶抑制剂。不受任何特定理论束缚,据信本发明缀合物和抗癌剂如CTLA-4抗体、EGFR抗体或酪氨酸激酶抑制剂的组合在癌细胞抑制中具有协同作用,其中一种或甚至所有较低剂量的所述抗癌剂不足以具有当在单独治疗中使用相应抗癌剂时的治疗效果。
图2A与图2B说明本发明缀合物通过引发免疫系统攻击癌细胞的作用机制。在一个实施方案中,如图2A所示,本发明的缀合物(GM-CSF/EGF)结合至树突细胞并且所述缀合物的GM-CSF充当有效佐剂以引发所述配体(EGF)特异性抗体的产生。在其他实施方案中,如图2B所示,所述缀合物的配体与癌细胞表面相互作用或与癌细胞受体具有亲和力(例如EGF配体与癌细胞的EGFR结合)。这触发了树突细胞并随后激活了抗癌T细胞。激活的T细胞攻击表达EGFR的癌细胞。
药物组合物
本发明还提供了药物组合物,其包含本文所述的缀合物和药学上可接受的媒介物、赋形剂或载体。在某些实施方案中,所述药物组合物还包含抗癌剂。在某些实施方案中,所述药物组合物包含约80%、约85%、约90%、约95%、约99%、约99.5%或约80-99.5%的所述缀合物和约0.5%、约1%、约5%、约10%、约15%、约20%或约0.5-20%的所述缀合物。
合适的媒介物是例如水、盐水、葡萄糖、甘油、乙醇等,以及它们的组合。另外,媒介物可以含有其他赋形剂,如湿润剂或乳化剂、pH缓冲剂或佐剂。药学上可接受的载体可含有生理上可接受的化合物,其起到例如稳定或增加或降低本发明药物组合物的吸收或清除速率的作用。生理学上可接受的化合物可包括例如碳水化合物如葡萄糖、蔗糖、葡聚糖,抗氧化剂如抗坏血酸或谷胱甘肽,螯合剂,低分子量蛋白质,去污剂,脂质体载体或其他稳定剂和/或缓冲剂。所述赋形剂可以是非离子表面活性剂、聚乙烯吡咯烷酮、人血清白蛋白、氢氧化铝、具有麻醉作用的物质以及各种未修饰和衍生的环糊精。更优选地,所述非离子表面活性剂可以包括聚山梨酯20、聚山梨酯40、聚山梨酯60和聚山梨酯80。聚乙烯吡咯烷酮可以优选地是Plasdone C15,一种药物级的聚乙烯吡咯烷酮。具有麻醉作用的物质优选是苯甲醇。其他生理上可接受的化合物包括湿润剂、乳化剂、分散剂或防腐剂。参见例如第21版Remington’s Pharmaceutical Science,Mack Publishing Company,Easton,Pa.(“Remington’s”)。本发明的药物组合物还可包括辅助物质,如药理学物质或其他生物反应调节剂。包含此类赋形剂或载体的药物组合物通过熟知的常规方法配制。
可以将所述药物组合物配制成用于以下施用途径:血管内,肌内,口服,皮肤,鼻,含服,直肠,阴道,通过吸入或通过皮下施用。只要可以诱导令人满意的免疫原性,其他施用方式也可适用。
本发明的药物组合物可以制备成注射剂,可以是液体溶液或悬浮液,或者作为适于在注射前在液体载体中的溶液或悬浮液的固体形式。所述药物组合物也可以固体形式、乳化的形式制备,或将活性成分包囊在脂质体媒介物或其他用于持续递送的颗粒载体中。例如,所述药物组合物可以是油乳液、油包水乳液、水包油包水乳液、部位特异性乳液、长效乳液、粘性乳液、微乳液、纳米乳液、脂质体、微粒、微球、纳米球、纳米颗粒和各种天然或合成聚合物如不可吸收的不可渗透聚合物如乙烯乙酸乙烯酯共聚物和共聚物、可溶胀聚合物如水凝胶或可吸收聚合物如胶原蛋白和某些多酸或聚酯如用于制造可吸收缝线的那些(其可持续释放疫苗)。
抑制癌细胞生长的方法
根据本发明,通过施用有效量的本文所述的包含GM-CSF多肽和配体的缀合物提供了抑制癌细胞生长的方法,其中所述有效量的缀合物抑制所述受试者中的癌细胞生长。
本发明的缀合物可以任何有效量施用。通过比较它们的体外活性和在动物模型中的体内活性来确定所述缀合物抑制癌细胞的有用剂量。在小鼠和其他动物中向人外推有效剂量的方法是本领域已知的;例如参见美国专利号4,938,949,其通过引用并入本文。所述缀合物抑制癌细胞的剂量将取决于所治疗状况的严重性,特定制剂以及其他临床因素如体重和接受者的一般状况以及施用途径。
在一些实施方案中,用于抑制癌细胞的所述方法还包括施用有效量的抗癌剂,其中所述抗癌剂是生物治疗剂、化学疗法、靶疗法、手术、放射疗法或其组合。
在另一个实施方案中,用于抑制癌细胞的所述方法包括向有需要的受试者施用本文所述的缀合物和选自CTLA-4抗体、EGFR抗体、酪氨酸激酶抑制剂或其组合的抗癌剂。
在一个实施方案中,癌细胞表达表皮生长因子受体(EGFR)。表达EGFR的癌症的非限制性实例是肺癌、头颈癌、皮肤癌、食道癌、胰腺癌、胃癌、结肠直肠癌、肾细胞癌、乳腺癌、卵巢癌、神经胶质瘤、膀胱癌、肝细胞癌、前列腺癌或食道癌。在另一个实施方案中,癌细胞表达血管内皮生长因子(VEGF)。表达VEGF的癌症的非限制性实例是肺癌、头颈癌、皮肤癌、食道癌、胰腺癌、胃癌、结肠直肠癌、肾细胞癌、乳腺癌、卵巢癌、神经胶质瘤、膀胱癌、肝细胞癌、前列腺癌或食道癌。
可以在适合于所治疗状况的时间段内以单剂量治疗或多剂量治疗施用所述缀合物。可以方便地以适当的间隔施用所述缀合物,例如一天一次、一天两次、一天三次、每两天一次、每三天一次或每周一次、每月一次、在至少3个月的时间内一次,或直到状况的症状和迹象消失。
诱导抗体产生的方法
还公开了诱导抗体产生的方法,其中所述抗体对癌细胞有效。
在一个实施方案中,提供了诱导抗EGF抗体的方法,包括将有效量的包含GM-CSF多肽和EGF配体的缀合物施用给需要癌症治疗的受试者,其中在所述受试者中诱导有效量的抗-EGF抗体。
在另一个实施方案中,提供了诱导抗VEGF抗体的方法,包括将有效量的包含GM-CSF多肽和VEGF配体的缀合物施用给需要癌症治疗的受试者,其中在所述受试者中诱导有效量的抗-VEGF抗体。
本发明的实施方案通过以下实施例说明,这些实施例不以任何方式解释为对本发明的范围施加限制。相反,应该清楚地理解,在阅读本文的描述之后,在不偏离本发明的精神的情况下,本领域技术人员可以进行多种其他实施方案、修改及其等价形式。在以下实施例中描述的研究过程中,除非另有说明,否则遵循常规程序。
实施例1:mGM-CSF-hEGF在大肠杆菌中的表达
为构建mGM-CSF-hEGF缀合物或融合蛋白,将GM-CSF和EGF克隆到大肠杆菌表达载体pET56中,然后将pET56 mGM-CSF-hEGF构建体转化大肠杆菌Rosetta(DE3)菌株。
大肠杆菌在含有50μg/ml氨苄青霉素的10ml的lysogeny broth(LB)培养基中于37℃生长过夜。次日早上,将10ml的LB培养物接种1升含氨苄青霉素的LB(在两个1L的Fernbach烧瓶中)。先前对各种培养条件的研究表明,在培养光密度(600nm)约0.6加入0.03mM异丙基b-D-1-硫代半乳糖苷(IPTG),然后在37℃培养16小时是提高mGM-CSF-hEGF包涵体产量的最理想条件。通过在4℃、5000g离心15分钟收集细胞并在-20℃保存。
将大肠杆菌重悬于150ml重悬缓冲液PBS(134mM NaCl,2.7mM KCl,10mM Na2HPO4和KH2PO4,pH 7.4)中。French Press机械破坏用于裂解细菌。通过在4℃、5000g离心20分钟从细胞上清液分离包涵体。将包涵体沉淀物溶解在PBS中(使包涵体反复通过滴管)并使用不同的洗涤缓冲液重复洗涤(第一次洗涤用在PBS中的0.1%SDC,第二次洗涤用PBS,第三次洗涤用PBS,及第4次洗涤用H2O。将洗涤过的包涵体在20ml变性缓冲液(50mM Tris-碱,150mMNaCl,6M尿素,pH 8)中以60rpm在4℃变性16小时以形成变性蛋白溶液。
通过离心(在4℃、13200g共20分钟)使变性蛋白溶液澄清。将上清液加载到在平衡缓冲液(50mM Tris碱,150mM NaCl和6M尿素,pH 8)中平衡的HiTrap His-tag亲和柱(GEHealthcare Life Sciences,USA)上。用过量的洗涤缓冲液(50mM Tris-碱,150mM NaCl和6M尿素,pH 8)洗涤该柱。mGM-CSF-hEGF用洗脱缓冲液(50mM Tris-碱,150mM NaCl和6M尿素)和增加浓度的咪唑(0-250mM)洗脱。图3是镍亲和层析图像,其中使用紫外光检测到蛋白质,浓度表示为蓝线。为可视化洗脱的蛋白质,通过用考马斯亮蓝染色20分钟的SDS聚丙烯酰胺凝胶检查5μl蛋白质级分的纯度。图4显示了在不同纯化步骤中的纯化蛋白质产物:1.初始细菌裂解物;2.细菌裂解物的上清液;3.沉淀;4.包涵体;5.洗涤的包涵体;6.包涵体透析;7.重新溶解的包涵体;8.分子量标记;9.mGM-CSF-hEGF(SEQ ID NO:1)和10.mGM-CSF-hEGF(SEQ ID NO:1)。
实施例2:GM-CSF-EGF融合蛋白与EGFR的结合
为检查实施例1的纯化的mGM-CSF-hEGF融合蛋白的生物活性,以5000个细胞/孔将鼠骨髓成纤维细胞白血病细胞系NFS-60铺板在96孔板中并用递增浓度的mGM-CSF-hEGF或mGM-CSF在37℃温育3天。使用比色的3-(4,5-二甲基噻唑-2-基)-2,5-二苯基溴化四氮唑(MTT)测定法测量存活的NFS-60细胞。使用ELISA酶标仪在540nm处检测到琥珀酸脱氢酶在活的NFS-60细胞中产生的紫色甲月替(formazan)。图8显示了mGM-CSF-EGF刺激GM-CSF依赖性NFS60增殖。在GM-CSF依赖性NSF60增殖测定中,GM-CSF-EGF融合蛋白的EC50为20pM,而纯化的野生型GM-CSF蛋白的EC50为31pM。
在EGF-EGFR结合测定中,实施例1的野生型EGF和mGM-CSF-hEGF融合蛋白均显示出高亲和力,Kd值约为10nM。
实施例1的mGM-CSF–hEGF和hEGF与纯化的EGFR的结合
将纯化的EGFR(R&D Systems,Minneapolis,MN)在包被缓冲液(0.2M碳酸钠/碳酸氢钠pH 9.4,0.5lg/mL)中稀释并通过在4℃孵育过夜而固定在ELISA板上。将各种浓度的mGM-CSF–hEGF和hEGF(0–50nM)与固定的EGFR在室温孵育1小时,然后用PBS缓冲液洗涤ELISA板3次。使用HRP标记的抗his6抗体检测his6标记的mGM-CSF–hEGF或hEGF蛋白与EGFR的体外结合,并通过添加HRP底物3,30,5,50-四甲基联苯胺(TMB)(100μL/孔)来显色。加入0.5M H2SO4(50mL/孔)30分钟后,过氧化物酶反应停止,使用多通道微量滴定板读数器在450nm处测量吸光度。如图9所示,实施例1的野生型hEGF和mGM-CSF-hEGF在EGF-EGFR结合测定中均显示出高亲和力,Kd值小于5nM。
实施例3:GM-CSF-EGF和GM-CSF-VEGF融合蛋白的抗癌功效
使用c57小鼠进行了体内研究以评估GM-CSF-EGF(SEQ ID NO:1)和GM-CSF-VEGF(SEQ ID NO:2)融合蛋白的抗癌功效。
小鼠皮下接种(a)2x105亲本B16-F10鼠黑色素瘤细胞,(b)与1x105稳定的表达mGM-CSF的B16-F10细胞(mGM-CSF)混合的1x105亲本B16-F10细胞,(c)与1x105稳定的表达mGM-CSF-hEGF(SEQ ID NO:1)的B16-F10细胞混合的1x105亲本B16-F10细胞,或(d)与1x105稳定的表达mGM-CSF-mVEGF(SEQ ID NO:2)的B16-F10细胞混合的1x105亲本B16-F10细胞。
图5显示了接种或未接种表达mGM-CSF-hEGF和mGM-CSF-mVEGF的B16-F10细胞的4组小鼠的肿瘤大小。与仅接种表达mGM-CSF的B16-F10细胞肿瘤的小鼠(b组)相比,接种了表达mGM-CSF-hEGF(c组)和mGM-CSF-mVEGF(d组)的B16-F10细胞的小鼠的肿瘤显著减小。
使用Balb/c小鼠进行了另外的动物研究。给小鼠腹膜内(i.p.)接种表达hEGFR和荧光素酶的RENCA-hEGFR-luc肿瘤细胞。在肿瘤接种的同一天,给小鼠每天注射PBS缓冲液(对照组)或每天注射10μg实施例1的GM-CSF-EGF融合蛋白10天(研究组)。接种肿瘤21天后,对小鼠进行体内成像以检测由RENCA-hEGFR-luc细胞表达的萤光素酶产生的生物发光强度(肿瘤负担标志)。如图6A和6B所示,与研究组相比,对照组显示显著更高的由RENCA-hEGFR-luc细胞引起的生物发光强度(高3倍)。
结果表明mGM-CSF-hEGF和mGM-CSF-hVEGF融合蛋白可有效抑制癌细胞。
实施例4:mGM-CSF-hEGF与癌细胞上EGFR的结合
进行了评估mGM-CSF-hEGF与表达人EGFR的癌细胞(包括RENCA-hEGFR-luc稳定细胞和MDA-468乳腺癌细胞)结合的体外研究。在MDA-468乳腺癌细胞和RENCA-hEGFR-luc细胞上表达的EGFR可以与纯化的his6标签的hEGF和mGM-CSF-hEGF结合。使用对his6标签特异的FITC标记的抗体和FACS分析可以检测hEGF和mGM-CSF-hEGF与EGFR的结合。图7A和图7B的荧光强度显示代表与EGFR偶联的his6标签的hEGF(亮蓝色)或his6标签的mGM-CSF-hEGF(橙色)的量。
FACS图像显示实施例1的GM-CSF-EGF缀合物与表达人EGFR的癌细胞的结合。该结果表明结合GM-CSF-EGF的癌细胞可以用作癌症疫苗。
实施例5:GM-CSF-EGF融合蛋白的免疫原性
使用balb/c小鼠进行了体内研究以评估GM-CSF-EGF融合蛋白的免疫原性。
每只Balb/c和c57/BL小鼠每天皮下注射10μg实施例1的GM-CSF-EGF融合蛋白(SEQID NO:1)或磷酸盐缓冲盐水(PBS),共2周。在最后一次注射后4周,测量血清抗EGF抗体。图10A显示在缀合物施用后四周,注射了GM-CSF-EGF融合蛋白的小鼠的血清中抗EGF抗体效价高达25600。在小鼠中未观察到明显的副作用,如体重减轻、皮毛褶皱或任何不适迹象。图10B显示注射了mGM-CSF-EGF融合蛋白的小鼠的血清抑制EGF与EGFR的结合。
检查血清阻断EGF和EGFR之间缔合的能力。将纯化的EGFR固定在96孔ELISA板上并与来自用GM-CSF-EGF融合蛋白或PBS免疫的小鼠的系列稀释的血清孵育。与先前描述的体外EGF-EGFR结合测定相似,在HRP底物3,30,5,50-四甲基联苯胺(TMB)存在下(100μL/孔),使用HRP缀合的抗his6标签抗体测量EGFR偶联的带有his6标签的EGF。加入0.5M H2SO4(50mL/孔)30分钟后,过氧化物酶反应停止,使用多通道微量滴定板读数器在450nm处测量吸光度。在无血清的情况下,将EGFR-EGF结合确定为100%。增加GM-CSF-EGF免疫小鼠的血清浓度,从4000倍稀释到20倍稀释,抑制了EGF和EGFR之间的缔合。
实施例6:mGM-CSF-hEGF融合蛋白和抗CTLA4抗体(9H10)组合的协同抗癌功效。
使用c57小鼠进行了体内研究以评估mGM-CSF-hEGF融合蛋白(SEQ ID NO:1)组合抗CTLA4抗体(9H10)的抗癌功效。
将小鼠分为4组,皮下接种如下:A组小鼠,1x105表达hEGFR的B16-F10鼠黑色素瘤细胞和1x105表达mGM-CSF的B16-F10鼠黑色素瘤细胞(B16F10 hEGFR/B16mGMCSF);B组,1x105表达EGFR的B16-F10鼠黑色素瘤细胞和1x105稳定的表达mGM-CSF-hEGF的B16-F10鼠黑色素瘤细胞(B16F10 hEGFR/B16mGMCSF-hE);C组,1x105稳定的表达hEGFR的B16-F10鼠黑色素瘤细胞混合1x105稳定的表达mGM-CSF的B16-F10鼠黑色素瘤细胞组合9H10抗体(B16F10hEGFR/B16F10 mG/9H10);和D组,1x105稳定的表达hEGFR的B16-F10鼠黑色素瘤细胞混合1x105稳定的表达mGM-CSF-hEGF的B16-F10鼠黑色素瘤细胞组合9H10抗体(B16F10hEGFR/B16F10 mG-hE/9H10)。
图11显示用表达mGM-CSF或mGM-CSF-hEGF的B16-F10细胞和或不和抗CTLA-4抗体一起接种的4组小鼠的肿瘤大小。与A组小鼠(接种表达mGM-CSF的细胞)或B组小鼠(接种表达mGM-CSF-hEGF的细胞)相比,C组和D组小鼠的肿瘤明显减小。与C组小鼠(接种表达mGM-CSF的细胞组合9H10抗体)相比,D组小鼠(接种表达mGM-CSF-hEGF的细胞组合9H10抗体)的肿瘤明显减小。
结果表明mGM-CSF-hEGF与抗CTLA-4抗体的组合在癌细胞抑制中具有协同作用。
实施例7:GM-CSF-PDGFA和GM-CSF-bFGF融合蛋白的抗癌功效
使用c57小鼠进行了体内研究以评估GM-CSF-PDGFA(SEQ ID NO:3)和GM-CSF-bFGF(SEQ ID NO:4)融合蛋白的抗癌功效。
小鼠皮下接种(a)5x104稳定的表达mGM-CSF的B16-F10鼠黑色素瘤细胞,(b)0.75x104亲本B16-F10鼠黑色素瘤细胞混合4.25x104稳定的表达mGM-CSF-mPDGFA的B16-F10鼠黑色素瘤细胞或(c)2.7x104亲本B16-F10鼠黑素瘤细胞混合2.3x104稳定的表达mGM-CSF-mbFGF的B16-F10鼠黑素瘤细胞。
参考图12,与仅接种表达mGM-CSF的B16-F10细胞肿瘤的小鼠(a组)相比,接种了表达mGM-CSF-mPDGFA(b组)和mGM-CSF-mbFGF(c组)的B16-F10细胞的小鼠具有明显的肿瘤减小。
结果表明mGM-CSF-mPDGFA和mGM-CSF-mbFGF融合蛋白有效抑制癌细胞。
尽管已经例证和描述了本发明的某些实施例,但是能够理解本教导的本领域技术人员将认识到本发明不仅限于这些实施方案。因此应理解,本发明旨在涵盖对本领域技术人员而言显而易见的许多修改、改变、变化、替代和等价形式。
序列表
<110> 蓝耿立
蔡政良
<120> 新缀合物及其用途
<130> 62/565,509
<150> US 62/565,509
<151> 2017-09-29
<160> 8
<170> PatentIn version 3.5
<210> 1
<211> 189
<212> PRT
<213> Artificial Sequence
<220>
<223> mGM-CSF-mVEGF
<400> 1
Ser Pro Ile Thr Val Thr Arg Pro Trp Lys His Val Glu Ala Ile Lys
1 5 10 15
Glu Ala Leu Asn Leu Leu Asp Asp Met Pro Val Thr Leu Asn Glu Glu
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Val Glu Val Val Ser Asn Glu Phe Ser Phe Lys Lys Leu Thr Cys Val
35 40 45
Gln Thr Arg Leu Lys Ile Phe Glu Gln Gly Leu Arg Gly Asn Phe Thr
50 55 60
Lys Leu Lys Gly Ala Leu Asn Met Thr Ala Ser Tyr Tyr Gln Thr Tyr
65 70 75 80
Cys Pro Pro Thr Pro Glu Thr Asp Cys Glu Thr Gln Val Thr Thr Tyr
85 90 95
Ala Asp Phe Ile Asp Ser Leu Lys Thr Phe Leu Thr Asp Ile Pro Phe
100 105 110
Glu Cys Lys Lys Pro Gly Gln Lys Val Pro Gly Val Gly Val Pro Gly
115 120 125
Val Gly Asn Ser Asp Ser Glu Cys Pro Leu Ser His Asp Gly Tyr Cys
130 135 140
Leu His Asp Gly Val Cys Met Tyr Ile Glu Ala Leu Asp Lys Tyr Ala
145 150 155 160
Cys Asn Cys Val Val Gly Tyr Ile Gly Glu Arg Cys Gln Tyr Arg Asp
165 170 175
Leu Lys Trp Trp Glu Leu Arg His His His His His His
180 185
<210> 2
<211> 256
<212> PRT
<213> Artificial Sequence
<220>
<223> mGM-CSF-mVEGF
<400> 2
Ser Pro Ile Thr Val Thr Arg Pro Trp Lys His Val Glu Ala Ile Lys
1 5 10 15
Glu Ala Leu Asn Leu Leu Asp Asp Met Pro Val Thr Leu Asn Glu Glu
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Val Glu Val Val Ser Asn Glu Phe Ser Phe Lys Lys Leu Thr Cys Val
35 40 45
Gln Thr Arg Leu Lys Ile Phe Glu Gln Gly Leu Arg Gly Asn Phe Thr
50 55 60
Lys Leu Lys Gly Ala Leu Asn Met Thr Ala Ser Tyr Tyr Gln Thr Tyr
65 70 75 80
Cys Pro Pro Thr Pro Glu Thr Asp Cys Glu Thr Gln Val Thr Thr Tyr
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Ala Asp Phe Ile Asp Ser Leu Lys Thr Phe Leu Thr Asp Ile Pro Phe
100 105 110
Glu Cys Lys Lys Pro Gly Gln Lys Val Pro Gly Val Gly Val Pro Gly
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Val Gly Ala Pro Thr Thr Glu Gly Glu Gln Lys Ser His Glu Val Ile
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Lys Phe Met Asp Val Tyr Gln Arg Ser Tyr Cys Arg Pro Ile Glu Thr
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Leu Val Asp Ile Phe Gln Glu Tyr Pro Asp Glu Ile Glu Tyr Ile Phe
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Lys Pro Ser Cys Val Pro Leu Met Arg Cys Ala Gly Cys Cys Asn Asp
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Glu Ala Leu Glu Cys Val Pro Thr Ser Glu Ser Asn Ile Thr Met Gln
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Ile Met Arg Ile Lys Pro His Gln Ser Gln His Ile Gly Glu Met Ser
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Phe Leu Gln His Ser Arg Cys Glu Cys Arg Pro Lys Lys Asp Arg Thr
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Lys Pro Glu Lys Cys Asp Lys Pro Arg Arg His His His His His His
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<210> 3
<211> 128
<212> PRT
<213> Artificial Sequence
<220>
<223> Recombinant human GM-CSF
<400> 3
Met Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His
1 5 10 15
Val Asn Ala Ile Gln Glu Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp
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Thr Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Glu Met Phe
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Asp Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys
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Gln Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met
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Met Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser
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Cys Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys
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Asp Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
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<210> 4
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> mGM-CSF
<400> 4
Ser Pro Ile Thr Val Thr Arg Pro Trp Lys His Val Glu Ala Ile Lys
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Gln Thr Arg Leu Lys Ile Phe Glu Gln Gly Leu Arg Gly Asn Phe Thr
50 55 60
Lys Leu Lys Gly Ala Leu Asn Met Thr Ala Ser Tyr Tyr Gln Thr Tyr
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Ala Asp Phe Ile Asp Ser Leu Lys Thr Phe Leu Thr Asp Ile Pro Phe
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Glu Cys Lys Lys Pro Gly Gln Lys
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<210> 5
<211> 5
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<213> Artificial Sequence
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Val Pro Gly Val Gly
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<210> 6
<211> 5
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<213> Artificial Sequence
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Gly Gly Gly Gly Ser
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<210> 7
<211> 5
<212> PRT
<213> Artificial Sequence
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Pro Ala Pro Ala Pro
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<213> Artificial Sequence
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Glu Ala Ala Ala Lys
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Claims (21)
1.一种缀合物,其包含
粒细胞巨噬细胞集落刺激因子(GM-CSF)多肽;和
配体。
2.权利要求1的缀合物,其中所述GM-CSF通过接头可操作地连接至所述配体或共价连接至所述配体。
3.权利要求1的缀合物,其中所述配体是肿瘤相关配体。
4.权利要求3的缀合物,其中所述肿瘤相关配体选自表皮生长因子(EGF)、C-X-C基序趋化因子12(CXCL12)、肝细胞生长因子-1(HGF)和胰岛素样生长因子(IGF)。
5.权利要求3的缀合物,其中所述肿瘤相关配体选自集落刺激因子(CSF-1)、巨噬细胞趋化蛋白-1(MCP-1)和巨噬细胞炎性蛋白-1α(MIP-1α)。
6.权利要求3的缀合物,其中所述肿瘤相关配体选自血管内皮生长因子(VEGF)、血小板衍生生长因子(PDGF)和成纤维细胞生长因子(FGF)。
7.权利要求1的缀合物,其中所述配体不是白介素、抗体或肿瘤细胞上的受体。
8.权利要求1的缀合物,其中所述缀合物与SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3或SEQ ID NO:4至少90%同源。
9.一种药物组合物,其包含
权利要求1的结合物;和
药学上可接受的赋形剂。
10.权利要求9的药物组合物,其还包含抗癌剂。
11.权利要求10的药物组合物,其中所述抗癌剂选自细胞毒性T淋巴细胞相关抗原4(CTLA-4)抗体、EGFR抗体或酪氨酸激酶抑制剂。
12.一种在受试者中抑制癌细胞生长的方法,包括施用有效量的包含GM-CSF和配体的缀合物,其中所述有效量的缀合物抑制所述受试者中的癌细胞。
13.权利要求12的方法,其中所述GM-CSF与所述配体共价或可操作地连接。
14.权利要求12的方法,其中所述配体是肿瘤相关配体。
15.权利要求14的方法,其中所述肿瘤相关配体选自表皮生长因子(EGF)、C-X-C基序趋化因子12(CXCL12)、肝细胞生长因子-1(HGF)和胰岛素样生长因子(IGF)、集落刺激因子(CSF-1)、巨噬细胞趋化蛋白I(MCP-1)和巨噬细胞炎性蛋白1α(MIP-1α)、血管内皮生长因子(VEGF)、血小板衍生生长因子(PDGF)或成纤维细胞生长因子(FGF)。
16.权利要求12的方法,其中所述缀合物与SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3或SEQ ID NO:4至少90%同源。
17.权利要求12的方法,其进一步包括施用有效量的抗癌剂。
18.权利要求17的方法,其中所述抗癌剂选自CTLA-4抗体、EGFR抗体或酪氨酸激酶抑制剂。
19.权利要求12的方法,其中所述癌细胞表达表皮生长因子受体(EGFR)或血管内皮生长因子(VEGF)。
20.一种在受试者中诱导抗EGF抗体的方法,包括在需要癌症治疗的受试者中施用有效量的包含GM-CSF和EGF的缀合物,其中在所述受试者中诱导有效量的抗EGF抗体。
21.一种在受试者中诱导抗VEGF抗体的方法,包括在需要癌症治疗的受试者中施用有效量的包含GM-CSF和VEGF的缀合物,其中在所述受试者中诱导有效量的抗VEGF抗体。
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