CN113906049A - 用于共施用针对c-kit和CD47的免疫治疗剂的方案 - Google Patents
用于共施用针对c-kit和CD47的免疫治疗剂的方案 Download PDFInfo
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Abstract
本发明提供了用于消融内源性HSPC的特异性结合c‑kit或抑制CD47‑SIRPa的免疫治疗剂的共施用方案。相对低水平的抗c‑kit导致与HSPC上的c‑kit的结合饱和,而不会显著降低HSPC的水平。当通过抑制CD47‑SIRPa的免疫治疗剂促进抗c‑kit的作用时,可以获得HSPC水平的显著降低。因此,可以使表达c‑kit的HSPC降低至可接受的水平,以允许引入替代HSPC而不会存在其间受试者的HSPC不足的有害延迟。
Description
相关申请的交叉引用
本申请要求2019年5月24日提交的US62/852,901的权益,其全文以引用方式并入用于所有目的。
序列表
本申请包括在txt文件2020-05-28 547773WO SL中公开的序列,该txt文件为37k字节,命名创建于2002年5月18日,以引用方式并入。
背景技术
干细胞为生物体提供了通过增殖产生分化细胞来维持和修复某些组织的手段。造血干细胞移植已用于为患者提供产生血细胞的能力,通常在患者已通过化学疗法或其他调理方案消融内源性造血干细胞的情况下。
造血细胞移植一般涉及静脉输注自体或同种异体成血细胞,包括造血干细胞。这些细胞从骨髓、外周血或脐带血中收集并移植以在骨髓或免疫系统受损或缺陷的患者中重建造血功能。该过程通常作为治疗的一部分进行,以消除骨髓浸润过程(诸如白血病)或纠正先天性免疫缺陷障碍。造血细胞移植也用于允许癌症患者接受比骨髓通常可耐受的更高剂量的化学疗法;然后通过用先前收获的干细胞替代骨髓来挽救骨髓功能(一般参见WO2004/002425和WO2018/140940)。
发明内容
本发明提供了在有相关需要的患者体内消融造血干细胞和祖细胞(HSPC)的方法,该方法包括向患者施用0.15-2mg/kg的特异性结合c-kit的免疫治疗剂和有效方案的特异性结合CD47或SIRPα的免疫治疗剂,其中HSPC在患者体内被消融。
任选地,向患者施用单次剂量的0.15-1mg/kg的特异性结合c-kit的免疫治疗剂。任选地,在长达七天的时间段内以多次剂量向患者施用特异性结合c-kit的免疫治疗剂,所述多次剂量产生与单次剂量的0.15-1mg/kg基本上相同的曲线下面积。任选地,向患者施用间隔3-7天的两次剂量的0.15-1mg/kg的特异性结合c-kit的免疫治疗剂。任选地,有效方案的特异性结合CD47的免疫治疗剂包括第一剂量和高于第一剂量的第二剂量。任选地,第一剂量为1mg/kg,并且第二剂量为10-30mg/kg,优选15-20mg/kg。任选地,特异性结合c-kit的免疫治疗剂与第二剂量的特异性结合CD47的免疫治疗剂同时作为单次剂量施用。任选地,单次剂量的特异性结合c-kit的免疫治疗剂和第二剂量的特异性结合CD47的免疫治疗剂通过共输注施用。任选地,在第一剂量的特异性结合CD47的免疫治疗剂之后3-15天、任选7天施用第二剂量的特异性结合CD47的免疫治疗剂和单次剂量的特异性结合c-kit的免疫治疗剂。任选地,在10-30天的时间段内以至少三次剂量施用特异性结合c-kit的免疫治疗剂。任选地,任选地以低于其他剂量并在其他剂量之前的附加剂量,在施用每次剂量的特异性结合c-kit的免疫治疗剂的同一天施用特异性结合CD47或SIRPα的免疫治疗剂。
任选地,该方法还包括将HSPC引入患者体内。任选地,在施用单次剂量的特异性结合c-kit的免疫治疗剂和第二剂量的特异性结合CD47的免疫治疗剂之后5-15天将HSPC引入患者体内。
任选地,在引入HSPC之前仅施用第一剂量和第二剂量的特异性结合CD47的免疫治疗剂以及单次剂量的特异性结合c-kit的免疫治疗剂。任选地,该方法还包括在第二剂量之后施用第三剂量的特异性结合CD47的免疫治疗剂,任选地第二剂量和第三剂量是相同量的免疫治疗剂。任选地,施用多次剂量的特异性结合c-kit的免疫治疗剂,并且施用多次剂量的特异性结合CD47或SIRPα的免疫治疗剂,并且在最后一次剂量的特异性结合c-kit的免疫治疗剂或特异性结合CD47或SIRPα的免疫治疗剂之后5-15天将HSPC引入患者体内,以较晚者为准。任选地,在同一天施用最后一次剂量的特异性结合c-kit的免疫治疗剂和最后一次剂量的特异性结合SIRPα的免疫治疗剂。
任选地,特异性结合CD47的免疫治疗剂是特异性结合CD47的抗体。任选地,特异性结合CD47的免疫治疗剂是人源化5F9,任选莫洛利单抗(magrolimab)。
任选地,施用有效方案的特异性结合SIRPα的免疫治疗剂。任选地,特异性结合SIRPα的免疫治疗剂是抗体。任选地,抗体包含具有包含SEQ ID NO:29的序列的重链可变区和具有包含SEQ ID NO:30的序列的轻链可变区。任选地,特异性结合SIRPα的抗体是FSI-189、ES-004、BI765063、ADU1805和CC-95251中的任一种。任选地,以10-30mg/kg的剂量施用特异性结合SIRPα的抗体。任选地,施用单次剂量的特异性结合SIRPα的抗体。任选地,施用多次剂量的特异性结合SIRPα的抗体。
任选地,特异性结合c-kit的免疫治疗剂是抗体。任选地,抗体是人IgG1同种型的人源化形式的SR1。任选地,抗体包含具有包含SEQ ID NO:7-9中任一个的序列的重链可变区和具有包含SEQ ID NO:10的序列的轻链可变区。任选地,重链可变区具有包含SEQ IDNO:7的序列。
任选地,免疫治疗剂的施用将c-kit阳性HSPC消融施用前水平的25-95%。任选地,免疫治疗剂的施用将c-kit阳性HSPC消融施用前水平的25-75%。
任选地,患者患有通过HSPC的消融来治疗的血液学癌症。任选地,还向患者施用有效治疗血液学癌症的药剂。任选地,在HSPC的消融之前或期间向患者施用药剂。任选地,药剂是化学治疗剂、抗血管生成剂、抗纤维化剂或针对癌症抗原的单克隆抗体。任选地,血液学癌症是淋巴瘤、白血病或骨髓瘤。任选地,患者患有实体瘤,并且在消融患者体内的HSPC之前,向患者施用有效治疗实体瘤并且损害患者的HSPC的药剂。任选地,药剂是化学治疗剂。任选地,在消融HSPC之后向患者施用CAR-T细胞。任选地,在HSPC的消融之后施用flt3激动剂或CISH抑制剂,以促进HSPC生长或细胞疗法。任选地,将MCL1抑制剂与特异性结合c-kit的免疫治疗剂和特异性结合CD47或SIRPα的免疫治疗剂共施用以消融NK细胞。
在任何上述方法中,患者可以是人。
本发明还提供了特异性结合c-kit的免疫治疗剂在制造用于消融造血干细胞和祖细胞(HSPC)的药物中的用途,其中该免疫治疗剂以0.15-2mg/kg的剂量与有效方案的特异性结合CD47或SIRPα的免疫治疗剂组合施用。本发明还提供了特异性结合CD47或SIRPα的免疫治疗剂在制造用于与剂量为0.15-2mg/kg的特异性结合c-kit的免疫治疗剂组合消融造血干细胞和祖细胞(HSPC)的药物中的用途。这些用途中的任一个可以与上文或本文所述的任何方法一致。
附图说明
图1A、B示出了在灵长类动物中施用(A)抗c-kit和(B)抗c-kit和抗CD47的治疗时间线。
图2示出了抗c-kit的血清浓度随时间的变化。
图3示出了不同剂量的抗c-kit的c-kit受体占有率。
图4示出了抗c-kit和抗CD47受体占有率随时间的变化。
图5A、B示出了c-kit阳性HSC相对于用(A)抗c-kit以及(B)抗c-kit和抗CD47治疗的基线的%变化。
图6A、B示出了用抗c-kit和抗CD47组合治疗时(A)外周血白细胞或(B)中性粒细胞随时间的变化。
图7A、B示出了组合抗c-kit抗CD47治疗相对于阴性对照随时间的(A)血红蛋白和(B)红血细胞水平。
图8示出了用多给药方案的抗c-kit和抗CD47两者消融HSC。
图9示出了通过抗c-kit和抗SIRPα消融HSPC。
定义
受试者或患者包括通过所公开的方法治疗的人类和其他动物,特别是哺乳动物,包括宠物和实验室动物,例如小鼠、大鼠、兔和非人类灵长类动物。因此,这些方法适用于人类治疗和兽医应用两者。
免疫治疗剂是指针对指定靶标的抗体或Fc融合蛋白。例如,针对CD47和SIRPα-Fc融合体的抗体是针对CD47的免疫治疗剂。
免疫治疗剂通常以分离的形式提供。这意味着这种药剂的纯度通常为至少50重量%的由其生产或纯化产生的干扰蛋白质和其他污染物,但不排除药剂与过量的药学上可接受的载体或旨在促进其使用的其他媒介物组合的可能性。有时药剂的纯度为至少60重量%、70重量%、80重量%、90重量%、95重量%或99重量%的来自生产或纯化的干扰蛋白质和污染物。通常,药剂是在其纯化之后剩余的主要大分子物质。
免疫治疗剂与其靶抗原的特异性结合意指亲和力为至少106、107、108、109或1010M-1。特异性结合在量值上可检测地更高并且可与发生在至少一个不相关靶标上的非特异性结合区分开。特异性结合可以是特定官能团之间形成键合或特定空间匹配(例如,锁和钥匙类型)的结果,而非特异性结合通常是范德华力的结果。
基本的抗体结构单元是亚基的四聚体。每个四聚体包括两对相同的多肽链,每对具有一条“轻”链(约25kDa)和一条“重”链(约50kDa-70kDa)。每条链的氨基末端部分包括约100至110或更多个氨基酸的可变区,其主要负责抗原识别。该可变区最初表达为与可切割信号肽连接。没有信号肽的可变区有时被称为成熟可变区。因此,例如,轻链成熟可变区意指没有轻链信号肽的轻链可变区。然而,提及可变区并不意味着必然存在信号序列;并且事实上,一旦已表达和分泌本发明的抗体或其他免疫治疗剂,信号序列就被切割。一对重链可变区和轻链可变区限定抗体的结合区。轻链和重链的羧基末端部分分别限定轻链恒定区和重链恒定区。重链恒定区主要负责效应子功能。在IgG抗体中,重链恒定区被分成CH1、铰链、CH2和CH3区。在IgA中,重链恒定区被分成CH1、CH2和CH3。CH1区通过二硫键和非共价键与轻链恒定区结合。铰链区提供抗体的结合区和效应子区之间的柔性,并且还提供四聚体亚基中两个重链恒定区之间的分子间二硫键合的位点。CH2和CH3区是效应子功能和FcRn结合的主要位点。
轻链被分类为κ或λ。重链被分类为γ、μ、α、δ或ε,并且将抗体的同种型分别定义为IgG、IgM、IgA、IgD和IgE。在轻链和重链内,可变区和恒定区通过约12个或更多个氨基酸的“J”片段连接,其中重链还包括约10个或更多个氨基酸的“D”片段。(一般参见FundamentalImmunology(Paul,W.编辑,第2版,Raven Press,N.Y.,1989),第7章)(全文以引用方式并入以用于所有目的)。
每个轻链/重链对的成熟可变区形成抗体结合位点。因此,完整抗体具有两个结合位点,即是二价的。在天然抗体中,结合位点是相同的。然而,在双特异性中,结合位点是不同的(参见例如Songsivilai和Lachmann,Clin.Exp.Immunol.,79:315-321(1990);Kostelny等人,J.Immunol.,148:1547-53(1992))。可变区全部表现出由三个高变区(也称为互补决定区或CDR)连接的相对保守的框架区(FR)的相同通用结构。来自每对的两条链的CDR通过框架区进行比对,使得能够结合到特异性表位。从N末端到C末端,轻链和重链均包含FR1、CDR1、FR2、CDR2、FR3、CDR3和FR4结构域。每个结构域的氨基酸分配根据以下文献中的定义进行:Kabat,Sequences of Proteins of Immunological Interest(NationalInstitutes of Health,Bethesda,Md.,1987和1991)或Chothia&Lesk,J.Mol.Biol.196:901-917(1987);Chothia等人,Nature 342:878-883(1989)。Kabat还提供了一种广泛使用的编号惯例(Kabat编号),其中不同重链可变区之间或不同轻链可变区之间的对应残基被分配相同的编号。尽管Kabat编号可以用于抗体恒定区,但EU索引更常用,如本申请中的情况。
术语“表位”是指双特异性抗体的臂结合的抗原上的位点。表位可由邻接氨基酸或通过一个或多个蛋白质的三级折叠而并置的非邻接氨基酸形成。由邻接氨基酸形成的表位(也称为线性表位)通常在暴露于变性溶药剂时保留,而由三级折叠形成的表位(也称为构象表位)通常在用变性溶药剂处理时丧失。一些抗体结合末端特异性表位,这意味着相对于融合至另一多肽的相同多肽,抗体优先结合具有游离末端的多肽,从而导致游离末端的丧失。表位通常在独特的空间构象中包含至少3个并且更常见的至少5个或8-10个氨基酸。确定表位的空间构象的方法包括例如X射线晶体学和二维核磁共振。参见例如EpitopeMapping Protocols,in Methods in Molecular Biology,第66卷,Glenn E.Morris编辑.(1996)。
可在显示一种抗体与另一种抗体与靶抗原的结合竞争的能力的简单免疫测定中鉴定识别相同或重叠表位的抗体。抗体的表位也可通过结合到其抗原以鉴定接触残基的抗体的X射线晶体学来定义。另选地,如果抗原中减少或消除一种抗体的结合的所有氨基酸突变减少或消除另一种抗体的结合,则两种抗体具有相同的表位。如果减少或消除一种抗体的结合的一些氨基酸突变减少或消除另一种抗体的结合,则两种抗体具有重叠表位。
抗体之间的竞争通过其中待测抗体抑制参考抗体与共同抗原的特异性结合的测定来确定(参见例如Junghans et al.,Cancer Res.50:1495,1990)。如在竞争性结合测定中所测量的,如果过量的测试抗体(例如,至少2倍、5倍、10倍、20倍或100倍)抑制参考抗体的结合至少50%但优选75%、90%或99%,则测试抗体与参考抗体竞争。通过竞争测定鉴定的抗体(竞争性抗体)包括结合到与参考抗体相同的表位的抗体,以及结合到与参考抗体所结合的表位足够接近的相邻表位以发生空间位阻的抗体。
出于将氨基酸置换分类为保守性或非保守性的目的,氨基酸分组如下:组I(疏水性侧链):met、ala、val、leu、ile;组II(中性亲水性侧链):cys、ser、thr;组III(酸性侧链):asp、glu;组IV(碱性侧链):asn、gln、his、lys、arg;组V(影响链取向的残基):gly、pro;和组VI(芳族侧链):trp、tyr、phe。保守置换涉及同一类别中的氨基酸之间的置换。非保守置换包括将这些类别中的一个类别的成员与另一个类别的成员交换。
用通过可变区的Kabat编号惯例或恒定区的EU编号最大程度地比对的抗体序列来确定序列同一性百分比。比对后,如果将主题抗体区(例如重链或轻链的整个成熟可变区)与参考抗体的相同区进行比较,主题抗体区和参考抗体区之间的序列同一性百分比是主题抗体区和参考抗体区两者中相同氨基酸占据的位置数除以两个区的比对位置总数,其中空位未计数,乘以100以转化为百分比。
当增加向受试者施用的抗c-kit的剂量不会使与c-kit结合的抗c-kit的量增加超过10%时,c-kit基本上被抗c-kit饱和。
“包括”一个或多个所列举的要素的组合物或方法可包括未具体列举的其他要素。例如,包含抗体的组合物可含有单独的或与其他成分组合的抗体。
术语“抗体依赖性细胞毒性”或ADCC是依赖于抗体包被的靶细胞(即,具有结合抗体的细胞)与具有裂解活性的免疫细胞(也称为效应细胞)的相互作用的诱导细胞死亡的机制。此类效应细胞包括自然杀伤细胞、单核细胞/巨噬细胞和中性粒细胞。ADCC由结合到细胞的抗体Fc区与免疫效应细胞(诸如中性粒细胞、巨噬细胞和自然杀伤细胞)上的Fcγ受体(尤其是FcγRI和FcγRIII)之间的相互作用触发。靶细胞通过吞噬作用或裂解而消除,这取决于介导效应细胞的类型。作为效应细胞活性的结果发生抗体包被的靶细胞死亡。
术语“抗体依赖性细胞吞噬作用”或ADCP是指抗体包被的细胞被结合免疫球蛋白Fc区的吞噬免疫细胞(例如巨噬细胞、中性粒细胞和树突状细胞)全部或部分地内化的过程。
术语“补体依赖性细胞毒性”或CDC是指诱导细胞死亡的机制,其中靶结合抗体的Fc效应结构域活化一系列酶促反应,最终在靶细胞膜中形成孔。通常,抗原-抗体复合物(诸如抗体包被的靶细胞上的那些)结合并活化补体成分C1q,其继而活化补体级联反应,从而导致靶细胞死亡。补体的活化还可导致补体成分在靶细胞表面上的沉积,这通过结合白细胞上的补体受体(例如CR3)来促进ADCC。
除非上下文中另外指明,否则对范围的引用应当理解为也公开了由该范围内的整数限定的所有子范围。
可以使用70kg的示例性人体重将本文提供的以mg/kg计的任何剂量或剂量范围转化为以mg计的绝对剂量,任选地将剂量或剂量的上限和下限四舍五入为最接近的整数,或涵盖所计算的绝对剂量的最接近的10、50、100、500或1000整数。因此,例如,可以将0.15-2mg/kg的剂量范围转化为10.5至140mg,或示例性四舍五入为10至150mg。同样,可以将10-30mg/kg的剂量范围转化为700-2100mg,或示例性四舍五入为500-2500mg。
具体实施方式
I.概述
本发明提供了用于消融内源性HSPC的特异性结合c-kit或抑制CD47-SIRPα的免疫治疗剂的共施用方案。这些方案部分地基于这样的见解:递送相对低水平的抗c-kit会导致与HSPC上的c-kit的结合饱和,而不会显著降低HSPC的水平。然而,当通过抑制CD47-SIRPα的免疫治疗剂促进抗c-kit的作用时,可以获得HSPC水平的显著降低。施用足够的抗c-kit以实现受体的基本饱和但不大量过量将有利于使表达c-kit的HSPC的水平降低至可接受的水平,以允许引入替代HSPC而不会存在其间受试者的HSPC不足的有害延迟。
II.HSPC
取决于应用,待引入受试者体内的HSPC可以是自体的(即,来自该受试者)、同种异体的(来自相同物种的另一个体)或异种的(来自不同物种)。如果是同种异体的,则HSPC可以与MHC等位基因完全或部分匹配或者不匹配。匹配的HSPC可以从亲属或陌生人获得。
尽管所有HSPC都能够增殖并分化成髓系或淋巴系或两者的细胞,但HSPC包括处于不同分化阶段的细胞。原始干细胞可以无限增殖并形成髓系和淋巴系的所有细胞类型。原始干细胞分化成多能祖细胞,其可以产生髓系和淋巴系两者的所有细胞,但不能无限增殖。多能祖细胞产生寡能祖细胞,包括共同淋巴样祖细胞CLP,其产生成熟B淋巴细胞、T淋巴细胞和自然杀伤(NK)细胞。多能祖细胞还产生共同髓样祖细胞(CMP),其进一步分化成粒细胞-巨噬细胞祖细胞(其分化成单核细胞/巨噬细胞和粒细胞)和巨核细胞/红细胞祖细胞(其分化成巨核细胞/血小板和红细胞)(参见Bryder等人,Am.J.Pathol.169,338-346(2006)的图1)。
原始造血干细胞(HC)和多能祖细胞(HPC)可以通过实验彼此区分,例如通过进行鹅卵石样区域形成细胞测定(Cobblestone-Forming Area Cell Assay)(Ploemacher等人,Blood.78:2527-33(1991))。祖细胞较早出现,在培养1至3周出现,而原始造血干细胞在培养4至5周出现。原始干细胞和多能祖细胞均可用于替代疗法。也可以使用进一步分化的细胞,诸如CMP或CLP,但由于它们的增殖能力有限并且它们能够形成的细胞系受限,它们的通用性可能较差。
HSPC可以通过从骨髓、外周血或脐带血中收获而获得。通常在供体处于局部或全身麻醉下时从后髂嵴抽吸骨髓。另外的骨髓可以从前髂嵴获得。骨髓可以用粒细胞集落刺激因子(G-CSF;非格司亭[Neupogen])引发,以增加干细胞计数。提及“全骨髓”通常是指未针对特定免疫细胞亚群选择的来源于骨髓的单核细胞的组合物。“分次骨髓”可例如去除T细胞,例如CD8+细胞、CD52+细胞、CD3+细胞等;富集CD34+细胞,等等。
HSPC也可以通过细胞因子诸如G-CSF、GM-CSF或Plerixafor(也称为AMD3100或Mozobil)将干细胞从骨髓动员到外周血中来获得。用于动员的G-CSF的示例性剂量为10μg/kg/天,但可以给予更高的剂量,例如可以给予高达40μg/kg/天。Mozobil可结合G-CSF使用,以将HSPC动员到外周血中以便收集。HSPC可以用单采(apheresis)装置从外周血中收获。
HSPC也可以从通常用于同种异体移植的脐带血(UBC)中获得。UCB富含能够在体内产生长期再生干细胞的原始干细胞/祖细胞。
从这些过程分离的血细胞可以通过特征细胞表面标志物的亲和富集来富集HSPC或其子集,例如原始干细胞和/或共同祖细胞。此类标志物包括CD34、CD90(thy-1)、CD59、CD1 10(c-mpl)、c-kit(CD-117)。可以通过亲和方法(包括磁珠选择、流式细胞术等)从供体造血细胞样品中选择细胞。若干免疫选择装置(包括Ceparte、Isolex 300i和CliniMACS)可商购获得用于CD34+细胞选择。
HSPC组合物的纯度可以为至少约50%,如由群体中的CD34+细胞的百分比所定义,可为至少约75%、至少约85%、至少约95%或更大。
表征HSPC的示例性市场组在CD11b、CD2、CD14、CD4、CD56、CD7、CD3、CD8a、CD16、CD19、CD20中的每一个中为CD34阳性和谱系阴性。
III.消融方案
消融方案用于减少或消除内源性HSPC。在引入替代HSPC之前,可以使内源性HSPC减少例如至少10%、25%、50%、75%或90%。一些方案在引入替代HSPC之前不使内源性HSPC减少超过例如90%、75%、50%、25%或10%。一些方案使内源性HSPC减少25-75%或25-95%。消融方案也可以由HSC或HPC(HSPC的组成细胞)的相应百分比减少来定义。因为两者均表达抗c-kit,所以两者均可以进行相似程度的消融。
此类消融方案涉及施用特异性结合c-kit(CD117)的抗体(一般参见WO2008067115)或结合抑制剂c-kit的其他药剂,如下文进一步例示。c-kit也称为PBT、SCFR、MASTC中的任一种。人c-kit(免疫治疗剂在人类治疗中的靶标)已被分配示例性登录号NCBI基因ID:3815和Uniprot-P10721。c-kit是用于鉴定骨髓中某些类型的HSPC的细胞表面标志物。造血干细胞(HSC)、多能祖细胞(MPP)和共同髓样祖细胞(CMP)表达高水平的c-kit。此类抗体可以通过抑制c-kit与其配体之间的相互作用并通过效应子介导的机制(诸如ADCC、ADCP和CDC)来减少内源性HSPC。c-kit是一种与干细胞因子(引起某些类型的细胞生长的物质)(也称为“钢因子”或“c-kit配体”)结合的III型受体酪氨酸激酶。当该受体与干细胞因子结合时,其形成激活其固有酪氨酸激酶活性的二聚体,该二聚体继而磷酸化并激活信号转导分子,该信号转导分子在细胞中传播信号。许多特异性结合人c-kit的抗体可商购获得,包括SR1、2B8、ACK2、YB5-B8、57A5、104D2(US20180214525)。AMG 191是人源化形式的SR1(美国专利8,436,150和7,915,391)。这些抗体(包括嵌合、饰面或人源化形式或结合相同表位或与其竞争结合c-kit的抗体)中的任一种可以用于所公开的方法中。其他针对c-kit的抗体可以通过标准免疫学技术从头产生,如下文进一步描述。
一些其他人源化形式的SR1由例如2018年11月26日提交的US62/771,526和2019年11月25日提交的PCT/US2019/063091描述。一些抗体分别包含重链CDR H1、H2和H3 SEQ IDNO:2-4,并且轻链CDR L1、L2和L3包含US62/771,526和PCT/US2019/063091的SEQ ID NO:6-8(即,如Kabat所定义),任选地具有以下CDR置换中的一个、两个或三个。这些CDR是本文的SEQ ID NO:1-6。CDR置换优选地选自重链位置60处的N至A、重链位置64处的K至Q以及轻链位置30处的N至Q,位置根据Kabat编号。本发明的一些优选抗体具有成熟重链可变区和成熟轻链可变区,该成熟重链可变区具有在US62/771,526和PCT/US2019/063091中指定为SEQID NO:13、17或21以及对应于AH2、AH3和AH4的本文的SEQ ID NO:7-9的链中任一个的序列,并且该成熟轻链可变区具有US62/771,526的SEQ ID NO:53和对应于NL2的PCT/US2019/063091(本文的SEQ ID NO:10)的序列。一般来讲,效应子功能诸如ADCP是有用的,但对于抗c-kit抗体不是必需的。因此,一些此类抗体具有人IgG1同种型。一些抗体具有人IgG1同种型,该同种型具有突变以增强一种或多种效应子功能(参见下文)。用于下文实施例中的示例性抗体是SR1的人源化形式,其包含本文SEQ ID NO:7的重链可变区和本文SEQ ID NO:10的轻链可变区以及人IgG1同种型。
抗c-kit免疫治疗剂的另外的示例包括FSI-174(Forty Seven,Inc.)和CDX-0158或CDX-0159(Celldex Therapeutics,Inc.)。c-kit的其他抑制剂在以下公开中描述:WO199203459、WO199221766、WO2007127317、WO2008115300、WO2012154480、WO2019155067和WO2020076105。
消融方案还可以包括抑制CD47-SIRPα相互作用的免疫治疗剂,以与针对c-kit的抗体组合使用(一般参见WO2016033201)。此类药剂促进效应子介导的由抗c-kit介导消除内源性HSPC。此类药剂包括特异性结合CD47或SIRPα的抗体。此类药剂还包括与Fc融合的CD47 ECD(其功能类似于针对SIRPα的抗体)或与Fc融合的SIRPα(其功能类似于针对CD47的抗体)。(参见Zhang等人,Antibody Therapeutics,1:27–32(2018))。优选的抗体拮抗CD47-SIRPα相互作用而不通过任一受体赋予激活信号。
CD47也被称为IAP、MER6和OA3中的任一种。人CD47(免疫治疗剂在人类治疗中的靶标)已被分配示例性登录号NCBI基因ID:961和UniProt Q08722。
合适的抗CD47抗体的示例包括克隆B6H12、5F9、8B6、C3(例如,如WO2011/143624中所述)、CC9002(Vonderheide,Nat Med 2015;21:1122–3,2015)和SRF231(SurfaceOncology)。合适的抗CD47抗体包括此类抗体的人、人源化或嵌合型式、结合相同表位或与其竞争结合CD47的抗体。人源化抗体(例如,hu5F9-IgG4-WO2011/143624)由于其抗原性低而特别适用于人的体内应用。已经报道人CD47中hu5F9-IgG4的直接接触残基为K39、K41、E97、T99和E104(LC)以及E29、R103和E104(HC)(Weiskopf等人,J.Clin.Invest 126,2610-262-(2016))。类似地,犬源化、猫源化抗体等尤其可用于分别在狗、猫和其他物种中的应用。
一些人源化抗体特异性结合人CD47,其包含WO2011/143624的可变重(VH)区和可变轻(VL)区,该可变重区含有分别在SEQ ID NO:20、21和22中示出的VH互补区CDR1、CDR2和CDR3;并且该可变轻区含有分别在SEQ ID NO:23、24和25中示出的VL互补区CDR1、CDR2和CDR3(本文的SEQ ID NO:11-16)。一些人源化抗体包括WO2011/143624的选自SEQ ID NO:36、SEQ ID NO:37和SEQ ID NO:38的重链可变区以及选自SEQ ID NO:41、SEQ ID NO:42和SEQ ID NO:43的轻链可变区(本文的SEQ ID NO:17-22)。莫洛利单抗(一种人源化形式的5F9)是优选的抗体。
针对CD47的抑制其与SIRPα相互作用的免疫治疗剂的其他示例包括抗CD47 mAb(Vx-1004)、抗人CD47 mAb(CNTO-7108)、CC-90002、CC-90002-ST-001、NI-1701、NI-1801、RCT-1938、ALX-148、RRx-001、DSP-107、VT-1021、TTI-621、TTI-622、IMM-02SGN-CD47M。
合适的抗SIRPα抗体特异性结合SIRPα(不激活/刺激足够的信号应答以抑制吞噬作用)并抑制SIRPα与CD47之间的相互作用。人SIRPα(免疫治疗剂在人类治疗中的靶标)已被分配示例性登录号NCBI基因ID:140885;和UniProt P78324。合适的抗SIRPα抗体包括此类抗体的完全人、人源化或嵌合型式。由Kabat CDR和可变区定义的一些示例性抗SIRPα抗体在下表1中提供。
表1:抗SIRPα抗体
用于下文实施例中的来自上表的示例性抗体是人源化1H9,其包含SEQ ID NO:29的重链可变区和SEQ ID NO:30的轻链可变区,以及突变以降低效应子功能的人IgG1恒定区(N297A,EU编号)。另外的示例性抗体为KWAR23(Ring等人,Proc Natl Acad Sci U SA.2017年12月5日;114(49):E10578–E10585、WO2015/138600)、My-1和Effi-DEM(也称为BI765063(Boehringer Ingelheim)(Zhang等人,Antibody Therapeutics,第1卷,第2期,2018年9月21日,第27-32页))。人源化抗体由于其抗原性低而特别适用于人的体内应用。类似地,犬源化、猫源化等抗体分别特别适用于狗、猫和其他物种中的应用。抗SIRPα抗体的其他示例包括FSI-189(Forty Seven,Inc.)、ES-004、ADU1805(Aduro Biotech以及Voets等人,J Immunother.Cancer.2019;7:340)和CC-95251(Celgene,Uger&Johnson,ExpertOpinion on Biological Therapy,20:1,5-8,DOI:10.1080/14712598.2020.1685976)。
免疫治疗剂还包括特异性结合SIRPα并减少HSPC上的CD47与吞噬细胞上的SIRPα之间的相互作用的可溶性CD47多肽(参见例如WO2016179399)。此类多肽可包括具有上述功能的整个ECD或其部分。合适的可溶性CD47多肽特异性结合SIRPα,而不活化或刺激通过SIRPα的信号传导,因为SIRPα的活化将抑制吞噬作用。相反,合适的可溶性CD47多肽促进内源性HCSP的吞噬作用。可溶性CD47多肽可与Fc融合(例如,如US20100239579中所述)。
结合SIRPα并抑制其与CD47相互作用的药剂的其他示例在以下文献中描述:WO200140307、WO2002092784、WO2007133811、WO2009046541、WO2010083253、WO2011076781、WO2013056352、WO2015138600、WO2016179399、WO2016205042、WO2017178653、WO2018026600、WO2018057669、WO2018107058、WO2018190719、WO2018210793、WO2019023347、WO2019042470、WO2019175218、WO2019183266、WO2020013170和WO2020068752。
免疫治疗剂还包括特异性结合CD47并抑制其与SIRPα相互作用的可溶性SIRPα多肽。示例性药剂包括ALX148(Kauder等人,Blood 2017 130:112)以及TTI-622和TTI-661Trillium。此类药剂可包括具有上述功能的整个SIRPαECD或其任何部分。SIRPα试剂通常将包含至少SIRPα的d1结构域。可溶性SIRPα多肽可与Fc区融合。称为“高亲和力SIRPα试剂”的示例性SIRPα多肽,其包括SIRPα衍生的多肽及其类似物(例如,CV1-hlgG4和CV1单体),在WO2013/109752中有所描述。高亲和力SIRPα试剂是天然SIRPα蛋白的变体。提供增加的亲和力的氨基酸变化位于d1结构域中,因此高亲和力SIRPα试剂包含人SIRPα的d1结构域,其相对于d1结构域中的野生型序列具有至少一个氨基酸变化。此类高亲和力SIRPα试剂任选地包含:附加的氨基酸序列,例如抗体Fc序列;野生型人SIRPα蛋白的除d1结构域以外的部分(包括但不限于天然蛋白质的残基150至374或其片段)通常是与d1结构域邻接的片段;等等。高亲和力SIRPα试剂可以是单体或多聚体,即二聚体、三聚体、四聚体等。在一些实施方案中,高亲和力SIRPα试剂是可溶的,其中多肽缺少SIRPα跨膜结构域并且包含相对于野生型SIRPα序列的至少一个氨基酸改变,并且其中该氨基酸变化例如通过将解离速率降低至少10倍、至少20倍、至少50倍、至少100倍、至少500倍或更多倍来增加SIRPα多肽与CD47结合的亲和力。
具有Fc区的针对CD47或SIRPα的免疫治疗剂可以具有人同种型(例如,IgG1、IgG2、IgG3或IgG4)中的任一种。可以使用经突变以降低效应子功能的人IgG4或IgG2同种型或IgG1,因为不需要效应子功能来抑制CD47-SIRPα相互作用。
包括抗体和Fc融合蛋白的免疫治疗剂以有效实现减少或消除内源性HSPC的期望目的的方案施用。有效方案是指剂量、施用频率和施用途径的组合。特异性结合c-kit的抗体的方案优选地递送足够的抗体以使c-kit受体在表达c-kit的HSPC的目标群体上基本饱和,但不会大量超过这种量,导致施用后抗c-kit不必要的长期持续(这可能导致施用替代HSPC的延迟或无意地杀死替代的HSPC)。已发现约0.15-2mg/kg的抗c-kit总量适用于此类目的。该量可以作为单次剂量、两次剂量或者三次或更多次剂量施用。一种方案涉及施用单次剂量的例如0.15-1mg/kg、0.25-1mg/kg、0.25-0.5mg/kg或0.3mg/kg抗c-kit。另一种方案涉及施用间隔3-7天的两次剂量的例如0.15-1mg/kg、0.25-1mg/kg、0.25-0.5mg/kg或0.3mg/kg抗c-kit。另一种方案涉及施用任选地间隔10-30天的三次或更多次剂量的0.15-1mg/kg、0.25-1mg/kg、0.25-0.5mg/kg或0.3mg/kg抗c-kit。同一天(即从头到尾24小时内)多次施用被认为是同一剂量的一部分。其他方案可以递送与单次、两次或三次给药方案基本上相同的曲线面积(例如,在90%以内),但在每次施用时施用更多的减少量。其他方案可以使表达c-kit的HSPC的减少水平与所描述的单次和双次给药方案基本上相同(例如,在90%以内)。所提供的剂量是针对c-kit的抗体,特别是如上所述的任何人源化SR1抗体。这些剂量也为其他免疫治疗剂提供指导;然而,可以针对分子量和/或结合亲和力的差异来调节此类药剂的剂量,以实现与针对人源化SR1所获得的表达c-kit的HSPC基本上相同的减少水平。
抑制CD47-SIRPα的免疫治疗剂以通过特异性结合c-kit的免疫治疗剂(抗c-kit)有效促进表达c-kit的HSPC减少的方案施用。在不存在抑制CD47-SIRPα的免疫治疗剂的促进的情况下,抗c-kit可影响或可不影响表达c-kit的HSPC的减少。抑制CD47-SIRPα的免疫治疗剂的示例性剂量为0.05mg/kg、0.1mg/kg、0.5mg/kg、1mg/kg中的至少任一者直至5mg/kg、10mg/kg、20mg/kg、30mg/kg、40mg/kg或50mg/kg中的任一者。一些示例性范围为0.05mg/kg至50mg/kg、0.1mg/kg至20mg/kg、1mg/kg至10mg/kg或10mg/kg至30mg/kg。任选地,此类免疫治疗剂(尤其是特异性结合CD47的那些)可以最初以一个或多个引发剂量施用,然后以一个或多个治疗剂量施用,以减少不期望的红细胞交联,如例如WO2017181033所述。优选的方案是0.5至5mg/kg(例如1mg/kg)的引发剂量,然后是10-30mg/kg或15-20mg/kg的治疗剂量。治疗剂量在引发剂量后例如3-15天或5-10天或7天施用。
用抗c-kit和抑制CD47-SIRPα的免疫治疗剂的组合或共施用治疗涉及在时间上足够接近后者施用相应药剂,以促进前者减少表达c-kit的HSPC。通常,在组合方案中,两种药剂同时以可检测水平存在于受试者血清中。在一些组合方案中,施用引发剂量的抑制CD47-SIRPα的免疫治疗剂,然后同时施用一定剂量的抗c-kit和治疗剂量的抑制CD47-SIRPα的免疫治疗剂。在一些此类方案中,通过共输注同时施用两种药剂。在一些方案中,任选地以成对方式(其中在同一天施用每对的一个剂量)施用多次剂量的特异性结合c-kit的免疫治疗剂和多次剂量的抑制CD47-SIRPα的免疫治疗剂。此类方案之前可以是引发剂量的抑制CD47-SIRPα的免疫治疗剂。
用特异性结合c-kit的免疫治疗剂和特异性结合CD47或SIRPα的免疫治疗剂进行组合治疗可以进一步与有效耗尽免疫系统的其他细胞的一种或多种药剂组合进行。例如,MCL1细胞凋亡调节剂、BCL2家族成员(MCL1)抑制剂可以用于消融NK细胞。在各种实施方案中,将如本文所述的消融方案与MCL1细胞凋亡调节子(BCL2家族成员)(MCL1、TM;EAT;MCL1L;MCL1S;Mcl-1;BCL2L3;MCL1-ES;bcl2-L-3;mcl1/EAT;NCBI基因ID:4170)的抑制剂组合。MCL1抑制剂的示例包括AMG-176、AMG-397、S-64315、AZD-5991、483-LM、A-1210477、UMI-77、JKY-5-037、APG-3526以及WO2018183418、WO2016033486和WO2017147410中所述的那些。
可以在施用组合方案的特异性结合c-kit并抑制CD47-SIRPα的免疫治疗剂之后施用替代HSPC。任选地,在施用抗c-kit或在施用最后一次剂量的抗c-kit(如果施用多于一次)之后5-15天施用替代HSPC。如果晚于最后一次剂量的抗c-kit施用最后一次剂量的抑制CD47-SIRPα的免疫治疗剂,则施用也可以在后者之后5-15天。任选地,当HSPC或表达c-kit的HSPC的水平下降到预处理水平的阈值%以下(例如,<90%、75%、50%、25%或5%或25-75%或25-95%)并且抗c-kit和/或抑制CD47-SIRPα的免疫治疗剂的水平下降到最大水平的25%、10%、5%、1%以下或达到不可检测的水平时,测量HSPC或表达c-kit的HSPC的水平和/或抗c-kit的水平和/或抑制CD47-SIRPα的免疫治疗剂的水平并施用替代HSPC。
用于重新引入的HSPC的示例性剂量为至少1×105、1×106、2×106、5×106、107、2×107个CD34+细胞/kg体重。示例性范围为1×105至5×107、1×106至2×107或5×105至6×106个CD34+细胞/kg体重。剂量可能受到可用细胞数量的限制。通常,无论来源如何,剂量通过存在的CD34+细胞数量计算。对于未分次骨髓或动员外周血,CD34+细胞的百分比数可能较低;在这种情况下,施用的细胞总数要高得多。作为施用的HSPC的替代方案,可以施用HSPC的组成细胞(诸如HSC或HPC)。
可以将替代HSPC或其他细胞疗法与一种或多种药剂一起施用以促进HSPC的生长。例如,可以将替代HSPC或其他细胞疗法与施用fms相关受体酪氨酸激酶3(FLT3);FLK2;STK1;CD135;FLK-2;NCBI基因ID:2322)的激动剂组合。FLT3激动剂的示例包括CDX-301和GS-3583。替代HSPC或其他细胞疗法也可以与细胞因子诱导型含SH2的蛋白(CISH;CIS;G18;SOCS;CIS-1;BACTS2;NCBI基因ID:1154)的抑制剂组合。CISH抑制剂的示例包括WO2017100861、WO2018075664和WO2019213610中所述的那些。
免疫治疗剂通常作为药物组合物施用,其中该药剂与一种或多种药学上可接受的载体组合。可以使用多种含水载体,例如缓冲盐水等。这些溶液是无菌的并且通常不含不期望的物质。这些组合物可通过常规技术灭菌。组合物可含有接近生理条件所需的药学上可接受的辅助物质,诸如pH调节和缓冲剂、毒性调节剂等,例如乙酸钠、氯化钠、氯化钾、氯化钙、乳酸钠等。活性剂在这些制剂中的浓度可以有很大差异,并且主要基于流体体积、粘度、体重等根据所选的具体施用模式和患者的需求进行选择(例如,Remington'sPharmaceutical Science(第15版,1980)以及Goodman&Gillman,The PharmacologicalBasis of Therapeutics(Hardman等人编辑,1996))。
IV.细胞疗法
在一些实施方案中,细胞疗法需要共施用经工程改造以表达嵌合抗原受体(CAR)或T细胞受体(TCR)TCR的免疫细胞。在特定实施方案中,免疫细胞群经工程改造以表达CAR,其中CAR包含癌症抗原结合结构域。在其他实施方案中,免疫细胞群经工程改造以表达经工程改造以靶向在肿瘤细胞表面上呈递的肿瘤衍生肽的T细胞受体(TCR)。在一个实施方案中,经工程改造以表达嵌合抗原受体(CAR)或T细胞受体(TCR)TCR的免疫细胞是T细胞。在另一个实施方案中,经工程改造以表达嵌合抗原受体(CAR)或T细胞受体(TCR)TCR的免疫细胞是NK细胞。
就CAR的结构而言,在一些实施方案中,CAR包含抗原结合结构域、跨膜结构域和胞内信号结构域。在一些实施方案中,胞内结构域包含初级信号结构域、共刺激结构域或初级信号结构域和共刺激结构域两者。在一些实施方案中,初级信号结构域包含选自由以下项组成的组的一种或多种蛋白质的功能信号结构域:CD3ζ、CD3γ、CD3δ、CD3ε、常见FcRγ(FCERIG)、FcR β(FcεRlb)、CD79a、CD79b、FcγRIIa、DAP10和DAP12 4-1BB/CD137、激活NK细胞受体、免疫球蛋白、B7-H3、BAFFR、BLAME(SLAMF8)、BTLA、CD100(SEMA4D)、CD103、CD160(BY55)、CD18、CD19、CD19a、CD2、CD247、CD27、CD276(B7-H3)、CD28、CD29、CD3δ、CD3ε、CD3γ、CD30、CD4、CD40、CD49a、CD49D、CD49f、CD69、CD7、CD84、CD8α、CD8β、CD96(Tactile)、CD11a、CD11b、CD11c、CD11d、CDS、CEACAM1、CRT AM、细胞因子受体、DAP-10、DNAM1(CD226)、Fcγ受体、GADS、GITR、HVEM(LIGHTR)、IA4、ICAM-1、ICAM-1、Igα(CD79a)、IL-2Rβ、IL-2Rγ、IL-7Rα、诱导型T细胞共刺激因子(ICOS)、整联蛋白、ITGA4、ITGA4、ITGA6、ITGAD、ITGAE、ITGAL、ITGAM、ITGAX、ITGB2、ITGB7、ITGB1、KIRDS2、LAT、LFA-1、LFA-1、与CD83结合的配体、LIGHT、LIGHT、LTBR、Ly9(CD229)、Ly108、淋巴细胞功能相关抗原-1(LFA-1;CD1-1a/CD18)、MHC 1类分子、NKG2C、NKG2D、NKp30、NKp44、NKp46、NKp80(KLRF1)、OX-40、PAG/Cbp、程序性死亡-1(PD-1)、PSGL1、SELPLG(CD162)、信号淋巴细胞活化分子(SLAM蛋白)、SLAM(SLAMF1;CD150;IPO-3)、SLAMF4(CD244;2B4)、SLAMF6(NTB-A、SLAMF7、SLP-76、TNF受体蛋白、TNFR2、TNFSF14、Toll配体受体、TRANCE/RANKL、VLA1或VLA-6,或它们的片段、截短形式或组合。
在一些实施方案中,共刺激结构域包含选自由以下项组成的组的一种或多种蛋白质的功能结构域:CD27、CD28、4-1BB(CD137)、OX40、CD30、CD40、PD-1、ICOS、CD2、CD7、LIGHT、NKG2C、淋巴细胞功能相关抗原-1(LFA-1)、MYD88、B7-H3、与CD83特异性结合的配体、CDS、ICAM-1、GITR、BAFFR、HVEM(LIGHTR)、SLAMF7、NKp80(KLRFI)、CD19、CD4、CD8α、CD8β、IL2Rβ、IL2Rγ、IL7Rα、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、ITGAE、CD103、ITGAL、CD1A(NCBI基因ID:909)、CD1B(NCBI基因ID:910)、CD1C(NCBI基因ID:911)、CD1D(NCBI基因ID:912)、CD1E(NCBI基因ID:913)、ITGAM、ITGAX、ITGB1、CD29、ITGB2(CD18、LFA-1)、ITGB7、TNFR2、TRANCE/RANKL、DNAM1(CD226)、SLAMF4(CD244、2B4)、CD84、CD96(Tactile)、CEACAM1、CRTAM、Ly9(CD229)、CD160(BY55)、PSGL1、CD100(SEMA4D)、CD69、SLAMF6(NTB-A、Ly108)、SLAM(SLAMF1、CD150、IPO-3)、BLAME(SLAMF8)、SELPLG(CD162)、LTBR、LAT、GADS、SLP-76、PAG/Cbp、NKp44、NKp30、NKp46和NKG2D。
在一些实施方案中,跨膜结构域包含来源于选自由以下项组成的组的蛋白质的跨膜结构域:T-细胞受体的α、β或ζ链、CD28、CD3ε、CD3δ、CD3γ、CD45、CD4、CD5、CD7、CD8α、CD8β、CD9、CD11a、CD11b、CD11c、CD11d、CD16、CD18、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137、CD154、KIRDS2、OX40、CD2、CD27、ICOS(CD278)、4-1BB(CD137)、GITR、CD40、BAFFR、HVEM(LIGHTR)、SLAMF7、NKp80(KLRF1)、CD19、CD19a、IL2Rβ、IL2Rγ、IL7Rα、ITGA1、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CD1A、CD1B、CD1C、CD1D、CD1E、ITGAE、CD103、ITGAL、ITGAM、ITGAX、ITGB1、ITGB2、ITGB7、CD29、ITGB2(LFA-1、CD18)、ITGB7、TNFR2、DNAM1(CD226)、SLAMF4(CD244、2B4)、CD84、CD96(TACTILE)、CEACAM1、CRTAM、Ly9(CD229)、CD160(BY55)、PSGL1、CD100(SEMA4D)、SLAMF6(NTB-A、Ly108)、SLAM(SLAMF1、CD150、IPO-3)、BLAME(SLAMF8)、SELPLG(CD162)、LTBR、PAG/Cbp、NKp44、NKp30、NKp46、NKG2D和NKG2C激活NK细胞受体、免疫球蛋白、BTLA、CD247、CD276(B7-H3)、CD30、CD84、CDS、细胞因子受体、Fcγ受体、GADS、ICAM-1、Igα(CD79a)、整联蛋白、LAT、与CD83结合的配体、LIGHT、MHC 1类分子、PAG/Cbp、TNFSF14、Toll配体受体、TRANCE/RANKL,或它们的片段、截短形式或组合。
在一些实施方案中,CAR包含铰链结构域。铰链结构域可来源于选自由以下项组成的组的蛋白质:CD2、CD3δ、CD3ε、CD3γ、CD4、CD7、CD8.α、CD8.β、CD11a(ITGAL)、CD11b(ITGAM)、CD11c(ITGAX)、CD11d(ITGAD)、CD18(ITGB2)、CD19(B4)、CD27(TNFRSF7)、CD28、CD28T、CD29(ITGB1)、CD30(TNFRSF8)、CD40(TNFRSF5)、CD48(SLAMF2)、CD49a(ITGA1)、CD49d(ITGA4)、CD49f(ITGA6)、CD66a(CEACAM1)、CD66b(CEACAM8)、CD66c(CEACAM6)、CD66d(CEACAM3)、CD66e(CEACAM5)、CD69(CLEC2)、CD79A(B细胞抗原受体复合物相关α链)、CD79B(B细胞抗原受体复合物相关β链)、CD84(SLAMF5)、CD96(Tactile)、CD100(SEMA4D)、CD103(ITGAE)、CD134(OX40)、CD137(4-1BB)、CD150(SLAMF1)、CD158A(KIR2DL1)、CD158B1(KIR2DL2)、CD158B2(KIR2DL3)、CD158C(KIR3DP1)、CD158D(KIRDL4)、CD158F1(KIR2DL5A)、CD158F2(KIR2DL5B)、CD158K(KIR3DL2)、CD160(BY55)、CD162(SELPLG)、CD226(DNAM1)、CD229(SLAMF3)、CD244(SLAMF4)、CD247(CD3-zeta)、CD258(LIGHT)、CD268(BAFFR)、CD270(TNFSF14)、CD272(BTLA)、CD276(B7-H3)、CD279(PD-1)、CD314(NKG2D)、CD319(SLAMF7)、CD335(NK-p46)、CD336(NK-p44)、CD337(NK-p30)、CD352(SLAMF6)、CD353(SLAMF8)、CD355(CRTAM)、CD357(TNFRSF18)、诱导型T细胞共刺激因子(ICOS)、LFA-1(CD11a/CD18)、NKG2C、DAP-10、ICAM-1、NKp80(KLRF1)、IL-2Rβ、IL-2Rγ、IL-7Rα、LFA-1、SLAMF9、LAT、GADS(GrpL)、SLP-76(LCP2)、PAG1/CBP、CD83配体、Fcγ受体、MHC 1类分子、MHC 2类分子、TNF受体蛋白、免疫球蛋白、细胞因子受体、整联蛋白、激活NK细胞受体或Toll配体受体、IgG1、IgG2、IgG3、IgG4、IgA、IgD、IgE、IgM,或它们片段或组合。
在一些实施方案中,TCR或CAR抗原结合结构域或本文所述的免疫治疗剂(例如,单特异性或多特异性抗体或其抗原结合片段或抗体模拟物)结合肿瘤相关抗原(TAA)。在一些实施方案中,肿瘤相关的抗原选自由以下项组成的组:CD19;CD123;CD22;CD30;CD171;CS-1(也称为CD2子集1、CRACC、SLAMF7、CD319和19A24);C型凝集素样分子-1(CLL-1或CLECLI);CD33;表皮生长因子受体变体III(EGFRvlll);神经节苷脂G2(GD2);神经节苷脂GD3(αNeuSAc(2-8)αNeuSAc(2-3)βDGaip(1-4)bDGIcp(1-1)Cer);神经节苷脂GM3(αNeuSAc(2-3)βDGalp(1-4)βDGlcp(1-1)Cer);GM-CSF受体;TNF受体超家族成员17(TNFRSF17、BCMA);B-淋巴细胞细胞粘附分子;Tn抗原((Tn Ag)或(GaINAcu-Ser/Thr));前列腺特异性膜抗原(PSMA);受体酪氨酸激酶样孤儿受体1(RORI);肿瘤相关糖蛋白72(TAG72);CD38;CD44v6;癌胚抗原(CEA);上皮细胞粘附分子(EPCAM);B7H3(CD276);KIT(CD117);白介素-13受体亚基α-2(IL-13Ra2或CD213A2);间皮素;白介素11受体α(IL-11Ra);前列腺干细胞抗原(PSCA);蛋白酶丝氨酸21(Testisin或PRSS21);血管内皮生长因子受体2(VEGFR2);HLA I类抗原A-2α;HLA抗原;Lewis(Y)抗原;CD24;血小板衍生生长因子受体β(PDGFR-β);阶段特异性胚胎抗原-4(SSEA-4);CD20;δ样3(DLL3);叶酸受体α;叶酸受体β、GDNFα4受体、受体酪氨酸蛋白激酶、ERBB2(Her2/neu);细胞表面相关粘蛋白1(MUC1);APRIL受体;ADP核糖基环化酶-1;Ephb4酪氨酸激酶受体、DCAMKL1丝氨酸苏氨酸激酶、天冬氨酸β-羟化酶、表皮生长因子受体(EGFR);神经细胞粘附分子(NCAM);前列腺酶;前列腺酸磷酸酶(PAP);突变的延伸因子2(ELF2M);肝配蛋白B2;成纤维细胞活化蛋白α(FAP);胰岛素样生长因子1受体(IGF-I受体)、碳酸酐酶IX(CAIX);蛋白酶体(Prosome、Macropain)亚基β型9(LMP2);糖蛋白100(gp100);由裂点簇区(BCR)和Abelson鼠白血病病毒癌基因同源物1(Abl)(bcr-abl)组成的癌基因融合蛋白;酪氨酸酶;肝配蛋白A型受体2(EphA2);肝配蛋白A型受体3(EphA3)、岩藻糖基GM1;唾液酸化Lewis粘附分子(sLe);转谷氨酰胺酶5(TGS5);高分子量黑素瘤相关抗原(HMWMAA);邻乙酰基-GD2神经节苷脂(OAcGD2);叶酸受体β;肿瘤内皮标志物1(TEM1/CD248);肿瘤内皮标志物7相关(TEM7R);前列腺六跨膜上皮抗原I(STEAP1);封闭蛋白6(CLDN6);甲状腺刺激激素受体(TSHR);G蛋白偶联受体C类5组成员D(GPRCSD);IL-15受体(IL-15);染色体X开放阅读框61(CXORF61);CD97;CD179a;间变性淋巴瘤激酶(ALK);聚唾液酸;胎盘特异性1(PLAC1);globoH糖神经酰胺的六糖部分(GloboH);乳腺分化抗原(NY-BR-1);尿母细胞蛋白(uroplakin)2(UPK2);甲型肝炎病毒细胞受体1(HAVCR1);肾上腺受体β3(ADRB3);泛连接蛋白3(PANX3);G蛋白偶联受体20(GPR20);淋巴细胞抗原6复合物,基因座K9(LY6K);嗅觉受体51E2(ORS IE2);TCRγ交替阅读框蛋白(TARP);Wilms肿瘤蛋白(WT1);癌症/睾丸抗原1(NY-ESO-1);癌症/睾丸抗原2(LAGE-la);黑素瘤相关抗原1(MAGE-A1);黑素瘤相关抗原3(MAGE-A3);黑素瘤相关抗原4(MAGE-A4);T细胞受体β2链C;位于染色体12p上的ETS易位变体基因6(ETV6-AML);精子蛋白17(SPA17);X抗原家族成员1A(XAGE1);促血管生成素结合细胞表面受体2(Tie 2);黑素瘤癌睾丸抗原-1(MADCT-1);黑素瘤癌睾丸抗原-2(MAD-CT-2);Fos相关抗原1;肿瘤蛋白p53(p53);p53突变体;prostein;生存素;端粒酶;前列腺癌肿瘤抗原-1(PCTA-1或半乳凝素8)、被T细胞1识别的黑素瘤抗原(MelanA或MARTI);大鼠肉瘤(Ras)突变体;人端粒酶逆转录酶(hTERT);肉瘤易位断点;黑素瘤细胞凋亡抑制剂(ML-IAP);ERG(跨膜蛋白酶、丝氨酸2(TMPRSS2)ETS融合基因);N-乙酰基葡糖胺转移酶V(NA17);配对盒蛋白Pax-3(PAX3);雄激素受体;细胞周期素A1;细胞周期素B1;v-myc禽骨髓细胞瘤病毒癌基因成神经细胞瘤衍生的同源物(MYCN);Ras同源物家族成员C(RhoC);酪氨酸酶相关蛋白2(TRP-2);细胞色素P450 1B1(CYP IBI);CCCTC结合因子(锌指蛋白)样(BORIS或印记位点调节物兄弟因子)、被T细胞识别的鳞状细胞癌抗原3(SART3);配对盒蛋白Pax-5(PAX5);前顶体素结合蛋白sp32(OY-TES I);淋巴细胞特异性蛋白酪氨酸激酶(LCK);A激酶锚定蛋白4(AKAP-4);肽聚糖识别蛋白、滑膜肉瘤、X断点2(SSX2);晚期糖基化终产物的受体(RAGE-I);肾遍在蛋白1(RUI);肾遍在蛋白2(RU2);豆荚蛋白;人乳头状瘤病毒E6(HPV E6);人乳头状瘤病毒E7(HPV E7);肠羧基酯酶;突变的热休克蛋白70-2(muthsp70-2);CD79a;CD79b;CD72;白细胞相关免疫球蛋白样受体1(LAIRI);IgA受体的Fc片段(FCAR或CD89);白细胞免疫球蛋白样受体亚家族A成员2(LILRA2);CD300分子样家族成员f(CD300LF);C型凝集素结构域家族12成员A(CLEC12A);骨髓基质细胞抗原2(BST2);含有粘蛋白样激素受体样的EGF样模块2(EMR2);淋巴细胞抗原75(LY75);磷脂酰肌醇蛋白聚糖-2(GPC2);磷脂酰肌醇蛋白聚糖-3(GPC3);Fc受体样5(FCRL5);以及免疫球蛋白λ样多肽1(IGLL1)。在一些实施方案中,靶标是在MHC中呈递的肿瘤相关抗原的表位。
在一些实施方案中,癌症抗原选自CD150、5T4、ActRIIA、B7、TNF受体超家族成员17(TNFRSF17、BCMA)、CA-125、CCNA1、CD123、CD126、CD138、CD14、CD148、CD15、CD19、CD20、CD200、CD21、CD22、CD23、CD24、CD25、CD26、CD261、CD262、CD30、CD33、CD362、CD37、CD38、CD4、CD40、CD40L、CD44、CD46、CD5、CD52、CD53、CD54、CD56、CD66a-d、CD74、CD8、CD80、CD92、CE7、CS-1、CSPG4、ED-B纤粘蛋白、EGFR、EGFRvIII、EGP-2、EGP-4、EPHa2、ErbB2、ErbB3、ErbB4、FBP、HER1-HER2组合、HER2-HER3组合、HERV-K、HIV-1包膜糖蛋白gp120、HIV-1包膜糖蛋白gp41、HLA-DR、HLA I类抗原αG、HM1.24、K-Ras GTP酶、HMW-MAA、Her2、Her2/neu、IGF-1R、IL-11Rα、IL-13R-α2、IL-2、IL-22R-α、IL-6、IL-6R、Ia、Ii、L1-CAM、L1细胞粘附分子、Lewis Y、Ll-CAM、MAGE A3、MAGE-A1、MART-1、MUC1、NKG2C配体、NKG2D配体、NYESO-1、OEPHa2、PIGF、PSCA、PSMA、ROR1、T101、TAC、TAG72、TIM-3、TRAIL-R1、TRAIL-R1(DR4)、TRAIL-R2(DR5)、VEGF、VEGFR2、WT-I、G蛋白偶联受体、α胎蛋白(AFP)、血管生成因子、外源同源结合分子(ExoCBM)、癌基因产物、抗叶酸受体、c-Met、癌胚抗原(CEA)、细胞周期素(D1)、肝配蛋白B2、上皮肿瘤抗原、雌激素受体、胎儿乙酰胆碱e受体、叶酸结合蛋白、gp100、乙型肝炎表面抗原、Epstein-Barr核抗原1、潜伏膜蛋白1、分泌蛋白BARF1、P2X7嘌呤受体、Syndecan-1、κ链、κ轻链、kdr、λ链、活素、黑素瘤相关抗原、间皮素、小鼠双分钟2同源物(MDM2)、粘蛋白16(MUC16)、突变p53、突变ras、坏死抗原、癌胚胎抗原、ROR2、孕酮受体、前列腺特异性抗原、tEGFR、腱生蛋白、P2-Microgiobuiin、Fc受体样5(FcRL5)。
细胞疗法的示例包括但不限于:AMG-119、Algenpantucel-L、Sipuleucel-T、(BPX-501)rivogenlecleucel US9089520、WO2016100236、AU-105、ACTR-087、活化的同种异体自然杀伤细胞CNDO-109-AANK、MG-4101、AU-101、BPX-601、FATE-NK100、LFU-835造血干细胞、Imilecleucel-T、baltaleucel-T、PNK-007、UCARTCS1、ET-1504、ET-1501、ET-1502、ET-190、CD19-ARTEMIS、ProHema、经FT-1050处理的骨髓干细胞疗法、CD4CARNK-92细胞、SNK-01、NEXI-001、CryoStim、AlloStim、慢病毒转导的huCART内消旋细胞、CART-22细胞、EGFRt/19-28z/4-1BBL CAR T细胞、自体4H11-28z/fIL-12/EFGRt T细胞、CCR5-SBC-728-HSPC、CAR4-1BBZ、CH-296、dnTGFbRII-NY-ESOc259T、Ad-RTS-IL-12、IMA-101、IMA-201、CARMA-0508、TT-18、CMD-501、CMD-503、CMD-504、CMD-502、CMD-601、CMD-602、CSG-005、LAAP T细胞疗法、PD-1敲除T细胞疗法(食管癌/NSCLC)、抗MUC1 CAR T细胞疗法(食管癌/NSCLC)、抗MUC1 CAR T细胞疗法+PD-1敲除T细胞疗法(食管癌/NSCLC)、抗KRASG12D mTCR PBL、抗CD123 CAR T细胞疗法、抗突变新抗原TCR T细胞疗法、肿瘤裂解物/MUC1/生存素加载PepTivator的树突状细胞疫苗、自体树突状细胞疫苗(转移性恶性黑素瘤,真皮内/静脉内)、抗LeY-scFv-CD28-ζCAR T细胞、PRGN-3005、iC9-GD2-CAR-IL-15T细胞、HSC-100、ATL-DC-101、MIDRIX4-LUNG、MIDRIXNEO、FCR-001、PLX干细胞疗法、MDR-101、GeniusVac-Mel4、ilixadencel、同种异体间充质干细胞疗法、romyelocel L、CYNK-001、ProTrans、ECT-100、MSCTRAIL、dilanubicel、FT-516、ASTVAC-2、E-CEL UVEC、CK-0801、同种异体α/βCD3+T细胞和CD19+B细胞耗尽的干细胞(血液病,TBX-1400、HLCN-061、脐带衍生的Hu-PHEC细胞(血液恶性肿瘤/再生障碍性贫血)、AP-011、apceth-201、apceth-301、SENTI-101、干细胞疗法(胰腺癌)、ICOVIR15-cBiTE、CD33HSC/CD33 CAR-T、PLX-免疫、SUBCUVAX、基于CRISPR同种异体γ-δT细胞的基因疗法(癌症)、基于离体CRISPR同种异体健康供体NK细胞的基因疗法(癌症)、基于离体同种异体诱导的多能干细胞衍生的NK细胞的基因疗法(实体瘤)和抗CD20 CAR T细胞疗法(非霍奇金淋巴瘤)。
V.用于治疗癌症的联合疗法
如前所述,HSPC的消融可以用于治疗造血系统癌症或替代作为治疗非造血系统癌症(例如实体瘤)的副作用而受损的HSPC。下文描述了可以与HSPC消融组合使用的有效治疗癌症的药剂的各种示例。
如本文所用,术语“化学治疗剂”或“化学疗剂”(或在用化学治疗剂治疗的情况下的“化学疗法”)意在涵盖可用于治疗癌症的任何非蛋白质性(例如非肽性)化合物。化学治疗剂的示例包括但不限于:烷基化剂,诸如噻替哌和环磷酰胺烷基磺酸盐,诸如白消安、英丙舒凡和哌泊舒凡;氮杂环丙烷,诸如苯佐替哌、卡波醌、美妥替哌和乌瑞替哌;乙撑亚胺和甲基蜜胺,包括六甲蜜胺、三乙撑蜜胺、三乙撑磷酰胺、三乙撑硫代磷酰胺和三羟甲蜜胺(trimemylolomelamine);内脂,例如布拉酸和布拉它辛酮;喜树碱,包括合成类似物拓扑替康;苔藓虫素、愈伤组织抑制素(callystatin);CC-1065,包括其阿多来新、卡折来新和比折来新合成类似物;念珠藻素,尤其是念珠藻素1和念珠藻素8;尾海兔素;倍癌霉素,包括合成类似物KW-2189和CBI-TMI;艾榴塞洛素(eleutherobin);5-氮杂胞苷;水鬼蕉碱(pancratistatin);匍枝珊瑚醇(sarcodictyin);海绵抑制素(spongistatin);氮芥,诸如苯丁酸氮芥、萘氮芥、环磷酰胺、葡磷酰胺、艾伏磷酰胺、苯达莫司汀、雌莫司汀、异环磷酰胺、二氯甲基二乙胺、盐酸氧化二氯甲基二乙胺、美法仑、新恩比兴、苯芥胆甾醇、泼尼莫司汀、曲洛磷胺和尿嘧啶氮芥;亚硝基脲,诸如卡莫司汀、氯脲霉素、福莫司汀、洛莫司汀、尼莫司汀和雷莫司汀;抗生素,诸如烯二炔抗生素(例如卡奇霉素,尤其是卡奇霉素γII和卡奇霉素)、包括达内霉素(包括达内霉素A)、双膦酸盐(诸如氯膦酸盐)、埃斯霉素、新抑癌素发色团和相关的色蛋白烯二炔抗生素发色团、阿克拉霉素、放线菌素、蒽霉素(authramycin)、重氮丝氨酸、博来霉素、放线菌素、卡拉比星、洋红霉素、嗜癌菌素(carzinophilin)、色霉素、放线菌素、柔红霉素、地托比星、6-重氮-5-氧代-L-正亮氨酸、多柔比星(包括吗啉代-多柔比星、氰基吗啉代-多柔比星、2-吡咯啉并-多柔比星和脱氧多柔比星)、表柔比星、依索比星、伊达比星、麻西罗霉素、丝裂霉素(诸如丝裂霉素C)、霉酚酸、诺加霉素、橄榄霉素、培洛霉素、泊非霉素、嘌呤霉素、奎拉霉素、罗多比星、链霉黑素、链脲佐菌素、杀结核菌素、乌苯美司、净司他丁和佐柔比星;抗代谢物,诸如甲氨蝶呤和5-氟尿嘧啶(5-FU);叶酸类似物,诸如去甲蝶呤、甲氨蝶呤、蝶罗呤和三甲曲沙;嘌呤类似物,诸如克拉屈滨、喷司他汀、氟达拉滨、6-巯基嘌呤、硫咪嘌呤和硫鸟嘌呤;嘧啶类似物,诸如安西他滨、阿扎胞苷、6-氮尿苷、卡莫氟、阿糖胞苷、双脱氧尿苷、去氧氟尿苷、依诺他滨和氟尿苷;雄激素,诸如卡普睾酮、丙酸屈他雄酮、环硫雄醇、美雄烷和睾内酯;抗肾上腺类,诸如氨鲁米特、米托坦和曲洛司坦;叶酸补充剂,诸如亚叶酸;放射治疗剂,诸如Radium-223、177-Lu-PSMA-617;单端孢霉烯,尤其是T-2毒素、疣孢菌素(verracurin)A、杆孢菌素(roridin)A和蛇形菌素(anguidine);紫杉烷类,诸如紫杉醇白蛋白结合型紫杉醇(abraxane)、多西他赛卡巴他赛、BIND-014、替司他赛;铂类似物,诸如顺铂和卡铂、NC-6004纳米铂;醋葡醛内酯;醛磷脂酰胺糖苷;氨基乙酰丙酸;恩尿嘧啶;安吖啶;赫布西尔(hestrabucil);比生群;依达曲沙;地磷酰胺(defofamine);秋水仙胺;地吖醌;依氟鸟氨酸(elformthine);依利醋铵;埃博霉素;依托格鲁;硝酸镓;羟基脲;香菇多糖;甲酰四氢叶酸;氯尼达明;美登木生物碱,诸如美登素和安丝菌素;米托胍腙;米托蒽醌;莫哌达醇;硝氨吖啶;蛋氨氮芥(phenamet);吡柔比星;洛索蒽醌;氟嘧啶;亚叶酸;鬼臼毒酸;2-乙基酰肼;丙卡巴肼;多糖-K(PSK);雷佐生;根霉素;西佐喃;锗螺胺;细交链孢菌酮酸;曲贝替定、三亚胺醌;2,2',2”-三氯三甲胺;氨基甲酸酯;长春地辛;达卡巴嗪;甘露莫司汀;二溴甘露醇(mitobronitol);二溴卫矛醇(mitolactol);哌泊溴烷(pipobroman);加西托新(gacytosine);阿拉伯糖苷(“Ara-C”);环磷酰胺;噻替派;苯丁酸氮芥;吉西他滨6-硫鸟嘌呤;巯基嘌呤;甲氨蝶呤;长春碱;铂;依托泊苷(VP-16);异环磷酰胺;米托蒽醌;长春新碱;长春瑞滨能灭瘤(novantrone);替尼泊苷;依达曲沙;道诺霉素;氨基蝶呤;昔洛达(xeoloda);伊班膦酸盐;CPT-11;拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(DFMO);类视色素,诸如视黄酸;卡培他滨;NUC-1031;FOLFOX(亚叶酸、5-氟尿嘧啶、奥沙利铂);FOLFIRI(亚叶酸、5-氟尿嘧啶、伊立替康);FOLFOXIRI(亚叶酸、5-氟尿嘧啶、奥沙利铂、伊立替康)、FOLFIRINOX(亚叶酸、5-氟尿嘧啶、伊立替康、奥沙利铂)以及上述任何物质的药学上可接受的盐、酸或衍生物。此类试剂可以缀合到抗体或本文所述的任何靶向剂上,以形成抗体-药物缀合物(ADC)或靶向药物缀合物。
“化学治疗剂”的定义中还包括抗激素剂,诸如抗雌激素和选择性雌激素受体调节剂(SERM)、芳香酶抑制剂、抗雄激素以及任何上述物质的药学上可接受的盐、酸或衍生物,其用于调节或抑制激素对肿瘤的作用。
抗雄激素的示例包括阿帕鲁胺、阿比特龙、恩杂鲁胺、氟他胺、加来特龙、尼鲁米特、比卡鲁胺、亮丙瑞林、戈舍瑞林、ODM-201、APC-100、ODM-204。
用于靶向癌症的药剂的附加示例包括:α-胎蛋白调节剂,诸如ET-1402和AFP-TCR;炭疽毒素受体1调节剂,诸如抗TEM8 CAR T细胞疗法;TNF受体超家族成员17(TNFRSF17、BCMA),诸如bb-2121(ide-cel)、bb-21217、JCARH125、UCART-BCMA、ET-140、MCM-998、LCAR-B38M、CART-BCMA、SEA-BCMA、BB212、ET-140、P-BCMA-101、AUTO-2(APRIL-CAR)、JNJ-68284528;抗CLL-1抗体(参见例如WO/2017/173384);抗PD-L1-CAR靶向活化自然杀伤细胞疗法,诸如KD-045;抗PD-L1 t-haNK,诸如PD-L1 t-haNK;抗CD45抗体,诸如131I-BC8(lomab-B);抗HER3抗体,诸如LJM716、GSK2849330;抗CD52抗体,诸如阿仑单抗(alemtuzumab);APRIL受体调节剂,诸如抗BCMA CAR T细胞疗法、Descartes-011;ADP核糖基环化酶-1/APRIL受体调节剂,诸如双重抗BCMA/抗CD38 CAR T细胞疗法;CART-ddBCMA;B7同源物6,诸如CAR-NKp30和CAR-B7H6;B淋巴细胞抗原CD19,诸如TBI-1501、CTL-119huCART-19 T细胞、liso-cel、JCAR-015US7446190、JCAR-014、JCAR-017(WO2016196388、WO2016033570、WO2015157386)、axicabtagene ciloleucel(KTE-C19、)、KTE-X19、US7741465、US6319494、UCART-19、EBV-CTL、T tisagenlecleucel-T(CTL019)、WO2012079000、WO2017049166、表达CD19CAR-CD28-CD3ζ-EGFRt的T细胞、装甲CD19/4-1BBL的CAR T细胞疗法、C-CAR-011、CIK-CAR.CD19、CD19CAR-28-ζT细胞、PCAR-019、MatchCART、DSCAR-01、IM19 CAR-T、TC-110;抗CD19 CAR T细胞疗法(B细胞急性成淋巴细胞性白血病,Universiti Kebangsaan Malaysia);抗CD19 CAR T细胞疗法(急性成淋巴细胞性白血病/非霍奇金淋巴瘤,University Hospital Heidelberg)、抗CD19 CAR T细胞疗法(IL-6表达沉默,癌症,Shanghai Unicar-Therapy Bio-medicine Technology)、MB-CART2019.1(CD19/CD20)、GC-197(CD19/CD7)、CLIC-1901、ET-019003、抗CD19-STAR-T细胞、AVA-001、BCMA-CD19 cCAR(CD19/APRIL)、ICG-134、ICG-132(CD19/CD20)、CTA-101、WZTL-002、双重抗CD19/抗CD20 CAR T细胞(慢性淋巴细胞性白血病/B细胞淋巴瘤)、HY-001、ET-019002、YTB-323、GC-012(CD19/APRIL)、GC-022(CD19/CD22)、表达CD19CAR-CD28-CD3ζ-EGFRt的Tn/mem;UCAR-011、ICTCAR-014、GC-007F、PTG-01、CC-97540;同种异体抗CD19CART细胞,诸如GC-007G;APRIL受体调节剂;SLAM家族成员7调节剂BCMA-CS1 cCAR;自体树突状细胞肿瘤抗原(ADCTA),诸如ADCTA-SSI-G;B-淋巴细胞抗原CD20,诸如ACTR707 ATTCK-20、PBCAR-20A;表达CD20 CAR的同种异体T细胞,诸如LB-1905;B-淋巴细胞抗原CD19/B-淋巴细胞抗原22,诸如TC-310;B-淋巴细胞抗原22细胞粘附,诸如UCART-22、JCAR-018 WO2016090190;NY-ESO-1调节剂,诸如GSK-3377794、TBI-1301、GSK3537142;碳酸酐酶,诸如DC-Ad-GMCAIX;半胱天冬酶9自杀基因,诸如CaspaCIDe DLI、BPX-501;CCR5,诸如SB-728;CCR5基因抑制剂/TAT基因/TRIM5基因刺激因子,诸如慢病毒载体CCR5 shRNA/TRIM5α/TAR诱饵转导的自体CD34阳性造血祖细胞;CDw123,诸如MB-102、IM-23、JEZ-567、UCART-123;CD4,诸如ICG-122;CD5调节剂,诸如CD5.28z CART细胞;抗CD22,诸如抗CD22 CART;抗CD30,诸如TT-11;CD33,诸如CIK-CAR.CD33、CD33CART;双重抗CD33/抗CLL1,诸如LB-1910;CD38,诸如T-007、UCART-38;CD40配体,诸如BPX-201、MEDI5083;CD56,诸如同种异体CD56阳性CD3阴性自然杀伤细胞(骨髓恶性肿瘤);CD19/CD7调节剂,诸如GC-197;T细胞抗原CD7调节剂,诸如抗CD7 CAR T细胞疗法(CD7阳性血液恶性肿瘤);CD123调节剂,诸如UniCAR02-T-CD123;抗CD276,诸如抗CD276CART;CEACAM蛋白5调节剂,诸如MG7-CART;封闭蛋白6,诸如CSG-002;封闭蛋白18.2,诸如LB-1904;氯毒素,诸如CLTX-CART;靶向EBV,诸如CMD-003;MUC16EGFR,诸如自体4H11-28z/fIL-12/EFGRt T细胞;内切核酸酶,诸如PGN-514、PGN-201;Epstein-Barr病毒特异性T淋巴细胞,诸如TT-10;Epstein-Barr核抗原1/潜伏膜蛋白1/分泌蛋白BARF1调节剂,诸如TT-10X;Erbb2,诸如CST-102、CIDeCAR;神经节苷脂(GD2),诸如4SCAR-GD2;γδT细胞,诸如ICS-200;叶酸水解酶1(FOLH1、谷氨酸羧肽酶II、PSMA;NCBI基因ID:2346),诸如CIK-CAR.PSMA、CART-PSMA-TGFβRDN、P-PSMA-101;磷脂酰肌醇蛋白聚糖-3(GPC3),诸如TT-16、GLYCAR;血红蛋白,诸如PGN-236;肝细胞生长因子受体,诸如抗cMet RNA CAR T;HLA I类抗原A-2α调节剂,诸如FH-MCVA2TCR;HLA I类抗原A-2α/黑素瘤相关抗原4调节剂,诸如ADP-A2M4CD8;HLA抗原调节剂,诸如FIT-001、NeoTCR-P1;人乳头瘤病毒E7蛋白,诸如KITE-439(参见例如WO/2015/184228);ICAM-1调节剂,诸如AIC-100;免疫球蛋白γFc受体III,诸如ACTR087;IL-12,诸如DC-RTS-IL-12;IL-12激动剂/粘蛋白16,诸如JCAR-020;IL-13α2,诸如MB-101;IL-15受体激动剂,诸如PRGN-3006、ALT-803;白介素-15/Fc融合蛋白(例如XmAb24306);重组白介素-15(例如AM0015、NIZ-985);聚乙二醇化IL-15(例如NKTR-255);IL-2,诸如CST-101;干扰素α配体,诸如自体肿瘤细胞疫苗+系统性CpG-B+IFN-α(癌症);K-Ras GTP酶,诸如抗KRASG12V mTCR细胞疗法;神经细胞粘附分子L1 L1CAM(CD171),诸如JCAR-023;潜伏膜蛋白1/潜伏膜蛋白2,诸如Ad5f35-LMPd1-2转导的自体树突状细胞;MART-1黑素瘤抗原调节剂,诸如MART-1 F5 TCR工程改造的PBMC;黑素瘤相关抗原10,诸如MAGE-A10C796T MAGE-A10 TCR;黑素瘤相关抗原3/黑素瘤相关抗原6(MAGE A3/A6),诸如KITE-718(参见例如WO/2014/043441);间皮素,诸如CSG-MESO、TC-210;粘蛋白1调节剂,诸如ICTCAR-052、Tn MUC-1 CAR-T、ICTCAR-053;抗MICA/MICB,诸如CYAD-02;NKG2D,诸如NKR-2;Ntrkr1酪氨酸激酶受体,诸如JCAR-024;PRAMET细胞受体,诸如BPX-701;前列腺干细胞抗原调节剂,诸如MB-105;环岛同源物1调节剂,诸如ATCG-427;肽聚糖识别蛋白调节剂,诸如Tag-7基因修饰的自体肿瘤细胞疫苗;PSMA,诸如PSMA-CAR T细胞疗法(慢病毒载体、去势抵抗性前列腺癌);SLAM家族成员7调节剂,诸如IC9-Luc90-CD828Z;TGFβ受体调节剂,诸如DNR.NPC T细胞;T-淋巴细胞,诸如TT-12;T-淋巴细胞刺激剂,诸如ATL-001;TSH受体调节剂,诸如ICTCAR-051;肿瘤浸润性淋巴细胞,诸如LN-144、LN-145;以及Wilms肿瘤蛋白,诸如JTCR-016、WT1-CTL或ASP-7517。孕酮受体拮抗剂的示例包括奥那司酮。
在各种实施方案中,如上所述的用于治疗癌症的药剂可以与抗血管生成剂组合。可以共施用的抗血管生成剂包括但不限于视黄酸及其衍生物、2-甲氧基雌二醇、瑞戈非尼、尼古帕尼、苏拉明、角鲨胺、金属蛋白酶-1的组织抑制剂、金属蛋白酶-2的组织抑制剂、纤溶酶原激活物抑制剂-1、纤溶酶原激活物抑制剂-2、软骨来源的抑制剂、紫杉醇(纳布-紫杉醇)、血小板因子4、硫酸鱼精蛋白(鲱精蛋白)、硫酸化甲壳素衍生物(由雪蟹壳制备)、硫酸化多糖肽聚糖复合物(sp-pg)、星形孢菌素、基质代谢调节剂(包括脯氨酸类似物,诸如l-氮杂环丁烷-2-羧酸(LACA)、顺式羟基脯氨酸、d,I-3,4-脱氢脯氨酸、硫代脯氨酸)、α,α'-联吡啶、β-氨基丙腈延胡索酸盐、4-丙基-5-(4-吡啶基)-2(3h)-噁唑酮、甲氨蝶呤、米托蒽醌、肝素、干扰素、2巨球蛋白-血清、鸡金属蛋白酶-3的抑制剂(ChIMP-3)、糜蛋白酶抑素、β-环糊精十四硫酸盐、依泊霉素、夫马菌素、硫代苹果酸金钠、右旋青霉胺、β-1-抗胶原酶-血清、α-2-抗纤溶酶、比生群、氯苯扎利二钠、n-2-羧基苯基-4-氯蒽酮酸二钠或“CCA”、沙利度胺、血管抑制性类固醇、羧基氨基咪唑、金属蛋白酶抑制剂(诸如BB-94)、S100A9的抑制剂(诸如他喹莫德)。其他抗血管新生剂包括抗体、优选针对这些血管生成生长因子的单克隆抗体:β-FGF、α-FGF、FGF-5、VEGF同种型、VEGF-C、HGF/SF和Ang-1/Ang-2。
在各种实施方案中,如上所述的用于治疗癌症的药剂与抗纤维化剂组合。可以共同施用的抗纤维化剂包括但不限于诸如β-氨基丙腈(BAPN)的化合物,以及US 4965288中公开的涉及赖氨酰氧化酶抑制剂及其在治疗与胶原异常沉积相关的疾病和病症中的用途和US 4997854中公开的涉及抑制LOX以治疗各种病理纤维化状态的化合物的化合物,这些专利以引用方式并入本文。另外的示例性抑制剂在涉及诸如2-异丁基-3-氟-、氯-或溴-烯丙胺的化合物的US 4943593、涉及2-(1-萘氧基甲基)-3-氟烯丙胺的US 5021456、US5059714、US 5120764、US 5182297、US 5252608以及US 2004-0248871中描述,这些专利以引用方式并入本文。
示例性抗纤维化剂还包括与赖氨酰氧化酶的活性位点的羰基基团反应的伯胺,并且更具体地,与羰基结合后产生通过共振稳定的产物的那些,诸如以下伯胺:乙二胺、肼、苯肼以及它们的衍生物;氨基脲和脲衍生物;氨基腈,诸如BAPN或2-硝基乙胺;不饱和或饱和的卤代胺,诸如2-溴-乙胺、2-氯乙胺、2-三氟乙胺、3-溴丙胺和对卤代苄胺;以及硒高半胱氨酸内酯。
其他抗纤维化剂是渗入或不渗入细胞的铜螯合剂。示例性化合物包括间接抑制剂,其阻断源自赖氨酰氧化酶对赖氨酰和羟基赖氨酰残基氧化脱氨基的醛衍生物。示例包括硫醇胺(特别是D-青霉胺)及其类似物,诸如2-氨基-5-巯基-5-甲基己酸、D-2-氨基-3-甲基-3-((2-乙酰氨基乙基)二硫代)丁酸、p-2-氨基-3-甲基-3-((2-氨基乙基)二硫代)丁酸、4-((p-1-二甲基-2-氨基-2-羧基乙基)二硫代)丁烷硫酸钠、2-乙酰氨基乙基-2-乙酰氨基乙硫醇硫酸盐和4-巯基丁烷亚磺酸钠三水合物。
一些化学治疗剂适用于治疗淋巴瘤或白血病。这些药剂包括阿地白介素、阿伏昔地、阿米福汀三水合物、氨基喜树碱、抗瘤酮A10、抗瘤酮AS2-1、抗胸腺细胞球蛋白、三氧化二砷、Bcl-2家族蛋白抑制剂ABT-263、β-阿理新(alethine)、BMS-345541硼替佐米(PS-341)、苔藓虫素1、布舒凡(bulsulfan)、坎帕斯(campath)-1H、卡铂、卡非佐米卡莫司汀、醋酸卡泊芬净、CC-5103、苯丁酸氮芥、CHOP(环磷酰胺、多柔比星、长春新碱和泼尼松)、顺铂、克拉屈滨、氯法拉滨、姜黄素、CVP(环磷酰胺、长春新碱和泼尼松)、环磷酰胺、环孢霉素、阿糖胞苷、地尼白介素(denileukin diftitox)、地塞米松、多西他赛、尾海兔素10、多柔比星、盐酸多柔比星、DT-PACE(地塞米松、沙利度胺、顺铂、多柔比星、环磷酰胺和依托泊苷)、恩扎妥林、阿法依泊汀、依托泊苷、依维莫司(RAD001)、FCM(氟达拉滨、环磷酰胺和米托蒽醌)、FCR(氟达拉滨、环磷酰胺和利妥昔单抗)、芬维A胺、非格司亭、夫拉平度(flavopiridol)、氟达拉滨、FR(氟达拉滨和利妥昔单抗)、格尔德霉素(17AAG)、hyperCVAD(高分次环磷酰胺、长春新碱、多柔比星、地塞米松、甲氨蝶呤和阿糖胞苷)、ICE(异磷酰胺、卡铂和依托泊苷)、异环磷酰胺、盐酸伊立替康、干扰素α-2b、伊沙匹隆、来那度胺(CC-5013)、泊马度胺淋巴因子活化的杀伤细胞、MCP(米托蒽醌、苯丁酸氮芥和泼尼松龙)、美法仑、美司钠、甲氨蝶呤、盐酸米托蒽醌、莫特沙芬钆、麦考酚酸莫酯、奈拉滨、奥巴克拉(obatoclax)(GX15-070)、奥利默森(oblimersen)、醋酸奥曲肽、ω-3脂肪酸、Omr-IgG-am(WNIG、Omrix)、奥沙利铂、紫杉醇、帕博西尼(PD0332991)、培非格司亭、PEG化脂质体盐酸多柔比星、派瑞弗辛(perifosin)、泼尼松龙、泼尼松、重组flt3配体、重组人血小板生成素、重组干扰素α、重组白介素-11、重组白介素-12、利妥昔单抗、R-CHOP(利妥昔单抗和CHOP)、R-CVP(利妥昔单抗和CVP)、R-FCM(利妥昔单抗和FCM)、R-ICE(利妥昔单抗和ICE)和R MCP(利妥昔单抗和MCP)、R-罗斯科维汀(R-roscovitine)(塞利西利布(seliciclib)、CYC202)、沙格司亭、柠檬酸西地那非、辛伐他汀、西罗莫司、苯乙烯基砜、他克莫司、坦螺旋霉素、替西罗莫司(CCl-779)、沙利度胺、治疗性同种异体淋巴细胞、噻替哌、替吡法尼、长春新碱、硫酸长春新碱、二酒石酸长春瑞滨、SAHA(辛二酸胺异羟肟酸或辛二酰、苯胺和异羟肟酸)、维莫非尼维奈托克(ABT-199)。
非霍奇金淋巴瘤(NHL)(尤其是B细胞来源的那些)的治疗包括使用单克隆抗体、标准化学疗法方法(例如CHOP(环磷酰胺、多柔比星、长春新碱和泼尼松)、CVP(环磷酰胺、长春新碱和泼尼松)、FCM(氟达拉滨、环磷酰胺和米托蒽醌)、MCP(米托蒽醌、苯丁酸氮芥、泼尼松龙),所有任选地包括利妥昔单抗(R)等)、放射免疫疗法以及它们的组合,尤其是抗体疗法与化学疗法的整合。
用于治疗NHL/B细胞癌症的未缀合单克隆抗体的示例包括利妥昔单抗、阿仑单抗、人或人源化抗CD20抗体、鲁米昔单抗(lumiliximab)、抗TNF相关细胞凋亡诱导配体(抗TRAIL)、贝伐珠单抗(bevacizumab)、加利昔单抗(galiximab)、依帕珠单抗(epratuzumab)、SGN-40和抗CD74。
用于治疗NHL/B细胞癌症的实验抗体药剂的示例包括奥法木单抗(ofatumumab)、ha20、PRO131921、阿仑单抗、加利昔单抗、SGN-40、CHIR-12.12、依帕珠单抗、鲁米昔单抗、阿泊珠单抗(apolizumab)、米拉妥珠单抗(milatuzumab)和贝伐珠单抗。
NHL/B细胞癌症的化学疗法的标准方案的示例包括CHOP、FCM、CVP、MCP、R-CHOP(利妥昔单抗、环磷酰胺、多柔比星、长春新碱和泼尼松)、R-FCM、R-CVP和R MCP。
套细胞淋巴瘤(MCL)的治疗性治疗包括组合化学疗法,诸如CHOP、hyperCVAD和FCM。这些方案也可以用单克隆抗体利妥昔单抗补充以形成组合疗法R-CHOP、hyperCVAD-R和R-FCM。上述疗法中的任一种可与干细胞移植或ICE组合以治疗MCL。
治疗MCL的替代方法是免疫疗法。一种免疫疗法使用单克隆抗体如利妥昔单抗。另一种使用癌症疫苗,诸如GTOP-99,这些癌症疫苗基于个体患者肿瘤的基因构成。
另一种治疗方法是与其他化学治疗剂组合施用导致Bcl-2蛋白降解并增加癌细胞对化学疗法(诸如奥利默森)的敏感性的药物。
另一种治疗方法包括施用可以导致对细胞生长的抑制甚至细胞死亡的mTOR抑制剂。非限制性示例为西罗莫司、替西罗莫司(CCI-779)、CC-115、CC-223、SF-1126、PQR-309(比拉利西布(bimiralisib))、沃塔西布(voxtalisib)、GSK-2126458以及与或其他化学治疗剂组合的替西罗莫司。
已经公开了其他最近的MCL疗法。此类示例包括夫拉平度、帕博西尼(PD0332991)、R-罗斯科维汀(塞利西利布、CYC202)、苯乙烯基砜、奥巴克拉(GX15-070)、TRAIL、抗TRAIL死亡受体DR4和DR5抗体、替西罗莫司(CCl-779)、依维莫司(RAD001)、BMS-345541、姜黄素、SAHA、沙利度胺、来那度胺(CC-5013)和格尔德霉素(17AAG)。
用于治疗华氏巨球蛋白血症(WM)的治疗剂包括阿地白介素、阿仑单抗、阿伏昔地、阿米福汀三水合物、氨基喜树碱、抗瘤酮A10、抗瘤酮AS2-1、抗胸腺细胞球蛋白、三氧化二砷、自体人肿瘤来源的HSPPC-96、Bcl-2家族蛋白抑制剂ABT-263、β-阿理新、硼替佐米苔藓虫素1、布舒凡、坎帕斯-1H、卡铂、卡莫司汀、醋酸卡泊芬净、CC-5103、顺铂、氯法拉滨、环磷酰胺、环孢霉素、阿糖胞苷、地尼白介素、地塞米松、多西他塞、尾海兔素10、盐酸多柔比星、DT-PACE、恩扎妥林、阿法依泊汀、依帕珠单抗(hLL2-抗-CD22人源化抗体)、依托泊苷、依维莫司、芬维A胺、非格司亭、氟达拉滨、依鲁替尼、异磷酰胺、铟-111单克隆抗体MN-14、碘-131托西莫单抗、盐酸伊立替康、伊沙匹隆、淋巴因子活化的杀伤细胞、美法仑、美司钠、甲氨蝶呤、盐酸米托蒽醌、单克隆抗体CD19(诸如tisagenlecleucel-T、CART-19、CTL-019)、单克隆抗体CD20、莫特沙芬钆、麦考酚酸莫酯、奈拉滨、奥利默森、醋酸奥曲肽、Ω-3脂肪酸、奥沙利铂、紫杉醇、培非格司亭、PEG化脂质体盐酸多柔比星、喷司他丁、派瑞弗辛、泼尼松、重组flt3配体、重组人血小板生成素、重组干扰素α、重组白介素-11、重组白介素-12、利妥昔单抗、沙格司亭、柠檬酸西地那非辛伐他汀、西罗莫司、他克莫司、坦螺旋霉素、沙利度胺、治疗性同种异体淋巴细胞、噻替哌、替吡法尼、托西莫单抗、优库路单抗(ulocuplumab)、维妥珠单抗(veltuzumab)、硫酸长春新碱、二酒石酸长春瑞滨、伏立诺他、WT1 126-134肽疫苗、WT-1类似肽疫苗、钇-90替伊莫单抗、钇-90人源化依帕珠单抗以及它们的任何组合。
用于治疗WM的治疗程序的示例包括外周血干细胞移植、自体造血干细胞移植、自体骨髓移植、抗体疗法、生物疗法、酶抑制剂疗法、全身辐照、干细胞输注、干细胞支持下进行骨髓消融、经体外处理的外周血干细胞移植、脐带血移植、免疫酶技术、低LET钴-60γ射线疗法、博来霉素、常规外科手术、放射疗法和非骨髓消融性同种异体造血干细胞移植。
用于治疗弥漫性大B细胞淋巴瘤(DLBCL)的治疗剂包括环磷酰胺、多柔比星、长春新碱、泼尼松、抗CD20单克隆抗体、依托泊苷、博来霉素、针对WM列出的许多药剂以及它们的任何组合,诸如ICE和R ICE。
用于治疗慢性淋巴细胞性白血病(CLL)的治疗剂的示例包括苯丁酸氮芥、环磷酰胺、氟达拉滨、喷司他丁、克拉屈滨、多柔比星、长春新碱、泼尼松、泼尼松龙、阿仑单抗、针对WM列出的许多药剂以及组合化学疗法和化学免疫疗法,包括以下常见组合方案:CVP、R-CVP、ICE、R-ICE、FCR和FR。
骨髓纤维化抑制剂包括但不限于刺猬蛋白(hedgehog)抑制剂、组蛋白脱乙酰酶(HDAC)抑制剂和酪氨酸激酶抑制剂。刺猬蛋白抑制剂的非限制性示例为萨瑞德吉(saridegib)和维斯莫吉布(vismodegib)。HDAC抑制剂的示例包括但不限于普西司他(pracinostat)和帕比司他(panobinostat)。酪氨酸激酶抑制剂的非限制性示例为来他替尼、博舒替尼、伊马替尼、雷多替尼和卡博替尼。
吉西他滨、纳布-紫杉醇和吉西他滨/纳布-紫杉醇可与JAK抑制剂和/或PI3Kδ抑制剂一起使用以治疗过度增生性障碍。
用于治疗膀胱癌的治疗剂包括阿特珠单抗(atezolizumab)、卡铂、顺铂、多西他赛、多柔比星、氟尿嘧啶(5-FU)、吉西他滨、伊多米德(idosfamide)、干扰素α-2b、甲氨蝶呤、丝裂霉素、纳布-紫杉醇、紫杉醇、培美曲塞、噻替哌、长春碱以及它们的任何组合。
用于治疗乳腺癌的治疗剂包括白蛋白结合的紫杉醇、阿那曲唑、卡培他滨、卡铂、顺铂、环磷酰胺、多西他赛、多柔比星、表柔比星、依维莫司、依西美坦、氟尿嘧啶、氟维司群、吉西他滨、伊沙匹隆、拉帕替尼、来曲唑、甲氨蝶呤、米托蒽醌、紫杉醇、聚乙二醇化脂质体多柔比星、帕妥珠单抗(pertuzumab)、他莫昔芬、托瑞米芬、曲妥珠单抗(trastuzumab)、长春瑞滨以及它们的任何组合。
用于治疗三阴性乳腺癌的治疗剂包括环磷酰胺、多西他赛、多柔比星、表柔比星、氟尿嘧啶、紫杉醇以及它们的组合。
用于治疗结肠直肠癌的治疗剂包括贝伐珠单抗、卡培他滨、西妥昔单抗(cetuximab)、氟尿嘧啶、伊立替康、甲酰四氢叶酸、奥沙利铂、帕尼单抗(panitumumab)、阿柏西普以及它们的任何组合。
用于治疗去势抵抗性前列腺癌的治疗剂包括阿比特龙、卡巴他赛、多西他赛、恩杂鲁胺、泼尼松、西普鲁塞-T以及它们的任何组合。
用于治疗食管和食管胃连接部癌的治疗剂包括卡培他滨、卡铂、顺铂、多西他赛、表柔比星、氟嘧啶、氟尿嘧啶、伊立替康、甲酰四氢叶酸、奥沙利铂、紫杉醇、雷莫芦单抗(ramucirumab)、曲妥珠单抗以及它们的任何组合。
用于治疗胃癌的治疗剂包括卡培他滨、卡铂、顺铂、多西他赛、表柔比星、氟嘧啶、氟尿嘧啶、伊立替康、甲酰四氢叶酸、丝裂霉素、奥沙利铂、紫杉醇、雷莫芦单抗、曲妥珠单抗以及它们的任何组合。
用于治疗头颈癌的治疗剂包括阿法替尼、博来霉素、卡培他滨、卡铂、西妥昔单抗、顺铂、多西他赛、氟尿嘧啶、吉西他滨、羟基脲、甲氨蝶呤、纳武单抗(nivolumab)、紫杉醇、帕博利珠单抗(pembrolizumab)、长春瑞滨以及它们的任何组合。
用于治疗肝胆癌的治疗剂包括卡培他滨、顺铂、氟嘧啶、5-氟尿苷、吉西他滨、奥沙利铂、索拉非尼以及它们的任何组合。
用于治疗肝细胞癌的治疗剂包括卡培他滨、多柔比星、吉西他滨、索拉非尼以及它们的任何组合。
用于治疗非小细胞肺癌(NSCLC)的治疗剂包括阿法替尼、白蛋白结合的紫杉醇、艾乐替尼、贝伐珠单抗、贝伐珠单抗生物仿制药、卡博替尼、卡铂、顺铂、克唑替尼、达拉菲尼、多西他赛、埃罗替尼、依托泊苷、吉西他滨、纳武单抗、紫杉醇、帕博利珠单抗、培美曲塞、雷莫芦单抗、曲美替尼、曲妥珠单抗、凡德他尼、维莫非尼、长春花碱、长春瑞滨以及它们的任何组合。
用于治疗小细胞肺癌(SCLC)的治疗剂包括苯达莫司汀、卡铂、顺铂、环磷酰胺、多西他赛、多柔比星、依托泊苷、吉西他滨、伊匹单抗(ipillimumab)、伊立替康、纳武单抗、紫杉醇、替莫唑胺、拓扑替康、长春新碱、长春瑞滨以及它们的任何组合。
用于治疗黑素瘤癌的治疗剂包括白蛋白结合的紫杉醇、卡铂、顺铂、克比替尼(cobiemtinib)、达拉菲尼、达卡巴嗪、IL-2、伊马替尼、干扰素α-2b、伊匹单抗、亚硝基脲、纳武单抗、紫杉醇、帕博利珠单抗、易普利单抗(ipilimumab)、替莫唑胺、曲美替尼、维莫非尼、长春碱以及它们的任何组合。
用于治疗卵巢癌的治疗剂包括5-氟尿嘧啶、白蛋白结合的紫杉醇、六甲蜜胺、阿那曲唑、贝伐珠单抗、卡培他滨、卡铂、顺铂、环磷酰胺、多西他赛、多柔比星、依托泊苷、依西美坦、吉西他滨、异磷酰胺、伊立替康、来曲唑、醋酸亮丙瑞林、脂质体多柔比星、醋酸甲地孕酮、美法仑、奥拉帕尼、奥沙利铂、紫杉醇、帕唑帕尼、培美曲塞、他莫昔芬、拓扑替康、长春瑞滨以及它们的任何组合。
用于治疗胰腺癌的治疗剂包括5-氟尿嘧啶、白蛋白结合的紫杉醇、卡培他滨、顺铂、多西他赛、埃罗替尼、氟嘧啶、吉西他滨、伊立替康、甲酰四氢叶酸、奥沙利铂、紫杉醇以及它们的任何组合。
用于治疗肾细胞癌的治疗剂包括阿昔替尼、贝伐珠单抗、卡博替尼、埃罗替尼、依维莫司、乐伐替尼(levantinib)、纳武单抗、帕唑帕尼、索拉非尼、舒尼替尼、替西罗莫司以及它们的任何组合。
VI.抗体的一般特性
针对抗原的其他非人单克隆抗体(例如,鼠、豚鼠、灵长类动物、兔或大鼠)的产生可通过例如用抗原或其片段或携带抗原的细胞免疫动物来实现。参见Harlow&Lane,Antibodies,A Laboratory Manual(CSHP NY,1988)(以引用方式并入以用于所有目的)。此类抗原可通过肽合成或通过重组表达从天然来源获得。任选地,抗原可与载体蛋白融合或以其他方式复合而施用。任选地,抗原可与佐剂一起施用。如下所述,可使用几种类型的佐剂。优选完全弗氏佐剂和随后的不完全佐剂用于实验室动物的免疫。
人源化抗体是基因工程抗体,其中来自非人“供体”抗体的CDR被移植到人“受体”抗体序列中(参见例如,Queen,美国专利5,530,101和5,585,089;Winter,美国专利5,225,539;Carter,美国专利6,407,213;Adair,美国专利5,859,205、6,881,557;Foote,美国专利6,881,557)。受体抗体序列可以是例如成熟人抗体序列、此类序列的复合物、人抗体序列的共有序列或种系区域序列。因此,人源化抗体是具有完全或基本上来自供体抗体的一些或全部CDR以及完全或基本上来自人抗体序列的可变区框架序列和恒定区(如果存在的话)的抗体。类似地,人源化重链具有完全或基本上来自供体抗体重链的至少一个、两个并且通常全部三个CDR,以及基本上来自人重链可变区框架和恒定区序列的重链可变区框架序列和重链恒定区(如果存在的话)。类似地,人源化轻链具有完全或基本上来自供体抗体轻链的至少一个、两个并且通常全部三个CDR,以及基本上来自人轻链可变区框架和恒定区序列的轻链可变区框架序列和轻链恒定区(如果存在的话)。除纳米抗体和dAb之外,人源化抗体还包含人源化重链和人源化轻链。当相应CDR之间至少85%、90%、95%或100%的对应残基(如Kabat所定义)相同时,人源化抗体中的CDR基本上来自非人抗体中的对应CDR。当由Kabat定义的对应残基的至少85%、90%、95%或100%是相同的时,抗体链的可变区构架序列或抗体链的恒定区基本上分别来自人可变区构架序列或人恒定区。
虽然人源化抗体通常并入了来自小鼠抗体的全部六个CDR(优选地如Kabat所定义),但它们也可用少于全部CDR的CDR(例如,来自小鼠抗体的至少3、4或5个CDR)制备(例如,Pascalis等人,J.Immunol.169:3076,2002;Vajdos等人,Journal of MolecularBiology,320:415-428,2002;Iwahashi等人,Mol.Immunol.36:1079-1091,1999;Tamura等人,Journal of Immunology,164:1432-1441,2000)。
嵌合抗体是其中非人抗体(例如,小鼠)的轻链和重链的成熟可变区与人轻链和重链恒定区组合的抗体。此类抗体基本上或完全保留小鼠抗体的结合特异性,并且为约三分之二的人序列。
镶饰抗体是一种人源化抗体,其保留了非人抗体的一些且通常全部CDR和一些非人可变区构架残基,但置换了可能对B细胞或T细胞表位有贡献的其他可变区构架残基,例如用来自人抗体序列的对应位置的残基替代暴露的残基(Padlan,Mol.Immunol.28:489,1991)。结果是这样的抗体,其中CDR完全或基本上来自非人抗体,并且非人抗体的可变区框架通过置换而变得更类似于人。
人抗体可从人分离,或以其他方式由人免疫球蛋白基因的表达(例如,在转基因小鼠中、在体外或通过噬菌体展示)产生。用于产生人抗体的方法包括:Oestberg等人,Hybridoma 2:361-367(1983);Oestberg,美国专利4,634,664;和Engleman等人,美国专利4,634,666的trioma方法,使用包括人免疫球蛋白基因的转基因小鼠(参见例如,Lonberg等人,WO93/12227(1993);美国专利5,877,397、5,874,299、5,814,318、5,789,650、5,770,429、5,661,016、5,633,425、5,625,126、5,569,825、5,545,806,Nature 148,1547-1553(1994),Nature Biotechnology 14,826(1996),Kucherlapati,WO 91/10741(1991))以及噬菌体展示方法(参见例如,Dower等人,WO 91/17271和McCafferty等人,WO 92/01047,美国专利5,877,218、5,871,907、5,858,657、5,837,242、5,733,743和5,565,332。
筛选抗体与它们的预期靶标的特异性结合。可进一步筛选抗体与靶标的特定区域(例如,含有所需表位)的结合、与参考抗体的竞争、带有抗原的细胞的激动作用或拮抗作用。非人抗体可以转化为如上所述的嵌合、镶饰或人源化形式。
恒定区的选择部分地取决于是否需要抗体依赖性细胞介导的细胞毒性、抗体依赖性细胞吞噬作用和/或补体依赖性细胞毒性。例如,人同种型IgG1和IgG3具有补体依赖性细胞毒性,而人同种型IgG2和IgG4则没有。轻链恒定区可以是λ或κ。人IgG1和IgG3还比人IgG2和IgG4诱导更强的细胞介导的效应子功能。
人恒定区显示不同个体之间的同种异型变异和异同种异型变异,即,恒定区在不同个体中在一个或多个多态性位置处可不同。异同种异型与同种异型的区别在于识别异同种异型的血清与一种或多种其他同种型的非多态性区域结合。提及人恒定区包括具有任何天然同种异型或占据天然同种异型中多态性位置的任何残基排列的恒定区。
轻链和/或重链的氨基或羧基末端处的一个或若干个氨基酸,诸如重链的C末端赖氨酸,可在分子的一部分或全部中缺失或衍生化。可以在恒定区中进行置换以降低或增加效应子功能,诸如补体介导的细胞毒性或ADCC(参见例如Winter等人,美国专利5,624,821;Tso等人,美国专利5,834,597;以及Lazar等人,Proc.Natl.Acad.Sci.USA 103:4005,2006),或延长在人体中的半衰期(参见例如,Hinton等人,J.Biol.Chem.279:6213,2004)。示例性置换包括位置250处的Gln和/或位置428处的Leu、位置434处的S或N、位置252处的Y、位置254处的T和位置256处的E。N434A(EU编号)。增加的FcRn结合有利于使本发明的杂合蛋白与内源IgG更强地竞争结合FcRn。还已知许多突变用于降低ADCC、ADP或CMC中的任一种。(参见例如,Winter等人,美国专利5,624,821;Tso等人,美国专利5,834,597;以及Lazar等人,Proc.Natl.Acad.Sci.USA 103:4005,2006)。例如,位置234、235、236和/或237中的任一者的置换降低了对Fcγ受体(特别是FcγRI受体)的亲和力(参见例如US 6,624,821)。任选地,人IgG2中的位置234、236和/或237被丙氨酸置换,并且位置235被谷氨酰胺或谷氨酸置换。(参见例如US 5,624,821。)降低效应子功能的其他置换包括位置268处的A、位置297处的G或A、位置309处的L、位置322处的A、位置327处的G、位置330处的S、位置331处的S、位置238处的S、位置268处的A、位置309处的L。增强效应子功能的突变的一些示例包括S239D、I332E、A330L以及它们的组合。
如所指出的,在一些实施方案中,抗体的Fc区包含促进抗结合分子的血清半衰期增加的一个或多个氨基酸修饰。已经描述了增加抗体的半衰期的突变。在一个实施方案中,CD3靶向重链和HIV抗原靶向重链中的一者或两者的Fc区或Fc结构域包含位置252(EU编号)处的甲硫氨酸至酪氨酸置换、位置254(EU编号)处的丝氨酸至苏氨酸置换以及位置256(EU编号)处的苏氨酸至谷氨酸置换。参见例如美国专利7,658,921。这种类型的突变体(命名为“YTE突变体”)相对于同一抗体的野生型型式表现出四倍增加的半衰期(Dall'Acqua等人,JBiol Chem,281:23514-24(2006);Robbie等人,Antimicrob.Agents Chemotherap.,57(12):6147-6153(2013))。在某些实施方案中,CD3靶向重链和HIV抗原靶向重链中的一者或两者的Fc区或Fc结构域包含IgG恒定结构域,该IgG恒定结构域包含位置251-257、285-290、308-314、385-389和428-436(EU编号)处的氨基酸残基的一个、两个、三个或更多个氨基酸置换。另选地,M428L和N434S(“LS”)置换可以增加多特异性抗原结合分子的药代动力学半衰期。在其他实施方案中,Fc区包含M428L和N434S置换(EU编号)。在其他实施方案中,CD3靶向重链和HIV抗原靶向重链中的一者或两者的Fc区或Fc结构域包含T250Q和M428L(EU编号)突变。在其他实施方案中,Fc区包含H433K和N434F(EU编号)突变。
如所指出的,抗体的Fc区可以包括增加效应子活性(例如,具有改善的FcγIIIa结合和增加的抗体依赖性细胞毒性(ADCC))的翻译后和/或氨基酸修饰。在一些实施方案中,抗体的Fc区或Fc结构域在Fc区中包含DE修饰(即,按EU编号的S239D和I332E)。在一些实施方案中,抗体的Fc区或Fc结构域在Fc区中包含DEL修饰(即,按EU编号的S239D、I332E和A330L)。在一些实施方案中,抗体的Fc区或Fc结构域在Fc区中包含DEA修饰(即,按EU编号的S239D、I332E和G236A)。在一些实施方案中,抗体的Fc区或Fc结构域在Fc区中包含DEAL修饰(即,按EU编号的S239D、I332E、G236A和A330L)。参见例如美国专利7,317,091、7,662,925、8,039,592、8,093,357、8,093,359、8,383,109、8,388,955、8,735,545、8,858,937、8,937,158、9,040,041、9,353,187、10,184,000和10,584,176。增加效应子活性(例如,具有改善的FcγIIIa结合和增加的抗体依赖性细胞毒性(ADCC))的另外的氨基酸修饰包括但不限于(EU编号)第一Fc结构域上的F243L/R292P/Y300L/V305I/P396L;S298A/E333A/K334A;或L234Y/L235Q/G236W/S239M/H268D/D270E/S298A以及第二Fc结构域上的D270E/K326D/A330M/K334E。增加C1q结合和补体依赖性细胞毒性(CDC)的氨基酸突变包括但不限于(EU编号)S267E/H268F/S324T或K326W/E333S。增强效应子活性的Fc结构区突变在例如Wang等人,Protein Cell(2018)9(1):63–73以及Saunders,Front Immunol.(2019)10:1296中综述。
在其他实施方案中,抗体或其抗原结合片段具有经修饰的糖基化,其例如可在翻译后引入或通过基因工程引入。在一些实施方案中,抗体或其抗原结合片段例如在抗体或其抗原结合片段中存在的糖基化位点处被无岩藻糖基化。大多数批准的单克隆抗体具有IgG1同种型,其中两个N连接的双分枝复合物型低聚糖结合到Fc区。Fc区通过其与FcγR家族的白细胞受体相互作用来发挥ADCC的效应子功能。无岩藻糖基化单克隆抗体是经工程改造使得抗体Fc区中的低聚糖不具有任何岩藻糖单位的单克隆抗体。
可测试用于消融的目的抗体诱导ADCC的能力。抗体相关的ADCC活性可以通过检测标记或乳酸脱氢酶从裂解细胞的释放或者检测降低的靶细胞活力(例如,膜联蛋白测定)来监测和定量。细胞凋亡测定可以通过末端脱氧核苷酸转移酶介导的地高辛-1 1-dUTP切口末端标记(TUNEL)测定(Lazebnik等人,Nature:371,346(1994))来进行。细胞毒性也可通过检测试剂盒直接检测,诸如来自Roche Applied Science(Indianapolis,Ind.)的细胞毒性检测试剂盒。同样可以测试抗体在例如AML LSC上诱导抗体依赖性吞噬作用(ADP)的能力,如WO/2009/091601所述。
在一些实施方案中,免疫治疗剂缀合至效应子部分。效应子部分可以是任何数量的分子,包括标记部分诸如放射性标记或荧光标记,或者可以是细胞毒性部分。细胞毒素剂包括细胞毒素药物或毒素或此类毒素的活性片段。合适的毒素及其相应的片段包括白喉A链、外毒素A链、蓖麻毒素A链、相思豆毒素A链、泻果素、巴豆素、酚霉素、伊诺霉素、皂草素、奥瑞他汀(auristatin)E等。细胞毒素剂还包括通过将放射性同位素缀合至抗体而制备的放射性化学品。将细胞毒性部分靶向跨膜蛋白用于增加靶向区域中细胞毒性部分的局部浓度。
VII.血细胞的遗传障碍
本发明的方法可以用于纠正血细胞的遗传障碍,特别是由单一蛋白质突变引起的单基因障碍。此类障碍可以是显性或非显性的,并且可导致部分或完全外显。一般来讲,此类障碍可以通过消融内源性HPLC并施用替代HPLC来治疗,该替代HPLC包括作为障碍基础的蛋白质的功能性(例如,野生型)形式。此类细胞也可以表达野生型蛋白质或代替蛋白质的突变形式,这取决于如何进行遗传修饰。
血细胞的遗传障碍包括血红蛋白病,诸如地中海贫血和镰状细胞病、X连锁重症联合免疫缺陷(X-SCID)、腺苷脱氨酶缺陷(ADA-SCID)、其他遗传形式的SCID(artemis、Rag1/2)、维斯科特-奥尔德里奇综合征(WAS)、慢性肉芽肿性疾病、噬血细胞性淋巴组织细胞增多症、X-连锁高IgM综合征、X-连锁淋巴增殖性疾病、X-连锁无丙种球蛋白血症、X-连锁肾上腺脑白质营养不良、异染性脑白质营养不良、血友病、血管性血友病、镰状细胞性贫血、遗传性再生障碍性贫血、纯红细胞再生障碍、阵发性睡眠性血红蛋白尿症、范可尼贫血、噬血细胞性淋巴组织细胞增多症(HLH)、先天性代谢缺陷(例如黏多糖病、戈谢病和其他脂质沉积)、大疱性表皮松解症、重型先天性中性粒细胞减少症、舒-戴二氏综合征、戴蒙德-布莱克范贫血、科斯曼综合症和白细胞粘附缺陷。
在镰状细胞性贫血中,血红蛋白β链的第六个氨基酸中的缬氨酸被谷氨酸取代。血红蛋白的缬氨酸突变体形式比谷氨酸形式的溶解度低得多;它形成杆状假体的半固体凝胶,导致RBC在低P02的部位呈镰状。畸变的僵化RBC附着到血管内皮并阻塞小动脉和毛细血管,从而导致闭塞和梗塞。由于镰状RBC太脆弱,无法承受循环的机械创伤,因此它们进入循环后会发生溶血。在纯合子中,临床表现是由贫血以及导致组织缺血和梗塞的血管闭塞事件引起的。生长发育受损,并且感染易感性增加。贫血通常很严重,但患者之间差异很大。镰状细胞性贫血可以通过以下方式来治疗:纠正遗传缺陷,表达额外的功能性血红蛋白转录单位或破坏BCL11A红细胞增强,从而抑制胎儿珠蛋白表达,使胎儿血红蛋白水平升高,以治疗镰状细胞性贫血(或β地中海贫血)。
地中海贫血是一组慢性遗传性小红细胞性贫血,其以血红蛋白合成缺陷和红细胞生成无效为特征,尤其常见于地中海、非洲和东南亚血统的人群。地中海贫血是最常见的遗传性溶血障碍之一。它是由至少一条珠蛋白多肽链(β、α、γ、δ)的产生减少引起的Hb合成不平衡所致。这可以通过基因调控区的突变或珠蛋白编码序列的突变导致表达降低而发生。
联合免疫缺陷是一组以先天性且通常为遗传性B和T细胞系统缺陷、淋巴发育不良和胸腺发育异常为特征的疾病。联合免疫缺陷包括重症联合免疫缺陷、瑞士无丙种球蛋白血症、联合免疫缺陷与腺苷脱氨酶或核苷磷酸化酶缺陷以及联合免疫缺陷与免疫球蛋白(Nezelof综合征)。大多数患者早发感染鹅口疮、肺炎和腹泻。如果不进行治疗,大多数会在2岁之前死亡。大多数患者严重缺乏B细胞和免疫球蛋白。以下症状是特征性的:淋巴细胞减少、T细胞水平低或缺乏、对有丝分裂原的增殖反应差、皮肤失能、胸腺影缺失和淋巴组织减少。肺孢子菌肺炎和其他机会性感染是常见的。
本发明的方法还可以用于通过修饰感染病毒所使用的免疫细胞受体(诸如就HIV而言,为CCR5)来治疗传染病。
这些本发明的方法还可以用于治疗其中病理至少部分地存在于血细胞中的血液恶性肿瘤和自身免疫疾病。血液恶性肿瘤包括白血病、淋巴瘤和骨髓瘤。此类恶性肿瘤的更具体示例包括多发性骨髓瘤、非霍奇金淋巴瘤、霍奇金病、急性髓性白血病、急性淋巴性白血病、急性成淋巴细胞性白血病、慢性髓性白血病;慢性淋巴细胞性白血病、骨髓增殖性障碍和多发性骨髓瘤。自身免疫疾病包括B和T细胞介导的障碍。常见示例为类风湿性关节炎、系统性红斑狼疮、炎性肠病、多发性硬化症、1型糖尿病、格-巴二氏综合征、慢性炎性脱髓鞘多神经病、牛皮癣、格雷夫病、桥本甲状腺炎、重症肌无力、血管炎和全身性硬化症。
本发明的方法还可以用于替代患有其他类型癌症(诸如实体瘤)的患者体内的内源性HSPC,这些患者已经接受了化学疗法,从而导致内源性HSPC受损。实体瘤包括乳腺、前列腺、脑、肺、肾、肝、胃、肠、结肠、甲状腺、胸腺、卵巢、黑素瘤和胰腺等的实体瘤。替代干细胞提供内源性HSPC的功能(例如,在对抗感染方面),并且如果是同种异体的,其可具有针对残余癌细胞的附加活性。
本发明的方法还可以用于替代器官移植、尤其是同种异体移植物中的HSPC。内源性HSPC很可能针对非MHC匹配的同种异体移植物产生宿主抗移植物反应。通过在器官移植前消融内源性HSPC并引入经过遗传修饰的替代HSPC,以在赋予移植器官(优选地来自同一来源(即受试者))的同时赋予增殖优势,可以降低宿主抗移植物反应。
针对替代HSPC在自体与同种异体来源之间选择取决于若干因素。自体移植容易获得,并且不需要确定HLA匹配的供体。自体移植发生危及生命的并发症的风险较低;没有GVHD的风险,并且不需要免疫抑制疗法来预防GVHD和移植物排斥。免疫重建比同种异体移植后更快,并且机会性感染的风险较低。移植物出现障碍很少发生。然而,癌症患者的自体移植存在被癌细胞污染的风险。
同种异体移植的优点是移植物没有污染的肿瘤细胞。移植物还包括供体来源的免疫活性细胞,其可产生免疫移植物抗恶性肿瘤效应。与自体移植相比,在同种异体移植后疾病复发的风险通常较低。然而,同种异体移植可能与许多潜在的致命并发症有关,诸如与治疗方案相关的器官毒性、移植失败和移植物抗宿主病。
一般来讲,同种异体移植主要用于治疗白血病和骨髓增生异常综合征。自体移植更常用于实体瘤、淋巴瘤和骨髓瘤。为了纠正遗传障碍,自体移植可以与遗传修饰一起使用以纠正障碍的遗传基础,或与同种异体移植一起使用而无需纠正。
VIII.用于施用替代干细胞的方案
通常通过静脉内输注非肠道施用替代干细胞。所施用的干细胞的剂量可以取决于输注的细胞组合物的所需纯度和细胞的来源。剂量还可以取决于HSPC的遗传修饰类型。由于HSPC的保护以及由于在引入替代HSPC之前基本上完全消除内源性HSPC是不必要的,因此剂量有时可以小于其中1-2×106个CD34+细胞/kg体重被认为是最小值的现有方法。用于重新引入的细胞的示例性剂量为至少1×105、1×106、2×106、5×106、107、2×107个CD34+细胞/kg体重。示例性范围为1×105至5×107、1×106至2×107或5×105至6×106个CD34+细胞/kg体重。剂量可能受到可用细胞数量的限制。通常,无论来源如何,剂量通过存在的CD34+细胞数量计算。对于未分次骨髓或动员外周血,CD34+细胞的百分比数可能较低;在这种情况下,施用的细胞总数要高得多。
IX.监测
在将经基因修饰的替代HSPC引入受试者体内之后,可以监测替代HSPC与总HSPC的比率。HSPC的样品可以从骨髓或外周血中获得,如前所述。可以通过例如核酸杂交测定或免疫测定将替代HSPC与内源性HSPC区分开。如果替代HSPC是同种异体的或异种的,则替代细胞与内源性细胞之间存在许多遗传差异,这些差异可以构成差异探针结合测定的基础,有时还存在允许免疫测定的受体差异。如果替代HSPC是自体的,则替代HSPC的遗传修饰可以通过核酸杂交测定或免疫测定将它们与内源性HSPC区分开。替代HSPC与总HSPC的比例可在引入后随时间增加。优选地,该比例在六个月后超过30%、50%、75%、90%或95%。
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实施例
实施例1
材料和方法
动物
将用于这些研究中的恒河猴(猕猴(macaca mulatta))(2-4岁女性,2-4kg)圈养并进行处理,并根据动物护理和使用委员会批准的方案中概述的指南进行手术。在第-7天、第2天、第9天、第16天、第29天和第57天以交替方式从较大转子或肱骨收集骨髓抽吸物。
试剂
FACS缓冲液(PBS、2%FBS(Life Technologies)、2mM EDTA(LifeTechnologies))。超彩虹珠(Ultra rainbow bead)(Spherotech)。所用抗体:CD34 PE(克隆563)、CD45RA APCH7(克隆5H9)、CD45 FITC(克隆D058-1283)、CD90 V605(克隆5E10)、CD3PerCPCy5.5(克隆SP34)、CD20 PerCPCy5.5(克隆2H7)、CD16 PerCPCy5.5(克隆3G8)、CD11bPerCPCy5.5(克隆ICRF44)、CD4 PerCPCy5.5(克隆L200)、CD8a(PerCPCy5.5克隆RPA-T8)、纯化的抗CD32(克隆FLI8.26)。Pharm Lyse 10X:用纯化水以1X制备。Sytox Blue和纯化水(Life Technologies)。未缀合人源化SR1(Forty Seven,Inc.)、未缀合莫洛利单抗(FortySeven Inc.)、抗IgG-AF647(克隆4E3,Southern Biotech)、抗IgG4-AF647(克隆G17-4,Forty Seven Inc.)
骨髓抽吸物的免疫表型分型
将骨髓用FACS缓冲液洗涤并将其沉淀。将红血细胞在室温下用1xPharm lyse裂解10-15分钟,洗涤到FACS缓冲液中。然后将细胞在冰上用抗CD32封闭10-15分钟,然后洗涤到FACS缓冲液中。通过将细胞在冰上用CD34、CD45、CD45RA、CD90和谱系(lin)标志物CD3、CD4、CD8a、CD11b、CD20、CD16染色30分钟来对细胞进行免疫表型分型。然后将细胞用FAC缓冲液再次洗涤,并且在流式细胞仪上采集之前添加活力染料(Sytox Blue)。目的靶细胞群体被定义为sytox(-)Lin(-)CD34(+)CD45(mid)CD90(+)CD45RA(-)cKIT(+)、sytox(-)Lin(-)CD34(+)CD45(mid)CD90(+)CD45RA(-)CD47(+)、sytox(-)Lin(-)CD34(+)CD45(mid)CD90(+)CD45RA(-)、sytox(-)Lin(-)CD34(+)CD90(+)、sytox(-)Lin(-)CD34(+)cKIT(+)。
靶细胞群体变化的计算
在第-7天评估每只动物的靶参考细胞群体,其为靶细胞参考值(靶参考)。通过靶群体细胞数量除以sytox(-)、sytox(-)Lin(-)CD34(+)、sytox(-)Lin(-)、sytox(-)Lin(-)CD34(+)、sytox(-)Lin(-)CD34(+)CD90(+)或sytox(-)Lin(-)CD34(+)cKIT(+)的细胞数量来计算靶参考。以与靶参考相同的方式计算每个时间点(t=2、9、16、29和57)的靶时间点。通过计算靶细胞群体相对于开始的%变化=(靶时间点/靶参考)*100来归一化每只动物。
cKIT的受体占有率
将骨髓抽吸物红血细胞在室温下用1x Pharm lyse裂解10-15分钟,并用FAC缓冲液洗涤。然后将细胞在冰上用抗CD32封闭10-15分钟,然后洗涤到FACs缓冲液中。为了测量总cKIT受体,将细胞与未缀合抗c-kit(人源化SR1)(5ug/ml)在冰上孵育35分钟,用FAC缓冲液洗涤两次,用抗IgG1-AF647(50ug/ml)在冰上染色20分钟,洗涤两次,然后在流式细胞仪上采集之前将细胞用免疫表型分型混合物方案染色。为了测量占用的受体,将制备的细胞(裂解的和封闭的)在没有另外的人源化SR1饱和的情况下孵育,并用抗IgG1-AF647(50ug/ml)染色,在冰上孵育20分钟,洗涤两次,然后用免疫表型分型混合物方案染色。
受体占有率的计算
将如下计算受体占有率:
RO计算:MFI测试/MFI总乘以100%。MFI总来自与MFI测试同一天评估的5ug/ml FSI-174染色试管。
结果
图1A、B示出了基础治疗方案。图1A示出了PBS对照以及用抗c-kit(人源化SR1)或抗CD47(莫洛利单抗)的单独治疗。图1B示出了PBS对照以及用抗c-kit和抗CD47的组合治疗。如图所示,测试了范围从0.3mg/kg到3mg/kg的不同剂量的抗C-kit。抗CD47的引发剂量为5mg/kg,随后的剂量为20mg/kg。
图2示出了抗c-kit的血清浓度随时间的变化。所有剂量均达到高于0.1μg/ml所需阈值的可测量血清水平。剂量0.3mg/kg在6天后下降到最低可测量血清水平以下,剂量1mg/kg在13天后下降到最低可测量血清水平以下,剂量3mg/kg在19天后下降到最低可测量血清水平以下。
图3示出了不同剂量的抗c-kit的c-kit受体占有率。所有剂量均达到100%HSC的c-kit受体占用。
图4示出了抗c-kit和抗CD47受体占有率随时间的变化。所有剂量的抗c-kit均在HSC上实现100%受体占用,5mg/kg-20mg/kg剂量的抗CD47也是如此。
图5A、B示出了c-kit阳性HSC相对于基线的%变化。单独用抗c-kit治疗相对于阴性对照未引起显著减少,而用抗c-kit和抗CD47的组合治疗引起显著减少。0.3和3mg/kg抗c-kit的减少无显著差异。
图6A、B示出了用抗c-kit和抗CD47组合治疗时外周血白细胞或中性粒细胞随时间的变化。治疗未导致白血细胞或中性粒细胞相对于阴性对照显著下降。未观察到中性粒细胞减少症或全血细胞减少症。
图7A、B示出了组合抗c-kit抗CD47治疗相对于阴性对照随时间的血红蛋白和红血细胞水平。由于抗CD47会消除老化的红血细胞,治疗会导致轻度和短暂的贫血。
在另一个实验中,在第1天、第8天和第15天给恒河猴施用抗c-kit和抗CD47抗体。在第-6天、第2天、第9天、第23天、37天收获骨髓抽吸物,并通过流式细胞术分析造血干细胞和祖细胞频率。所有猴子在治疗给药前一周接受CD47 ab引发剂量。图8示出了从第2-25天HSC减少约85-90%,并在此后恢复。
实施例2
该实施例示出了用针对c-kit和SIRPα的抗体组合耗尽HSPC细胞。
方法:
在第-6天、第-4天和第-2天向表达人SIRPα的转基因小鼠腹膜内注射400ug抗SIRPα(1H9),或者在第-6天向小鼠静脉内注射500ug抗c-kit(ACK2)。在第0天收获骨髓,对造血干细胞和祖细胞染色,并通过流式细胞术评估。
用如下染色面板在骨髓中评估HSC耗尽:
表2:FACS染色面板
表3:骨髓免疫表型分型:染色面板
铺板和染色
使用多通道移液管在100uL的最终体积中分配至少200万个细胞/孔。对于细胞量不足的样品,将所有细胞铺板。将FC用4uL/孔在4℃下封闭5-10分钟。纯化的大鼠抗小鼠CD16/CD32(Mouse BD Fc BlockTM)(BD Biosciences目录号:553141)。制备完整小鼠HSC染色面板和小鼠BM免疫染色面板的主混合物。将混合物在4℃、1600RPM下旋转5分钟进行沉淀。在不另外洗涤的情况下去除Fc,将100uL染色溶液主混合物添加到其相应样品中,并在4℃下在黑暗中孵育90分钟。添加100uL FACS缓冲液,然后在落地式离心机上在4℃、1600RPM下离心5分钟。用200uL FACS缓冲液再进行两次洗涤。在250uL FACS缓冲液+5uL 7AAD/孔中进行重悬。
结果
在第-6天、第-4天和第-2天向表达人SIRPα的小鼠注射400ug抗SIRPα抗体(人源化1H9),或者在第-6天向小鼠注射500ug抗c-kit(人源化SR1)。该概念验证实验被设计成测试抗SIRPα与抗c-kit组合以将允许受体饱和的剂量耗尽HSPC。在第0天收获骨髓并通过流式细胞术分析HSPC细胞,HSPC细胞是谱系阴性、Sca-1阳性、c-kit阳性细胞(并且也可以称为LKS细胞)。图9示出了抗c-kit和抗SIRPα的组合在从骨髓中耗尽HSPC方面是高度有效的。
序列表
<110> FORTY SEVEN, INC.
GIBBS, CRAIG
VOLKMER, JENS-PETER
WEISSMAN, IRVING L.
MARJON, KRISTOPHER
<120> 用于共施用针对c-kit和CD47的免疫治疗剂的方案
<130> 063673-547773
<150> US 62/852,901
<151> 2019-05-24
<160> 58
<170> PatentIn版本3.5
<210> 1
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 1
Ser Tyr Asn Met His
1 5
<210> 2
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 2
Val Ile Tyr Ser Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 3
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 3
Glu Arg Asp Thr Arg Phe Gly Asn
1 5
<210> 4
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 4
Arg Ala Ser Glu Ser Val Asp Ile Tyr Gly Asn Ser Phe Met His
1 5 10 15
<210> 5
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 5
Leu Ala Ser Asn Leu Glu Ser
1 5
<210> 6
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 6
Gln Gln Asn Asn Glu Asp Pro Tyr Thr
1 5
<210> 7
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 7
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Asn Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Val Ile Tyr Ser Gly Asn Gly Asp Thr Ser Tyr Ala Gln Lys Phe
50 55 60
Lys 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 Glu Arg Asp Thr Arg Phe Gly Asn Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 8
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 8
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Asn Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Val Ile Tyr Ser Gly Asn Gly Asp Thr Ser Tyr Asn 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 Glu Arg Asp Thr Arg Phe Gly Asn Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 9
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 9
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Asn Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Val Ile Tyr Ser Gly Asn Gly Asp Thr Ser 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 Glu Arg Asp Thr Arg Phe Gly Asn Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 10
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 10
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Ile Tyr
20 25 30
Gly Gln Ser Phe Met His Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro
35 40 45
Gln Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser
65 70 75 80
Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gln Gln Asn Asn
85 90 95
Glu Asp Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 11
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 5F9重链CDR1
<400> 11
Asn Tyr Asn Met His
1 5
<210> 12
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 5F9重链CDR2
<400> 12
Thr Ile Tyr Pro Gly Asn Asp Asp Thr Ser Tyr Asn Gln Lys Phe Lys
1 5 10 15
Asp
<210> 13
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 5F9重链CDR3
<400> 13
Gly Gly Tyr Arg Ala Met Asp Tyr
1 5
<210> 14
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 5F9轻链CDR1
<400> 14
Arg Ser Ser Gln Ser Ile Val Tyr Ser Asn Gly Asn Thr Tyr Leu Gly
1 5 10 15
<210> 15
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 5F9轻链CDR2
<400> 15
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 16
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 5F9轻链CDR3
<400> 16
Phe Gln Gly Ser His Val Pro Tyr Thr
1 5
<210> 17
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 人源化的抗体hu5F9-vh1
<400> 17
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Asn Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Thr Ile Tyr Pro Gly Asn Asp Asp Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu 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 Gly Gly Tyr Arg Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 18
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 人源化的抗体hu5F9-vh2
<400> 18
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Asn Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Thr Ile Tyr Pro Gly Asn Asp Asp Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Val Thr Ile Thr Ala Asp Thr Ser Ala 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 Gly Gly Tyr Arg Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 19
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 人源化的抗体hu5F9-vh3
<400> 19
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Asn Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile
35 40 45
Gly Thr Ile Tyr Pro Gly Asn Asp Asp Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Ala Thr Leu Thr Ala Asp Lys Ser Ala 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 Gly Gly Tyr Arg Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 20
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 人源化的抗体hu5F9-vl1
<400> 20
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val Tyr Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Gly Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr His Cys Phe Gln Gly
85 90 95
Ser His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 21
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 人源化的抗体hu5F9-vl2
<400> 21
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val Tyr Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Gly Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 22
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 人源化的抗体hu5F9-vl3
<400> 22
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val Tyr Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Gly Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr His Cys Phe Gln Gly
85 90 95
Ser His Val Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 23
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 1H9 CDR-H1
<400> 23
Ser Tyr Trp Ile Thr
1 5
<210> 24
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 1H9 CDR-H2
<400> 24
Asp Ile Tyr Pro Gly Ser Gly Ser Thr Asn His Ile Glu Lys Phe Lys
1 5 10 15
Ser
<210> 25
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 1H9 CDR-H3
<400> 25
Gly Tyr Gly Ser Ser Tyr Gly Tyr Phe Asp Tyr
1 5 10
<210> 26
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 1H9 CDR-L1
<400> 26
Arg Ala Ser Glu Asn Ile Tyr Ser Tyr Leu Ala
1 5 10
<210> 27
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 1H9 CDR-L2
<400> 27
Thr Ala Lys Thr Leu Ala Glu
1 5
<210> 28
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 1H9 CDR-L3
<400> 28
Gln His Gln Tyr Gly Pro Pro Phe Thr
1 5
<210> 29
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 人源化的1H9 VH
<400> 29
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Ile Thr Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Asp Ile Tyr Pro Gly Ser Gly Ser Thr Asn His Ile Glu Lys Phe
50 55 60
Lys Ser Lys Ala Thr Leu Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Gly Tyr Gly Ser Ser Tyr Gly Tyr Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 30
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人源化的1H9 VL
<400> 30
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Thr Ala Lys Thr Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His Gln Tyr Gly Pro Pro Phe
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 31
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 3C2 CDR-H1
<400> 31
Ser Tyr Trp Met His
1 5
<210> 32
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 3C2 CDR-H2
<400> 32
Asn Ile Asp Pro Ser Asp Ser Asp Thr His Tyr Asn Gln Lys Phe Lys
1 5 10 15
Asp
<210> 33
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 3C2 CDR-H3
<400> 33
Gly Tyr Ser Lys Tyr Tyr Ala Met Asp Tyr
1 5 10
<210> 34
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 3C2 CDR-L1
<400> 34
Arg Ser Ser Gln Ser Ile Val His Ser Tyr Gly Asn Thr Tyr Leu Glu
1 5 10 15
<210> 35
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 3C2 CDR-L2
<400> 35
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 36
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 3C2 CDR-L3
<400> 36
Phe Gln Gly Ser His Val Pro Tyr Thr
1 5
<210> 37
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 人源化的3C2 VH
<400> 37
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asn Ile Asp Pro Ser Asp Ser Asp Thr His Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val 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 Gly Tyr Ser Lys Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 38
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 人源化的3C2 VL
<400> 38
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Tyr Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 39
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 人源化的1H9 HC (全长)
<400> 39
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Ile Thr Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Asp Ile Tyr Pro Gly Ser Gly Ser Thr Asn His Ile Glu Lys Phe
50 55 60
Lys Ser Lys Ala Thr Leu Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Gly Tyr Gly Ser Ser Tyr Gly Tyr Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu 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 Ala 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> 40
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 人源化的1H9 LC (全长)
<400> 40
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Thr Ala Lys Thr Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His Gln Tyr Gly Pro Pro Phe
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 41
<211> 448
<212> PRT
<213> 人工序列
<220>
<223> 人源化的3C2 HC (全长)
<400> 41
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asn Ile Asp Pro Ser Asp Ser Asp Thr His Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val 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 Gly Tyr Ser Lys Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 42
<211> 219
<212> PRT
<213> 人工序列
<220>
<223> 人源化的3C2 LC (全长)
<400> 42
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly
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Claims (47)
1.一种在有相关需要的患者体内消融造血干细胞和祖细胞(HSPC)的方法,所述方法包括向所述患者施用0.15-2mg/kg的特异性结合c-kit的免疫治疗剂和有效方案的特异性结合CD47或SIRPα的免疫治疗剂,其中HSPC在所述患者体内被消融。
2.根据权利要求1所述的方法,其中向所述患者施用单次剂量的0.15-1mg/kg的特异性结合c-kit的免疫治疗剂。
3.根据权利要求1所述的方法,其中在长达七天的时间段内以多次剂量向所述患者施用所述特异性结合c-kit的免疫治疗剂,所述多次剂量产生与单次剂量的0.15-1mg/kg基本上相同的曲线下面积。
4.根据权利要求1所述的方法,其中向所述患者施用间隔3-7天的两次剂量的0.15-1mg/kg的特异性结合c-kit的免疫治疗剂。
5.根据权利要求1所述的方法,其中施用所述特异性结合CD47的免疫治疗剂,并且所述有效方案的特异性结合CD47的免疫治疗剂包括第一剂量和高于所述第一剂量的第二剂量。
6.根据权利要求5所述的方法,其中所述第一剂量为1mg/kg,并且所述第二剂量为10-30mg/kg,优选15-20mg/kg。
7.根据权利要求5或6所述的方法,其中作为单次剂量的所述特异性结合c-kit的免疫治疗剂与所述第二剂量的所述特异性结合CD47的免疫治疗剂同时施用。
8.根据权利要求7所述的方法,其中所述单次剂量的所述特异性结合c-kit的免疫治疗剂和所述第二剂量的所述特异性结合CD47的免疫治疗剂通过共输注施用。
9.根据权利要求7或8所述的方法,其中在所述第一剂量的所述特异性结合CD47的免疫治疗剂之后3-15天、任选7天施用所述第二剂量的所述特异性结合CD47的免疫治疗剂和所述单次剂量的所述特异性结合c-kit的免疫治疗剂。
10.根据权利要求1所述的方法,其中在10-30天的时间段内以至少三次剂量施用所述特异性结合c-kit的免疫治疗剂。
11.根据权利要求10所述的方法,其中任选地以低于其他剂量并在其他剂量之前的附加剂量,在施用每次剂量的所述特异性结合c-kit的免疫治疗剂的同一天施用所述特异性结合CD47或SIRPα的免疫治疗剂。
12.根据任一项前述权利要求所述的方法,所述方法还包括将HSPC引入所述患者体内。
13.根据权利要求7或8所述的方法,其中在施用所述单次剂量的所述特异性结合c-kit的免疫治疗剂和所述第二剂量的所述特异性结合CD47的免疫治疗剂之后5-15天将HSPC引入所述患者体内。
14.根据权利要求13所述的方法,其中在引入所述HSPC之前仅施用所述第一剂量和所述第二剂量的所述特异性结合CD47的免疫治疗剂以及所述单次剂量的所述特异性结合c-kit的免疫治疗剂。
15.根据权利要求5-9中任一项所述的方法,所述方法还包括在所述第二剂量之后施用第三剂量的所述特异性结合CD47的免疫治疗剂,任选地所述第二剂量和所述第三剂量是相同量的所述免疫治疗剂。
16.根据权利要求1所述的方法,其中施用多次剂量的所述特异性结合c-kit的免疫治疗剂,并且施用多次剂量的所述特异性结合CD47或SIRPα的免疫治疗剂,并且在最后一次剂量的所述特异性结合c-kit的免疫治疗剂或所述特异性结合CD47或SIRPα的免疫治疗剂之后5-15天将所述HSPC引入所述患者体内,以较晚者为准。
17.根据权利要求16所述的方法,其中在同一天施用所述最后一次剂量的所述特异性结合c-kit的免疫治疗剂和所述最后一次剂量的所述特异性结合SIRPα的免疫治疗剂。
18.根据任一项前述权利要求所述的方法,其中所述特异性结合CD47的免疫治疗剂是特异性结合CD47的抗体。
19.根据权利要求18所述的方法,其中所述特异性结合CD47的免疫治疗剂是人源化5F9。
20.根据权利要求19所述的方法,其中所述抗体是莫洛利单抗。
21.根据权利要求1所述的方法,其中施用有效方案的特异性结合SIRPα的免疫治疗剂。
22.根据权利要求21所述的方法,其中所述特异性结合SIRPα的免疫治疗剂是抗体。
23.根据权利要求22所述的方法,其中所述抗体包含具有包含SEQ ID NO:29的序列的重链可变区和具有包含SEQ ID NO:30的序列的轻链可变区。
24.根据权利要求22所述的方法,其中所述特异性结合SIRPα的抗体是FSI-189、ES-004、BI765063、ADU1805和CC-95251中的任一种。
25.根据权利要求21-24中任一项所述的方法,其中所述特异性结合SIRPα的抗体以10-30mg/kg的剂量施用。
26.根据权利要求1-25中任一项所述的方法,其中施用单次剂量的所述特异性结合SIRPα的抗体。
27.根据权利要求1-25中任一项所述的方法,其中施用多次剂量的所述特异性结合SIRPα的抗体。
28.根据任一项前述权利要求所述的方法,其中所述特异性结合c-kit的免疫治疗剂是抗体。
29.根据权利要求28所述的方法,其中所述抗体是人IgG1同种型的人源化形式的SR1。
30.根据权利要求29所述的方法,其中所述抗体包含具有包含SEQ ID NO:7-9中任一个的序列的重链可变区和具有包含SEQ ID NO:10的序列的轻链可变区。
31.根据权利要求30所述的方法,其中所述重链可变区具有包含SEQ ID NO:7的序列。
32.根据任一项前述权利要求所述的方法,其中所述免疫治疗剂的施用将c-kit阳性HSPC消融施用前水平的25-95%。
33.根据任一项前述权利要求所述的方法,其中所述免疫治疗剂的施用将c-kit阳性HSPC消融施用前水平的25-75%。
34.根据任一项前述权利要求所述的方法,其中所述患者患有通过所述HSPC的消融来治疗的血液学癌症。
35.根据权利要求34所述的方法,其中还向所述患者施用有效治疗所述血液学癌症的药剂。
36.根据权利要求34所述的方法,其中在所述HSPC的消融之前或期间向所述患者施用所述药剂。
37.根据权利要求34-36中任一项所述的方法,其中所述药剂是化学治疗剂、抗血管生成剂、抗纤维化剂或针对癌症抗原的单克隆抗体。
38.根据权利要求34-37中任一项所述的方法,其中所述血液学癌症是淋巴瘤、白血病或骨髓瘤。
39.根据权利要求1-33中任一项所述的方法,其中所述患者患有实体瘤,并且在消融所述患者体内的所述HSPC之前,向所述患者施用有效治疗所述实体瘤并且损害所述患者的HSPC的药剂。
40.根据权利要求39所述的方法,其中所述药剂是化学治疗剂。
41.根据权利要求1-18中任一项所述的方法,其中在消融所述HSPC之后向所述患者施用CAR-T细胞。
42.根据任一项前述权利要求所述的方法,所述方法还包括在所述HSPC的消融之后施用flt3激动剂或CISH抑制剂,以促进HSPC生长或细胞疗法。
43.根据任一项前述权利要求所述的方法,所述方法还包括将MCL1抑制剂与所述特异性结合c-kit的免疫治疗剂和所述特异性结合CD47或SIRPα的免疫治疗剂共施用以消融NK细胞。
44.根据任一项前述权利要求所述的方法,其中所述患者是人。
45.特异性结合c-kit的免疫治疗剂在制造用于消融造血干细胞和祖细胞(HSPC)的药物中的用途,其中所述免疫治疗剂以0.15-2mg/kg的剂量与有效方案的特异性结合CD47或SIRPα的免疫治疗剂组合施用。
46.特异性结合CD47或SIRPα的免疫治疗剂在制造药物中的用途,所述药物用于与剂量为0.15-2mg/kg的特异性结合c-kit的免疫治疗剂组合消融造血干细胞和祖细胞(HSPC)。
47.根据权利要求45或46所述的用途,其与根据权利要求2-44中任一项所述的方法一致。
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WO2022216965A1 (en) * | 2021-04-07 | 2022-10-13 | Actinium Pharmaceuticals, Inc. | Radioimmunotherapy directed to ccr8 for depletion of tumor infiltrating regulatory t cells |
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CA3140639A1 (en) | 2020-12-03 |
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EP3976658A4 (en) | 2023-06-07 |
TW202110886A (zh) | 2021-03-16 |
JP2022533253A (ja) | 2022-07-21 |
US20200369767A1 (en) | 2020-11-26 |
WO2020242895A1 (en) | 2020-12-03 |
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