CN117615791A - 使用抗体药物缀合物的组合疗法 - Google Patents
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Abstract
本公开涉及抗CD19抗体药物缀合物与抗CD79b缀合物的组合,以及它们在治疗中的用途,诸如治疗增生性病症。
Description
早期申请
本申请要求2021年6月29日提交的英国申请号GB2109373.7;2021年6月29日提交的GB2109375.2;以及2021年6月29日提交的GB2109377.8的优先权。所述优先权申请以全文引用的方式并入本文中并且用于任何和所有目的,如同在本文中完整阐述一般。
技术领域
本公开涉及用于治疗病理性疾患(诸如癌症)的组合疗法。具体地说,本公开涉及包括使用抗CD19抗体药物缀合物(抗CD19 ADC)和抗CD79b剂的治疗的组合疗法。
背景技术
抗体疗法
已建立用于靶向治疗患有癌症、免疫以及血管生成病症的受试者的抗体疗法。使用抗体-药物缀合物(ADC)(即免疫缀合物)局部递送细胞毒性剂或细胞抑制剂(即癌症治疗中用于杀死或抑制肿瘤细胞的药物)以将药物部分递送至肿瘤以及其中的细胞内累积为目标,而这些非缀合药物剂的全身施用可能会对正常细胞产生不可接受的毒性水平。
CD19
CD19是一种95kDa膜受体,在B细胞分化的早期表达,并且持续表达,直到B细胞被触发终末分化。CD19细胞外结构域含有两个C2型免疫球蛋白(IG)样结构域,这两个C2型免疫球蛋白样结构域由一个更小的潜在二硫键连接结构域分隔。CD19胞质结构域在结构上是独特的,但在人、小鼠以及豚鼠之间高度保守。CD19是在B淋巴细胞的细胞表面发现的蛋白质复合物的一部分。蛋白复合物包括CD 19、CD 21(补体受体,2型)、CD 81(TAPA-1)以及CD225(Leu-13)。
CD19为B细胞中跨膜信号的重要调节因子。CD19的细胞表面密度增加或降低影响B细胞发育和功能,从而导致疾病,诸如自体免疫或低丙种球蛋白血症。CD19复合物通过交联存在于B细胞薄膜上的两种单独的信号转导复合物增强B细胞在体内对抗原的反应。这两种与膜IgM和CD19相关的信号转导复合物通过不同机制活化磷脂酶C(PLC)。CD19和B细胞受体交联降低活化PLC所需的IgM分子的数目。CD19还充当用于扩增Arc家族激酶的特化衔接蛋白。
CD19结合已显示根据发生的交联的量增强与抑制B细胞活化和增殖。CD19在大于90%的B细胞淋巴瘤上表达并且预期影响体外和体内淋巴瘤的生长。
抗CD19 ADC的治疗用途
包含抗CD19抗体的抗体药物缀合物(抗CD19-ADC)在例如癌症的治疗中的功效已确定,参见例如WO2014/057117和WO2016/166298。
继续研究以进一步改善抗CD19 ADC的功效、耐受性以及临床功效。为此目的,本发明作者鉴定了临床上有利的组合疗法,其中抗CD19 ADC与至少一种抗CD79b剂组合施用。
发明内容
本作者已确定向个体施用抗CD19 ADC与抗CD79b剂的组合引起出乎意料的临床优势。本作者还确定向已用抗CD79b剂治疗或正在用抗CD79b剂治疗的个体施用抗CD19 ADC和抗CD79b剂引起治疗功效的协同增加。
因此,在第一方面中,本公开提供了一种选择适合用抗CD19ADC治疗的个体的方法,其中如果个体已用抗CD79b剂治疗或正在用抗CD79b剂治疗,那么选择所述个体用于用抗CD19 ADC治疗。如果个体用抗CD79b剂治疗或进一步治疗为难以治疗的,那么可选择所述个体用于治疗。
在另一方面中,本公开提供了一种用于治疗个体的病症的方法,所述方法包括通过第一方面的方法选择适合治疗的个体,然后向个体施用有效量的抗CD19 ADC。治疗方法还可包括施用抗CD79b剂与抗CD19 ADC的组合。
在另一方面中,本公开提供了一种用于治疗个体的病症的方法,所述方法包括向个体施用有效量的抗CD19 ADC和抗CD79b剂。可根据符合第一方面的方法选择个体用于治疗。
病症可为增殖性疾病,例如癌症,诸如非霍奇金氏淋巴瘤,包括弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、伯基特淋巴瘤、套细胞淋巴瘤(MCL)、慢性淋巴性淋巴瘤(CLL)、华登斯特罗姆巨球蛋白血症(Macroglobulinemia)(WM)以及边缘区B细胞淋巴瘤(MZBL);以及白血病,诸如毛细胞白血病(HCL)、变异型毛细胞白血病(HCL-v)、慢性淋巴细胞性白血病(CLL)(包括里希特综合征),以及急性成淋巴细胞性白血病(ALL),诸如费城染色体(Philadelphia chromosome)阳性ALL(Ph+ALL)或费城染色体阴性ALL(Ph-ALL)。
抗CD19 ADC可为泰朗妥昔单抗(Loncastuximab tesirine)。
抗CD19 ADC可为本文所描述的ADCx19。
抗CD79b剂可为维普拉土珠单抗(Polatuzumab vedotin)。
个体可为人。个体可患有癌症,或可已被确定患有癌症。个体可患有或已被确定患有CD19+癌症或具有或已被确定具有CD19+肿瘤相关非肿瘤细胞,诸如CD19+浸润B细胞。
在所公开的方法中,可在抗CD79b剂之前,与抗CD79b剂同时或在抗CD79b剂之后施用抗CD19 ADC。所公开的方法可包括向个体施用另一化学治疗剂。
在另一方面中,本公开提供了一种用于如本文所描述的治疗方法中的抗CD19 ADC或包含抗CD19 ADC的组合物。
在一个方面中,本公开提供了用于如本文所描述的治疗方法中的抗CD79b剂或包含抗CD79b剂的组合物
在另一方面中,本公开提供了抗CD19 ADC或抗CD79b剂在用于治疗个体的病症的药剂的制造中的用途,其中治疗包括如本文所描述的治疗方法。
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在另一方面中,本公开提供了一种用于治疗个体的病症的方法中的包含抗CD19ADC的第一组合物,其中治疗包括施用第一组合物与包含抗CD79b剂的第二组合物的组合。
此方面还提供了一种用于治疗个体的病症的方法中的包含抗CD79b剂的第一组合物,其中治疗包括施用第一组合物与包含抗CD19 ADC的第二组合物的组合。
病症可为增殖性疾病,例如癌症,诸如非霍奇金氏淋巴瘤,包括弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、伯基特淋巴瘤、套细胞淋巴瘤(MCL)、慢性淋巴性淋巴瘤(CLL)、华登斯特罗姆巨球蛋白血症(WM)以及边缘区B细胞淋巴瘤(MZBL);以及白血病,诸如毛细胞白血病(HCL)、变异型毛细胞白血病(HCL-v)、慢性淋巴细胞性白血病(CLL)(包括里希特综合征)以及急性成淋巴细胞性白血病(ALL),诸如费城染色体阳性ALL(Ph+ALL)或费城染色体阴性ALL(Ph-ALL)。
抗CD19 ADC可为泰朗妥昔单抗。
抗CD19 ADC可为本文所描述的ADCx19。
抗CD79b剂可为维普拉土珠单抗。
个体可为人。个体可患有癌症,或可已被确定患有癌症。个体可患有或已被确定患有CD19+癌症或具有或已被确定具有CD19+肿瘤相关非肿瘤细胞,诸如CD19+浸润B细胞。
可在第二组合物之前、与第二组合物同时或在第二组合物之后施用第一组合物。治疗可包括向个体施用另一化学治疗剂。
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在另一方面中,本公开提供了抗CD19 ADC在用于治疗个体的病症的药剂的制造中的用途,其中药剂包含抗CD19 ADC,并且其中治疗包括施用药剂与包含抗CD79b剂的组合物的组合。
此方面还提供了抗CD79b剂在用于治疗个体的病症的药剂的制造中的用途,其中药剂包含抗CD79b剂,并且其中治疗包括施用药剂与包含抗CD19 ADC的组合物的组合。
病症可为增殖性疾病,例如癌症,诸如非霍奇金氏淋巴瘤,包括弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、伯基特淋巴瘤、套细胞淋巴瘤(MCL)、慢性淋巴性淋巴瘤(CLL)、华登斯特罗姆巨球蛋白血症(WM)以及边缘区B细胞淋巴瘤(MZBL);以及白血病,诸如毛细胞白血病(HCL)、变异型毛细胞白血病(HCL-v)、慢性淋巴细胞性白血病(CLL)(包括里希特综合征)以及急性成淋巴细胞性白血病(ALL),诸如费城染色体阳性ALL(Ph+ALL)或费城染色体阴性ALL(Ph-ALL)。
抗CD19 ADC可为泰朗妥昔单抗。
抗CD19 ADC可为本文所描述的ADCx19。
抗CD79b剂可为维普拉土珠单抗。
个体可为人。个体可患有癌症,或可已被确定患有癌症。个体可患有或已被确定患有CD19+癌症或具有或已被确定具有CD19+肿瘤相关非肿瘤细胞,诸如CD19+浸润B细胞。
可在组合物之前、与组合物同时或在组合物之后施用药剂。治疗可包括向个体施用另一化学治疗剂。
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本公开的另一方面提供了一种药盒,所述药盒包含:
第一药剂,所述第一药剂包含抗CD19 ADC;
包装插页,所述包装插页包含关于根据如本文所公开的治疗方法施用所述第一药剂的说明书。药盒可还包含第二药剂,所述第二药剂包含抗CD79b剂。
本公开的另一方面提供了一种药盒,所述药盒包含:
第一药剂,所述第一药剂包含抗CD19 ADC;
第二药剂,所述第二药剂包含抗CD79b剂;以及任选地,
包装插页,所述包装插页包含关于将所述第一药剂与所述第二药剂组合施用给个体以治疗病症的说明书。
此方面还提供了一种药盒,所述药盒包含药剂,所述药剂含有抗CD19 ADC;以及包装插页,所述包装插页包含关于将药剂与包含抗CD79b剂的组合物组合施用给个体以治疗病症的说明书。
此方面还提供了一种药盒,所述药盒包含药剂,药剂包含抗CD79b剂;以及包装插页,所述包装插页包含关于将药剂与包含抗CD19 ADC的组合物组合施用给个体以治疗病症的说明书。
病症可为增殖性疾病,例如癌症,诸如非霍奇金氏淋巴瘤,包括弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、伯基特淋巴瘤、套细胞淋巴瘤(MCL)、慢性淋巴性淋巴瘤(CLL)、华登斯特罗姆巨球蛋白血症(WM)以及边缘区B细胞淋巴瘤(MZBL);以及白血病,诸如毛细胞白血病(HCL)、变异型毛细胞白血病(HCL-v)、慢性淋巴细胞性白血病(CLL)(包括里希特综合征)以及急性成淋巴细胞性白血病(ALL),诸如费城染色体阳性ALL(Ph+ALL)或费城染色体阴性ALL(Ph-ALL)。
抗CD19 ADC可为泰朗妥昔单抗。
抗CD19 ADC可为本文所描述的ADCx19。
抗CD79b剂可为维普拉土珠单抗。
个体可为人。个体可患有癌症,或可已被确定患有癌症。个体可患有或已被确定患有CD19+癌症或具有或已被确定具有CD19+肿瘤相关非肿瘤细胞,诸如CD19+浸润B细胞。
可在包含抗CD79b剂的药剂或组合物之前,与包含抗CD79b剂的药剂或组合物同时或在包含抗CD79b剂的药剂或组合物之后施用包含抗CD19 ADC的药剂或组合物。治疗可包括向个体施用另一化学治疗剂。
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在另一方面中,本公开提供了一种组合物,所述组合物包含抗CD19 ADC和抗CD79b剂,以及此类组合物在本文所公开的方法中的用途。
本公开的此方面中还提供了一种治疗个体的病症的方法,所述方法包括向个体施用有效量的包含抗CD19 ADC和抗CD79b剂的组合物。
本公开的此方面中还提供了一种用于治疗个体的病症的方法中的包含抗CD19ADC和抗CD79b剂的组合物。
本公开的此方面中还提供了包含抗CD19 ADC和抗CD79b剂的组合物在用于治疗个体的病症的药剂的制造中的用途。
本公开的此方面中还提供了一种药盒,所述药盒包含组合物,所述组合物包含抗CD19 ADC和抗CD79b剂;以及一组说明书,所述说明书是关于向个体施用药剂以治疗病症。
病症可为增殖性疾病,例如癌症,诸如非霍奇金氏淋巴瘤,包括弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、伯基特淋巴瘤、套细胞淋巴瘤(MCL)、慢性淋巴性淋巴瘤(CLL)、华登斯特罗姆巨球蛋白血症(WM)以及边缘区B细胞淋巴瘤(MZBL);以及白血病,诸如毛细胞白血病(HCL)、变异型毛细胞白血病(HCL-v)、慢性淋巴细胞性白血病(CLL)(包括里希特综合征)以及急性成淋巴细胞性白血病(ALL),诸如费城染色体阳性ALL(Ph+ALL)或费城染色体阴性ALL(Ph-ALL)。
抗CD19-ADC可为如本文所描述的ADCX19。
抗CD79b剂可为维普拉土珠单抗。
个体可为人。个体可患有癌症,或可已被确定患有癌症。个体可患有或已被确定患有CD19+癌症或具有或已被确定具有CD19+肿瘤相关非肿瘤细胞,诸如CD19+浸润B细胞。
治疗可包括向个体施用另一化学治疗剂。
本公开还更一般地涉及包含PBD二聚体作为弹头的抗体药物缀合物(诸如本文所描述的PBD)与包含单甲基澳瑞他汀E(monomethyl auristatin E)作为弹头的抗体药物缀合物的组合,以及如本文所描述的治疗方法,所述治疗方法包括施用这两种抗体药物缀合物的组合。选择针对个别剂中的每一者的抗体来结合至不同的靶分子。包含单甲基澳瑞他汀E的抗体药物缀合物的一个实例为其中抗体靶向抗CD79b。包含PBD二聚体的抗体药物缀合物的实例为如上文所描述靶向CD19的那些抗体药物缀合物以及如下文所描述靶向CD25或CD22的那些抗体药物缀合物。
因此,在另一方面中,本公开提供了(i)包含PBD二聚体的抗体药物缀合物;与(ii)包含单甲基澳瑞他汀E的抗体药物缀合物的组合,其中(i)的抗体结合至与(ii)的抗体不同的靶分子(例如不同的细胞表面分子,诸如蛋白质、受体等)。
在一个相关方面中,本公开提供了一种治疗罹患增殖性病症的个体的方法,所述方法通过向个体施用(i)包含PBD二聚体的抗体药物缀合物;与(ii)包含单甲基澳瑞他汀E的抗体药物缀合物的组合来进行,其中(i)的抗体结合至与(ii)的抗体不同的靶分子(例如不同的细胞表面分子,诸如蛋白质、受体等)。此类施用可为同时或单独的。
本领域技术人员将理解,下文针对抗CD19 ADC和抗CD79bADC详细描述的其他实施方案,诸如PBD的选择、要治疗的病症、患者选择以及施用,加以必要的变更可适用于结合至不同靶标的(i)和(ii)的ADC。其他靶标的特定实例为下文更详细描述的CD25和CD22。
CD25
I型跨膜蛋白CD25存在于活化的T细胞和B细胞、一些胸腺细胞、骨髓样前体以及寡树突神经胶质细胞上。在活化的T细胞上,它与β亚单位和γ亚单位形成异二聚体(CD122和CD132),因此包含对IL-2的高亲和力受体。此配体表示活化的T细胞的存活因子,因为IL-2的移除导致这些细胞立即死亡。
在B细胞的情况下,CD25在生理学上在晚期祖B和前B细胞的早期发育阶段表达。因此,由此阶段的B细胞分化产生的恶性肿瘤可能也表达CD25。肥大细胞病变也为CD25阳性的,因此CD25被认为是用于确定系统性肥大细胞增多症的重要诊断准则。在霍奇金氏淋巴瘤中,CD25被报告为不在结节性淋巴细胞为主型的霍奇金氏淋巴瘤(NLPHL)中的霍奇金-/里德-斯德伯格氏细胞中表达,而相同细胞类型在混合细胞类型的经典霍奇金氏淋巴瘤中以不同的水平表达CD25。总体表达水平被报告为比肿瘤浸润性淋巴细胞(TIL)中低,在这些情况下这可能会产生展示CD25肿瘤细胞的问题(Levi等,Merz等,1995)。
若干B细胞和T细胞源性亚型的非霍奇金-淋巴瘤(即B细胞慢性淋巴细胞性白血病、毛细胞白血病、小细胞淋巴细胞性淋巴瘤/慢性淋巴细胞性白血病以及成人T细胞白血病/淋巴瘤以及间变性大细胞淋巴瘤)中也报告了靶抗原的表达。
CD25可定位于膜上,并且在细胞质中观测到一些表达。还可在细胞外(诸如在血清中)观测到可溶性CD25。
抗CD25 ADC的治疗用途
已确定包含抗CD25抗体的抗体药物缀合物(抗CD25-ADC)在例如癌症的治疗中的功效,参见例如WO2014/057119、WO2016/083468、WO2016/166341以及WO2019/224275。
研究继续以进一步改善抗CD25 ADC的功效、耐受性以及临床功效。为此目的,本发明作者鉴定了临床上有利的组合疗法,其中抗CD25 ADC与与至少一种抗CD79b剂组合施用。
因此,在本发明的其他方面中,使用抗CD25-ADC与抗CD79b剂的组合,而不是抗CD19-ADC与抗CD76b剂的组合。因此以上实施方案中所有提到“抗CD19-ADC”处在其他实施方案中可替换为“抗CD25-ADC”。
CD22
CD22为免疫球蛋白(Ig)超家族的135-kDa I型跨膜唾液酸糖蛋白。CD22表达为B细胞特有的并且受发育调节以使得表达被限制在祖B和前B细胞中。随着B细胞成熟,表达增加并且CD22的定位转向细胞表面。CD22在滤泡、套细胞以及边缘区B细胞上强烈表达,但弱存在于胚B细胞中。CD22为抑制共受体,所述抑制共受体通过设定防止B细胞过度刺激的信号阈值下调B细胞受体(BCR)信号传导。
针对CD22的抗体(诸如依帕珠单抗(epratuzumab)(hLL2))已用于治疗多种癌症和自体免疫疾病,包括但不限于急性成淋巴细胞性白血病、慢性淋巴细胞性白血病、非霍奇金氏淋巴瘤、滤泡性淋巴瘤、弥漫性大B细胞淋巴瘤、套细胞淋巴瘤、系统性红斑狼疮以及原发性休格兰氏综合征(syndrome)。依帕珠单抗在系统性红斑狼疮中的阶段III临床试验当前在进行中(参见例如ClinicalTrials.gov,“Study of Epratuzumab versusPlacebo in Subjects with Moderate to Severe General Systemic LupusErythematosus(EMBODY 1)”)。因为CD22调控B细胞功能和存活,所以它是调节体液免疫性和B细胞淋巴瘤的增殖的重要环节并且是治疗性抗体在癌症和自体免疫疾病中的靶标。
抗CD22 ADC的治疗用途
已确定包含抗CD22抗体的抗体药物缀合物(抗CD22-ADC)在例如癌症的治疗中的功效,参见例如WO2014/057122和WO2016/166307,或如Kantarjian等,(2016,New Eng JMed)中所描述。
研究继续以进一步改善抗CD22 ADC的功效、耐受性以及临床功效。为此目的,本发明作者鉴定了临床上有利的组合疗法,其中抗CD22 ADC与至少一种抗CD79b剂组合施用。
因此,在本发明的其他方面中,使用抗CD22-ADC与抗CD79b剂的组合,而不是抗CD19-ADC与抗CD79b剂的组合。因此,以上实施方案中所有提到“抗CD19-ADC”处在其他实施方案中可替换为“抗CD22-ADC”。
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具体实施方式
抗体药物缀合物(ADC)
本公开涉及ADC与抗CD79b剂的组合的改善的功效。
ADC可将药物递送至目标位置。目标位置优选为增殖细胞群体。抗体为针对存在于增殖细胞群体上的抗原的抗体。在一个方面中,与存在于增殖细胞群体(例如肿瘤细胞群体)中的抗原的量相比,在非增殖细胞群体中抗原不存在或以降低的水平存在。
ADC可包含的接头,所述接头可裂解以便在目标位置释放药物。药物可为选自RelA、RelB、RelC、RelD或RelE的化合物。因此,可使用缀合物选择性地将化合物RelA、RelB、RelC、RelD或RelE提供至目标位置。
接头可由存在于目标位置的酶裂解。
本公开具体地说涉及使用WO2014/057117中所公开并且如本文所描述的抗CD19ADC的治疗。
抗CD19 ADC
如本文所用,术语“抗CD19 ADC”或“CD19-ADC”是指其中抗体组分为抗CD19抗体的ADC。术语“PBD-ADC”是指其中药物组分为吡咯并苯并二氮杂卓(PBD)弹头的ADC。术语“抗CD19-ADC”是指其中抗体组分为抗CD19抗体并且药物组分为PBD弹头的ADC。
ADC可包含式L-(DL)p的缀合物,其中DL具有式I或II:
其中:
L为抗体(Ab),抗体(Ab)为结合至CD19的抗体;
当C2'与C3'之间存在双键时,R12选自由以下组成的组:
(ia)任选由一个或多个选自包含以下的组的取代基取代的C5-10芳基:卤基、硝基、氰基、醚、羧基、酯、C1-7烷基、C3-7杂环基以及双氧基-C1-3亚烷基;
(ib)C1-5饱和脂族烷基;
(ic)C3-6饱和环烷基;
(id)其中R21、R22以及R23中的每一者独立地选自H、C1-3饱和烷基、C2-3烯基、C2-3炔基以及环丙基,其中R12基团中碳原子的总数目不超过5;
(ie)其中R25a和R25b中的一者为H并且另一者选自:苯基,所述苯基任选由选自卤基、甲基、甲氧基的基团取代;吡啶基;以及苯硫基;以及
(if)其中R24选自:H;C1-3饱和烷基;C2-3烯基;C2-3炔基;环丙基;苯基,所述苯基任选由选自卤基、甲基、甲氧基的基团取代;吡啶基;以及苯硫基;
当C2'与C3'之间存在单键时,
R12为其中R26a和R26b独立地选自H、F、C1-4饱和烷基、C2-3烯基,所述烷基和烯基任选由选自C1-4烷基酰胺基和C1-4烷基酯的基团取代;或当R26a和R26b中的一者为H时,另一者选自腈和C1-4烷基酯;
R6和R9独立地选自H、R、OH、OR、SH、SR、NH2、NHR、NRR’、硝基、Me3Sn以及卤基;
其中R和R'独立地选自任选取代的C1-12烷基、C3-20杂环基以及C5-20芳基;
R7选自H、R、OH、OR、SH、SR、NH2、NHR、NHRR'、硝基、Me3Sn以及卤基;
R″为C3-12亚烷基,所述链可由一个或多个杂原子(例如O、S、NRN2(其中RN2为H或C1-4烷基))间断开;和/或芳族环,例如苯或吡啶;
Y和Y'选自O、S或NH;
R6’、R7’、R9’选自分别与R6、R7以及R9相同的组;
[式I]
RL1’为用于连接至抗体(Ab)的接头;
R11a选自OH、ORA(其中RA为C1-4烷基)以及SOzM,其中z为2或3并且M为单价药学上可接受的阳离子;
R20和R21一起形成与它们所结合的氮与碳原子之间的双键;或
R20选自H和RC,其中RC为封端基团;
R21选自OH、ORA以及SOzM;
当C2与C3之间存在双键时,R2选自由以下组成的组:
(ia)任选由一个或多个选自包含以下的组的取代基取代的C5-10芳基:卤基、硝基、氰基、醚、羧基、酯、C1-7烷基、C3-7杂环基以及双氧基-C1-3亚烷基;
(ib)C1-5饱和脂族烷基;
(ic)C3-6饱和环烷基;
(id)其中R11、R12以及R13中的每一者独立地选自H、C1-3饱和烷基、C2-3烯基、C2-3炔基以及环丙基,其中R2基团中碳原子的总数目不超过5;
(ie)其中R15a和R15b中的一者为H并且另一者选自:苯基,所述苯基任选由选自卤基、甲基、甲氧基的基团取代;吡啶基;以及苯硫基;以及
(if)其中R14选自:H;C1-3饱和烷基;C2-3烯基;C2-3炔基;环丙基;苯基,所述苯基任选由选自卤基、甲基、甲氧基的基团取代;吡啶基;以及苯硫基;
当C2与C3之间存在单键时,
R2为其中R16a和R16b独立地选自H、F、C1-4饱和烷基、C2-3烯基,所述烷基和烯基任选由选自C1-4烷基酰胺基和C1-4烷基酯的基团取代;或当R16a和R16b中的一者为H时,另一者选自腈和C1-4烷基酯;
[式II]
R22具有式IIIa、式IIIb或式IIIc:
(a)
其中A为C5-7芳基,并且
(i)Q1为单键,并且Q2选自单键和-Z-(CH2)n-,其中Z选自单键、O、S以及NH并且n为1至3;或
(ii)Q1为-CH=CH-,并且Q2为单键;
(b)
其中;
RC1、RC2以及RC3独立地选自H和未取代的C1-2烷基;
(c)
其中Q选自O-RL2'、S-RL2'以及NRN-RL2',并且RN选自H、甲基以及乙基
X选自包含以下的组:O-RL2’、S-RL2’、CO2-RL2’、CO-RL2’、NH-C(=O)-RL2’、NHNH-RL2’、CONHNH-RL2’、 NRNRL2’,其中RN选自包含H和C1-4烷基的组;
RL2’为用于连接至抗体(Ab)的接头;
R10和R11一起形成与它们所结合的氮与碳原子之间的双键;或
R10为H并且R11选自OH、ORA以及SOzM;
R30和R31一起形成与它们所结合的氮与碳原子之间的双键;或
R30为H并且R31选自OH、ORA以及SOzM。
在一些实施方案中,L-RL1’或L-RL2’为以下基团:
其中星号指示与PBD的连接点,Ab为抗体,L1为可裂解接头,A为将L1连接至抗体的连接基团,L2为共价键或与-OC(=O)-一起形成自分解接头。
在这些实施方案中的一些中,L1为酶可裂解的。
在一个实施方案中,PBD具有式(III):
其中RLL为用于连接至Ab的接头。
在另一实施方案中,PBD具有式(IV):
其中RLL为用于连接至Ab的接头并且RLLA为用于连接至Ab或封端基团RC的接头。
先前已证实此类ADC可用于治疗表达CD19的癌症(参见例如WO2014/057117、WO2018/193105以及WO2018/229222,所述专利以全文引用的方式并入本文中)。
术语抗CD19-ADC可包括WO2014/057117中所描述的任何实施方案。特别地,在优选实施方案中,ADC可具有以下化学结构:
其中Ab为CD19抗体,并且DAR介于1与8之间。
抗体可包含具有根据SEQ ID NO.1、2、3、4、5或6中的任一者的序列的VH结构域,任选还包含具有根据SEQ ID NO.7、8、9、10、11或12中的任一者的序列的VL结构域。
在一些方面中,抗CD19-ADC的抗体组分为一种抗体,所述抗体包含VH和VL结构域,所述VH和VL结构域分别具有以下序列:SEQ ID NO.1和SEQ ID NO.7、SEQ ID NO.2和SEQ IDNO.8、SEQ ID NO.3和SEQ ID NO.9、SEQ ID NO.4和SEQ ID NO.10、SEQ ID NO.5和SEQ IDNO.11或SEQ ID NO.6和SEQ ID NO.12。
在一些实施方案中,抗体具有包含VH CDR1、VH CDR2以及VH CDR3的VH结构域,其中抗体包含具有根据SEQ ID NO:2的序列的VH结构域的CDR序列。在一些实施方案中,抗体具有包含VL CDR1、VL CDR2以及VL CDR3的VL结构域,其中抗体包含具有根据SEQ ID NO:8的序列的VL结构域的CDR序列。
在优选实施方案中,抗体包含VH结构域和VL结构域,
所述VH结构域包含VH CDR1、VH CDR2以及VH CDR3,其中抗体包含具有根据SEQ IDNO:2的序列的VH结构域的CDR序列;并且
所述VL结构域包含VL CDR1、VL CDR2以及VL CDR3,其中抗体包含具有根据SEQ IDNO:8的序列的VL结构域的CDR序列。
本文所描述的抗体可变结构域的CDR可通过本领域已知的任何适合的方法(例如使用任何适合的抗体编号方案)来鉴定。CDR可使用以下中的任一者来鉴定:Kabat编号方案(Kabat等,U.S.Department of Health and Human Services,1991)、Chothia编号方案(Chothia C,Lesk AM.J Mol Biol.(1987)196:901-17)或IMGT编号方案(Giudicelli V等Nucleic Acids Res.(1997)25:206-11;Lefranc MP.Immunol Today(1997)18:509)。熟练人员将了解,这些不同的CDR标记系统可给出稍微不同的结果,但在每种情况下,CDR均可容易地由熟练人员鉴定。
在优选实施方案中,抗体包含具有根据SEQ ID NO.2的序列的VH结构域。在优选实施方案中,抗体包含具有根据SEQ ID NO.8的序列的VL结构域。
在优选实施方案中,抗体包含VH结构域和VL结构域,所述VH结构域具有SEQ IDNO.2的序列并且VL结构域具有SEQ ID NO.8的序列。
一个或多个VH和VL结构域可配对以便形成结合CD19的抗体抗原结合位点。
在一些实施方案中,抗体为包含VH结构域和VL结构域的完整抗体,所述VH和VL结构域具有SEQ ID NO.2和SEQ ID NO.8的序列。
在一些实施方案中,抗体为包含具有SEQ ID NO.13的序列的重链以及具有SEQ IDNO.14的序列的轻链的抗体。
在一些实施方案中,抗体为完全人单克隆IgG1抗体,优选为IgG1,κ。
在一些实施方案中,抗体为WO2014/057117中所描述的RB4v1.2抗体。
在一个方面中,抗体为如下文所描述已修饰(或进一步修饰)的如本文所描述的抗体。在一些实施方案中,抗体为本文所公开的抗体的人源化、去免疫或表面重修型式。
用于本公开的方面中的最优选的抗CD19-ADC为如本文以下所描述的ADCx19。
用于本公开的方面的第二优选的抗CD19-ADC为ADCT-402。
ADCx19
ADCx19为由针对人CD19的人源化抗体经由可裂解接头连接至吡咯并苯并二氮杂卓(PBD)弹头组成的抗体药物缀合物。ADCx19的作用机制取决于CD19结合。CD19特异性抗体使抗体药物缀合物(ADC)靶向至表达CD19的细胞。在结合后,ADC内化并且转运至溶酶体,其中蛋白酶敏感接头裂解并且在靶细胞内部释放游离PBD二聚体。释放的PBD二聚体因直接抑制RNA聚合酶或抑制相关转录因子的相互作用以序列选择性方式抑制转录。PBD二聚体产生共价交联,这不扭曲DNA双螺旋并且不被核苷酸切除修复因子识别,从而允许更长的有效期(Hartley 2011)。
它具有以下化学结构:
Ab表示抗体RB4v1.2(分别具有VH和VL序列SEQ ID NO.2和SEQ ID NO.8的抗体)。它如WO2014/057117(RB4v1.2-E)中所描述进行合成并且通常具有2+/-0.5(诸如+/-0.3)的DAR(药物与抗体比)。
CD19结合
如本文所用,“结合CD19”用于意指与非特异性配偶体(诸如牛血清白蛋白,BSA,基因库登录号CAA76847,版本号CAA76847.1GI:3336842,记录更新日期:2011年1月7日下午02:30)相比,抗体以更高的亲和力结合CD19。在一些实施方案中,当在生理条件下测量时,抗体以比抗体对BSA的缔合常数高至少2、3、4、5、10、20、50、100、200、500、1000、2000、5000、104、105或106倍的缔合常数(Ka)结合CD19。本发明的抗体可以高亲和力结合CD19。举例来说,在一些实施方案中,抗体可以等于或小于约10-6M(诸如1x 10-6、10-7、10-8、10-9、10-10、10-11、10-12、10-13或10-14)的KD结合CD19。
在一些实施方案中,CD19多肽对应于基因库登录号NP_001171569,版本号NP_001171569.1GI:296010921,记录更新日期:2012年9月10日上午12:43。在一个实施方案中,编码CD19多肽的核酸对应于基因库登录号NM_001178098,版本号NM_001178098.1GI:296010920,记录更新日期:2012年9月10日上午12:43。在一些实施方案中,CD19多肽对应于Uniprot/Swiss-Prot登录号P15391。
本公开还更一般地涉及包含PBD二聚体作为弹头(诸如本文所描述的PBD)的抗体药物缀合物与包含单甲基澳瑞他汀E作为弹头的抗体药物缀合物的组合,以及如本文所描述的治疗方法,所述治疗方法包括施用两种抗体药物缀合物的组合。选择针对个别剂中的每一者的抗体来结合至不同的靶分子。
包含单甲基澳瑞他汀E的抗体药物缀合物的一个实例为其中抗体靶向抗CD79b。
包含PBD二聚体的抗体药物缀合物的实例为如上文所描述靶向CD19的那些抗体药物缀合物以及如下文所描述靶向CD25或CD22的那些抗体药物缀合物。
本领域技术人员将理解,通篇针对抗CD19 ADC和抗CD79b详细描述的其他实施方案,诸如PBD的选择、要治疗的病症、患者选择以及施用,加以必要的变更可适用于结合至不同靶标的本文所描述的其他ADC。其他靶标的特定实例为下文更详细描述的CD25和CD22。
抗CD25-ADC
本公开还涉及使用WO2014/057119中所公开并且如本文描述的抗CD25 ADC的治疗。
如本文所用,术语“抗CD25 ADC”或“CD25-ADC”是指其中抗体组分为抗CD25抗体的ADC。术语“PBD-ADC”是指其中药物组分为吡咯并苯并二氮杂卓(PBD)弹头的ADC。术语“抗CD25-ADC”是指其中抗体组分为抗CD25抗体并且药物组分为PBD弹头的ADC。ADC组分如上文针对抗CD19-ADC所定义。
在一些实施方案中,抗体具有包含VH CDR1、VH CDR2以及VH CDR3的VH结构域,其中抗体包含具有根据SEQ ID NO:25的序列的VH结构域的CDR序列。在一些实施方案中,抗体具有包含VL CDR1、VL CDR2以及VL CDR3的VL结构域,其中抗体包含具有根据SEQ ID NO:25的序列的VL结构域的CDR序列。
在优选实施方案中,抗体包含VH结构域和VL结构域,
所述VH结构域包含VH CDR1、VH CDR2以及VH CDR3,其中抗体包含具有根据SEQ IDNO:25的序列的VH结构域的CDR序列;并且
所述VL结构域包含VL CDR1、VL CDR2以及VL CDR3,其中抗体包含具有根据SEQ IDNO:26的序列的VL结构域的CDR序列。
抗体可包含VH结构域,所述VH结构域包含具有SEQ ID NO.27的氨基酸序列的VHCDR1、具有SEQ ID NO.28的氨基酸序列的VH CDR2以及具有SEQ ID NO.29的氨基酸序列的VH CDR3。
在一些方面中,抗CD25-ADC的抗体组分为包含VH结构域的抗体,所述VH结构域包含具有SEQ ID NO.27的氨基酸序列的VH CDR1、具有SEQ ID NO.28的氨基酸序列的VH CDR2以及具有SEQ ID NO.29的氨基酸序列的VH CDR3。在一些实施方案中,抗体包含具有根据SEQ ID NO.25的序列的VH结构域。
抗体还可包含VL结构域,所述VL结构域包含具有SEQ ID NO.30的氨基酸序列的VLCDR1、具有SEQ ID NO.31的氨基酸序列的VL CDR2以及具有SEQ ID NO.32的氨基酸序列的VL CDR3。在一些实施方案中,抗体还包含具有根据SEQ ID NO.26的序列的VL结构域。
在一些实施方案中,抗体包含VH结构域和VL结构域,所述VH和VL结构域具有与SEQID NO.26配对的SEQ ID NO.25的序列。
一个或多个VH和VL结构域可配对以便形成结合CD25的抗体抗原结合位点。
在优选实施方案中,抗体为包含VH结构域和VL结构域的完整抗体,VH和VL结构域具有SEQ ID NO.25和SEQ ID NO.26的序列。
在一些实施方案中,抗体为完全人单克隆IgG1抗体,优选为IgG1,κ。
在一些实施方案中,抗体为WO 2004/045512中所描述的AB12抗体(Genmab A/S)。
在一个方面中,抗体为如下文所描述已修饰(或进一步修饰)的如本文所描述的抗体。在一些实施方案中,抗体为本文所公开的抗体的人源化、去免除或表面重修型式。
如本文以下所描述,用于本公开的方面中的优选抗CD25-ADC为ADCX25。
用于本公开的方面中的另一优选抗CD25-ADC为泰卡利尤单抗(camidanlumabtesirine)。
ADCx25
ADCx25为由针对人CD25的人抗体经由可裂解接头连接至吡咯并苯并二氮杂卓(PBD)弹头组成的抗体药物缀合物。ADCX25的作用机制取决于CD25结合。CD25特异性抗体使抗体药物缀合物(ADC)靶向表达CD25的细胞。在结合后,ADC内化并且转运至溶酶体,其中蛋白酶敏感接头裂解并且在靶细胞内部释放游离PBD二聚体。由于直接抑制RNA聚合酶或抑制相关转录因子的相互作用,所释放的PBD二聚体以序列选择性方式抑制转录。PBD二聚体产生共价交联,共价交联不扭曲DNA双螺旋并且不由核苷酸切除修复因子识别,从而允许更长的有效期(Hartley 2011)。
它具有以下化学结构:
Ab表示抗体AB12(完全人单克隆IgG1,K抗体分别具有VH和VL序列SEQ ID NO.25和SEQ ID NO.26,也称为HuMax-TAC)。它如WO 2014/057119(Conj AB12-E)中所描述来合成并且典型地具有2.0+/-0.3的DAR(药物与抗体比)。
CD25结合
如本文所用,“结合CD25”用于意指与非特异性配偶体(诸如牛血清白蛋白,BSA,Genbank登录号CAA76847,版本号CAA76847.1GI:3336842,记录更新日期:2011年1月7日下午02:30)相比,抗体以更高亲和力结合CD25。在一些实施方案中,当在生理条件下测量时,抗体以比抗体对BSA的缔合常数高至少2、3、4、5、10、20、50、100、200、500、1000、2000、5000、104、105或106倍的缔合常数(Ka)结合CD25。本公开的抗体可以高亲和力结合CD25。举例来说,在一些实施方案中,抗体可以等于或小于约10-6M(诸如等于或小于1x 10-6、10-7、10-8、10-9、10-10、10-11、10-12、10-13或10-14中的一者)的KD结合CD25。
在一些实施方案中,CD25多肽对应于Genbank登录号NP_000408,版本号NP_000408.1GI:4557667,记录更新日期:2012年9月9日下午04:59。在一个实施方案中,编码CD25多肽的核酸对应于Genbank登录号NM_000417,版本号NM_000417.2GI:269973860,记录更新日期:2012年9月9日下午04:59。在一些实施方案中,CD25多肽对应于Uniprot/Swiss-Prot登录号P01589。
抗CD22-ADC
本公开还涉及使用WO2014/057122中所公开并且如本文描述的抗CD22 ADC的治疗。
如本文所用,术语“抗CD22 ADC”或“CD22-ADC”是指其中抗体组分为抗CD22抗体的ADC。术语“PBD-ADC”是指其中药物组分为吡咯并苯并二氮杂卓(PBD)弹头的ADC。术语“抗CD22-ADC”是指其中抗体组分为抗CD22抗体并且药物组分为PBD弹头的ADC。ADC组分如上文针对抗CD19-ADC所定义。
抗CD22 ADC的抗体组分
抗体可包含不为半胱氨酸的氨基酸对链间半胱氨酸残基的氨基酸取代,其中药物部分在链间半胱氨酸残基处缀合至抗体。
抗体优选包含:(i)具有根据如Kabat中所阐述的EU索引的链间半胱氨酸残基HC226和HC229中的每一者的氨基酸取代的重链;(ii)具有根据如Kabat中所阐述的EU索引的链间半胱氨酸残基κLC214或λLC213的氨基酸取代的轻链;以及(iii)保留根据如Kabat中所阐述的EU索引的未取代的链间半胱氨酸HC220的重链。
优选地,药物部分缀合至未取代的链间半胱氨酸HC220。链间半胱氨酸残基HC226和HC229可各自针对缬氨酸进行取代。链间半胱氨酸残基κLC214或λLC213可针对丝氨酸进行取代。
在一些实施方案中,本文所描述的抗体缀合物包含含有SEQ ID NO.45的氨基酸序列轻链或其片段,其中如果存在105位置的半胱氨酸,那么用不为半胱氨酸的氨基酸取代。举例来说,SEQ ID NO.46公开了包含SEQ ID NO.45的氨基酸序列的轻链,其中在位置105的半胱氨酸用丝氨酸残基取代。
在一些实施方案中,本文所描述的缀合物的抗体包含含有SEQ ID NO.47的氨基酸序列的轻链或其片段,其中如果存在位置102的半胱氨酸,那么用不为半胱氨酸的氨基酸取代。举例来说,SEQ ID NO.48公开了包含SEQ ID NO.47的氨基酸序列的轻链,其中在位置102的半胱氨酸用丝氨酸残基取代。
在一些实施方案中,抗体包含:
(i)具有根据如Kabat中所阐述的EU索引的链间半胱氨酸残基HC226和HC229中的每一者的氨基酸取代的重链,任选其中HC226和HC229各自针对缬氨酸进行取代;
(ii)具有根据如Kabat中所阐述的EU索引的链间半胱氨酸残基κLC214或λLC213的氨基酸取代的轻链,任选其中κLC214或λLC213针对丝氨酸进行取代;
(iii)保留根据如Kabat中所阐述的EU索引的未取代的链间半胱氨酸HC220的重链,任选其中药物部分缀合至HC220处的半胱氨酸。在这些实施方案中,抗体优选还包含如下文所定义的VH结构域和VL结构域。轻链可包含以下氨基酸序列:(i)SEQ ID NO.45,或其片段,其中如果存在位置105的半胱氨酸,那么用不为半胱氨酸的氨基酸取代(诸如在SEQID NO.46中);或SEQ ID NO.47,或其片段,其中如果存在位置102的半胱氨酸,那么用不为半胱氨酸的氨基酸取代(诸如在SEQ ID NO.48中)。
抗体可包含含有SEQ ID NO.43的氨基酸序列的重链,以及含有SEQ ID NO.45或SEQ ID NO.47的氨基酸序列的轻链;
其中SEQ ID NO:43中在位置109和112的半胱氨酸中的每一者用不为半胱氨酸的氨基酸取代;
并且其中SEQ ID NO:45中在位置105的半胱氨酸或SEQ ID NO:47中在位置102的半胱氨酸用不为半胱氨酸的氨基酸取代。优选地,药物部分缀合至在SEQ ID NO.43的位置103的半胱氨酸。在一些实施方案中,SEQ ID NO:43中在位置109和112的半胱氨酸取代缬氨酸,诸如在SEQ ID NO:44中。在一些实施方案中,SEQ ID NO:45中在位置105的半胱氨酸或SEQ ID NO:47中在位置102的半胱氨酸用丝氨酸取代,诸如在SEQ ID NO:46和48中。
在一些实施方案中,抗体为完全人单克隆IgG1抗体,优选为IgG1,κ。
VH和VL结构域
在一些实施方案中,抗体具有包含VH CDR1、VH CDR2以及VH CDR3的VH结构域,其中抗体包含具有根据SEQ ID NO:1的序列的VH结构域的CDR序列。在一些实施方案中,抗体具有包含VL CDR1、VL CDR2以及一种VL CDR3的VL结构域,其中抗体包含具有根据SEQ IDNO:34的序列的VL结构域的CDR序列。
在优选实施方案中,抗体包含VH结构域和VL结构域,
所述VH结构域包含VH CDR1、VH CDR2以及VH CDR3,其中抗体包含具有根据SEQ IDNO:33的序列的VH结构域的CDR序列;并且
所述VL结构域包含VL CDR1、VL CDR2以及VL CDR3,其中抗体包含具有根据SEQ IDNO:34的序列的VL结构域的CDR序列。
抗体可包含VH结构域,所述VH结构域包含具有SEQ ID NO.35的氨基酸序列的VHCDR1、具有SEQ ID NO.36的氨基酸序列的VH CDR2以及具有SEQ ID NO.37的氨基酸序列的VH CDR3。
在一些方面中,抗CD22-ADC的抗体组分为包含VH结构域的抗体,所述VH结构域包含具有SEQ ID NO.35的氨基酸序列的VH CDR1、具有SEQ ID NO.36的氨基酸序列的VH CDR2以及具有SEQ ID NO.37的氨基酸序列的VH CDR3。在一些实施方案中,抗体包含具有根据SEQ ID NO.22的序列的VH结构域。
抗体还可包含VL结构域,所述VL结构域包含具有SEQ ID NO.38的氨基酸序列的VLCDR1、具有SEQ ID NO.39的氨基酸序列的VL CDR2以及具有SEQ ID NO.40的氨基酸序列的VL CDR3。在一些实施方案中,抗体还包含具有根据SEQ ID NO.34的序列的VL结构域。
在一些实施方案中,抗体包含VH结构域和VL结构域,所述VH和VL结构域具有与SEQID NO.34配对的SEQ ID NO.33的序列。
一个或多个VH和VL结构域可配对以便形成结合CD22的抗体抗原结合位点。
在一些方面中,抗CD22-ADC的抗体组分为包含具有根据SEQ ID NO.33的序列的VH结构域的抗体。
抗体还可包含具有根据SEQ ID NO.34的序列的VL结构域。
在一些实施方案中,抗体包含如本文以下所描述的VH结构域和VL结构域。在一些实施方案中,抗体包含:
具有根据SEQ ID NO:44的序列的重链;
具有根据SEQ ID NO:46的序列的轻链;
具有根据SEQ ID NO.33的序列的VH结构域;以及
具有根据SEQ ID NO.32的序列的VL结构域。
优选地,药物部分缀合至在SEQ ID NO.44的位置103的半胱氨酸。
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在一些实施方案中,抗体为WO2014/057122中所描述的依帕珠单抗抗体。
在一些实施方案中,抗体包含具有根据SEQ ID NO.47的序列的重链以及具有根据SEQ ID NO.48的序列的轻链。优选地,药物部分缀合至在SEQ ID NO.47的位置219的半胱氨酸。
在一个方面中,抗体为如下文所描述已修饰(或进一步修饰)的如本文所描述的抗体。在一些实施方案中,抗体为本文所公开的抗体的人源化、去免疫或表面重修型式。
用于本公开的方面的最优选抗CD22-ADC为如本文以下所描述的ADCx22。
ADCx22
ADCx22为由针对人CD22的人抗体经由可裂解接头连接至吡咯并苯并二氮杂卓(PBD)弹头组成的抗体药物缀合物。ADCX22的作用机制取决于CD22结合。CD22特异性抗体使抗体药物缀合物(ADC)靶向至表达CD22的细胞。在结合后,ADC内化并且转运至溶酶体,其中蛋白酶敏感接头裂解并且在靶细胞内部释放游离PBD二聚体。释放的PBD二聚体因直接抑制RNA聚合酶或抑制相关转录因子的相互作用以序列选择性方式抑制转录。PBD二聚体产生共价交联,这不扭曲DNA双螺旋并且不被核苷酸切除修复因子识别,从而允许更长的有效期。
它具有以下化学结构:
其中Ab表示包含具有SEQ ID NO.33的序列的VH结构域以及具有SEQ ID NO.34的序列的VL结构域的抗体。通常抗体还包含:(i)具有根据如Kabat中所阐述的EU索引的链间半胱氨酸残基HC226和HC229中的每一者(例如对缬氨酸)的氨基酸取代的重链;(ii)具有根据如Kabat中所阐述的EU索引的链间半胱氨酸残基κLC214(例如对丝氨酸)的氨基酸取代的轻链;以及(iii)保留根据如Kabat中所阐述的EU索引的未取代的链间半胱氨酸HC220的重链。通常,药物部分缀合至HC220处的半胱氨酸。
因此,抗体通常包含具有根据SEQ ID NO.41的序列的重链以及具有根据SEQ IDNO.42的序列的轻链。键联至药物发生在重链链间半胱氨酸Cys220(EU编号)上。HC220对应于SEQ ID NO.41的位置219。
应注意,“具有序列”与“包含序列”具有相同的含义;具体地说,在一些实施方案中,ADCx22的重链被表达为具有额外的端点‘K’残基(因此,以……SPGK结束),端点K任选在翻译后移除以改善最终治疗性ADC产物的均质性。
CD22结合
如本文所用,“结合CD22”用于意指与非特异性配偶体(诸如牛血清白蛋白,BSA,基因库登录号CAA76847,版本号CAA76847.1GI:3336842,记录更新日期:2011年1月7日下午02:30)相比,抗体以更高的亲和力结合CD22。在一些实施方案中,当在生理条件下测量时,抗体以比抗体对BSA的缔合常数高至少2、3、4、5、10、20、50、100、200、500、1000、2000、5000、104、105或106倍的缔合常数(Ka)结合CD22。本发明的抗体可以高亲和力结合CD22。举例来说,在一些实施方案中,抗体可以等于或小于约10-6M(诸如1x 10-6、10-7、10-8、10-9、10-10、10-11、10-12、10-13或10-14)的KD结合CD22。
在一些实施方案中,CD22多肽对应于基因库登录号BAB15489,版本号BAB15489.1GI:10439338,记录更新日期:2006年9月11日下午11:24。在一个实施方案中,编码CD22多肽的核酸对应于基因库登录号AK026467,版本号AK026467.1GI:10439337,记录更新日期:2006年9月11日下午11:24。
抗CD79b剂
CD79b
CD79(由亚单位CD79a和CD79b组成)为B细胞受体的异二聚信号转导组分。CD79b膜表达限制于B细胞隔室并且在成熟B细胞淋巴瘤中普遍表达并且在免疫球蛋白μ表达之前通过最早定向的B细胞祖细胞位于细胞表面。针对CD79b的抗体诱导阴性细胞信号并且抑制对T细胞依赖性抗原的反应(Nakamura等,Int J Hematol.1996;64:39-46)。然而,非缀合抗CD79b抗体诱导适度的B细胞消耗并且显示中度抗体依赖性和补体依赖性细胞毒性(如果有)(Fuh等,Br J Pharmacol.2017;174:628-640)。相反地,抗CD79b ADC被运输至B细胞的溶酶体样隔室作为抗原呈现的一部分(Polson等,Blood.2007;110:616-623)并且诱导延长和维持的增殖B细胞的消耗(Fuh等,同前)。
抗CD79b剂
‘抗CD79b剂’在本文中用于指特异性结合至CD79b和/或表达CD79b的细胞的任何剂。优选地,所述剂诱导B细胞消耗。
如本文所用,“特异性结合CD79b”用于意指与非特异性配偶体(诸如牛血清白蛋白,BSA,基因库登录号CAA76847,版本号CAA76847.1 GI:3336842,记录更新日期:2011年1月7日下午02:30)相比,所述剂以更高的亲和力结合CD79b。在一些实施方案中,当在生理条件下测量时,所述剂以比所述剂对BSA的缔合常数高至少2、3、4、5、10、20、50、100、200、500、1000、2000、5000、104、105或106倍的缔合常数(Ka)结合CD79b。所述剂可以高亲和力结合CD79b。举例来说,在一些实施方案中,所述剂可以等于或小于约10-6M(诸如1x 10-6、10-7、10-8、10-9、10-10、10-11、10-12、10-13或10-14)的KD结合CD79b。
抗CD79b ADC
抗CD79b ADC在本文中用于意指包含缀合至有效负荷的特异性结合至CD79b的部分的缀合物。
在一些实施方案中,特异性结合至CD79b的部分为抗体。在一些情况下,抗体为普拉土珠单抗。
在一些实施方案中,有效负荷包含药物,诸如细胞毒性药物。在一些情况下,细胞毒性药物为澳瑞他汀,诸如单甲基澳瑞他汀。在一些情况下,细胞毒性药物为单甲基澳瑞他汀(MMAE)。
在一些情况下,有效负荷包含使有效负荷I缀合至特异性结合至CD79b的部分的接头部分。在一些实施方案中,有效负荷为药物-接头,其中药物-接头包含药物部分和接头部分。接头部分可由诸如蛋白酶等酶裂解。举例来说,在一些实施方案中,接头为二肽,诸如缬氨酸-瓜氨酸(val-cit或vc)。
在一些实施方案中,ADC具有以下结构:
其中星号指示与药物部分的连接点,Ab为抗体,L1为可裂解接头,A为连接L1与抗体的连接基团,L2为共价键或与-OC(=O)-一起形成自分解接头。在这些实施方案中的一些中,L1为酶可裂解的。
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在优选实施方案中,ADC可为式(I)的缀合物:
Ab-(DL)p (I)
其中:
Ab为结合至CD79b的抗体;
DL为
并且p介于1与8之间,诸如3与4之间,例如约3.5。
在一些实施方案中,抗体具有包含VH CDR1、VH CDR2以及VH CDR3的VH结构域,其中抗体包含具有根据SEQ ID NO:17的序列的VH结构域的CDR序列。在一些实施方案中,抗体具有包含VL CDR1、VL CDR2以及VL CDR3的VL结构域,其中抗体包含具有根据SEQ ID NO:18的序列的VL结构域的CDR序列。
在优选实施方案中,抗体包含VH结构域和VL结构域,
所述VH结构域包含VH CDR1、VH CDR2以及VH CDR3,其中抗体包含具有根据SEQ IDNO:17的序列的VH结构域的CDR序列;并且
所述VL结构域包含VL CDR1、VL CDR2以及VL CDR3,其中抗体包含具有根据SEQ IDNO:18的序列的VL结构域的CDR序列。
在一些实施方案中,抗体包含VH结构域,所述VH结构域具有含有SEQ ID NO.21的氨基酸序列的VH CDR3。在一些实施方案中,VH结构域还包含具有SEQ ID NO.20的氨基酸序列的VH CDR2,和/或具有SEQ ID NO.19的氨基酸序列的VH CDR1。在一些实施方案中,抗体包含VH结构域,所述VH结构域具有含有SEQ ID NO.19的氨基酸序列的VH CDR1、含有SEQ IDNO.20的氨基酸序列的VH CDR2以及含有SEQ ID NO.21的氨基酸序列的VH CDR3。在一些实施方案中,抗体具有包含VH CDR1、VH CDR2以及VH CDR3的VH结构域,其中抗体包含具有SEQID NO:17的序列的VH结构域的CDR序列。在优选实施方案中,抗体包含具有根据SEQ IDNO.17的序列的VH结构域。
抗体还可包含VL结构域。在一些实施方案中,抗体包含VL结构域,所述VL结构域具有含有SEQ ID NO.24的氨基酸序列的VL CDR3。在一些实施方案中,VL结构域还包含具有SEQ ID NO.23的氨基酸序列的VL CDR2和/或具有SEQ ID NO.22的氨基酸序列的VL CDR1。在一些实施方案中,抗体包含VL结构域,所述VL结构域具有含有SEQ ID NO.22的氨基酸序列的VL CDR1、含有SEQ ID NO.23的氨基酸序列的VL CDR2以及含有SEQ ID NO.24的氨基酸序列的VL CDR3。在一些实施方案中,抗体具有VL结构域,所述VL结构域包含VL CDR1、VLCDR2以及VL CDR3,其中抗体包含具有SEQ ID NO:18的序列的VL结构域的CDR序列。在优选实施方案中,抗体包含具有根据SEQ ID NO.18的序列的VL结构域。
本文所描述的抗体可变结构域的CDR可通过本领域已知的任何适合的方法(例如使用任何适合的抗体编号方案)来鉴定。CDR可使用以下中的任一者来鉴定:Kabat编号方案(Kabat等,U.S.Department of Health and Human Services,1991)、Chothia编号方案(Chothia C,Lesk AM.J Mol Biol.(1987)196:901-17)或IMGT编号方案(Giudicelli V等Nucleic Acids Res.(1997)25:206-11;Lefranc MP.Immunol Today(1997)18:509)。熟练人员将了解,这些不同的CDR标记系统可给出稍微不同的结果,但在每种情况下,CDR均可容易地由熟练人员鉴定。
一个或多个VH和VL结构域可形成结合CD79b的抗体抗原结合位点。
在一些实施方案中,抗体为包含VH结构域和VL结构域的完整抗体,所述VH和VL结构域具有与SEQ ID NO.18配对的SEQ ID NO.17的序列。
在一些实施方案中,抗体为完全人单克隆IgG1抗体,优选为IgG1,κ。
在一个方面中,抗体为如下文所描述已修饰(或进一步修饰)的如本文所描述的抗体。在一些实施方案中,抗体为本文所公开的抗体的人源化、去免疫或表面重修型式。
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最优选的抗CD79b剂为维普拉土珠单抗。
维普拉土珠单抗
维普拉土珠单抗(Polivy,Roche)为CD79b定向的包含经由蛋白酶可裂解接头vc(Val-Cit)缀合至单甲基澳瑞他汀E(MMAE)的人源化IgG1抗CD79b mAb的抗体-药物缀合物。
它具有以下化学结构:
Ab表示抗体普拉土珠单抗(分别具有VH和VL序列SEQ ID NO.17和SEQ ID NO.18的抗体)。它通常具有3.5的DAR(药物与抗体比)。
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所描述的组合的有利性质
抗CD19 ADC(或抗CD25 ADC或抗CD22 ADC)与抗CD79b剂当单独用作单一剂时例如在癌症的治疗中均具有已证实的临床效用。然而,如本文所描述,与单独使用抗CD19 ADC或抗CD79b剂的治疗相比,抗CD19 ADC与抗CD79b剂的组合预期提供以下优点中的一者或多者:
1)更广泛范围的癌症的有效治疗;
2)抗性或难治性形式的病症(诸如癌症)以及一段时间缓和之后复发的患有诸如癌症等病症的个体的有效治疗;
3)增加的对治疗的反应率;和/或
4)增加的治疗持久性。
如本文所用的更广泛范围的癌症的有效治疗意味着在用组合治疗之后在更大范围的所识别的癌症类型中观测到完全反应。换句话说,从先前未报道对单独抗CD19 ADC或抗CD79b剂作出完全反应的癌症类型观察到完全反应。
不希望受理论束缚,在其中抗CD19 ADC和抗CD79b剂包含具有不同作用模式(PBD二聚体为DNA交联剂,而MMAE为微管蛋白抑制剂)的不同类别的细胞毒性药物(例如其中抗CD19 ADC为泰朗妥昔单抗并且抗CD79b剂为Pola-V)的实施方案中,通过两种独特路径起作用的细胞毒性据信促进相加或协同细胞毒性。此外,这两种剂靶向两种不同的细胞表面抗原的事实意味着它们不竞争结合于细胞表面的相同抗原。这有助于细胞毒性药物递送至靶细胞中。
如本文所用的抗性、难治性或复发形式的有效治疗意味着在用组合治疗之后,在对用单独抗CD19 ADC或抗CD79b剂治疗具部分或完全抗性或难治性的个体(例如在用单独任一剂治疗之后显示无反应或仅部分反应的个体,或病症复发的个体)中观测到完全反应。在一些实施方案中,在用抗CD19 ADC/抗CD79b剂组合治疗之后,在至少10%的对用单独抗CD19 ADC或抗CD79b剂治疗具部分或完全抗性或难治性的个体中观测到完全反应。在一些实施方案中,在用抗CD19 ADC/抗CD79b剂组合治疗之后,在至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少95%、至少98%或至少99%的对用单独抗CD19 ADC或抗CD79b剂治疗具部分或完全抗性或难治性的个体中观测到完全反应。
如本文所用的增加的对治疗的反应率意味着与在用单独抗CD19ADC或抗CD79b剂治疗之后观测的相比,在用组合治疗之后在更大比例的个体中观测到完全反应。在一些实施方案中,在用抗CD19ADC/抗CD79b剂组合治疗之后,在至少10%的所治疗的个体中观测到完全反应。在一些实施方案中,在用抗CD19 ADC/抗CD79b剂组合治疗之后,在至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少95%、至少98%或至少99%的所治疗的个体中观测到完全反应。
如本文所用的增加的治疗持久性意味着与在用单独抗CD19ADC或抗CD79b剂治疗之后实现完全反应的个体中相比,用组合治疗的个体中的完全反应的平均持续时间更长。在一些实施方案中,用抗CD19 ADC/抗CD79b剂组合治疗之后的完全反应的平均持续时间为至少6个月。在一些实施方案中,用抗CD19 ADC/抗CD79b剂组合治疗之后的完全反应的平均持续时间为至少12个月、至少18个月、至少24个月、至少3年、至少4年、至少5年、至少6年、至少7年、至少8年、至少9年、至少10年、至少15年或至少20年。
‘完全反应’在本文中用于意指在个体中不存在疾病的任何临床证据。证据可使用本领域中的适当方法(例如CT或PET扫描)或活组织切片检查(在适当时)来进行评估。实现完全反应所需的剂量数目可为一个、两个、三个、四个、五个、十个或更多个。在一些实施方案中,所述个体在施用第一剂量之后不超过一年(诸如施用第一剂量之后不超过6个月、不超过3个月、不超过一个月、不超过两星期或不超过一周)时实现完全反应。
除非特别指示,否则加以必要的变更,本节中以及所有以下章节中提到抗CD19处在其他实施方案中可替换为抗CD22和抗CD25。
所治疗的病症
本文所描述的组合疗法包括具有针对抗癌活性的效用的那些组合疗法。具体来说,在某些方面中,所述疗法包括通过接头缀合(即共价连接)至PBD药物部分(即毒素)的抗体。当药物未缀合至抗体时,PBD药物具有细胞毒性效应。因此通过缀合至抗体来调节PBD药物部分的生物活性。本公开的抗体-药物缀合物(ADC)选择性地将有效剂量的细胞毒性剂递送至肿瘤组织,借此可实现更大的选择性,即更低的有效剂量。
因此,在一个方面中,本公开提供了组合疗法,所述组合疗法包括施用结合CD19以便用于疗法中的抗CD19 ADC,其中所述方法包括基于靶蛋白的表达选择受试者。
在一个方面中,本公开提供了一种组合疗法以及一个标签,所述标签指明所述疗法适合用于经确定适合于此类用途的受试者。所述标签可指明所述疗法适合用于具有CD19表达(诸如CD19过表达)的受试者中。所述标签可指明受试者患有特定类型的癌症。
癌症可为淋巴瘤,诸如非霍奇金氏淋巴瘤。标记可指示受试者具有CD19+淋巴瘤。
在另一方面中,还提供了一种如本文所描述用于治疗增殖性疾病的组合疗法。本公开的另一方面提供了缀合物化合物在用于治疗增殖性疾病的药剂的制造中的用途。
本领域技术人员能够容易地确定针对任何特定细胞类型候选组合疗法是否治疗增殖性疾患。举例来说,下文描述可适宜地用于评估由特定化合物提供的活性的分析。
本文所描述的组合疗法可用于治疗增殖性疾病。术语“增殖性疾病”是有关体外或体内不需要的过量或异常细胞的不想要的或不受控制的细胞增殖,诸如赘生性或增生性生长。
增殖性疾患的实例包括但不限于良性、癌变前及恶性细胞增殖,包括但不限于赘瘤和肿瘤(例如组织细胞瘤、神经胶质瘤、星形细胞瘤、骨瘤)、癌症(例如肺癌、小细胞肺癌、胃肠道癌、肠癌、结肠癌、乳腺癌、卵巢癌、前列腺癌、睾丸癌、肝癌、肾癌、膀胱癌、胰腺癌、脑癌、肉瘤、骨肉瘤、卡波西氏肉瘤(Kaposi's sarcoma)、黑素瘤)、淋巴瘤、白血病、银屑病、骨骼病、纤维增殖性病症(例如结缔组织的纤维增殖性病症)以及动脉粥样硬化。所关注的癌症包括但不限于白血病和卵巢癌。
可治疗的任何细胞类型包括但不限于肺、胃肠道(包括例如肠、结肠)、乳房(乳腺细胞)、卵巢、前列腺、肝脏(肝细胞)、肾脏(肾细胞)、膀胱、胰腺、脑以及皮肤。
特别关注的增殖性病症包括但不限于非霍奇金氏淋巴瘤,包括弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、伯基特淋巴瘤、套细胞淋巴瘤(MCL)、慢性淋巴性淋巴瘤(CLL)、华登斯特罗姆巨球蛋白血症(WM)以及边缘区B细胞淋巴瘤(MZBL);以及白血病,诸如毛细胞白血病(HCL)、变异型毛细胞白血病(HCL-v)、慢性淋巴细胞性白血病(CLL)(包括里希特综合征)以及急性成淋巴细胞性白血病(ALL),诸如费城染色体阳性ALL(Ph+ALL)或费城染色体阴性ALL(Ph-ALL)。[Fielding A.,Haematologica.2010年1月;95(1):8-12]。
预期本公开的组合疗法可用于治疗例如以肿瘤抗原的过表达为特征的各种疾病或病症。示例性疾患或过度增殖性病症包括良性或恶性肿瘤;白血病、血液学恶性肿瘤以及淋巴恶性肿瘤。其他疾病包括神经元、神经胶质、星形胶质细胞、下丘脑、腺体、巨噬细胞、上皮、基质、囊胚腔、炎性、血管生成以及免疫学疾病,包括自体免疫病症和移植物抗宿主疾病(GVHD)。
通常,所要治疗的疾病或病症为过度增殖性疾病,诸如癌症。本文中所要治疗的癌症的实例包括但不限于癌瘤、淋巴瘤、胚细胞瘤、肉瘤以及白血病或淋巴系统恶性肿瘤。此类癌症的更具体实例包括鳞状细胞癌(例如上皮鳞状细胞癌)、肺癌(包括小细胞肺癌、非小细胞肺癌、肺腺癌以及肺鳞状癌)、腹膜癌、肝细胞癌、胃癌或胃部癌症(包括胃肠道癌)、胰腺癌、成胶质细胞瘤、宫颈癌、卵巢癌、肝癌、膀胱癌、肝细胞瘤、乳腺癌、结肠癌、直肠癌、结肠直肠癌、子宫内膜或子宫癌、唾液腺癌、肾脏癌症或肾癌、前列腺癌、外阴癌、甲状腺癌、肝癌、肛门癌、阴茎癌以及头颈癌。
治疗中可使用组合疗法的自体免疫疾病包括风湿性病症(诸如类风湿性关节炎、休格兰氏综合征、硬皮病、狼疮(诸如SLE和狼疮性肾炎)、多肌炎/皮肌炎、冷球蛋白血症、抗磷脂抗体综合征以及银屑病性关节炎)、骨关节炎、自体免疫胃肠道和肝脏病症(诸如炎性肠道疾病(例如溃疡性结肠炎和克罗恩氏病(Crohn's disease))、自体免疫胃炎和恶性贫血、自体免疫肝炎、原发性胆汁性肝硬化、原发性硬化性胆管炎以及乳糜泻)、血管炎(诸如ANCA相关血管炎,包括查格-施特劳斯血管炎(Churg-Strauss vasculitis)、韦格纳氏肉芽肿病(Wegener'sgranulomatosis)以及多动脉炎)、自体免疫神经病症(诸如多发性硬化、眼阵挛肌阵挛综合征、重症肌无力、视神经脊髓炎、帕金森氏病(Parkinson's disease)、阿茨海默氏病(Alzheimer's disease)以及自体免疫多发性神经病变)、肾脏病症(诸如肾小球性肾炎、古德帕斯彻氏综合征(Goodpasture's syndrome)以及伯杰氏病(Berger'sdisease))、自体免疫皮肤病症(诸如银屑病、荨麻疹、风疹、寻常天疱疮、大疱性类天疱疮以及皮肤红斑狼疮)、血液学病症(诸如血小板减少性紫癜、血栓性血小板减少性紫癜、输血后紫癜以及自体免疫性溶血性贫血)、动脉粥样硬化、葡萄膜炎、自体免疫听力疾病(诸如内耳疾病和听力损失)、白塞氏病(Behcet's disease)、雷诺氏综合征(Raynaud's syndrome)、器官移植、移植物抗宿主疾病(GVHD)以及自体免疫内分泌病症(诸如糖尿病性相关自体免疫疾病,诸如胰岛素依赖性糖尿病(IDDM)、阿狄森氏病(Addison's disease)以及自体免疫甲状腺病(例如格雷夫斯病(Graves'disease)和甲状腺炎))。更优选的此类疾病包括例如类风湿性关节炎、溃疡性结肠炎、ANCA相关血管炎、狼疮、多发性硬化、休格兰氏综合征、格雷夫斯病、IDDM、恶性贫血、甲状腺炎以及肾小球性肾炎。
在一些方面中,受试者患有选自以下的增殖性病症:非霍奇金氏淋巴瘤,包括弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、伯基特淋巴瘤、套细胞淋巴瘤(MCL)、慢性淋巴性淋巴瘤(CLL)、华登斯特罗姆巨球蛋白血症(WM)以及边缘区B细胞淋巴瘤(MZBL);以及白血病,诸如毛细胞白血病(HCL)、变异型毛细胞白血病(HCL-v)、慢性淋巴细胞性白血病(CLL)(包括里希特综合征)以及急性成淋巴细胞性白血病(ALL),诸如费城染色体阳性ALL(Ph+ALL)或费城染色体阴性ALL(Ph-ALL)。
CD25
增殖性疾病的特征可为存在包含CD25+ve与CD25-ve细胞两者的赘瘤。增殖性疾病的特征可为存在由CD25-ve赘生性细胞组成的赘瘤,任选其中CD25-ve赘生性细胞与CD25+ve非赘生性细胞(诸如CD25+ve T细胞)相关。靶赘瘤或赘生性细胞可为实体肿瘤的全部或一部分。
“实体肿瘤”在本文中将应理解为包括本文更详细论述的固体血液学癌症,诸如淋巴瘤(霍奇金氏淋巴瘤或非霍奇金氏B细胞和T细胞淋巴瘤)。
实体肿瘤可为包括包含CD25+ve赘生细胞或由其组成的非血液学癌症的赘瘤。实体肿瘤可为包括浸润CD25+ve细胞(诸如CD25+ve T细胞)的非血液学癌症的赘瘤;此类实体肿瘤可缺乏CD25的表达(换句话说,包含CD25-ve赘生性细胞或由其组成)。
举例来说,实体肿瘤可为具有高水平的浸润T细胞(诸如浸润调控T细胞(Treg;Ménétrier-Caux,C.等,Targ Oncol(2012)7:15-28;Arce Vargas等,2017,Immunity 46,1-10;Tanaka,A.等,Cell Res.2017年1月;27(1):109-118))的肿瘤。因此,实体肿瘤可为胰腺癌、乳腺癌、结肠直肠癌、胃和食管癌、白血病和淋巴瘤、黑素瘤、非小细胞肺癌、卵巢癌、肝细胞癌、肾细胞癌以及头颈癌。
患者选择
在某些方面中,在施以治疗之前选择适合用组合治疗进行治疗的个体。
如本文所用,被认为适合治疗的个体为预期受益于治疗或对治疗作出反应的那些个体。个体可患有或疑似患有癌症或处于患癌症的风险中。个体可已收到癌症诊断。特别地,个体可患有或疑似患有淋巴瘤或处于患淋巴瘤的风险中。在一些情况下,个体可患有或疑似患有实体癌症或处于患实体癌症的风险中,所述实体癌症具有表达CD19的肿瘤相关性非肿瘤细胞,诸如表达CD19的浸润细胞。
在一些方面中,基于CD19的量或表达模式来选择个体。在一些方面中,基于细胞表面的CD19表达来进行选择。
在某些方面中,靶标为CD79b。在一些方面中,选择是基于CD79b的表达。
在一些方面中,选择是基于细胞表面CD19与CD79b的水平。
在一些情况下,确定靶标在所关注的特定组织中的表达。举例来说,在淋巴组织或肿瘤组织的样品中。在一些情况下,确定靶标的系统性表达。举例来说,在循环流体(诸如血液、血浆、血清或淋巴)的样品中。
在一些方面中,选择因样品中存在靶标表达而适合治疗的个体。在这些情况下,没有靶标表达的个体可被认为不适合用于治疗。
在其他方面中,使用靶标表达的水平来选择适合治疗的个体。在靶标的表达水平超过阈值水平的情况下,将个体确定为适合治疗。
在一些方面中,样品中的细胞中存在CD19和/或表明个体适合用包含抗CD19 ADC和抗CD79b剂的组合进行治疗。在其他方面中,CD19的量和/或表达必须在阈值水平以上以表明个体适合治疗。在一些方面中,观测到与对照相比在样品中CD19和/或定位有所改变表明个体适合治疗。
在一些方面中,如果如通过IHC所测定从淋巴结或结外位点获得的细胞与针对CD19和/或的抗体反应,那么指示个体适合治疗。
在一些方面中,如果样品中的所有细胞中的至少5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%或更多表达CD19,那么将患者确定为适合治疗的。在本文所公开的一些方面中,如果样品中至少10%的细胞表达CD19,那么将患者确定为适合治疗的。
在一些方面中,如果样品中的所有细胞中至少5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%或更多表达,那么将患者确定为适合治疗的。在本文所公开的一些方面中,如果样品中至少10%的细胞表达,那么将患者确定为适合治疗的。
在一些方面中,基于当前或先前治疗方案来选择适合治疗的个体。在一些实施方案中,如果个体已用抗CD79b剂治疗,那么选择个体用于用抗CD19 ADC治疗。在一些实施方案中,如果个体正在用抗CD79b剂治疗,那么选择个体用于用抗CD19 ADC治疗。在一些情况下,如果个体用抗CD79b剂治疗(或进一步治疗)为难以治疗的,那么选择个体用于治疗。在一些情况下,抗CD79b剂可为维普拉土珠单抗。在个体正在经历或已经历用抗CD79b剂治疗的实施方案中,可将抗CD19 ADC与抗CD79b剂组合施用,或不继续施用抗CD79b剂。
在一些实施方案中,将抗CD19 ADC与抗CD79b剂组合施用给所选择的个体。在一些实施方案中,在不继续施用抗CD79b剂的情况下,将抗CD19 ADC施用给所选择的个体。抗CD79b剂优选为维普拉土珠单抗。
术语‘用抗CD79b剂治疗(或进一步治疗)为难以治疗的’在本文中用于意指当作为单一疗法施用时,病症(诸如癌症)对抗CD79b剂的施用未作出反应,或已停止反应。在一些实施方案中,使用Cheson等,2014(South Asian J Cancer.2014年1月-3月;3(1):66-70)中所公开的反应准则来鉴定患有难治性NHL的个体。在所述文档中,非反应者定义为(i)相较于任何先前所鉴定的异常结节的直径总和的最低点增加>50%,或(ii)在治疗期间或结束时出现任何新的病变的个体。在一些实施方案中,患有难治性白血病的个体被鉴定为已完成一个完整治疗周期的患有稳定或进行性疾病的个体,或在两个或更多个完整治疗周期之后实现部分反应的个体。
CD25
在一些方面中,基于具有包含CD25+ve与CD25-ve细胞的赘瘤来选择受试者。赘瘤可由CD25-ve赘生性细胞组成,任选其中CD25-ve赘生性细胞与CD25+ve非赘生性细胞(诸如CD25+ve Treg)相关。赘瘤或赘生性细胞可为实体肿瘤的全部或一部分。实体肿瘤可部分或完全为CD25-ve,并且可浸润CD25+ve细胞,诸如CD25+ve Treg。在优选方面中,实体肿瘤与高水平的CD25+ve浸润细胞(诸如Treg细胞)相关。在一些方面中,实体肿瘤与低水平的CD25+ve浸润细胞(诸如Treg细胞)相关。在一些方面中,实体肿瘤不与CD25+ve浸润细胞(诸如Treg细胞)相关;举例来说,CD25+ve细胞的水平可低于检测极限。
样品
样品可包括或可来源于:一定量的血液;来源于个体的血液并且可包含在移除纤维蛋白凝块和血细胞之后获得的血液的流体部分的一定量的血清;一定量的胰液;组织样品或活组织切片;或从所述个体分离的细胞。
样品可取自任何组织或体液。在某些方面中,样品可包括或可来源于组织样品、活组织切片、切除物或从个体分离的细胞。
在某些方面中,样品为组织样品。样品可为肿瘤组织(诸如癌性肿瘤组织)的样品。可已通过肿瘤活组织切片获得样品。在一些方面中,样品为淋巴组织样品,诸如淋巴系统病变样品或淋巴结活组织切片。在一些情况下,样品为皮肤活组织切片。
在一些方面中,样品取自体液,更优选地在身体中循环的体液。因此,样品可为血液样品或淋巴样品。在一些情况下,样品为尿液样品或唾液样品。
在一些情况下,样品为血液样品或血液源性样品。血液源性样品可为个体血液的所选部分,例如所选含细胞部分或血浆或血清部分。
所选含细胞部分可含有所关注的细胞类型,所述所关注的细胞类型可包括白血细胞(WBC),特别是外周血单核细胞(PBC)和/或粒细胞,和/或红血细胞(RBC)。因此,根据本公开的方法可涉及检测血液中、白血细胞、外周血单核细胞、粒细胞和/或红血细胞中的CD19蛋白或核酸。
样品可为新鲜或存档的。举例来说,存档组织可来自个体的首次诊断,或为复发时的活组织切片。在某些方面中,样品为新鲜活组织切片。
个体状况
个体可为动物、哺乳动物、胎盘哺乳动物、有袋动物(例如袋鼠、袋熊)、单孔目动物(例如鸭嘴兽)、啮齿动物(例如豚鼠、仓鼠、大鼠、小鼠)、鼠类(例如小鼠)、兔类(例如兔子)、禽类(例如鸟)、犬类(例如狗)、猫类(例如猫)、马类(例如马)、猪类(例如猪)、绵羊类(例如绵羊)、牛类(例如奶牛)、灵长类动物、猿猴(例如猴或猿)、猴类(例如狨猴、狒狒)、猿类(例如大猩猩、黑猩猩、猩猩、长臂猿)或人类。
此外,个体可为其发育形式中的任一者,例如胎儿。在一个优选实施方案中,个体为人。术语“受试者”、“患者”以及“个体”在本文中可互换使用。
在本文所公开的一些方面中,个体患有或疑似患有癌症或已被鉴定为处于癌症风险中。在本文所公开的一些方面中,个体已收到癌症诊断。个体可能已收到以下诊断:非霍奇金氏淋巴瘤,包括弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、伯基特淋巴瘤、套细胞淋巴瘤(MCL)、慢性淋巴性淋巴瘤(CLL)、华登斯特罗姆巨球蛋白血症(WM)以及边缘区B细胞淋巴瘤(MZBL);以及白血病,诸如毛细胞白血病(HCL)、变异型毛细胞白血病(HCL-v)、慢性淋巴细胞性白血病(CLL)(包括里希特综合征)以及急性成淋巴细胞性白血病(ALL),诸如费城染色体阳性ALL(Ph+ALL)或费城染色体阴性ALL(Ph-ALL)。
在一些情况下,个体已收到以下诊断:非霍奇金氏淋巴瘤,包括弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、伯基特淋巴瘤、套细胞淋巴瘤(MCL)、慢性淋巴性淋巴瘤(CLL)、华登斯特罗姆巨球蛋白血症(WM)以及边缘区B细胞淋巴瘤(MZBL);以及白血病,诸如毛细胞白血病(HCL)、变异型毛细胞白血病(HCL-v)、慢性淋巴细胞性白血病(CLL)(包括里希特综合征)以及急性成淋巴细胞性白血病(ALL),诸如费城染色体阳性ALL(Ph+ALL)或费城染色体阴性ALL(Ph-ALL)[Fielding A.,Haematologica.2010年1月;95(1):8-12]。
在一些情况下,个体已收到含有表达CD19+的浸润细胞的实体癌症的诊断。
个体可正在经历或已经历针对所述癌症的治疗性治疗。受试者可能先前已接受或可能尚未接受ADCX19。在一些情况下,癌症为淋巴瘤,包括非霍奇金氏淋巴瘤。
个体可正在经历或已经历用抗CD79b剂治疗。在一些情况下,个体可为用抗CD79b剂治疗(或进一步治疗)难以治疗的。在一些情况下,抗CD79b剂可为维普拉土珠单抗。。在个体正在经历或已经历用抗CD79b剂治疗的实施方案中,可将抗CD19 ADC与抗CD79b剂组合施用,或不继续施用抗CD79b剂。
对照
在一些方面中,将个体中的靶标表达与对照中的靶标表达相比较。对照可用于支持染色的有效性,并且鉴定实验伪迹。
在一些情况下,对照可为参考样品或参考数据集。参考可为先前已从具有已知程度的适合性的个体获得的样品。参考可为由分析参考样品获得的数据集。
对照可为阳性对照,其中靶分子已知存在,或以高水平表达;或阴性对照,其中靶分子已知不存在或以低水平表达。
对照可为来自已知受益于治疗的个体的组织的样品。组织可与正在测试的样品类型相同。举例来说,可将来自个体的肿瘤组织的样品与来自已知适合治疗的个体(诸如先前已对治疗作出反应的个体)的肿瘤组织的对照样品相比较。
在一些情况下,对照可为从与测试样品相同的个体获得但来自已知健康的组织的样品。因此,可将来自个体的癌组织的样品与非癌组织样品相比较。
在一些情况下,对照为细胞培养样品。
在一些情况下,在与抗体一起孵育之前对测试样品进行分析,以测定所述样品固有的背景染色水平。
在一些情况下,使用同型对照。同型对照使用与靶特异性抗体相同类别的抗体,但与样品不具免疫反应性。此类对照可用于区别靶特异性抗体的非特异性相互作用。
所述方法可包括血液病理学家对形态和免疫组织化学的解释,以确保对测试结果的准确解释。所述方法可涉及确认表达模式与预期模式有关。举例来说,在对CD19的量和/或CD79b表达进行分析的情况下,所述方法可涉及确认在测试样品中在细胞质组分情况下以膜染色形式观测到表达。所述方法可涉及确认目标信号与噪音的比率在阈值水平以上,由此允许清楚地辨别特异性与非特异性背景信号。
治疗方法
如本文所用,术语“治疗”在治疗疾患的情形中,通常是有关于人或动物(例如在兽医学应用中)的实现某种所需治疗作用(例如抑制疾患进展)的治疗和疗法,并且包括降低进展速率、阻止进展速率、疾患消退、疾患改善以及疾患治愈。还包括作为预防措施的治疗(即预防、防止)。
如本文所用,术语“治疗有效量”或“有效量”是有关于活性化合物或包含活性化合物的材料、组合物或剂型当根据所需治疗方案施用时有效产生某种所需治疗作用并且符合合理效益/风险比的量。
类似地,如本文所用,术语“预防有效量”是有关于活性化合物或包含活性化合物的材料、组合物或剂型当根据所需治疗方案施用时有效产生某种所需预防作用并且符合合理效益/风险比的量。
本文公开了治疗方法。还提供了一种治疗方法,所述治疗方法包括向需要治疗的受试者施用治疗有效量的抗CD19 ADC和抗CD79b剂。术语“治疗有效量”为足以对受试者展示益处的量。此类益处可为至少改善至少一种症状。所施用的实际量以及施用的速率和时程将取决于正在治疗的目标的性质和严重程度。治疗的处方(例如剂量的确定)在全科医师和其他医生的职责范围内。可已对受试者进行了测试以根据本文所公开的方法确定它们有资格接受治疗。治疗方法可包括使用本文所公开的方法确定受试者是否有资格进行治疗的步骤。
抗CD19 ADC包含抗CD19抗体。抗CD19抗体可为RB4v1.2抗体。ADC可包含为PBD二聚体的药物。ADC可为ADCx19。ADC可为WO2014/057117中公开的ADC。
抗CD25 ADC包含抗CD25抗体。抗CD25抗体可为HuMax-TACTM。ADC可包含为PBD二聚体的药物。ADC可为抗CD25-ADC,并且特别是ADCX25或泰卡利尤单抗。ADC可为WO2014/057119中公开的ADC。
抗CD22 ADC包含抗CD22抗体。抗CD22抗体可为EMabC220。ADC可包含为PBD二聚体的药物。ADC可为抗CD22-ADC,诸如ADCT-602或ADCx22。ADC可为WO2014/057122或WO2016/166307中公开的ADC。
通常,施以本文所公开的治疗的个体需要所述治疗,或已被鉴定或将诊断为需要所述治疗。
抗CD79b剂可为维普拉土珠单抗。
治疗可涉及单独施用抗CD19 ADC/抗CD79b剂组合或与其他治疗进一步组合,根据所要治疗的疾患同时或依序施用。
用治疗的方法的实例涉及:
(1)鉴定已用抗CD79b剂(诸如维普拉土珠单抗)治疗或正在用抗CD79b剂治疗的个体;
(2)向个体施用抗CD19 ADC,诸如ADCx19;以及任选地
(3)与抗CD19 ADC组合(例如与ADC同时,或在ADC之后)向个体施用抗CD79b剂,诸如维普拉土珠单抗。
治疗和疗法的实例包括但不限于化学疗法(施用活性剂,包括例如药物,诸如化学治疗剂);手术;以及放射疗法。
“化学治疗剂”为可用于治疗癌症的化合物,无论作用机制如何。化学治疗剂的类别包括但不限于:烷基化剂、抗代谢物、纺锤体毒物植物生物碱、细胞毒性剂/抗肿瘤抗生素、拓扑异构酶抑制剂、抗体、光敏剂以及激酶抑制剂。化学治疗剂包括“靶向疗法”和常规化学疗法中所用的化合物。
化学治疗剂的实例包括:来那度胺(Celgene)、伏立诺他(/>Merck)、帕比司他(/>Novartis)、莫西司他(MGCD0103)、依维莫司(Novartis)、苯达莫司汀(/> Mundipharma International)、埃罗替尼(/>Genentech/OSIPharm.)、多西他赛(/>Sanofi-Aventis)、5-FU(氟尿嘧啶、5-氟尿嘧啶,CAS号51-21-8)、吉西他滨(/>Lilly)、PD-0325901(CAS号391210-10-9,Pfizer)、顺铂(顺-二胺、二氯铂(II),CAS号15663-27-1)、卡铂(CAS号41575-94-4)、帕西他赛(paclitaxel)(/>Bristol-Myers Squibb Oncology,Princeton,N.J.)、曲妥珠单抗(/>Genentech)、替莫唑胺(4-甲基-5-氧代-2,3,4,6,8-五氮杂双环[4.3.0]壬-2,7,9-三烯-9-甲酰胺,CAS号85622-93-1,/>ScheringPlough)、他莫昔芬(tamoxifen)((Z)-2-[4-(1,2-二苯基丁-1-烯基)苯氧基]-N,N-二甲基乙胺,/>)以及多柔比星/>Akti-1/2、HPPD以及雷帕霉素。
更多化学治疗剂的实例包括:奥沙利铂(Sanofi)、硼替佐米(Millennium Pharm.)、索坦(sutent)(/>SU11248,Pfizer)、来曲唑(/>Novartis)、伊马替尼甲磺酸盐(imatinib mesylate)(/>Novartis)、XL-518(Mek抑制剂,Exelixis,WO 2007/044515)、ARRY-886(Mek抑制剂,AZD6244,Array BioPharma、Astra Zeneca)、SF-1126(抗CD79b剂,SemaforePharmaceuticals)、BEZ-235(抗CD79b剂,Novartis)、XL-147(抗CD79b剂,Exelixis)、PTK787/ZK 222584(Novartis)、氟维司群(fulvestrant)(/>AstraZeneca)、甲酰四氢叶酸(亚叶酸)、雷帕霉素(西罗莫司,/>Wyeth)、拉帕替尼(/>GSK572016,Glaxo Smith Kline)、洛那法尼(lonafarnib)(SARASARTM,SCH 66336,ScheringPlough)、索拉非尼(sorafenib)(/>BAY43-9006,Bayer Labs)、吉非替尼(gefitinib)(/>AstraZeneca)、伊立替康(irinotecan)(/>CPT-11,Pfizer)、替匹法尼(tipifarnib)(ZARNESTRATM,Johnson&Johnson)、ABRAXANETM(不含克列莫佛(Cremophor))、帕西他赛的白蛋白工程化纳米粒子制剂(American PharmaceuticalPartners,Schaumberg,Il)、凡德他尼(vandetanib)(rINN,ZD6474,/>AstraZeneca)、苯丁酸氮芥(chloranmbucil)、AG1478、AG1571(SU 5271;Sugen)、替西罗莫司(/>Wyeth)、帕唑帕尼(pazopanib)(GlaxoSmithKline)、坎磷酰胺(canfosfamide)(/>Telik)、噻替派(thiotepa)和环磷酰胺烷基磺酸盐,诸如白消安(busulfan)、英丙舒凡(improsulfan)以及哌泊舒凡(piposulfan);氮杂环丙烷,诸如苯并多巴(benzodopa)、卡波醌(carboquone)、美妥多巴(meturedopa)以及乌瑞多巴(uredopa);乙烯亚胺和甲基蜜胺,包括六甲蜜胺、三亚乙基蜜胺、三亚乙基磷酰胺、三亚乙基硫代磷酰胺以及三羟甲基蜜胺;番荔枝内酯(acetogenin)(尤其布拉它辛(bullatacin)和布拉它辛酮);喜树碱(包括合成类似物拓扑替康(topotecan));薯司他汀(bryostatin);卡利他汀(callystatin);CC-1065(包括其阿多来新(adozelesin)、卡折来新(carzelesin)以及比折来新(bizelesin)合成类似物);念珠藻素(特别是念珠藻素1和念珠藻素8);多拉司他汀(dolastatin);多卡霉素(duocarmycin)(包括合成类似物KW-2189和CB1-TM1);伊斯罗宾(eleutherobin);水鬼蕉碱;匍枝珊瑚醇;海绵抑素;氮芥,诸如氮芥苯丁酸、萘氮芥、胆磷酰胺、雌莫司汀(estramustine)、异环磷酰胺、二氯甲基二乙胺、二氯甲基二乙胺氧化物盐酸盐、美法仑(melphalan)、新恩比兴(novembichin)、苯芥胆甾醇、泼尼莫司汀(prednimustine)、曲磷胺、尿嘧啶氮芥;亚硝基脲,诸如卡莫司汀(carmustine)、氯脲霉素、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)以及雷莫司汀(ranimnustine);抗生素,诸如烯二炔抗生素(例如卡奇霉素(calicheamicin)、卡奇霉素γ1l、卡奇霉素ωI1(Angew Chem.Intl.Ed.Engl.(1994)33:183-186);达内霉素(dynemicin)、达内霉素A;双膦酸盐,诸如氯膦酸盐;埃斯培拉霉素(esperamicin);以及新制癌菌素生色团和相关色蛋白烯二炔抗生素生色团)、阿克拉霉素(aclacinomysin)、放线菌素(actinomycin)、安曲霉素(authramycin)、氮杂丝氨酸、博来霉素(bleomycin)、放线菌素C、卡拉比星(carabicin)、洋红霉素(carminomycin)、嗜癌霉素、色霉素、更生霉素(dactinomycin)、柔红比星(daunorubicin)、地托比星(detorubicin)、6-重氮基-5-氧代-L-正亮氨酸、吗啉基-多柔比星、氰基吗啉基-多柔比星、2-吡咯啉基-多柔比星以及脱氧多柔比星)、表柔比星、依索比星(esorubicin)、伊达比星、奈莫柔比星(nemorubicin)、麻西罗霉素(marcellomycin)、丝裂霉素(诸如丝裂霉素C)、霉酚酸、诺加霉素(nogalamycin)、橄榄霉素、培洛霉素(peplomycin)、泊非霉素(porfiromycin)、嘌呤霉素、三铁阿霉素、罗多比星(rodorubicin)、链黑菌素(streptonigrin)、链佐星(streptozocin)、杀结核菌素、乌苯美司(ubenimex)、净司他丁(zinostatin)、佐柔比星(zorubicin);抗代谢物,诸如甲氨蝶呤和5-氟尿嘧啶(5-FU);叶酸类似物,诸如二甲叶酸、甲氨蝶呤、蝶罗呤(pteropterin)、三甲曲沙(trimetrexate);嘌呤类似物,诸如氟达拉滨(fludarabine)、6-巯基嘌呤、硫咪嘌呤、硫鸟嘌呤;嘧啶类似物,诸如环胞苷、阿扎胞苷(azacitidine)、6-氮尿苷、卡莫氟(carmofur)、阿糖胞苷、双脱氧尿苷、脱氧氟尿苷、依诺他滨(enocitabine)、氟尿苷;雄激素,诸如卡普睾酮(calusterone)、屈他雄酮丙酸盐(dromostanolone propionate)、表硫雄醇、美雄酮(mepitiostane)、睾内酯;抗肾上腺剂,诸如氨鲁米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);叶酸补充剂,诸如亚叶酸;乙酰葡醛内酯;醛磷酰胺糖苷;氨基乙酰丙酸;恩尿嘧啶(eniluracil);安吖啶(amsacrine);倍曲布西(bestrabucil);比生群(bisantrene);依达曲沙(edatraxate);多弗酰胺(defofamine);地美可辛(demecolcine);地吖醌(diaziquone);艾弗利散(elfornithine);依利醋铵(elliptiniumacetate);埃博霉素(epothilone);依托格鲁(etoglucid);硝酸镓;羟基脲;香菇多糖;氯尼达明(lonidainine);类美登素(maytansinoid),诸如美登素(maytansine)和安丝菌素(ansamitocins);米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌达醇(mopidanmol);尼曲吖啶(nitraerine);喷司他汀(pentostatin);蛋氨氮芥;吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);足叶草酸;2-乙肼;丙卡巴肼(procarbazine);多糖复合物(JHS Natural Products,Eugene,OR);雷佐生(razoxane);根霉素;西佐喃(sizofiran);锗螺胺;细交链孢菌酮酸;三亚胺醌;2,2',2"-三氯三乙胺;单端孢霉烯(尤其T-2毒素、疣孢菌素A(verracurin A)、杆孢菌素A以及蛇形菌素);乌拉坦(urethan);长春地辛(vindesine);达卡巴嗪(dacarbazine);甘露醇氮芥;二溴甘露醇;二溴卫矛醇;哌泊溴烷(pipobroman);加西托星(gacytosine);阿拉伯糖苷(“Ara-C”);环磷酰胺;噻替派;6-硫鸟嘌呤;巯基嘌呤;甲氨蝶呤;铂类似物,诸如顺铂和卡铂;长春花碱;依托泊苷(etoposide)(VP-16);异环磷酰胺;米托蒽醌;长春新碱;长春瑞滨/>双羟蒽醌;替尼泊苷(teniposide);依达曲沙;道诺霉素;氨基喋呤;卡培他滨(capecitabine)(/>Roche);依班膦酸盐(ibandronate);CPT-11;拓扑异构酶抑制剂RFS2000;二氟甲基鸟氨酸(DMFO);类视黄醇,诸如视黄酸;以及以上中的任一者的药学上可接受的盐、酸以及衍生物。可使用剂的组合,诸如CHP(多柔比星、泼尼松、环磷酰胺)或CHOP(多柔比星、泼尼松、环磷酰胺、长春新碱)。
“化学治疗剂”的定义中还包括:(i)起到调控或抑制激素对肿瘤的作用的作用的抗激素剂,诸如抗雌激素和选择性雌激素受体调节剂(SERM),包括例如他莫昔芬(包括他莫昔芬柠檬酸盐)、雷洛昔芬(raloxifene)、屈洛昔芬(droloxifene)、4-羟基他莫昔芬、曲沃昔芬(trioxifene)、那洛昔芬(keoxifene)、LY117018、奥那司酮(onapristone)以及/>(托瑞米芬柠檬酸盐(toremifine citrate));(ii)抑制调控肾上腺中的雌激素产生的芳香酶的芳香酶抑制剂,诸如4(5)-咪唑、氨鲁米特、(甲地孕酮乙酸盐)、/>(依西美坦(exemestane);Pfizer),福美斯坦(formestanie)、法屈唑(fadrozole)、/>(伏罗唑(vorozole))、/>(来曲唑;Novartis),以及/>(阿那曲唑(anastrozole);AstraZeneca);(iii)抗雄激素剂,诸如氟他米特(flutamide)、尼鲁米特(nilutamide)、比卡米特(bicalutamide)、亮丙瑞林(leuprolide)以及戈舍瑞林(goserelin);以及曲沙他滨(troxacitabine)(1,3-二氧杂环戊烷核苷胞嘧啶类似物);(iv)蛋白激酶抑制剂,诸如MEK抑制剂(WO 2007/044515);(v)脂质激酶抑制剂;(vi)反义寡核苷酸,特别是抑制异常细胞增殖中所涉及的信号传导路径中的基因(例如PKC-α、Raf以及H-Ras)的表达的那些反义寡核苷酸,诸如奥利默森(Genta Inc.);(vii)核酶,诸如VEGF表达抑制剂(例如/>)和HER2表达抑制剂;(viii)疫苗,诸如基因疗法疫苗,例如/>以及/> rIL-2;拓扑异构酶1抑制剂,诸如/> rmRH;(ix)抗血管生成剂,诸如贝伐单抗(bevacizumab)(/>Genentech);以及以上中的任一者的药学上可接受的盐、酸以及衍生物。
“化学治疗剂”的定义中还包括治疗性抗体,诸如阿仑单抗(alemtuzumab)(Campath)、贝伐单抗(Genentech);西妥昔单抗(cetuximab)(/>Imclone);帕尼单抗(panitumumab)(/>Amgen)、帕妥珠单抗(pertuzumab)(PERJETATM、OMNITARGTM,2C4,Genentech)、曲妥珠单抗(/>Genentech),MDX-060(Medarex)以及抗体药物结合物奥星-吉妥珠单抗(gemtuzumab ozogamicin)(Wyeth)。/>
具有作为与本公开的缀合物组合的化学治疗剂的治疗潜能的人源化单克隆抗体包括:阿仑单抗、阿泊珠单抗(apolizumab)、阿塞珠单抗(aselizumab)、阿利珠单抗(atlizumab)、巴匹珠单抗(bapineuzumab)、贝伐单抗、莫星-比伐珠单抗(bivatuzumabmertansine)、莫星-坎妥珠单抗(cantuzumab mertansine)、西利珠单抗(cedelizumab)、培戈-赛妥珠单抗(certolizumab pegol)、西弗丝妥珠单抗(cidfusituzumab)、西地妥珠单抗(cidtuzumab)、达利珠单抗(daclizumab)、依库珠单抗(eculizumab)、依法利珠单抗(efalizumab)、依帕珠单抗(epratuzumab)、厄利珠单抗(erlizumab)、非维珠单抗(felvizumab)、芳妥珠单抗(fontolizumab)、奥星-吉妥珠单抗、奥星-艾诺妥珠单抗(inotuzumab ozogamicin)、伊匹单抗(ipilimumab)、拉贝珠单抗(labetuzumab)、林妥珠单抗(lintuzumab)、马妥珠单抗(matuzumab)、美泊利单抗(mepolizumab)、莫维珠单抗(motavizumab)、莫托珠单抗(motovizumab)、那他珠单抗(natalizumab)、尼妥珠单抗(nimotuzumab)、诺洛维珠单抗(nolovizumab)、奴马维珠单抗(numavizumab)、奥马珠单抗(omalizumab)、帕利珠单抗(palivizumab)、帕考珠单抗(pascolizumab)、派弗西妥珠单抗(pecfusituzumab)、派妥珠单抗(pectuzumab)、帕妥珠单抗(pertuzumab)、培克珠单抗(pexelizumab)、来利珠单抗(ralivizumab)、雷珠单抗(ranibizumab)、瑞利伟珠单抗(reslivizumab)、瑞利珠单抗(reslizumab)、来西维珠单抗(resyvizumab)、罗维珠单抗(rovelizumab)、芦利珠单抗(ruplizumab)、西罗珠单抗(sibrotuzumab)、西利珠单抗(siplizumab)、松妥珠单抗(sontuzumab)、泰坦-他卡妥珠单抗(tacatuzumabtetraxetan)、他度珠单抗(tadocizumab)、他利珠单抗(talizumab)、特非珠单抗(tefibazumab)、托珠单抗(tocilizumab)、托利珠单抗(toralizumab)、曲妥珠单抗、妥考妥珠单抗(tucotuzumab)西莫白介素、土库西妥珠单抗(tucusituzumab)、恩维珠单抗(umavizumab)、乌珠单抗(urtoxazumab)以及维西珠单抗(visilizumab)。
根据本公开的组合物优选为药物组合物。除活性成分(即缀合物化合物)外,根据本公开并且用于根据本公开的用途的药物组合物还可包含药学上可接受的赋形剂、载体、缓冲剂、稳定剂或本领域技术人员熟知的其他材料。此类材料应为无毒的并且不应妨碍活性成分的功效。载体或其他材料的准确特征将取决于施用途径,施用途径可为口服,或通过注射,例如经皮肤、皮下或静脉内注射。
用于口服施用的药物组合物可呈片剂、胶囊、粉末或液体形式。片剂可包含固体载体或佐剂。液体药物组合物通常包含液体载体,诸如水、石油、动物或植物油、矿物油或合成油。可包括生理盐水溶液、右旋糖或其他糖溶液或二醇,诸如乙二醇、丙二醇或聚乙二醇。胶囊可包含固体载体,诸如明胶。
对于静脉内、经皮肤或皮下注射或在痛苦位点注射,活性成分将呈肠胃外可接受的水溶液形式,所述肠胃外可接受的水溶液为无热原的并且具有适合的pH值、等张性以及稳定性。本领域相关技术人员完全能够使用例如等张媒介物来制备适合的溶液,诸如氯化钠注射液、林格氏注射剂(Ringer's Injection)、乳酸林格氏液注射剂。按需要可包括防腐剂、稳定剂、缓冲剂、抗氧化剂和/或其他添加剂。
剂量
本领域技术人员将了解,抗CD19 ADC和/或抗CD79b剂以及包含这些活性元素的组合物的适当的剂量在不同受试者间可不同。确定最佳剂量通常将涉及平衡治疗益处水平与任何风险或有害副作用。所选剂量水平将取决于多种因素,包括但不限于特定化合物的活性、施用途径、施用时间、化合物的排泄速率、治疗的持续时间、组合使用的其他药物、化合物和/或材料、疾患的严重程度以及受试者的种类、性别、年龄、体重、状况、一般健康以及现有病史。化合物的量和施用途径最终将由医师、兽医或临床医师决断,不过通常剂量将被选择为在作用位点实现局部浓度,所述局部浓度实现所需效应而不会引起实质性的有害或不利的副作用。
在某些方面中,通过在从受试者获得的样品中观测到的CD19表达来确定抗CD19ADC的剂量。因此,样品中的CD19表达的水平或定位可指示需要更高或更低剂量的抗CD19ADC。举例来说,高CD19表达水平可表明更高剂量的抗CD19 ADC将为适合的。在一些情况下,高CD19表达水平可指示需要施用除抗CD19 ADC外的另一剂。举例来说,结合化学治疗剂施用抗CD19 ADC。高CD19表达水平可指示更具侵袭性的疗法。
在某些方面中,通过在从受试者获得的样品中所观测的表达来确定抗CD79b剂的剂量。因此,样品中的表达的水平或定位可指示需要更高或更低剂量的抗CD79b剂。举例来说,高CD79b表达水平可表明更高剂量的抗CD79b剂将为适合的。在一些情况下,高CD79b表达水平可指示需要施用除抗CD79b剂外的另一剂。举例来说,结合化学治疗剂施用抗CD79b剂。高CD79b表达水平可指示更具侵袭性的疗法。
施用可在整个治疗过程中以一个剂量、连续地或间断地(例如按适当的间隔以分开的剂量)实现。确定最有效的施用手段和剂量的方法为本领域技术人员熟知的,并且将随疗法中所用的制剂、疗法的目的、所处理的一种或多种靶细胞以及所治疗的受试者而改变。可进行单次或多次施用,并且由治疗医师、兽医或临床医师选择剂量水平和模式。
一般而言,每种活性化合物的适合的剂量在每千克受试者体重每天约100ng至约25mg(更典型地约1μg至约10mg)范围内。在活性化合物为盐、酯、酰胺、前药等的情况下,基于母体化合物来计算施用的量并且因此所用的实际重量按比例增加。
在一个实施方案中,根据以下剂量方案向人受试者施用每种活性化合物:约100mg,每天3次。
在一个实施方案中,根据以下剂量方案向人受试者施用每种活性化合物:约150mg,每天2次。
在一个实施方案中,根据以下剂量方案向人受试者施用每种活性化合物:约200mg,每天2次。
然而,在一个实施方案中,根据以下剂量方案向人受试者施用每种缀合物化合物:约50或约75mg,每天3或4次。
在一个实施方案中,根据以下剂量方案向人受试者施用每种缀合物化合物:约100或约125mg,每天2次。
对于抗CD19 ADC,在它为带有PBD的ADC的情况下,上文所描述的剂量可适用于缀合物(包括PBD部分和与抗体的接头)或适用于所提供的有效量的PBD化合物,例如在接头裂解之后可释放的量的化合物。
抗CD19 ADC包含抗CD19抗体。抗CD19抗体可为RB4v1.2抗体。ADC可包含为PBD二聚体的药物。抗CD19-ADC可为ADCx19。抗CD19 ADC可为泰朗妥昔单抗。ADC可为WO2014/057117中公开的ADC。
抗CD79b剂可为维普拉土珠单抗。
抗体
术语“抗体”在本文中以广义使用并且具体来说涵盖单克隆抗体、多克隆抗体、二聚体、多聚体、多特异性抗体(例如双特异性抗体)、完整抗体(也描述为“全长”抗体)和抗体片段,只要它们展现所需生物活性,例如结合CD19的能力(Miller等(2003)Jour.ofImmunology 170:4854-4861)。抗体可为鼠抗体、人抗体、人源化抗体、嵌合抗体或来源于其他物种,诸如兔、山羊、绵羊、马或骆驼。
附图说明
现将参考附图论述说明本公开的原理的实施方案和实验,其中:
图1.示出ADCx19和Pola-V组合的体内功效的中值肿瘤体积的绘图
本公开包括所描述的方面和优选特征的组合,除非此类组合为明显不许可的或明确避免的。
本文所用的章节标题仅用于组织目的,而不应被认为限制所描述的主题。
现将例如参考附图来说明本公开的方面和实施方案。其他方面和实施方案将对本领域技术人员来说为显而易见的。此文本中提到的所有文件以引用的方式并入本文中。
在本说明书通篇中,包括随后的权利要求书,除非上下文另有需要,否则词语“包含(comprise)”和诸如“包含(comprises)”和“包含(comprising)”等变化型式将理解为暗示包括所陈述的整体或步骤或整体或步骤的组,但不排除任何其他整体或步骤或整体或步骤的组。
除非上下文另外明确指示,否则如本说明书和随附权利要求书中所用,单数形式“一个(种)(a/an)”和“所述”包括复数指示物。范围在本文中可表述从“约”一个特定值和/或至“约”另一特定值。当表述此类范围时,另一实施方案包括从所述一个特定值和/或至所述另一特定值。类似地,当通过使用先行词“约”以近似值来表示值时,应了解特定值形成另一实施方案。
发明声明
1.一种用于治疗个体的病症的方法,所述方法包括向所述个体施用有效量的抗CD19 ADC(或抗CD22 ADC或抗CD25 ADC)以及抗CD79b剂。
2.根据声明1所述的方法,其中选择所述个体用于治疗。
3.根据声明2所述的方法,其中如果所述个体已用抗CD79b剂治疗,那么选择所述个体用于用抗CD19 ADC(或抗CD22 ADC或抗CD25 ADC)治疗。
4.根据声明2所述的方法,其中如果所述个体正在用抗CD79b剂治疗,那么选择所述个体用于用抗CD19 ADC(或抗CD22 ADC或抗CD25 ADC)治疗。
5.根据先前声明中任一项所述的方法,其中如果所述个体用所述抗CD79b剂治疗或进一步治疗为难以治疗的,那么选择所述个体用于治疗。
6.一种用于治疗个体的病症的方法,所述方法包括:
(i)选择适合通过根据声明3至5中任一项所述的方法治疗的个体;以及
(ii)向所述个体施用有效量的抗CD19 ADC(或抗CD22 ADC或抗CD25 ADC)。
7.根据声明6所述的方法,所述方法还包括施用抗CD79b剂与所述抗CD19 ADC(或抗CD22 ADC或抗CD25 ADC)的组合。
8.根据声明1至5或7中任一项所述的方法,其中所述治疗包括在所述抗CD79b剂之前、与所述抗CD79b剂同时或在所述抗CD79b剂之后施用所述抗CD19 ADC(或抗CD22 ADC或抗CD25ADC)。
9.根据任何先前声明所述的方法,其中所述治疗还包括施用化学治疗剂。
10.根据任何先前声明所述的方法,其中所述个体为人。
11.根据任何先前声明所述的方法,其中所述个体患有病症或已被确定患有病症。
12.根据声明11所述的方法,其中所述个体患有或已被确定患有表达CD19(或CD22或CD25)或CD19+ve(或CD22+ve或CD25+ve)肿瘤相关非肿瘤细胞,诸如CD19+ve(或CD22+ve或CD25+ve)浸润细胞的癌症。
13.根据任何先前声明所述的方法,其中所述个体正在经历用抗CD79b剂治疗。
14.根据任何先前声明所述的方法,其中所述个体已经历用抗CD79b剂治疗。
15.根据任何先前声明所述的方法,其中所述个体用所述抗CD79b剂治疗或进一步治疗为难以治疗的。
16.根据先前声明中任一项所述的方法,其中与单独使用抗CD19 ADC(或抗CD22ADC或抗CD25 ADC)或抗CD79b剂的单一疗法相比,所述治疗具有增加的功效。
17.根据任何先前声明所述的方法,其中所述病症为增殖性疾病。
18.如声明17所述的方法,其中所述病症的特征为存在包含CD19+ve细胞(或CD22+ve细胞或CD25+ve细胞)的赘瘤。
19.如声明17所述的方法,其中所述个体患有或已被确定患有以存在包含CD25+ve与CD25-ve细胞的赘瘤为特征的病症。
20.如声明17所述的方法,其中所述个体患有或已被确定患有以存在包含CD25-ve赘生性细胞或由其组成的赘瘤为特征的病症。
21.根据声明18至20中任一项所述的方法,其中所述赘瘤为实体肿瘤的全部或一部分。
22.如声明21所述的方法,其中所述实体肿瘤与CD25+ve浸润细胞相关;
任选其中所述实体肿瘤与高水平的CD25+ve浸润细胞相关。
23.如声明21或122所述的方法,其中所述实体肿瘤选自由以下组成的组:胰腺癌、乳腺癌(包括三阴性乳腺癌)、结肠直肠癌、胃和食管癌、黑素瘤、非小细胞肺癌、卵巢癌、肝细胞癌、肾细胞癌、膀胱以及头颈癌。
24.如任何先前声明所述的方法,其中所述病症为癌症。
25.如任何先前声明所述的方法,其中所述病症选自包含以下的组:非霍奇金氏淋巴瘤,包括弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、伯基特淋巴瘤、套细胞淋巴瘤(MCL)、慢性淋巴性淋巴瘤(CLL)、华登斯特罗姆巨球蛋白血症(WM)以及边缘区B细胞淋巴瘤(MZBL);以及白血病,诸如毛细胞白血病(HCL)、变异型毛细胞白血病(HCL-v)、慢性淋巴细胞性白血病(CLL)(包括里希特综合征)以及急性成淋巴细胞的白血病(ALL)诸如费城染色体阳性ALL(Ph+ALL)或费城染色体阴性ALL(Ph-ALL)。
26.如任何先前声明所述的方法,其中所述抗CD79b剂为抗CD79b ADC。
27.如声明26所述的方法,其中所述CD79b ADC为式(I)的缀合物:
Ab-(DL)p(I)
其中:
Ab为结合至CD79b的抗体;
DL为
并且p介于1与8之间,诸如3与4之间,例如约3.5。
28.如任何先前声明所述的方法,其中所述抗CD79b剂或ADC包含具有VH结构域的抗体,所述VH结构域包含VH CDR1、VH CDR2以及VH CDR3,其中所述抗体包含具有根据SEQID NO:17的序列的所述VH结构域的CDR序列。
29.如声明28所述的方法,其中所述抗体还包含VL结构域,所述VL结构域包含VLCDR1、VL CDR2以及VL CDR3,其中所述抗体包含具有根据SEQ ID NO:18的序列的所述VL结构域的CDR序列。
30.如声明1至27中任一项所述的方法,其中所述抗CD79b剂或ADC包含具有VH结构域和VL结构域的抗体,
所述VH结构域具有含有SEQ ID NO.19的氨基酸序列的VH CDR1、含有SEQ IDNO.20的氨基酸序列的VH CDR2以及含有SEQ ID NO.21的氨基酸序列的VH CDR3;并且
所述VL结构域具有含有SEQ ID NO.22的氨基酸序列的VL CDR1、含有SEQ IDNO.23的氨基酸序列的VL CDR2以及含有SEQ ID NO.24的氨基酸序列的VL CDR3。
31.如声明1至27中任一项所述的方法,其中所述抗CD79b剂或ADC包含抗体,所述抗体具有含有根据SEQ ID NO:17的序列的VH结构域以及含有根据SEQ ID NO:18的序列的VL结构域。
32.如声明1至27中任一项所述的方法,其中所述抗CD79b剂为维普拉土珠单抗。
33.根据任何先前声明所述的方法,其中所述抗CD19 ADC(或抗CD22 ADC或抗CD25ADC)包含式L-(DL)p的缀合物,其中DL具有式I或II:
其中:
L为抗体(Ab),所述抗体为结合至CD19(或CD22或CD25)的抗体;
当C2’与C3’之间存在双键时,R12选自由以下组成的组:
(ia)C5-10芳基,任选用一个或多个选自包含以下的组的取代基取代:卤基、硝基、氰基、醚、羧基、酯、C1-7烷基、C3-7杂环基以及双氧基-C1-3亚烷基;
(ib)C1-5饱和脂族烷基;
(ic)C3-6饱和环烷基;
(id)其中R21、R22以及R23中的每一者独立地选自H、C1-3饱和烷基、C2-3烯基、C2-3炔基以及环丙基,其中所述R12基团中碳原子的总数目不超过5;
(ie)其中R25a和R25b中的一者为H并且另一者选自:苯基,所述苯基任选用选自卤基、甲基、甲氧基的基团取代;吡啶基;以及苯硫基;以及
(if)其中R24选自:H;C1-3饱和烷基;C2-3烯基;C2-3炔基;环丙基;苯基,所述苯基任选用选自卤基、甲基、甲氧基的基团取代;吡啶基;以及苯硫基;
当C2’与C3’之间存在单键时,
R12为其中R26a和R26b独立地选自H、F、C1-4饱和烷基、C2-3烯基,所述烷基和烯基任选用选自C1-4烷基酰胺基和C1-4烷基酯的基团取代;或,当R26a和R26b中的一者为H时,另一者选自腈和C1-4烷基酯;
R6和R9独立地选自H、R、OH、OR、SH、SR、NH2、NHR、NRR’、硝基、Me3Sn以及卤基;
其中R和R'独立地选自任选取代的C1-12烷基、C3-20杂环基以及C5-20芳基;
R7选自H、R、OH、OR、SH、SR、NH2、NHR、NHRR’、硝基、Me3Sn以及卤基;
R″为C3-12亚烷基,所述链可由一个或多个杂原子间断开,例如O、S、NRN2(其中RN2为H或C1-4烷基),和/或芳族环,例如苯或吡啶;
Y和Y’选自O、S或NH;
R6’、R7’、R9’选自分别与R6、R7以及R9相同的基团;
[式I]
RL1’为用于连接至所述抗体(Ab)的接头;
R11a选自OH、ORA(其中RA为C1-4烷基)以及SOzM,其中z为2或3并且M为单价药学上可接受的阳离子;
R20和R21一起形成与它们所结合的氮与碳原子之间的双键,或;
R20选自H和RC,其中RC为封端基团;
R21选自OH、ORA以及SOzM;
当C2与C3之间存在双键时,R2选自由以下组成的组:
(ia)C5-10芳基,任选用一个或多个选自包含以下的组的取代基取代:卤基、硝基、氰基、醚、羧基、酯、C1-7烷基、C3-7杂环基以及双氧基-C1-3亚烷基;
(ib)C1-5饱和脂族烷基;
(ic)C3-6饱和环烷基;
(id)其中R11、R12以及R13中的每一者独立地选自H、C1-3饱和烷基、C2-3烯基、C2-3炔基以及环丙基,其中所述R2基团中碳原子的总数目不超过5;
(ie)其中R15a和R15b中的一者为H并且另一者选自:苯基,所述苯基任选用选自卤基、甲基、甲氧基的基团取代;吡啶基;以及苯硫基;以及
(if)其中R14选自:H;C1-3饱和烷基;C2-3烯基;C2-3炔基;环丙基;苯基,所述苯基任选用选自卤基、甲基、甲氧基的基团取代;吡啶基;以及苯硫基;
当C2与C3之间存在单键时,
R2为其中R16a和R16b独立地选自H、F、C1-4饱和烷基、C2-3烯基,所述烷基和烯基任选用选自C1-4烷基酰胺基和C1-4烷基酯的基团取代;或,当R16a和R16b中的一者为H时,另一者选自腈和C1-4烷基酯;
[式II]
R22具有式IIIa、式IIIb或式IIIc:
(a)
其中A为C5-7芳基,并且
(i)Q1为单键,并且Q2选自单键和-Z-(CH2)n-,其中Z选自单键、O、S以及NH,并且n为1至3;或
(ii)Q1为-CH=CH-,并且Q2为单键;
(b)
其中;
RC1、RC2以及RC3独立地选自H和未取代的C1-2烷基;
(c)
其中Q选自O-RL2’、S-RL2’以及NRN-RL2’,并且RN选自H、甲基以及乙基
X选自包含以下的组:O-RL2’、S-RL2’、CO2-RL2’、CO-RL2’、NH-C(=O)-RL2’、NHNH-RL2’、CONHNH-RL2’、 NRNRL2’,其中RN选自包含H和C1-4烷基的组;
RL2’为用于连接至所述抗体(Ab)的接头;
R10和R11一起形成与它们所结合的氮与碳原子之间的双键,或;
R10为H并且R11选自OH、ORA以及SOzM;
R30和R31一起形成与它们所结合的氮与碳原子之间的双键,或;
R30为H并且R31选自OH、ORA以及SOzM。
34.根据声明33所述的方法,其中所述抗CD19 ADC(或抗CD22ADC或抗CD25 ADC)具有以下化学结构:
其中Ab为结合至CD19(或CD22或CD25)的抗体,并且p介于1与8之间。
35.如任何先前声明所述的方法,其中所述抗CD19 ADC包含抗体,所述抗体具有包含VH CDR1、VH CDR2以及VH CDR3的VH结构域,其中所述抗体包含具有根据SEQ ID NO:2的序列的所述VH结构域的CDR序列。
36.如声明35所述的方法,其中所述抗体还包含VL结构域,所述VL结构域包含VLCDR1、VL CDR2以及VL CDR3,其中所述抗体包含具有根据SEQ ID NO:8的序列的所述VL结构域的CDR序列。
37.如任何先前声明所述的方法,其中所述抗CD19 ADC包含抗体,所述抗体具有含有根据SEQ ID NO:2的序列的VH结构域。
38.如声明37所述的方法,其中所述抗CD19 ADC还包含抗体,所述抗体具有含有根据SEQ ID NO:8的序列的VH结构域。
39.根据任何先前声明所述的方法,其中所述抗CD19 ADC包含具有SEQ ID NO.13的氨基酸序列的重链和/或具有SEQ ID NO.14的氨基酸序列的轻链。
40.根据任何先前声明所述的方法,其中所述抗CD19 ADC为ADCx19。
41.根据声明1至39中任一项所述的方法,其中所述抗CD19ADC为泰朗妥昔单抗。
42.一种抗CD19 ADC(或抗CD22 ADC或抗CD25 ADC),所述抗CD19 ADC用于根据任何先前声明所述的治疗方法中。
43.一种包含抗CD19 ADC(或抗CD22 ADC或抗CD25 ADC)的组合物,所述组合物用于根据任何先前声明所述的治疗方法中。
44.一种组合物,所述组合物包含抗CD19 ADC(或抗CD22 ADC或抗CD25 ADC)和抗CD79b剂。
45.根据声明42所述的供使用的抗CD19 ADC(或抗CD22 ADC或抗CD25 ADC)、根据声明43所述的供使用的组合物或根据声明44所述的组合物,其中所述抗CD19 ADC如声明33至39中任一项中所定义和/或所述抗CD79b剂如声明27至32中任一项中所定义。
46.一种抗CD79b剂,所述抗CD79b剂用于根据任何先前声明所述的治疗方法中。
47.一种包含抗CD79b剂的组合物,所述组合物用于根据任何先前声明所述的治疗方法中。
48.根据声明46所述的供使用的抗CD79b剂或根据声明42所述的供使用的组合物,其中所述抗CD79b剂为维普拉土珠单抗。
49.抗CD19 ADC(或抗CD22 ADC或抗CD25 ADC)在用于治疗个体的病症的药剂的制造中的用途,其中所述治疗包括任何先前声明所述的方法。
50.根据声明49所述的抗CD19 ADC的用途,其中所述抗CD19ADC如声明33至39中任一项中所定义。
51.抗CD79b剂在用于治疗个体的病症的药剂的制造中的用途,其中所述治疗包括如任何先前声明所述的方法。
52.根据声明51所述的抗CD79b剂的用途,其中所述抗CD79b剂为维普拉土珠单抗。
53.一种药盒,所述药盒包括:
第一药剂,所述第一药剂包含抗CD19 ADC(或抗CD22 ADC或抗CD25 ADC);
包装插页,所述包装插页包含根据如声明1至41中任一项所述的方法施用所述第一药剂的说明。
54.根据声明53所述的药盒,其中所述抗CD19 ADC如声明28至36中任一项中所定义。
55.根据声明53或54所述的药盒,所述药盒还包含:
第二药剂,所述第二药剂包含抗CD79b剂。
56.根据声明55所述的药盒,其中所述抗CD79b剂为维普拉土珠单抗。
实施例
实施例1:ADCx19和Pola-V组合的体外功效
方法
对暴露(120h)于增加的ADCx19和Pola-V浓度的细胞系的MTT增殖分析。通过Chou-Talalay组合指数(CI)(协同CI<0.9,相加CI=0.9-1.1,拮抗/无益处CI>1.1)对活化的B细胞样(ABC)DLBCL细胞系(TMD8)、生发中心(GCB)DLBCL(WSU-DLCL2)细胞系以及伯基特淋巴瘤(Ramos)细胞系在120h时的协同作用进行评估。
结果
将ADCx19与GCB-DLBCL和ABC-DLBCL细胞系以及伯基特淋巴瘤细胞系中的抗CD79b剂维普拉土珠单抗(Pola-V)组合。在组合ADCx19与Pola-V的Ramos和TMD8细胞系中实现协同作用(分别中值CI 0.74和0.764),在WSU-DLCL2情况下显示相加功效(中值CI 0.96)。
数据显示于下表中(Fa=受影响的分数)。
表1.细胞系:Ramos
RRID细胞登录标识:CVCL_0597
表2.细胞系:TMD8
RRID细胞登录标识:CVCL_A442
参考文献:Tohda等,Leuk.Res.30:1385-1390(2006)
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表3.细胞系:WSU-DLCL2
RRID细胞登录标识:CVCL_1902
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实施例2:ADCx19和Pola-V组合的体内功效
方法
在研究第1天,雌性重度联合免疫缺陷小鼠(Fox ChaseCB17/Icr-Prkdcscid/IcrIcoCrl,Charles River)为九周龄,体重(BW)范围为17.3至24.1g。
在植入当天,将1x 107个WSU-DLCL2细胞(0.1mL悬浮液)皮下植入各个测试动物右侧并且随着肿瘤的体积接近目标范围监测肿瘤。
肿瘤植入之后十天(命名为研究第1天),将动物分选至个别肿瘤体积为88至126mm3并且组平均肿瘤体积为109至111mm3的组中(n=10)。
在第1天经由尾部静脉注射一次(qd x 1)静脉内施用所有媒介物和ADC剂量。给药体积为每20克体重0.2mL(10mL/kg)并且针对各个别动物的体重按比例调整。
每周两次使用卡尺测量肿瘤,并且当其肿瘤达到1000mm3的终点体积时或研究结束时(以先到者为准),使各动物安乐死。研究在第62天结束。
使用卡尺二维地测量肿瘤,并且使用以下公式计算体积
肿瘤体积(mm3)=w2 x l/2,其中w=肿瘤的宽度并且l=长度(mm)。
肿瘤重量可用1mg等效于1mm3肿瘤体积的假设来估计。
结果
在此研究中,Pola-V为所用的CD79bxADC并且泰朗妥昔单抗为所用的CD19xADC。
图1示出了中值肿瘤体积的绘图。下表阐述了研究反应汇总,其中PR=部分反应,CR=完全反应,TFS=无肿瘤幸存者。
表4
实施例3:ADCx19和Pola-V组合的体内功效
类似于实施例2进行另一体内研究,但使用Ramos异种移植模型。
方法
在研究第1天,雌性重度联合免疫缺陷小鼠(Fox ChaseCB17/Icr-Prkdcscid/IcrIcoCrl,Charles River)为八周龄,体重(BW)范围为15.6至22.9g。
在植入当天,将1x 107个Ramos细胞(0.1mL悬浮液)皮下植入各个测试动物右侧并且随着肿瘤的体积接近目标范围监测肿瘤。在第1天经由尾部静脉注射一次(qd x 1)静脉内施用所有媒介物和ADC剂量。给药体积为每20克体重0.2mL(10mL/kg)并且针对各个别动物的体重按比例调整。
肿瘤植入之后十四天(命名为研究第1天),将动物分选至个别肿瘤体积为108至144mm3并且组平均肿瘤体积为130至134mm3的组中(n=10)。
每周两次使用卡尺测量肿瘤,并且当其肿瘤达到1000mm3的终点体积时或研究结束时(以先到者为准),使各动物安乐死。研究在第62天结束。
结果
表5
在体内,在WSU-DLCL2和Ramos异种移植模型中,CD19xADC与CD79bxADC的组合使得抗肿瘤活性改善并且反应率更佳。所述组合在两种模型中均为可接受地良好耐受的。当前在评估泰朗妥昔单抗与维普拉土珠单抗的组合在患有r/r NHL(NCT04970901)的患者中的安全性和耐受性的阶段I试验中正在研究对这些在诊所中的临床前数据的转化。
实施例4:SG3199(PBD)和MMAE组合的体外功效
我们测试了CD19xADC(PBD SG3199)与CD79bxADC(单甲基澳瑞他汀E(MMAE))中所用的单独弹头的组合。在TMD8细胞中,基本上根据实施例1进行此测试。以50,000个细胞/mL的密度接种细胞。我们使用SG3199和MMAE进行以下滴定:SG3199-7点1/4连续滴定,从230pM到0.06pM;MMAE:7点1比3连续滴定,从50nM到0.08nM。
将细胞孵育24小时,然后使用CellTiterGlo分析测量活力。
在分析结果时,首先对数据进行空白校正(将3个重复的空白平均值从各个数据值扣除)。在GraphPad分析中,相较于未处理的细胞对各个重复进行归范化(3个重复的平均值)。通过GraphPad Prism分析数据,以产生剂量反应曲线,X轴上为对数药物浓度并且Y轴上为细胞活力(%)。在CalcuSyn分析中,相较于未处理的细胞对3个重复的平均值进行校正。
中值Chou-Talalay组合指数(CI)为0.85(<0.9指示协同作用)。
表6
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实施例5:ADCx25和Pola-V组合的体外功效
方法
对要暴露(120h)于增加的ADCx25和Pola-V浓度的细胞系的MTT增殖分析。将通过Chou-Talalay组合指数(CI)(协同CI<0.9,相加CI=0.9-1.1,拮抗/无益处CI>1.1)评估在120h时的协同作用。
实施例6:ADCx25和Pola-V组合的体内功效
方法
在研究第1天,雌性重度联合免疫缺陷小鼠(Fox ChaseCB17/Icr-Prkdcscid/IcrIcoCrl,Charles River)将为九周龄,体重(BW)范围为17.3至24.1g。
研究将根据实施例2和3进一步进行。
实施例7:ADCx22和Pola-V组合的体外功效
方法
对要暴露(120h)于增加的ADCx22和Pola-V浓度的细胞系的MTT增殖分析。将通过Chou-Talalay组合指数(CI)(协同CI<0.9,相加CI=0.9-1.1,拮抗/无益处CI>1.1)对生发中心(GCB)DLBCL(WSU-DLCL2)细胞系和伯基特淋巴瘤(Ramos)细胞系在120h时的协同作用进行评估。
实施例8:ADCx22和Pola-V组合的体内功效
方法
将向雌性重度联合免疫缺陷小鼠(Fox Chase CB17/Icr-Prkdcscid/IcrIcoCrl,Charles River)的各个测试动物右侧皮下植入WSU-DLCL2或Ramos细胞并且将随着肿瘤的体积接近目标范围监测肿瘤。
研究将根据实施例2和3进一步进行。
********
以上引用了许多出版物以更全面地描述和公开本公开以及本文的发明可属的现有技术水平。本公开中提到的参考文献中的每一者的全文以引用的方式并入本文中。
本发明的序列表部分
SEQ ID NO.1(RB4v1.0 VH):
QVQLVQPGAEVVKPGASVKLSCKTSGYTFTSNWMHWVKQRPGQGLEWIGEIDPSDSYTNYNQNFKGKAKLTVDKSTSTAYMEVSSLRSDDTAVYYCARGSNPYYYAMDYWGQGTSVTVS
SEQ ID NO.2(RB4v1.2 VH):
QVQLVQPGAEVVKPGASVKLSCKTSGYTFTSNWMHWVKQAPGQGLEWIGEIDPSDSYTNYNQNFQGKAKLTVDKSTSTAYMEVSSLRSDDTAVYYCARGSNPYYYAMDYWGQGTSVTVS
SEQ ID NO.3(B43 VH):
QVQLLESGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIWPGDGDTNYNGKFKGKATLTADESSSTAYMQLSSLRSEDSAVYSCARRETTTVGRYYYAMDYWGQGTTVT
SEQ ID NO.4(HD37 VH):
QVQLQQSGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIWPGDGDTNYNGKFKGKATLTADESSSTAYMQLSSLASEDSAVYFCARRETTTVGRYYYAMDYWGQGTSVTVS
SEQ ID NO.5(4G7 VH):
EVQLQQSGPELIKPGASVKMSCKASGYTFTSYVMHWVKQKPGQGLEWIGYINPYNDGTKYNEKFKGKATLTSDKSSSTAYMELSSLTSEDSAVYYCARGTYYYGSRVFDYWGQGTTLTVS
SEQ ID NO.6(FMC63 VH):
EVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVS
SEQ ID NO.7(RB4v1.0 VK):
EIVLTQSPAIMSASPGERVTMTCSASSGVNYMHWYQQKPGTSPRRWIYDTSKLASGVPARFSGSGSGTSYSLTISSMEPEDAATYYCHQRGSYTFGGGTKLEIK
SEQ ID NO.8(RB4v1.2 VK):
EIVLTQSPAIMSASPGERVTMTCSASSGVNYMHWYQQKPGTSPRRWIYDTSKLASGVPARFSGSGSGTSYSLTISSMEPEDAATYYCHQRGSYTFGGGTKLEIK
SEQ ID NO.9(B43 VK):
ELVLTQSPASLAVSLGQRATISCKASQSVDYDGDSYLNWYQQIPGQPPKLLIYDASNLVSGIPPRFSGSGSGTDFTLNIHPVEKVDAATYHCQQSTEDPWTFGGGTKLEIK
SEQ ID NO.10(HD37 VK):
DILLTQTPASLAVSLGQRATISCKASQSVDYDGDSYLNWYQQIPGQPPKLLIYDASNLVSGIPPRFSGSGSGTDFTLNIHPVEKVDAATYHCQQSTEDPWTFGGGTKLEIK
SEQ ID NO.11(4G7 VK):
DIVMTQAAPSIPVTPGESVSISCRSSKSLLNSNGNTYLYWFLQRPGQSPQLLIYRMSNLASGVPDRFSGSGSGTAFTLRISRVEAEDVGVYYCMQHLEYPFTFGAGTKLELK
SEQ ID NO.12(FMC63 VK):
DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEIT
SEQ ID NO.13(RB4v1.2-HC):
QVQLVQPGAEVVKPGASVKLSCKTSGYTFTSNWMHWVKQAPGQGLEWIGEIDPSDSYTNYNQNFQGKAKLTVDKSTSTAYMEVSSLRSDDTAVYYCARGSNPYYYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
SEQ ID NO.14(RB4v1.2-LC):
EIVLTQSPAIMSASPGERVTMTCSASSGVNYMHWYQQKPGTSPRRWIYDTSKLASGVPARFSGSGSGTSYSLTISSMEPEDAATYYCHQRGSYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO.15(evi-5 POLA.VH-h1.HC):
EVQLVESGGGLVQPGGSLRLSCAASGYTFSSYWIEWVRQAPGKGLEWIGEILPGGGDTNYNEIFKGRATFSADTSKNTAYLQMNSLRAEDTAVYYCTRRVPIRLDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO.16(evi-5 POLA.VL-hk.LC):
DIQLTQSPSSLSASVGDRVTITCKASQSVDYEGDSFLNWYQQKPGKAPKLLIYAASNLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSNEDPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF
SEQ ID NO.17(evi-5 POLA.VH):
EVQLVESGGGLVQPGGSLRLSCAASGYTFSSYWIEWVRQAPGKGLEWIGEILPGGGDTNYNEIFKGRATFSADTSKNTAYLQMNSLRAEDTAVYYCTRRVPIRLDYWGQGTLVTVSS
SEQ ID NO.18(evi-5 POLA.VL):
DIQLTQSPSSLSASVGDRVTITCKASQSVDYEGDSFLNWYQQKPGKAPKLLIYAASNLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSNEDPLTFGQGTKVEIK
SEQ ID NO.19(evi-5 POLA.VH.CDR1):
SYWIE
SEQ ID NO.20(evi-5 POLA.VH.CDR2):
EILPGGGDTNYNEIFKG
SEQ ID NO.21 (evi-5 POLA.VH.CDR3):
RVPIRLDY
SEQ ID NO.22(evi-5 POLA.VL.CDR1):
KASQSVDYEGDSFLN
SEQ ID NO.23(evi-5 POLA.VL.CDR2):
AASNLES
SEQ ID NO.24(evi-5 POLA.VL.CDR3):
QQSNEDPLT
SEQ ID NO.25 (AB12 VH):
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSRYIINWVRQAPGQGLEWMGRIIPILGVENYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARKDWFDYWGQGTLVTVSSASTKGPSVFPLA
SEQ ID NO.26(AB12 VL):
EIVLTQSPGTLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPLTFGGGTKVEIKRTVAAPSVFIFP
SEQ ID NO.27(VH CDR1):
RYIIN
SEQ ID NO.28(VH CDR2):
RIIPILGVENYAQKFQG
SEQ ID NO.29(VH CDR3):
KDWFDY
SEQ ID NO.30(VL CDR1):
RASQSVSSYLA
SEQ ID NO.31(VL CDR2):
GASSRAT
SEQ ID NO.32(VL CDR3):
QQYGSSPLT
SEQ ID NO. 33(依帕珠单抗VH):
QVQLVQSGAEVKKPGSSVKVSCKASGYTFTSYWLHWVRQAPGQGLEWIGYINPRNDYTEYNQNFKDKATITADESTNTAYMELSSLRSEDTAFYFCARRDITTFYWGQG
SEQ ID NO.34(依帕珠单抗VL):
DIQLTQSPSSLSASVGDRVTMSCKSSQSVLYSANHKNYLAWYQQKPGKAPKLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCHQYLSSWTFGQG
SEQ ID NO.35(依帕珠单抗.VH.CDR1):
YTFTSYWLH
SEQ ID NO.36(依帕珠单抗.VH.CDR2):
WIGYINPRNDYTEY
SEQ ID NO.37(依帕珠单抗.VH.CDR3):
RRDITTFY
SEQ ID NO.38(依帕珠单抗.VL.CDR1):
QSVLYSANHKNYLA
SEQ ID NO.39(依帕珠单抗.VL.CDR2):
LLIYWASTRES
SEQ ID NO.40(依帕珠单抗.VL.CDR3):
HQYLSSW
SEQ ID NO.41(EMabC220-HC):
QVQLVQSGAEVKKPGSSVKVSCKASGYTFTSYWLHWVRQAPGQGLEWIGYINPRNDYTEYNQNFKDKATITADESTNTAYMELSSLRSEDTAFYFCARRDITTFYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTVPPVPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
SEQ ID NO.42(EMabC220-LC):
DIQLTQSPSSLSASVGDRVTMSCKSSQSVLYSANHKNYLAWYQQKPGKAPKLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCHQYLSSWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGES
SEQ ID NO.43(IgG1 HC恒定区)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
SEQ ID NO.44(IgG1 HC恒定区,BJ C→V)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTVPPVPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
SEQ ID NO.45(κLC恒定区)
VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO.46(κLC恒定区,C105S)
VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGES
SEQ ID NO.47(λLC恒定区)
KAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS
SEQ ID NO.48(λLC恒定区,C102S)
KAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTESS
序列表
<110> ADC治疗有限公司(ADC Therapeutics S.A.)
免疫医疗有限公司(MedImmune Limited)
<120> 使用抗体药物缀合物的组合疗法
<130> PAT142-WO
<150> GB2109373.7
<151> 2021-06-29
<150> GB2109375.2
<151> 2021-06-29
<150> GB2109377.8
<151> 2021-06-29
<160> 48
<170> PatentIn version 3.5
<210> 1
<211> 119
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 1
Gln Val Gln Leu Val Gln Pro Gly Ala Glu Val Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Ser Asn
20 25 30
Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp Pro Ser Asp Ser Tyr Thr Asn Tyr Asn Gln Asn Phe
50 55 60
Lys Gly Lys Ala Lys Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Val Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ser Asn Pro Tyr Tyr Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser
115
<210> 2
<211> 119
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 2
Gln Val Gln Leu Val Gln Pro Gly Ala Glu Val Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Ser Asn
20 25 30
Trp Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp Pro Ser Asp Ser Tyr Thr Asn Tyr Asn Gln Asn Phe
50 55 60
Gln Gly Lys Ala Lys Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Val Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ser Asn Pro Tyr Tyr Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser
115
<210> 3
<211> 121
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 3
Gln Val Gln Leu Leu Glu Ser Gly Ala Glu Leu Val Arg Pro Gly Ser
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Gln Ile Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Arg Ser Glu Asp Ser Ala Val Tyr Ser Cys
85 90 95
Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Thr Val Thr
115 120
<210> 4
<211> 123
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 4
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Gln Ile Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser
115 120
<210> 5
<211> 120
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 5
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Ile Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Thr Tyr Tyr Tyr Gly Ser Arg Val Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Leu Thr Val Ser
115 120
<210> 6
<211> 119
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 6
Glu Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr
20 25 30
Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys
50 55 60
Ser Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser
115
<210> 7
<211> 104
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 7
Glu Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Arg Val Thr Met Thr Cys Ser Ala Ser Ser Gly Val Asn Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Thr Ser Pro Arg Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Pro Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys His Gln Arg Gly Ser Tyr Thr Phe Gly
85 90 95
Gly Gly Thr Lys Leu Glu Ile Lys
100
<210> 8
<211> 104
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 8
Glu Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Arg Val Thr Met Thr Cys Ser Ala Ser Ser Gly Val Asn Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Thr Ser Pro Arg Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Pro Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys His Gln Arg Gly Ser Tyr Thr Phe Gly
85 90 95
Gly Gly Thr Lys Leu Glu Ile Lys
100
<210> 9
<211> 111
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 9
Glu Leu Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Lys Ala Ser Gln Ser Val Asp Tyr Asp
20 25 30
Gly Asp Ser Tyr Leu Asn Trp Tyr Gln Gln Ile Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Asp Ala Ser Asn Leu Val Ser Gly Ile Pro Pro
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His
65 70 75 80
Pro Val Glu Lys Val Asp Ala Ala Thr Tyr His Cys Gln Gln Ser Thr
85 90 95
Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 10
<211> 111
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 10
Asp Ile Leu Leu Thr Gln Thr Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Lys Ala Ser Gln Ser Val Asp Tyr Asp
20 25 30
Gly Asp Ser Tyr Leu Asn Trp Tyr Gln Gln Ile Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Asp Ala Ser Asn Leu Val Ser Gly Ile Pro Pro
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His
65 70 75 80
Pro Val Glu Lys Val Asp Ala Ala Thr Tyr His Cys Gln Gln Ser Thr
85 90 95
Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 11
<211> 112
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 11
Asp Ile Val Met Thr Gln Ala Ala Pro Ser Ile Pro Val Thr Pro Gly
1 5 10 15
Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu Asn Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His
85 90 95
Leu Glu Tyr Pro Phe Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105 110
<210> 12
<211> 107
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 12
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr
100 105
<210> 13
<211> 449
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人源化小家鼠
<400> 13
Gln Val Gln Leu Val Gln Pro Gly Ala Glu Val Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Ser Asn
20 25 30
Trp Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp Pro Ser Asp Ser Tyr Thr Asn Tyr Asn Gln Asn Phe
50 55 60
Gln Gly Lys Ala Lys Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Val Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ser Asn Pro Tyr Tyr Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly
<210> 14
<211> 211
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人源化小家鼠
<400> 14
Glu Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Arg Val Thr Met Thr Cys Ser Ala Ser Ser Gly Val Asn Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Thr Ser Pro Arg Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Pro Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys His Gln Arg Gly Ser Tyr Thr Phe Gly
85 90 95
Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val
100 105 110
Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser
115 120 125
Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln
130 135 140
Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val
145 150 155 160
Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu
165 170 175
Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu
180 185 190
Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg
195 200 205
Gly Glu Cys
210
<210> 15
<211> 447
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 15
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Ser Ser Tyr
20 25 30
Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Leu Pro Gly Gly Gly Asp Thr Asn Tyr Asn Glu Ile Phe
50 55 60
Lys Gly Arg Ala Thr Phe Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Arg Val Pro Ile Arg Leu Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 16
<211> 213
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 16
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Asp Tyr Glu
20 25 30
Gly Asp Ser Phe Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe
210
<210> 17
<211> 117
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 17
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Ser Ser Tyr
20 25 30
Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Leu Pro Gly Gly Gly Asp Thr Asn Tyr Asn Glu Ile Phe
50 55 60
Lys Gly Arg Ala Thr Phe Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Arg Val Pro Ile Arg Leu Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 18
<211> 111
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 18
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Asp Tyr Glu
20 25 30
Gly Asp Ser Phe Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 19
<211> 5
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 19
Ser Tyr Trp Ile Glu
1 5
<210> 20
<211> 17
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 20
Glu Ile Leu Pro Gly Gly Gly Asp Thr Asn Tyr Asn Glu Ile Phe Lys
1 5 10 15
Gly
<210> 21
<211> 8
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 21
Arg Val Pro Ile Arg Leu Asp Tyr
1 5
<210> 22
<211> 15
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 22
Lys Ala Ser Gln Ser Val Asp Tyr Glu Gly Asp Ser Phe Leu Asn
1 5 10 15
<210> 23
<211> 7
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 23
Ala Ala Ser Asn Leu Glu Ser
1 5
<210> 24
<211> 9
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 24
Gln Gln Ser Asn Glu Asp Pro Leu Thr
1 5
<210> 25
<211> 127
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 25
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Arg Tyr
20 25 30
Ile Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Ile Pro Ile Leu Gly Val Glu Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Lys Asp Trp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
<210> 26
<211> 119
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 26
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro
115
<210> 27
<211> 5
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 27
Arg Tyr Ile Ile Asn
1 5
<210> 28
<211> 17
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 28
Arg Ile Ile Pro Ile Leu Gly Val Glu Asn Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 29
<211> 6
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 29
Lys Asp Trp Phe Asp Tyr
1 5
<210> 30
<211> 11
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 30
Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala
1 5 10
<210> 31
<211> 7
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 31
Gly Ala Ser Ser Arg Ala Thr
1 5
<210> 32
<211> 9
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 32
Gln Gln Tyr Gly Ser Ser Pro Leu Thr
1 5
<210> 33
<211> 109
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 33
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Leu His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Arg Asn Asp Tyr Thr Glu Tyr Asn Gln Asn Phe
50 55 60
Lys Asp Lys Ala Thr Ile Thr Ala Asp Glu Ser Thr Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Phe Tyr Phe Cys
85 90 95
Ala Arg Arg Asp Ile Thr Thr Phe Tyr Trp Gly Gln Gly
100 105
<210> 34
<211> 106
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 34
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Met Ser Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ala Asn His Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys
35 40 45
Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr
65 70 75 80
Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys His Gln
85 90 95
Tyr Leu Ser Ser Trp Thr Phe Gly Gln Gly
100 105
<210> 35
<211> 9
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 35
Tyr Thr Phe Thr Ser Tyr Trp Leu His
1 5
<210> 36
<211> 14
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 36
Trp Ile Gly Tyr Ile Asn Pro Arg Asn Asp Tyr Thr Glu Tyr
1 5 10
<210> 37
<211> 8
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 37
Arg Arg Asp Ile Thr Thr Phe Tyr
1 5
<210> 38
<211> 14
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 38
Gln Ser Val Leu Tyr Ser Ala Asn His Lys Asn Tyr Leu Ala
1 5 10
<210> 39
<211> 11
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 39
Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser
1 5 10
<210> 40
<211> 7
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 40
His Gln Tyr Leu Ser Ser Trp
1 5
<210> 41
<211> 445
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 41
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Leu His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Arg Asn Asp Tyr Thr Glu Tyr Asn Gln Asn Phe
50 55 60
Lys Asp Lys Ala Thr Ile Thr Ala Asp Glu Ser Thr Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Phe Tyr Phe Cys
85 90 95
Ala Arg Arg Asp Ile Thr Thr Phe Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
210 215 220
Val Pro Pro Val Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
260 265 270
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 42
<211> 219
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 42
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Met Ser Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ala Asn His Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys
35 40 45
Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr
65 70 75 80
Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys His Gln
85 90 95
Tyr Leu Ser Ser Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Ser
210 215
<210> 43
<211> 329
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 43
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly
325
<210> 44
<211> 329
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 44
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Val Pro Pro Val
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly
325
<210> 45
<211> 105
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 45
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
1 5 10 15
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
20 25 30
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
35 40 45
Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr
50 55 60
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
65 70 75 80
Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val
85 90 95
Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 46
<211> 105
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 46
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
1 5 10 15
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
20 25 30
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
35 40 45
Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr
50 55 60
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
65 70 75 80
Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val
85 90 95
Thr Lys Ser Phe Asn Arg Gly Glu Ser
100 105
<210> 47
<211> 103
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 47
Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu
1 5 10 15
Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro
20 25 30
Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala
35 40 45
Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala
50 55 60
Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg
65 70 75 80
Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr
85 90 95
Val Ala Pro Thr Glu Cys Ser
100
<210> 48
<211> 103
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 48
Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu
1 5 10 15
Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro
20 25 30
Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala
35 40 45
Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala
50 55 60
Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg
65 70 75 80
Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr
85 90 95
Val Ala Pro Thr Glu Ser Ser
100
Claims (24)
1.一种包含抗CD19抗体和吡咯并苯并二氮杂卓二聚体的抗体药物缀合物(ADC),所述抗体药物缀合物用于治疗个体的病症的方法中,所述方法包括向所述个体施用有效量的所述ADC和维普拉土珠单抗。
2.根据权利要求1所述的供使用的包含抗CD19抗体和吡咯并苯并二氮杂卓二聚体的抗体药物缀合物(ADC),其中选择所述个体用于治疗。
3.根据权利要求2所述的供使用的包含抗CD19抗体和吡咯并苯并二氮杂卓二聚体的抗体药物缀合物(ADC),其中如果所述个体已用维普拉土珠单抗治疗,那么选择所述个体用于用所述ADC治疗。
4.根据权利要求2所述的供使用的包含抗CD19抗体和吡咯并苯并二氮杂卓二聚体的抗体药物缀合物(ADC),其中如果所述个体正在用维普拉土珠单抗治疗,那么选择所述个体用于用所述ADC治疗。
5.根据前述权利要求中任一项所述的供使用的包含抗CD19抗体和吡咯并苯并二氮杂卓二聚体的抗体药物缀合物(ADC),其中如果所述个体用维普拉土珠单抗治疗或进一步治疗为难以治疗的,那么选择所述个体用于治疗。
6.一种包含抗CD19抗体和吡咯并苯并二氮杂卓二聚体的抗体药物缀合物(ADC),所述抗体药物缀合物用于治疗个体的病症的方法中,所述方法包括:
(i)选择适合通过根据权利要求3至5中任一项所述的方法治疗的个体;以及
(ii)向所述个体施用有效量的所述ADC。
7.根据权利要求6所述的供使用的包含抗CD19抗体和吡咯并苯并二氮杂卓二聚体的抗体药物缀合物(ADC),所述使用还包括施用维普拉土珠单抗与所述ADC的组合。
8.根据权利要求1至5或7中任一项所述的供使用的包含抗CD19抗体和吡咯并苯并二氮杂卓二聚体的抗体药物缀合物(ADC),其中所述治疗包括在所述维普拉土珠单抗之前、与所述维普拉土珠单抗同时或在所述维普拉土珠单抗之后施用所述ADC。
9.根据前述权利要求中任一项所述的供使用的包含抗CD19抗体和吡咯并苯并二氮杂卓二聚体的抗体药物缀合物(ADC),其中所述治疗还包括施用化学治疗剂。
10.根据任何前述权利要求所述的供使用的包含抗CD19抗体和吡咯并苯并二氮杂卓二聚体的抗体药物缀合物(ADC),其中所述个体为人。
11.根据前述权利要求中任一项所述的供使用的包含抗CD19抗体和吡咯并苯并二氮杂卓二聚体的抗体药物缀合物(ADC),其中所述个体患有病症或已被确定患有病症。
12.根据权利要求11所述的供使用的包含抗CD19抗体和吡咯并苯并二氮杂卓二聚体的抗体药物缀合物(ADC),其中所述个体患有或已被确定患有表达CD19或CD19+ve肿瘤相关非肿瘤细胞,诸如CD19+ve浸润细胞的癌症。
13.根据任何前述权利要求所述的供使用的包含抗CD19抗体和吡咯并苯并二氮杂卓二聚体的抗体药物缀合物(ADC),其中所述个体正在经历用维普拉土珠单抗治疗。
14.根据任何前述权利要求所述的供使用的包含抗CD19抗体和吡咯并苯并二氮杂卓二聚体的抗体药物缀合物(ADC),其中所述个体经历过用维普拉土珠单抗治疗。
15.根据任何前述权利要求所述的供使用的包含抗CD19抗体和吡咯并苯并二氮杂卓二聚体的抗体药物缀合物(ADC),其中所述个体用维普拉土珠单抗治疗或进一步治疗为难以治疗的。
16.根据前述权利要求中任一项所述的供使用的包含抗CD19抗体和吡咯并苯并二氮杂卓二聚体的抗体药物缀合物(ADC),其中与单独使用所述ADC或维普拉土珠单抗的单一疗法相比,所述治疗具有增加的功效。
17.根据任何前述权利要求所述的供使用的包含抗CD19抗体和吡咯并苯并二氮杂卓二聚体的抗体药物缀合物(ADC),其中所述病症为增殖性疾病。
18.根据权利要求17所述的供使用的包含抗CD19抗体和吡咯并苯并二氮杂卓二聚体的抗体药物缀合物(ADC),其中所述病症的特征为存在包含CD19+ve细胞的赘瘤。
19.根据前述权利要求中任一项所述的供使用的包含抗CD19抗体和吡咯并苯并二氮杂卓二聚体的抗体药物缀合物(ADC),其中所述病症为癌症。
20.根据前述权利要求中任一项所述的供使用的包含抗CD19抗体和吡咯并苯并二氮杂卓二聚体的抗体药物缀合物(ADC),其中所述病症选自包含以下的组:非霍奇金氏淋巴瘤,包括弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、伯基特淋巴瘤、套细胞淋巴瘤(MCL)、慢性淋巴性淋巴瘤(CLL)、华登斯特罗姆巨球蛋白血症(WM)以及边缘区B细胞淋巴瘤(MZBL);以及白血病,诸如毛细胞白血病(HCL)、变异型毛细胞白血病(HCL-v)、慢性淋巴细胞性白血病(CLL)(包括里希特综合征)以及急性成淋巴细胞性白血病(ALL),诸如费城染色体阳性ALL(Ph+ALL)或费城染色体阴性ALL(Ph-ALL)。
21.根据前述权利要求中任一项所述的供使用的包含抗CD19抗体和吡咯并苯并二氮杂卓二聚体的抗体药物缀合物(ADC),其中所述抗体包含SEQ ID NO:2和8的CDR。
22.根据前述权利要求中任一项所述的供使用的包含抗CD19抗体和吡咯并苯并二氮杂卓二聚体(PBD)的抗体药物缀合物(ADC),其中所述PBD具有式(III):
其中RLL为用于连接至所述抗体的接头。
23.根据前述权利要求中任一项所述的供使用的包含抗CD19抗体和吡咯并苯并二氮杂卓二聚体的抗体药物缀合物(ADC),其中所述ADC具有以下结构:
其中Ab为所述抗CD19抗体。
24.一种组合物,所述组合物包含(i)包含抗CD19抗体和吡咯并苯并二氮杂卓二聚体(PBD)的抗体药物缀合物(ADC),任选其中所述PBD如权利要求22中所定义,任选其中所述抗CD19抗体包含SEQ ID NO:2和8的CDR;以及(ii)维普拉土珠单抗。
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GBGB2109377.8A GB202109377D0 (en) | 2021-06-29 | 2021-06-29 | Combination therapy |
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