CN111108123A - 癌症相关的免疫抑制抑制剂 - Google Patents
癌症相关的免疫抑制抑制剂 Download PDFInfo
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- CN111108123A CN111108123A CN201880048764.4A CN201880048764A CN111108123A CN 111108123 A CN111108123 A CN 111108123A CN 201880048764 A CN201880048764 A CN 201880048764A CN 111108123 A CN111108123 A CN 111108123A
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Abstract
本发明涉及糖工程化Fc片段承载化合物在治疗癌症相关的免疫抑制中作为免疫抑制抑制剂的用途。本发明还涉及包含至少该糖工程化Fc片段承载化合物的药物组合物。
Description
技术领域
本发明涉及在癌症疾病期间发生的免疫抑制状态的治疗。
背景技术
癌症免疫逃逸是设计有效的抗癌治疗策略的主要障碍。尽管在理解癌症如何逃逸破坏性免疫方面取得了长足的进步，但抵消肿瘤逃逸的措施却没有跟上。
患者的长期存活被认为是癌症治疗成功的“金标准”，尽管从患者的角度来看，无病存活是最终目标。越来越相信，长期存活和无疾病存活很大程度上取决于增强患者自身的免疫系统以加强有效的抗肿瘤响应。对疗法有强的免疫应答(甚至是诱导自身免疫症状的免疫应答)的证据也可以是癌症患者中长期存活的阳性指标(Burkholder等人,2014,Biochimica et Biophysica Acta,第1845卷:182-201)。
尽管已筛选了多种药剂的抗肿瘤作用，并已批准其选择用于治疗癌症患者，但化学疗法、放射疗法和手术仍然是标准癌症治疗策略的主要手段(Vinay等人,2015,Seminarsin cancer biology,第35卷:5185-5198)。这些疗法的缺点是它们能够引起短暂的免疫抑制，继而增加感染的风险，并且还可能降低免疫系统抑制癌症进一步发展的能力。
鉴定合适的总癌症治疗策略涵盖确定免疫增强疗法可以增强标准抗癌疗法的程度。在本领域中强烈建议，大多数(如果不是全部)总癌症治疗策略应包括增加抗肿瘤免疫性的相关手段，不论所使用的抗肿瘤治疗类型如何。
免疫疗法具有治疗癌症的潜力，因为基于免疫的疗法通过不同于化学疗法或放射疗法的机制起作用，并且因为它们代表了具有完全不同的毒性谱的非交叉抗性治疗。T细胞和B细胞都能够通过其各自受体的遗传重组来识别各种潜在的肿瘤抗原，并且更重要的是，T细胞和B细胞都可以区分正常细胞和转化细胞之间的微小抗原差异，从而在最小化毒性的同时提供特异性
数十年来，已经知道免疫应答对癌症的重要性。然而，免疫肿瘤学的最新进展大大提高了对免疫系统和癌症相互作用的理解。免疫编辑是指免疫系统可以改变肿瘤进展的过程。它调节肿瘤的数量和质量。癌症免疫编辑过程具有三个不同的阶段：分别是消除、平衡和逃逸阶段。逃逸阶段可以在肿瘤水平或肿瘤微环境水平上发生。在微环境水平上，在免疫浸润物中募集调节性T细胞(Treg)和骨髓来源的抑制细胞(MDSC)或表达程序性死亡–1(PD-1)/程序性死亡-配体1(PD-L1)可以产生免疫抑制性肿瘤微环境。
肿瘤相关的巨噬细胞(TAM)、肿瘤相关的成纤维细胞、Treg和由抑制细胞产生的可溶因子均有助于癌症诱导的免疫抑制。TAM可以驱动多个促肿瘤(protumor)过程，包括免疫抑制、血管生成和直接肿瘤生长因子分泌。
因此，免疫系统在控制和根除癌症中起着重要作用。然而，在恶性肿瘤的情况下，可能存在多种免疫抑制机制，其阻止了有效的抗肿瘤免疫。
如今，针对几种阴性免疫调节剂(检查点)的抗体疗法已显示出巨大的成功，并且可能成为各种恶性肿瘤患者治疗的主要组分。
此类分子中第一个显示出抑制T细胞增殖和IL2产生的分子是细胞毒性T淋巴细胞相关的蛋白4(CTLA-4)。有了这个发现，工作转向阻断这种抑制途径，以试图活化针对癌细胞的休眠T细胞。针对CTLA-4的第一抗体伊匹单抗迅速被引入临床试验，并于2011年获得美国食品药品管理局(FDA)批准用于治疗转移性黑素瘤。伊匹单抗成功后，研究了其他免疫检查点作为抑制的可能靶点。一种这样的相互作用是程序性细胞死亡-1(PD-1)T细胞受体及在许多癌细胞上发现的其配体、即程序性死亡配体1(PD-L1)。
然而，这些抗体在有限类型的肿瘤(主要是黑素瘤、肺癌、肾癌)中有效，并且甚至在敏感性肿瘤中也有很大一部分患者仍然具有抗性。
从目前获得的有关抗癌治疗策略的知识中得出，在大多数情况下，应遵循双重方法，该双重方法寻求(i)消除免疫抑制因子/机制，和(ii)增强肿瘤杀伤活性，以便实现成功的癌症疗法。
因此，本领域仍然需要提供另外的治疗策略来治疗癌症。尤其需要用于减少或阻断癌症患者中可能发生的免疫抑制的新手段，以定义新型成功的抗癌治疗策略。
发明内容
本发明涉及糖工程化Fc片段承载化合物在治疗癌症相关的免疫抑制中作为免疫抑制抑制剂的用途。
值得注意的是，本发明涉及糖工程化Fc片段承载化合物在治疗癌症相关的免疫抑制中作为T细胞免疫抑制抑制剂的用途。
本发明涵盖了糖工程化Fc片段承载化合物在治疗癌症相关的免疫抑制中作为CD8+T细胞免疫抑制抑制剂的用途。
在一些实施方式中，所述糖工程化Fc片段承载化合物是低岩藻糖基化Fc片段承载化合物。
在一些实施方式中，糖工程化Fc片段承载化合物包含SEQ ID NO.70的两条氨基酸链。
在一些实施方式中，所述糖工程化Fc片段承载化合物是糖工程化抗体、特别是低岩藻糖基化抗体。
在一些实施方式中，所述糖工程化抗体针对肿瘤相关抗原。
在一些实施方式中，所述肿瘤相关抗原选自包括以下的组：HER2、HER3、HER4和AMHRII。
在一些实施方式中，所述抗体选自包括以下的组：本文公开的称为3C23K、9F7F11、H4B121和HE4B33的抗体以及其变体。
在一些实施方式中，所述癌症治疗包括向所述个体施用另外的抗癌剂。
在一些实施方式中，所述癌症治疗包括向所述个体施用抑制性免疫检查点抑制剂，诸如PD-1的抑制剂、PD-L1的抑制剂、PD-L2的抑制剂、BTLA的抑制剂、CTLA-4的抑制剂、A2AR的抑制剂、B7-H3(CD276)的抑制剂、B7-H4(VTCN1)的抑制剂、IDO的抑制剂、KIR的抑制剂、LAG3的抑制剂、TIM-3的抑制剂、VISTA的抑制剂、CD137的抑制剂、OX40的抑制剂、OX40L的抑制剂和B7S1的抑制剂。
在一些实施方式中，所述抑制剂由针对所述抑制性免疫检查点的抗体或其抗原结合片段组成。
本发明还涉及包含以下的药物组合物：(i)糖工程化Fc片段承载化合物和(ii)抑制性免疫检查点抑制剂。
附图说明
图1：糖工程化3C23K mAb(GM102)减少巨噬细胞诱导的T细胞抑制。
图1A：与靶向COV434-AMHRII肿瘤细胞的MDM2巨噬细胞共培养的PBT增殖的测量。将MDM2用使用无关的mAb R565(同种型对照)、抗AMHRII FcKO或抗AMHRII 3C23K调理的COV434-AMHRII细胞系攻击4天，然后与抗CD3/CD28预活化的外周血T细胞(也称为“PBT”)共培养另外的4天。数据代表预活化的CD8+T细胞的分裂指数(即原始群体中细胞已经历的平均细胞分裂数)+/-标准偏差。(数据代表三个独立的实验。P值*<0.05)。横坐标，从左到右：(i)n.a.T细胞对照，(ii)a.T细胞对照，(iii)同种型对照，(iv)FcKO和(v)3C23K。
图1B：与靶向经mAb处理的聚苯乙烯珠的MDM2巨噬细胞共培养的PBT增殖的测量。用未涂覆的聚苯乙烯珠攻击MDM2作为对照，或用涂覆有抗AMHRII FcKO或抗AMHRII 3C23K的聚苯乙烯珠攻击MDM2 24小时，然后与预活化的细胞痕量violet负载的PBT共培养另外的4天。数据代表预活化的CD8+T细胞的分裂指数(即原始群体中的细胞已经历的平均细胞分裂数)+/-标准偏差。(数据代表三个独立的实验。P值**<0.01)。n.a.是指未活化的T细胞，a.是指活化的T细胞。横坐标，从左到右：(i)n.a.T细胞对照，(ii)a.T细胞对照，(iii)未处理的珠，(iv)FcKO和(v)3C23K。
图2：糖工程化3C23K(GM102)抗体不影响人T淋巴细胞的增殖。在存在或不存在10μg/ml的抗AMHRII 3C23K mAb的情况下，通过CD3/CD28涂覆的珠活化CellTrace Violet负载的T细胞。3天后，通过流式细胞术评价CellTrace Violet的稀释度，并将其表示为原始数据(图2A)和分裂1次、2次、3次或4次的T细胞的％(图2B)。在图2B中，纵坐标表示每个峰中的百分比；从下到上：(i)0次分裂，(ii)1次分裂，(iii)2次分裂，(iv)3次分裂，和(v)4次分裂。
图3：糖工程化Fc承载化合物活化TAM样巨噬细胞
图3A示出与M2表型的巨噬细胞相关的标记物表达减少，诸如Sepp1(mRNA-图3A-1)、Stab1(mRNA-图3A-2)、FOLFR2(m-RNA-图3A-3)和CD163(蛋白质-图3A-4)。
左侧框示出在没有抗体的孔中生长的M2型巨噬细胞。中心框示出在有FcKO抗体的孔中培养的M2型巨噬细胞。右侧框示出在有低岩藻糖基化R18H2抗体的孔中培养的M2型巨噬细胞。
图3B-1(mRNA表达)和图3B-2(蛋白表达)示出CD16表达增加。
左侧框示出在没有抗体的孔中生长的M2型巨噬细胞。中心框示出在有FcKO抗体的孔中培养的M2型巨噬细胞。右侧框示出在有低岩藻糖基化R18H2抗体的孔中培养的M2型巨噬细胞。
图3C-1(mRNA表达)、图3C-2(mRNA表达)和图3C-3(蛋白质表达)示出CD64表达增加。
左侧框示出在没有抗体的孔中生长的M2型巨噬细胞。中心框示出在有FcKO抗体的孔中培养的M2型巨噬细胞。右侧框示出在有低岩藻糖基化R18H2抗体的孔中培养的M2型巨噬细胞。
图3D示出通常由M1巨噬细胞表达的促炎性因子(诸如TNFα(图3D-1)、IL1β(图3D-2))增加。
左侧框示出在没有抗体的孔中生长的M2型巨噬细胞。中心框示出在有FcKO抗体的孔中培养的M2型巨噬细胞。右侧框示出在有低岩藻糖基化R18H2抗体的孔中培养的M2型巨噬细胞。
图3E示出mRNA基因水平和编码免疫抑制因子TGFβ的降低。
左侧框示出在没有抗体的孔中生长的M2型巨噬细胞。中心框示出在有FcKO抗体的孔中培养的M2型巨噬细胞。右侧框示出在有低岩藻糖基化R18H2抗体的孔中培养的M2型巨噬细胞。
图3F示出mRNA基因水平和编码免疫抑制因子IDO1的降低。
左侧框示出在没有抗体的孔中生长的M2型巨噬细胞。中心框示出在有FcKO抗体的孔中培养的M2型巨噬细胞。右侧框示出在有低岩藻糖基化R18H2抗体的孔中培养的M2型巨噬细胞。
图3G-1(mRNA表达)和图3G-2(蛋白表达)示出免疫抑制因子IL10减少。
左侧框示出在没有抗体的孔中生长的M2型巨噬细胞。中心框示出在有FcKO抗体的孔中培养的M2型巨噬细胞。右侧框示出在有低岩藻糖基化R18H2抗体的孔中培养的M2型巨噬细胞。
图3H(mRNA表达)示出促血管生成因子PDGFα减少。
左侧框示出在没有抗体的孔中生长的M2型巨噬细胞。中心框示出在有FcKO抗体的孔中培养的M2型巨噬细胞。右侧框示出在有低岩藻糖基化R18H2抗体的孔中培养的M2型巨噬细胞。
图3I(mRNA表达)示出促血管生成因子VEGFβ减少。
左侧框示出在没有抗体的孔中生长的M2型巨噬细胞。中心框示出在有FcKO抗体的孔中培养的M2型巨噬细胞。右侧框示出在有低岩藻糖基化R18H2抗体的孔中培养的M2型巨噬细胞。
图3J(mRNA表达)示出促血管生成因子HGF减少。
左侧框示出在没有抗体的孔中生长的M2型巨噬细胞。中心框示出在有FcKO抗体的孔中培养的M2型巨噬细胞。右侧框示出在有低岩藻糖基化R18H2抗体的孔中培养的M2型巨噬细胞。
图3K M2巨噬细胞表面处的PDL2表达。
白框示出在有FcKO抗体的孔中培养的M2型巨噬细胞。黑框示出在有低岩藻糖基化R18H2抗体的孔中培养的M2型巨噬细胞。
图4：糖工程化3C23K(GM102)抗体阻断免疫抑制，这导致免疫系统活化。
图4A：由与抗AMHRII抗体在37℃下孵育4h的TAM样巨噬细胞在SKOV3-AMHRII细胞上产生的ADCC。从左至右：3C23K-FcKO、3C23K CHO和3C23K YB20(意指3C23K YB2/0)。呈现了来自以一式三份测试的巨噬细胞的3名供体的数据。图4B：与抗AMHRII抗体孵育4天的TAM样巨噬细胞对SKOV3-AMHRII癌细胞的细胞溶解。从左至右：3C23K-FcKO、3C23K CHO和3C23KYB20(意指3C23K YB2/0)。呈现了来自以一式三份测试的巨噬细胞的3名供体的数据。
图4C：TAM样巨噬细胞与SKOV3-AMHRII癌细胞和抗AMHRII抗体共孵育四天后，CD8记忆(CD8+CD25+)巨噬细胞的百分比。从左至右：3C23K-FcKO、3C23K CHO和3C23K YB20(意指3C23K YB2/0)。呈现了来自以一式三份测试的巨噬细胞的3名供体的数据。
图4D：TAM样巨噬细胞与SKOV3-AMHRII癌细胞和抗AMHRII抗体共孵育四天后，Th1(CD4+CD183+)巨噬细胞的百分比。从左至右：3C23K-FcKO、3C23K CHO和3C23K YB20(意指3C23K YB2/0)。呈现了来自以一式三份测试的巨噬细胞的3名供体的数据。图4E：TAM样巨噬细胞与SKOV3-AMHRII癌细胞和SKOV3-AMHRII共孵育四天后，Th2(CD4+CD183-)巨噬细胞的百分比。从左至右：3C23K-FcKO、3C23K CHO和3C23K YB20(意指3C23K YB2/0)。呈现了来自以一式三份测试的巨噬细胞的3名供体的数据。
图4F：TAM样巨噬细胞与SKOV3-AMHRII癌细胞和抗AMHRII抗体共孵育四天后，检测培养基中的CXCL9。从左至右：3C23K-FcKO、3C23K CHO和3C23K YB20(意指3C23K YB2/0)。呈现了来自以一式三份测试的巨噬细胞的3名供体的数据。
图4G：TAM样巨噬细胞与SKOV3-AMHRII癌细胞和抗AMHRII抗体共孵育四天后，检测培养基中的CXCL10。从左至右：3C23K-FcKO、3C23K CHO和3C23K YB20(意指3C23K YB2/0)。呈现了来自以一式三份测试的巨噬细胞的3名供体的数据。
图4H：TAM样巨噬细胞与SKOV3-AMHRII癌细胞和抗AMHRII抗体共孵育四天后，检测培养基中的CCL2。由于每名供体的基线不同，因此将3名供体的数据(一式三份)进行了个性化处理。对于从左到右的每名供体：3C23K-FcKO、3C23K CHO和3C23K YB20(意指3C23K YB2/0)。
图4I：TAM样巨噬细胞与SKOV3-AMHRII癌细胞和抗AMHRII抗体共孵育四天后，检测培养基中的IL1β。从左至右：3C23K-FcKO、3C23K CHO和3C23K YB20(意指3C23K YB2/0)。呈现了来自以一式三份测试的巨噬细胞的3名供体的数据。
图4J：TAM样巨噬细胞与SKOV3-AMHRII癌细胞和抗AMHRII抗体共孵育四天后，检测培养基中的IL6。从左至右：3C23K-FcKO、3C23K CHO和3C23K YB20。呈现了来自以一式三份测试的巨噬细胞的3名供体的数据。
图4K：TAM样巨噬细胞与SKOV3-AMHRII癌细胞和抗AMHRII抗体共孵育四天后，检测培养基中的CCL5。从左至右：3C23K-FcKO、3C23K CHO和3C23K YB20(意指3C23K YB2/0)。呈现了来自以一式三份测试的巨噬细胞的3名供体的数据。
图4L：未分化的巨噬细胞与SKOV3-AMHRII癌细胞和抗AMHRII抗体共孵育四天后，检测培养基中的IL12。从左至右：3C23K-FcKO、3C23K CHO和3C23K YB20(意指3C23K YB2/0)。呈现了来自以一式三份测试的巨噬细胞的3名供体的数据。
图4M：未分化的巨噬细胞与SKOV3-AMHRII癌细胞和抗AMHRII抗体共孵育四天后，检测培养基中的IL6。从左至右：3C23K-FcKO、3C23K CHO和3C23K YB20(意指3C23K YB2/0)。呈现了来自以一式三份测试的巨噬细胞的3名供体的数据。
图4N：未分化的巨噬细胞与SKOV3-AMHRII癌细胞和抗AMHRII抗体共孵育四天后，检测培养基中的IL1β。从左至右：3C23K-FcKO、3C23K CHO和3C23K YB20(意指3C23K YB2/0)。呈现了来自以一式三份测试的巨噬细胞的3名供体的数据。
图4O：未分化的巨噬细胞与SKOV3-AMHRII癌细胞和抗AMHRII抗体共孵育四天后，检测培养基中的IL23。从左至右：3C23K-FcKO、3C23K CHO和3C23K YB20(意指3C23K YB2/0)。呈现了来自以一式三份测试的巨噬细胞的3名供体的数据。
图4P：未分化的巨噬细胞与SKOV3-AMHRII癌细胞和抗AMHRII抗体共孵育四天后，检测培养基中的CXCL9。从左至右：3C23K-FcKO、3C23K CHO和3C23K YB20(意指3C23K YB2/0)。呈现了来自以一式三份测试的巨噬细胞的3名供体的数据。
图4Q：未分化的巨噬细胞与SKOV3-AMHRII癌细胞和抗AMHRII抗体共孵育四天后，检测培养基中的CXCL10。从左至右：3C23K-FcKO、3C23K CHO和3C23K YB20(意指3C23K YB2/0)。呈现了来自以一式三份测试的巨噬细胞的3名供体的数据。
图5：施用有糖工程化抗体的癌症患者的肿瘤组织中存在的巨噬细胞的活化
图5A(cd16)和图5B(颗粒酶)：在施用有3C23K抗体的癌症患者的肿瘤组织中进行的细胞标记物的免疫荧光测定的结果。
图5A：治疗前(基线)和治疗中的患者04-01和患者01-01中CD16阳性肿瘤组织的百分比。黑框示出患者04-01，灰框示出患者01-01。
图5B：治疗前(基线)和治疗中的患者01-01中的细胞百分比。黑框示出细胞CD8+GZB+/mm2的百分比；灰框示出细胞CD16+GZB+/mm2的百分比；白框示出NKp46+GZB+/mm2的百分比。
图6：NK细胞、单核细胞和ICOS+T细胞在施用有糖工程化抗体的癌症患者中的活化
图6A：GM102(3C23K)治疗的患者的血液样品中CD4+ICOS+细胞通过流式细胞术(平均流动强度)定量。在GM102(3C23K)注射之前(C1J0)和期间(C1J0+4H)的第1个周期取得样品，然后在第2个周期和第3个周期之前(分别为C2J1和C3J1)取得样品。
图6B：在古斯塔夫鲁西肿瘤医院(Gustave Roussy)，经GM102 3C23K治疗的患者的血液样品中CD8+ICOS+细胞通过流式细胞术(平均流强度)定量。在GM102(3C23K)注射之前(C1J0)和期间(C1J0+4H)的第1个周期取得样品，然后在第2个周期和第3个周期之前(分别为C2J1和C3J1)取得样品。
图7：治疗后和治疗中的患者中CD14+细胞内的典型单核细胞亚群、中间单核细胞亚群和非典型单核细胞亚群的百分比。
具体实施方式
使用包含癌细胞和免疫系统细胞(诸如T细胞和巨噬细胞)的癌组织的体外模型，本发明人发现T细胞活化的抑制可以是由肿瘤相关的巨噬细胞(TAM)M2出人意料地诱导的。
此外，发明人已经表明，可以通过向这种体外癌症组织模型中添加糖工程化抗体来减少或阻断此类TAM诱导的T细胞活化的抑制。糖工程化抗体、特别是低岩藻糖基化抗体在本领域中已知以高亲和力结合至Fc受体、特别是巨噬细胞膜处存在的Fc受体、特别是FcγRIIIa(在本领域中也称为“CD16a”)。
不希望受任何特定理论的束缚，本发明人认为糖工程化抗体与巨噬细胞膜处存在的Fc受体的结合诱导了可溶因子释放(例如细胞因子释放)，从而对存在于肿瘤组织环境中的T细胞发挥抑制阻断作用，或可替选地，对存在于肿瘤组织环境中的T细胞发挥活化。因此，本发明人认为，糖工程化抗体通过阻断T细胞抑制或活化T细胞，能够减少或阻断在某些患有癌症的个体中发生的针对癌细胞的免疫应答的抑制。
本发明人在本文中进一步表明，在糖工程化抗体存在下获得的免疫活化作用中，肿瘤细胞本身为非必要的。
更进一步，本发明人已经表明，显示以高亲和力与TAM样巨噬细胞的Fc-γ受体结合的所述糖工程化抗体诱导了免疫抑制性M2表型的TAM样巨噬细胞朝向非免疫抑制性M1表型，同时减少了免疫抑制性细胞因子(诸如IL-10)。本发明人还表明，在存在如本文所述的糖工程化抗体的情况下，所述TAM样巨噬细胞具有较高的促炎性细胞因子(诸如IL-1β)表达，而促肿瘤基因(诸如VEGFα、VEGFβ、PDGFβ和肝细胞生长因子)的表达没有明显变化。
本文还显示如本文所述的糖工程化抗体的施用诱导癌症患者的CD8+T细胞水平升高。不希望受任何特定理论的束缚，本发明人认为糖工程化抗体由于诱导巨噬细胞释放T细胞活化细胞因子，因此可以允许去除在经历免疫抑制状态的癌症患者中发生的T细胞抑制，从而导致CD8+T细胞活化。
更进一步，本文显示了如本文所述的糖工程化抗体诱导Th1表型的CD4+T细胞增加和Th2表型的CD4+T细胞减少。预期Th1T细胞和Th2 T细胞之间的这种平衡的变化以促进针对肿瘤细胞的免疫应答增加。
发明人还表明，如本文所述的糖工程化抗体调节细胞因子(诸如IL1β、IL6、IL10、IL12和IL23)的表达。
本文还显示了如本文所述的糖工程化抗体诱导天然巨噬细胞减少其免疫抑制细胞因子(诸如IL-10)的产生。
本发明人进一步表明，向癌症患者施用如本文所述的糖工程化抗体诱导了肿瘤组织中CD16+(FcγRIII+)细胞的数量增加。因此，向癌症患者施用如本文所述的糖工程化抗体导致肿瘤组织内抗肿瘤活化的巨噬细胞增加。进一步表明，向癌症患者施用如本文所述的糖工程化抗体提高了肿瘤组织中产生颗粒酶B的活化巨噬细胞水平，其免疫抑制状态的抑制将有助于肿瘤细胞的细胞溶解。更进一步，向癌症患者施用如本文所述的糖工程化抗体也增加了肿瘤组织中的NK细胞的数量，其免疫抑制的抑制将同样有助于杀灭肿瘤细胞。
本发明人还表明，向癌症患者施用如本文所述的糖工程化抗体(i)增加了NK细胞对CD16(FcγRIII)的表达，(ii)增加了单核细胞上CD69的表达和(iii)增加了T细胞上ICOS(诱导性T细胞CO刺激剂)的表达，其是使癌症患者所经历的免疫抑制状态实现抑制的其他因素。
总之，发明人的发现表明，糖工程化抗体能够减少或阻断巨噬细胞诱导的T细胞抗肿瘤活性抑制。
本发明人的结果使他们能够构思出基于施用糖工程化抗体的治疗性工具，所述治疗性工具旨在减少或阻断可能在患有癌症的个体中发生的免疫抑制状态。
不希望受任何特定理论的束缚，本发明人相信，糖工程化抗体诱导的免疫刺激作用是由于所述糖工程化抗体对细胞膜处存在的Fc受体、特别是对巨噬细胞膜处存在的Fc受体的高亲和力所致，无论所述抗体是否具有相关的抗原结合区。
如本文的示例中所示，即使在其中不存在肿瘤抗原表达细胞的模型中，也可以得到免疫抑制状态的减少或阻断，这可以意味着所述糖工程化抗体与肿瘤抗原的结合以及吞噬作用本身诱导的肿瘤负载降低可能不为诱导其免疫活化作用所需、特别是可能不为减少或阻断巨噬细胞诱导的T细胞抑制所需。换句话说，本发明人认为，所述糖工程化抗体对T细胞抑制的阻断涉及这些抗体作为糖工程化Fc片段承载化合物的行为。
本发明涉及糖工程化Fc片段承载化合物在治疗个体癌症中作为免疫抑制抑制剂的用途。
本发明涉及糖工程化Fc片段承载化合物用于预防或治疗患有癌症的个体中的免疫抑制状态的用途。
本发明涉及糖工程化Fc片段承载化合物作为用于制备治疗癌症的药剂的免疫抑制抑制剂的用途。
本发明涉及糖工程化Fc片段承载化合物用于制备预防或治疗患有癌症的个体中的免疫抑制状态的药剂的用途。
本发明涉及用于治疗癌症的方法，该方法包括向有需要的个体施用作为免疫抑制抑制剂的糖工程化Fc片段承载化合物的步骤。
本发明涉及用于预防或治疗患有癌症的个体的免疫抑制状态的方法，该方法包括向有需要的个体施用糖工程化Fc片段承载化合物的步骤。
本发明涉及糖工程化Fc片段承载化合物用于减少或阻断由患有癌症的个体中发生的巨噬细胞诱导的T细胞抑制所引起的免疫抑制状态的用途。
本发明涉及糖工程化Fc片段承载化合物用于制备药剂的用途，所述药剂用于减少或阻断由患有癌症的个体中发生的巨噬细胞诱导的T细胞抑制所引起的免疫抑制状态。
本发明还涉及用于减少或阻断由患有癌症的个体中发生的巨噬细胞诱导的T细胞抑制所引起的免疫抑制状态的方法，该方法包括向有需要的个体施用糖工程化Fc片段承载化合物的步骤。
从前面的实施方式可以得出，本发明所关注的癌症个体是也受到免疫抑制影响的那些癌症个体。
在一些实施方式中，本发明所涉及的癌症个体是也受到由抗癌症治疗引起的免疫抑制的影响的那些癌症个体。
定义
根据本发明，诸如在“包括以下步骤”中的表述“包括”也被理解为诸如在“由以下步骤组成”中的“由以下组成”。
如本文所用，术语“癌症相关的免疫抑制”、“癌症有关的免疫抑制”、“免疫抑制状态”当涉及患有癌症的个体时，意指涵盖其中CD8+T细胞使其待活化的能力被减少或阻断、即其待活化的能力被部分抑制或完全抑制的情形的生理状态。
说明性地，根据本发明，可以通过体外测试方法来确定经历免疫抑制状态的患有癌症的个体，该体外测试方法包括以下步骤：测量先前收集自所述个体的样品中所含的外周血CD8+T细胞的增殖能力，在测量其增殖能力之前，所述外周血T细胞已经经受了预活化步骤。
因此，在一些实施方式中，当测试个体的CD8+T细胞的增殖能力低于参考CD8+T细胞增殖能力值时，可以在所述测试个体中检测到免疫抑制状态。在一些实施方式中，所述参考CD8+T细胞增殖能力值可以是在未免疫抑制的健康个体中发现的平均CD8+T细胞增殖能力值。在一些其他实施方式中，所述参考值可以是阈值，其允许区分(i)指示免疫抑制状态的低于(或可替选地高于，根据所使用的测量单位)该阈值的CD8+T细胞增殖能力值与(ii)指示不存在免疫抑制状态的高于(或可替选地低于，根据所使用的测量单位)该阈值的CD8+T细胞增殖能力值。
在一些实施方式中，CD8+T细胞增殖能力值是CD8+T细胞的分裂指数值，如本文的示例所示。
如本文所用，术语“治疗(treat)”、“治疗(treating)”、“治疗(treatment)”等是指减少或缓解与其相关的疾病和/或症状。应该理解，尽管不排除，但治疗病症或疾患并不需要与其相关的病症、疾患或症状被完全消除。
如本文所用，术语“预防(prevent)”、“预防(preventing)”、“预防(prevention)”、“预防性治疗(prophylatic treatment)”等是指减少没有病症或疾患或有病症或疾患风险或易于发展病症或疾患的对象中发展病症或疾患的可能性。
如本文所用，糖工程化Fc片段承载化合物涵盖包含具有改变的糖基化抗体的Fc片段的任何化合物，从而使所述Fc片段以高亲和力结合至Fc受体、特别是结合至存在于巨噬细胞膜处的Fc受体，包括存在于肿瘤相关的巨噬细胞膜处的Fc受体。
在一些实施方式中，含Fc的蛋白质包括一种或多种多肽。
如本文所用，“Fc片段承载蛋白质”是指与至少一个其他异源蛋白质单元或多肽融合的Fc片段的蛋白质。
糖工程化Fc片段承载化合物涵盖(i)糖工程化Fc片段本身，(ii)杂合化合物，其包含与非蛋白质部分共价连接的糖工程化Fc片段和(iii)蛋白质化合物，其包含与蛋白质部分连接的糖工程化Fc片段。
糖工程化Fc片段承载蛋白质化合物涵盖其中所述糖工程化Fc片段共价连接至抗体的抗原结合结构域(诸如共价连接至抗体可变区)的蛋白质。
糖工程化Fc片段承载蛋白质化合物涵盖其中所述糖工程化Fc片段直接或间接共价连接至一个或多个其他Fc片段、诸如共价连接至一个或多个其他糖工程化Fc片段。此类糖工程化Fc片段承载化合物的说明性实例涵盖本领域已知为“Fc多聚体”的化合物，诸如例如Thiruppathi等人(2014,J Autoimmun,第52卷:64-73)、Jain等人(2012,ArthritisResearch and Therapy,第14卷:R192)或Zhou等人(2017,Blood advances,第1卷(第6期):DOI10.1182/biooadvances.2016001917)所述。
在一些优选的实施方式中，根据本发明的糖工程化Fc片段承载化合物涵盖糖工程化抗体。
在一些优选的实施方式中，糖工程化抗体涵盖针对肿瘤相关抗原的抗体。
如本文所用，术语“抗体”是指对感兴趣的抗原具有显著的已知特异性免疫反应活性、特别是对感兴趣的肿瘤相关抗原具有免疫反应活性的装配体(例如，完整的抗体分子、抗体片段或其变体)。抗体和免疫球蛋白包含轻链和重链，该轻链和重链之间有或没有链间共价键。
免疫球蛋白的轻链被分类为卡帕或兰姆达(κ，λ)。每个重链类别可以与κ轻链或λ轻链结合。通常，轻链和重链相互共价键合，并且当免疫球蛋白由杂交瘤、B细胞或经遗传工程化的宿主细胞生成时，两条重链的“尾”部分通过共价二硫键或非共价键相互键合。
轻链和重链均分为结构同源性区和功能同源性区。术语“区”是指免疫球蛋白或抗体链的一部分或部分，并且包括恒定区或可变区，以及所述区域的更离散的一部分或部分。例如，轻链可变区包括如本文所定义的散布在“框架区”或“FR”中的“互补决定区”或“CDR”。
基于在“恒定区”的情况下各类别成员的区内序列变化的相对缺乏、或者在“可变区”的情况下各类别成员的区内序列的显著变化，可以将免疫球蛋白的重链区或轻链定义为“恒定”区(C)区或“可变”(V)区。
按照惯例，可变恒定区结构域的编号随着它们距免疫球蛋白或抗体的抗原结合位点或氨基末端越远而越大。免疫球蛋白的每条重链和轻链的N末端是可变区，并且在C末端是恒定区；CH3结构域和CL结构域分别包含重链和轻链的羧基末端。因此，免疫球蛋白轻链的结构域以VL-CL取向排列，而重链的结构域以VH-CH1-铰链-CH2-CH3取向排列。
重链恒定区中的氨基酸位置包括CH1、铰链、CH2、CH3和CL结构域中的氨基酸位置，可以根据Kabat索引编号系统进行编号(参见Kabat等人,“Sequences of Proteins ofImmunological Interest”,美国卫生与公众服务部,第5版,1991)。可替选地，抗体氨基酸位置可以根据EU索引编号系统进行编号(参见Kabat等人，同上)。
如本文所用，术语“Fc区”被定义为重链恒定区的一部分，开始于紧接木瓜蛋白酶裂解位点(即IgG中的残基216，取重链恒定区的第一残基为114)上游的铰链区并在抗体的C末端结束。因此，完整的Fc区至少包含铰链结构域、CH2结构域和CH3结构域。
如本文所用的术语“Fc片段”是指包含由抗体消化产生的或通过其他方式产生的非抗原结合片段序列的分子(无论是单体形式还是多聚体形式)，并且可以含有铰链区。Fc片段的原始免疫球蛋白来源可以是人源的，并且可以是任何免疫球蛋白，诸如IgG1或IgG2。Fc片段由可以通过共价(即二硫键)和非共价缔合而连接为二聚体或多聚体形式的单体多肽组成。Fc片段的单体亚基之间的分子间二硫键的数量为1至4，这取决于类别(例如IgG、IgA和IgE)或子类别(例如IgG1、IgG2、IgG3、IgA1和IgGA2)。Fc片段的一个实例是由木瓜蛋白酶消化IgG产生的二硫化物键合的二聚体。如本文所用的术语“Fc片段”是单体形式、二聚体形式和多聚体形式的通用形式。
如本文所用，术语“Fc片段承载蛋白质”或“含有Fc片段的蛋白质”是指包含Fc结构域或其Fc受体结合片段的蛋白质，其包括N-聚糖。在某些实施方式中，N-聚糖是存在于免疫球蛋白恒定(Fc)区的CH2结构域(例如，在EU位置297处)中的N-连接的双触角聚糖。“N-聚糖”经由N-乙酰葡萄糖胺残基附接在蛋白质中的天冬酰胺或精氨酸残基的酰胺氮处。这些“N-连接的糖基化位点”出现在含有例如氨基酸序列天冬酰胺-X-丝氨酸/苏氨酸的肽一级结构中，其中，X是除了脯氨酸和天冬氨酸之外的任何氨基酸残基。此类N-聚糖充分地描述于例如Drickamer K,Taylor ME(2006).Introduction to Glycobiology,第2版，其通过引用整体并入本文。
在一个实施方式中，“N聚糖”是指存在于免疫球蛋白恒定(Fc)区的CH2结构域中的Asn-297 N-连接的双触角聚糖。这些寡糖可以含有末端甘露糖、N-乙酰基-葡萄糖胺、半乳糖或唾液酸。
如本文所用，术语“糖工程化”是指任何公认的用于改变结合蛋白质组合物的糖型特性的方法。此类方法包括在经遗传工程化以表达异源糖基转移酶或糖苷酶的遗传工程化的宿主细胞(例如，CHO细胞)中表达结合蛋白质组合物。在其他实施方式中，糖工程化方法包括在偏向特定糖型特性的条件下培养宿主细胞。
如本文所用，“糖工程化Fc片段”涵盖(i)高半乳糖基化Fc片段，(ii)低甘露糖基化Fc片段，其涵盖了甘露糖基化Fc片段，和(iii)低岩藻糖基化Fc片段，其涵盖了无岩藻糖基化Fc片段。如本文所用，糖工程化片段涵盖具有选自包括以下经改变的糖基化中的一种或多种的经改变的糖基化的Fc片段：(i)高半乳糖基化、(ii)低甘露糖基化和(iii)低岩藻糖基化。因此，如根据本发明使用的糖工程化Fc片段涵盖了高半乳糖基化Fc片段、低甘露糖基化Fc片段和低岩藻糖基化Fc片段的说明性实例。
本领域技术人员可以参考众所周知的用于获得已知以比未修饰的Fc片段更高的亲和力与Fc受体结合的低半乳糖基化Fc片段、低甘露糖基化Fc片段和低岩藻糖基化Fc片段的技术。
如本文所用，术语“高半乳糖基化群体”是指其中与具有相同氨基酸序列的含Fc结构域的结合蛋白的参考群体相比，N聚糖的半乳糖含量增加的含Fc结构域的结合蛋白的群体。与含Fc结构域的结合蛋白的参考群体相比，高半乳糖基化群体可以表示为具有增加数量的G1和G2糖形式。
如本文所用，术语“低甘露糖基化群体”是指其中与具有相同氨基酸序列的含Fc结构域的结合蛋白的参考群体相比，N聚糖的甘露糖含量降低的含Fc结构域的结合蛋白群体。与含Fc结构域的结合蛋白的参考群体相比，低甘露糖基化群体可以表示为具有减少数量的寡甘露糖糖型(例如，M3至M9糖型)。在一些实施方式中，通过测量选自由以下组成的组的一种或多种寡甘露糖糖型的含量来确定甘露糖含量：Man3、Man4、Man5、Man 6、Man 7、Man 8和Man 9。在其他实施方式中，通过测量至少Man 5、Man 6和Man 7来确定寡甘露糖含量。在某些实施方式中，通过测量所有M3至M9糖型来确定寡甘露糖含量。如本文所用，术语“GO糖形式”、“G1糖形式”和“G2糖形式”是指分别具有零个、一个或两个末端半乳糖残基的N-聚糖糖型。这些术语包括被岩藻糖基化GO、G1和G2糖型或包含二等分N-乙酰葡萄糖胺残基的GO、G1和G2糖型。在某些实施方式中，G1和G2糖型还包含与末端半乳糖残基中的一个或两个连接的唾液酸残基，以形成G1S1、G2S1和G2S2糖型。如本文所用，术语“G1S1糖型”、“G2S1糖型”和“G2S2糖型”是指以下N-聚糖糖型：其唾液酸残基分别连接至G1糖型中的单个末端半乳糖残基，连接至G2糖型中的末端半乳糖残基中的一者，或连接至G2糖型中的两个末端半乳糖残基。这些术语包括被岩藻糖基化G1S1、G2S1和G2S2糖型或包含二等分N-乙酰葡萄糖胺残基的G1S1、G2S1和G2S2糖型。在某些实施方式中，G1S1、G2S1和G2S2糖型的唾液残基通过α-2,6-唾液酸键连接至每个糖型的末端半乳糖残基，以便增强结合分子的抗炎活性(参见，例如Anthony等人,PNAS 105:19571-19578,2008)。
以下如适用于由抗体组成的糖工程化Fc承载化合物的特定实施方式的“低岩藻糖基化的”或“无岩藻糖基化”的定义与感兴趣的糖工程化Fc承载化合物的一般性相关。
“低岩藻糖基化”抗体制备物是指其中少于50％的N-连接的寡糖链含有附接至CH2结构域的α1,6-岩藻糖的抗体制备物。通常，在“低岩藻糖基化”抗体制备物中，少于约40％、少于约30％、少于约20％、少于约10％或少于5％或少于1％的N-连接的寡糖链含有附接至CH2结构域的α1,6-岩藻糖。如本文所用，其中少于50％的N-连接的寡糖链含有附接至CH2结构域的α1,6-岩藻糖的抗体制备物涵盖了其中少于49％、少于48％、少于47％、少于46％、少于45％、少于44％、少于43％、少于42％、少于41％、少于40％、少于39％、少于38％、少于37％、少于36％、少于35％、少于34％、少于33％、少于32％、少于31％、少于30％、少于29％、少于28％、少于27％、少于26％、少于25％、少于24％、少于23％、少于22％、少于21％、少于20％、少于19％、少于18％、少于17％、少于16％、少于15％、少于14％、少于13％、少于12％、少于11％、少于10％、少于9％、少于8％、少于7％、少于6％、少于5％、少于4％、少于3％、少于2％或少于1％的N-连接的寡糖链含有附接至CH2结构域的α1,6-岩藻糖的制备物。
因此，术语“无岩藻糖基化”和“非岩藻糖基化”在本文可互换使用来指代在附接至IgG重链的CH2结构域的碳水化合物中缺乏α1,6-岩藻糖的抗体。Umana等人,Nat.Biotechnol 17:176-180,1999，描述了产生10倍ADCC的二等分GlcNac。Umana注意到此类二等分分子导致更少的岩藻糖基化。Davies,等人,Biotechnol.Bioeng.74:288-294,2001描述了具有插入酶β1-4-N-乙酰葡萄糖胺转移酶III(GnTIII)的CHO细胞(其导致二等分的GlcNac结构)，从而导致抗CD20抗体的ADCC增加。说明性地，美国专利No.US 6,602,684描述了经工程化以产生二等分GlcNac糖蛋白的细胞。
Shields等人,J Biol Chem 277:26733-26740,2002中提供了减少抗体制备物的岩藻糖基化的方法的另外示例，其描述了岩藻糖基化有缺陷以产生IgG1的CHO细胞(Lec13)并进一步描述了岩藻糖缺陷型IgG1与人FcγRIIIA的结合可以提高至50倍并增加ADCC。此外，Shinkawa等人,J Biol Chem 278:3466-3473,2003；比较了YB2/0和CHO细胞中产生的IgG。YB2/0细胞具有减少的岩藻糖基化和增加的二等分GlcNac含量。Niwa等人,Clinc.Cancer Res.1-:6248-6255,2004比较了抗CD20抗体与在YB2/0细胞中制备的抗体(低岩藻糖基化)，并观察到该细胞中ADCC增强。例如，在Kanda等人,Glycobiology 17:104-118,2006中提供了产生无岩藻糖基化抗体的技术的示例。美国专利No.6,946,292(Kanda)描述了岩藻糖基转移酶敲除细胞以产生无岩藻糖基化抗体。美国专利No.US7,214,775和PCT申请No.WO 00/61739描述了其中100％抗体是无岩藻糖基化的抗体制备物。
还已知有其他技术来修饰糖基化，诸如在美国专利申请No.US 2007/248600；US2007/178551(采用经工程化的低等真核细胞(酵母)产生“人”糖基化结构的GlycoFi技术方法)；US 2008/060092(采用经工程化的植物产生“人”糖基化结构的Biolex技术方法)和US2006/253928(也描述了植物工程化以产生“人”抗体)的那些技术。
用于减少岩藻糖的另外技术包括ProBioGen技术(von Horsten等人,Glycobiology,(提前获得出版2010年7月23日)；PotelligentTM技术(Biowa,Inc.纽约州普林斯顿)；和GlycoMAbTM糖基化工程化技术(GLYCART生物技术AG,瑞士苏黎世)。
抗体的N-连接的寡糖含量可以通过本领域已知的方法进行分析。以下是这种方法的实例：抗体经受用酶N-糖苷酶F(罗氏；宝生物)的消化。通过基质辅助的激光解吸/电离飞行时间质谱(MALDI-TOF MS)以正离子模式分析释放的碳水化合物(Papac等人,Glycobiol.8:445-454,1998)。然后，单糖组合物通过改进的高能阴离子交换色谱(HPAEC)表征(Shinkawa等人,J.Biol.Chem.278:3466-3473,2003)。
在某些实施方式中，本发明的糖工程化Fc片段承载化合物在培养的哺乳动物宿主细胞系(例如CHO细胞系)中产生。在某些实施方式中，宿主细胞系已被糖工程化以产生本发明的高半乳糖基化结合蛋白和/或低甘露糖基化结合蛋白。在某些示例性实施方式中，本发明的结合蛋白获自糖工程化的CHO细胞。在一个示例性实施方式中，经糖工程化的CHO细胞含有异源半乳糖基转移酶基因(例如，小鼠半乳糖基转移酶β1,4)。在另一个示例性实施方式中，经糖工程化的CHO细胞含有β半乳糖苷酶基因的等位基因中的一者的敲低。
根据本公开，术语“3C23K”意指抗AMHRII人源化单克隆抗体3C23K。AMHRII还可以称为MSRII。
根据本公开，术语“GM102”意指具有与3C23K抗体有相同氨基酸序列的轻链和重链的抗AMHRII人源化抗体，但已经糖工程化、更特别是低岩藻糖基化。“GM102”还可以在本文中称为“R18H2”。
根据本公开，“YB2/0细胞”(
)或“YB20”意指用于制造重组单克隆低岩藻糖基化抗体的细胞系。
根据本公开，3C23K-CHO由具有正常糖基化的3C23K抗体组成，其涵盖了已由CHO细胞系产生的3C23K抗体。
根据本公开，3C23K-FcKO由不含Fc片段的3C23K抗体组成。
糖工程化Fc片段承载化合物
术语“糖工程化Fc片段承载化合物”、“糖工程化Fc片段承载分子”、“含有糖工程化Fc片段的化合物”和“含有糖工程化Fc片段的分子”在本文中可互换使用，用于意指包含抗体的Fc片段的化合物，所述抗体的Fc片段具有向所述Fc片段提供与具有未改变的糖基化的相同Fc片段相比对Fc受体的更高亲和力的经改变的糖基化。
在一些优选的实施方式中，糖工程化Fc片段承载化合物对FcγRIIIa(也称为“CD16a”)的亲和力比未经历糖工程化的相同Fc片段更高。
在示例中，这通过称为“3C23K”的低岩藻糖基化Fc片段承载化合物所阐明，该化合物对人FcγRIIIa(CD16a)具有很高的亲和力并具有如用公知的
方法所测量为小于50nM的Kd常数值。
在一些优选的实施方式中，糖工程化Fc片段承载化合物由糖工程化Fc片段本身组成，因此化合物不包含抗原结合区。
在一些优选的实施方式中，糖工程化Fc片段承载化合物由糖工程化Fc片段承载蛋白质组成，其中，所述糖工程化Fc片段共价连接至另一个蛋白质部分，其是(i)包含抗原结合区的蛋白质或(ii)不包含抗原结合区的蛋白质。
在这些优选的实施方式的一些实施方式中，所述糖工程化Fc片段承载化合物仅包含一种糖工程化Fc片段。
因此，本发明涵盖糖工程化Fc片段承载化合物的用途，所述糖工程化Fc片段承载化合物包含(i)包含糖工程化Fc片段的多肽单体单元和(ii)共价连接至所述多肽单体单元的另一种多肽。所述另一种多肽可以为抗体的抗原结合区，诸如抗体的VH链和VL链。所述另一种多肽可以为配体结合蛋白质部分，诸如受体蛋白，如例如VEGF受体或VEGF受体的VEGF结合结构域等，例如TNFα受体或TNFα受体的TNF结合结构域。
在这些优选的实施方式的一些实施方式中，所述其他蛋白质部分可以包含另一Fc片段，并且特别是另一糖工程化Fc片段。在一些实施方式中，两种糖工程化Fc片段具有相同的氨基酸序列。在一些其他实施方式中，两种糖工程化Fc片段具有不同的氨基酸序列。在一些实施方式中，两种Fc片段具有相同的氨基酸序列但具有不同的改变的糖基化模式。在一些其他实施方式中，两种Fc片段具有相同的氨基酸序列并且具有相同的改变的糖基化模式。
因此，糖工程化Fc片段承载化合物涵盖包含多于一个Fc片段的蛋白质化合物，前提是其中所含的Fc片段中的至少一者是经糖工程化的，诸如其中所含的Fc片段中的至少一者是低甘露糖基化的、高半乳糖基化的或低岩藻糖基化的。
如本说明书的其他地方已经提及的，包含多于一个Fc片段，诸如包含两个、三个、四个、五个或六个Fc片段的Fc片段承载化合物在本领域中是公知的并且可以称为“Fc多聚体”。此类Fc多聚体构建体尤其由Thiruppathi等人(2014,J Autoimmun,第52卷:64-73)、Jain等人(2012,Arthritis Research and Therapy,第14卷:R192)或Zhou等人(2017,Blood advances,第1卷(第6期):DOI 10.1182/biooadvances.2016001917)公开。
因此，可以根据本发明使用的糖工程化Fc承载化合物涵盖了包含两个或多个多肽单体单元的多聚体融合蛋白(i)其中每个多肽单体单元包含Fc片段和(ii)其中至少一个多肽单体单元包含糖工程化Fc片段，诸如包含低甘露糖基化Fc片段、低半乳糖基化Fc片段或低岩藻糖基化Fc片段。
此类Fc多聚体还在美国专利申请No.US 2017/088063中公开。
在Fc多聚体化合物的一些实施方式中，所述化合物还包含其中的是抗原结合结构域，诸如例如Zhang等人(2016,J Immunol,第196卷:1165-1176)公开的那些。
在一些其他优选的实施方式中，糖工程化Fc片段承载化合物由糖工程化抗体组成，如在本文示例中所示。
在一些优选的实施方式中，糖工程化Fc片段承载化合物由低岩藻糖基化Fc片段承载化合物(诸如低岩藻糖基化抗体)组成，如在本文示例中所示。
在一些其他实施方式中，糖工程化Fc片段承载化合物、更精确的是低岩藻糖基化Fc片段承载化合物由无岩藻糖基化Fc片段承载化合物(诸如无岩藻糖基化抗体)组成。
在其他实施方式中，糖工程化Fc片段承载化合物由高半乳糖基化Fc片段承载化合物(诸如高半乳糖基化抗体)组成。
在另外其他实施方式中，糖工程化Fc片段承载化合物由低甘露糖基化Fc片段承载化合物(诸如低甘露糖基化抗体)组成。
如本说明书中其他地方已经描述的，由糖工程化Fc片段承载化合物(诸如糖工程化抗体)减少或阻断在癌症疾病期间发生的免疫抑制、诸如巨噬细胞诱导的免疫抑制不需要肿瘤细胞的存在，并因此不需要所述抗体结合至靶肿瘤细胞。
这解释了为什么本发明人认为减少或阻断免疫抑制、特别是抑制T细胞活化应通过不包含抗原结合区、诸如不包含肿瘤相关抗原结合区的糖工程化Fc片段承载化合物来获得。
然而，在本文的示例中还示出了当使用糖工程化抗体作为糖工程化Fc片段承载化合物时，达到了减少或阻断免疫抑制。
此外，本发明人认为，当使用由针对有关肿瘤相关抗原的糖工程化抗体(其意指针对由存在于待治疗的癌症个体的肿瘤组织或体液中的肿瘤细胞表达的肿瘤相关抗原的糖工程化抗体)组成的糖工程化Fc片段承载化合物时，可以进一步增加本文定义的糖工程化Fc片段承载化合物的有益作用。
因此，在一些优选的实施方式中，糖工程化Fc片段承载化合物由针对由待治疗的癌症个体的肿瘤细胞表达的肿瘤相关抗原的糖工程化抗体组成。
在一些优选的实施方式中，所述糖工程化抗体由低岩藻糖基化抗体组成，如在本文示例中所示。
不希望受任何特定理论的束缚，本发明人相信，使用针对由待治疗的癌症个体的肿瘤细胞表达的肿瘤相关抗原的糖工程化抗体(i)允许减少或阻断免疫抑制，诸如抑制T细胞活化，特别是抑制CD8+T细胞活化，诸如巨噬细胞诱导的免疫抑制，以及(ii)允许破坏表达所述糖工程化抗体所针对的肿瘤相关抗原的肿瘤细胞，诸如通过ADCC活性或ADC活性。
如本文所用的术语“肿瘤相关抗原”是指存在或可以存在于位于肿瘤细胞之上或之内的表面上的抗原。这些抗原可以用通常与分子的跨膜和细胞质部分组合的胞外部分呈递在细胞表面上。这些抗原在一些实施方式中只能由肿瘤细胞呈递，而不能由正常细胞(即非肿瘤细胞)呈递。肿瘤抗原可以仅在肿瘤细胞上表达，或者与非肿瘤细胞相比可以代表肿瘤特异性突变。在此类实施方式中，相应的抗原可以被称为肿瘤特异性抗原或肿瘤相关抗原(也称为“TAA”)。一些抗原由肿瘤细胞和非肿瘤细胞两者呈递，其也可以称为肿瘤相关抗原。与非肿瘤细胞相比，这些肿瘤相关抗原可以在肿瘤细胞上过表达，或者由于与非肿瘤组织相比肿瘤组织较不紧凑的结构导致易于在肿瘤细胞中进行抗体结合。在一些实施方式中，肿瘤相关的表面抗原位于肿瘤的血管系统上。
Liu等人(2016,European Journal of Cancer Care,doi:10/1111/ecc.12446)特别公开了本领域技术人员可以参考的肿瘤相关抗原的列表。
本领域技术人员也可以参考的Renkvist等人(2001,Cancer immunology andimmunotherapy,第50卷(第1期)3-15)公开了T细胞识别的肿瘤抗原列表。
肿瘤相关表面抗原的说明性实例是CD10、CD19、CD20、CD22、CD33、Fms样酪氨酸激酶3(FLT-3、CD135)、硫酸软骨素蛋白聚糖4(CSPG4、黑素瘤相关的硫酸软骨素蛋白聚糖)、表皮生长因子受体(EGFR)、Her2neu、Her3、IGFR、CD133、IL3R、成纤维细胞活化蛋白(FAP)、CDCP1、Derlinl、腱生蛋白、卷曲蛋白1-10、血管抗原VEGFR2(KDR/FLK1)、VEGFR3(FLT4、CD309)、PDGFR-a(CD140a)、PDGFR-β(CD140b)内皮糖蛋白、CLEC14、Tem1-8和Tie2。另外的实例可以包括A33、CAM PATH-1(CDw52)、癌胚抗原(CEA)、碳酸酐酶IX(MN/CA IX)、CD21、CD25、CD30、CD34、CD37、CD44v6、CD45、CD133、de2-7 EGFR、EGFRvlll、EpCAM、Ep-CAM、叶酸结合蛋白、G250、Fms样酪氨酸激酶3(FLT-3、CD135)、c-Kit(CD1 17)、CSF1 R(CD1 15)、HLA-DR、IGFR、IL-2受体、IL3R、MCSP(黑素瘤相关的细胞表面硫酸软骨素蛋白聚糖)、Muc-1、前列腺特异性膜抗原(PSMA)、前列腺干细胞抗原(PSCA)、前列腺特异性抗原(PSA)和TAG-72。在肿瘤的胞外基质上表达的抗原的实例是腱生蛋白和成纤维细胞活化蛋白(FAP)。
优选的肿瘤相关抗原(TAA)可以选自包括以下的组：CD45、IL-3Ra(也称为CD123)、CD33、CD20、CD22、CD19、EpCAM(也称为“上皮细胞粘附分子”)、HER2、TROP-2(也称为“滋养层细胞表面抗原2”)、GNMB(也称为“糖蛋白非转移性B”)、MMP9、EGFR、PD-L1(CD274)、CTLA4、GM3、间皮素、叶酸受体1、纤连蛋白胞外域B、内皮糖蛋白、CD22、IL-1α、HER3、cMet、磷脂酰丝氨酸、MUC5AC、NeuGc神经节甘脂、CD2、CD38、EGFR、HGF/SF、PD1、GD2、ST4和叶酸受体α。
根据本发明，最优选的肿瘤相关抗原是选自包括HER2、HER3、HER4和AMHRII的组的那些。
可以根据本发明使用的糖工程化抗体的优选实施方式选自包括在本文中称为3C23K、9F7F11、H4B121和HE4B33的糖工程化抗体。
糖工程化Fc片段承载化合物的说明性实施方式
Fc片段承载化合物的说明性实施方式涵盖了包含含本文所述的SEQ ID NO.70的两条氨基酸链的糖工程化Fc片段的化合物。
SEQ ID NO.70的氨基酸链由人IgG1抗体的重链恒定区组成，该重链恒定区包含CH1结构域、铰链区、CH2结构域和CH3结构域。
如在示例中所公开的，糖工程化Fc片段承载化合物、特别是低岩藻糖基化Fc片段承载化合物可以通过包括在YB2/0细胞中表达编码所述Fc片段的核酸序列的步骤的方法来获得。此类方法可以是在示例中描述的称为
的众所周知的方法。
在一些实施方式中，糖工程化Fc片段承载化合物、特别是低岩藻糖基化Fc片段承载化合物可以通过包括在YB2/0细胞中表达SEQ ID NO.69的核酸序列的步骤的方法获得。
在一些实施方式中，所述糖工程化Fc片段承载化合物由糖工程化抗体、特别是低岩藻糖基化抗体组成；其包括含两条SEQ ID NO.70的氨基酸链的所述糖工程化Fc片段。
包含糖工程化Fc片段的糖工程化抗体的实施方式描述如下。
作为糖工程化Fc片段承载化合物的抗体
因此，糖工程化Fc片段承载化合物的实施方式由抗体、特别是针对肿瘤相关抗原的糖工程化抗体组成。
在一些实施方式中，糖工程化Fc片段承载化合物涵盖了糖工程化多特异性抗体、特别是糖工程化双特异性抗体。说明性地，那些糖工程化抗体涵盖了以下抗体：其包含如本文所述的糖工程化Fc片段和(i)结合至肿瘤抗原的第一抗原结合区和(ii)结合至T细胞抗原(诸如CD3或抑制性免疫检查点蛋白)的第二抗原结合区，例如为了同时(i)靶向肿瘤抗原表达细胞和(ii)活化T细胞。
此类糖工程化抗体的说明性实例涵盖了针对肿瘤相关抗原(诸如AMHRII、HER2、HER3和HER4)的那些。
此类抗体可以就其抗原结合区、特别是其重链可变区(VH)和轻链可变区(VL)来描述。
抗AMHRII抗体的说明性实施方式
PCT申请No.PCT/FR2011/050745(国际公开No.WO/2011/141653)和美国专利No.9,012,607，其各自在此通过引用整体并入，公开了来源于鼠12G4抗体的新型人源化抗体。这些人源化抗体可以用作AMHRII结合剂以用于本发明的目的。在PCT申请No.WO/2011/141653中公开的具体实施方式中，抗体是鉴定为3C23和3C23K的那些。这些抗体的核酸序列和多肽序列在本文中提供为SEQ ID NO:1至SEQ ID NO:16。在本发明的一些方面，感兴趣的抗AMHRII抗体可以被称为“包含含SEQ ID NO:的轻链和含SEQ ID NO:的重链”。因此，在各种实施方式中，特别优选的抗体包含：
a)包含SEQ ID NO:2的轻链和包含SEQ ID NO:4的重链(无前导序列的3C23 VL序列和3C23 VH序列)；
b)包含SEQ ID NO:6的轻链和包含SEQ ID NO:8的重链(无前导序列的3C23K VL序列和3C23K VH序列)；
c)包含SEQ ID NO:10的轻链和包含SEQ ID NO:12的重链(无前导序列的3C23轻链和3C23重链)；
d)包含SEQ ID NO:14的轻链和包含SEQ ID NO:16的重链(无前导序列的3C23K轻链和3C23K重链)。
其他抗体(例如，人源化抗体或嵌合性抗体)可以基于本文所述的重链序列和轻链序列。
包含/含有CDR的抗AMHRII抗体的说明性实施方式包含以下序列(或由以下序列组成)：
-CDRL-1：RASX1X2VX3X4X5A(SEQ ID NO:71)，其中，X1和X2独立地是S或P，X3是R或W或G，X4是T或D，以及X5是I或T；
-CDRL-2是PTSSLX6S(SEQ ID NO:72)，其中，X6是K或E；和
-CDRL-3是LQWSSYPWT(SEQ ID NO:73)；
-CDRH-1是KASGYX7FTX8X9HIH(SEQ ID NO:74)，其中，X7是S或T，X8是S或G和X9是Y或N；
-CDRH-2是WIYPX10DDSTKYSQKFQG(SEQ ID NO:75)，其中，X10是G或E，和
-CDRH-3是GDRFAY(SEQ ID NO:76)。
在本申请的范围内的抗体(例如，嵌合性抗体或人源化抗体)包括下表中公开的那些：3C23K抗体由以下定义：
-对于VH氨基酸序列的SEQ ID NO:17，
-对于VL氨基酸序列的SEQ ID NO:34，
下文表1列出了可以根据本发明使用的抗AMHRII人源化抗体。
表1：抗AMHRII抗体
抗HER3抗体的说明性实施方式
糖工程化抗HER3抗体的说明性实施方式是在本文中称为9F7F11和H4B121的那些糖工程化抗HER3抗体。
9F7F11抗体包含(i)SEQ ID NO.63的重链可变区和(ii)SEQ ID NO.63的轻链可变区。
H4B121抗体包含(i)SEQ ID NO.65的重链可变区和(ii)SEQ ID NO.66的轻链可变区。
抗HER4抗体的说明性实施方式
抗HER4抗体的说明性实施方式是在本文中被称为HE4B33的抗体。
HE4B33抗体包含(i)SEQ ID NO.67的重链可变区和(ii)SEQ ID NO.68的轻链可变区
为了清楚起见，所述上述抗体均包含如本文所述的糖工程化Fc片段、特别是包含如本文所述的低岩藻糖基化Fc片段。
在一些优选的实施方式中，这些抗体包含具有SEQ ID NO.70的两条糖工程化氨基酸链的糖工程化Fc片段、特别是具有SEQ ID NO.70的两条低岩藻糖基化氨基酸链的低岩藻糖基化Fc片段。
糖工程化Fc片段承载化合物与一种或多种其他活性剂的组合
如本文所定义的糖工程化Fc片段承载化合物，因为其允许减少或阻断癌症患者中的免疫抑制状态，因此可用于增强已知抗癌治疗的抗癌活性，所述抗癌治疗包括手术治疗、放疗治疗和化学治疗。
此外，如本文所定义的糖工程化Fc片段承载化合物，因为允许减少或阻断癌症患者中的免疫抑制状态，因此被认为可以充当应增加目标在于阻断免疫抑制或目标在于诱导免疫刺激或免疫活化的其他化合物在免疫抑制的癌症患者中的有益作用的活性剂。此外，糖工程化Fc片段承载化合物也可以有助于用于抵抗癌细胞对那些免疫抑制抑制剂(检查点抑制剂)或免疫刺激剂的抗性。
因此，在另外的方面，如本文定义的糖工程化Fc片段承载化合物可以与另一种抗癌治疗组合使用，并且特别是与一种或多种由抗癌剂组成的不同化合物组合使用。
在另一方面，本发明涉及与一种或多种不同的抗癌剂组合的糖工程化Fc片段承载化合物在个体癌症治疗中作为免疫抑制抑制剂的用途。
本发明还涉及与一种或多种不同的抗癌剂组合的糖工程化Fc片段承载化合物用于制备用于治疗癌症的药剂的用途。
本发明还涉及用于治疗癌症的方法，该方法包括向有需要的个体施用糖工程化Fc片段承载化合物与一种或多种不同的抗癌剂组合的步骤。
抗癌剂涵盖了具有抗癌活性的化合物(诸如抗增殖活性剂)，其中，这些化合物中的许多化合物是本领域技术人员众所周知的。抗癌剂也涵盖了抑制性免疫检查点蛋白的抑制剂，如本说明书其他地方所详述。
“抗癌剂”根据其一般的普通含义使用，并且是指具有抗肿瘤性质或抑制细胞生长或增殖的能力的组合物(例如化合物、药物、拮抗剂、抑制剂、调节剂)。在一些实施方式中，抗癌剂是化学治疗剂。在一些实施方式中，抗癌剂是本文鉴定的在治疗癌症的方法中有用的药剂。在一些实施方式中，抗癌剂是FDA或除美国以外国家的类似监管机构批准的用于治疗癌症的药剂。
在一些实施方式中，所述癌症剂不由抗体来源的化合物、诸如抗体本身或其抗原结合片段或抗原结合格式组成。
不由抗体组成的抗癌剂的实例包括但不限于MEK(例如MEK1、MEK2、或MEK1和MEK2)抑制剂(例如XL518、CI-1040、PD035901、司美替尼/AZD6244、GSK1120212/曲美替尼、GDC-0973、ARRY-162、ARRY-300、AZD8330、PD0325901、U0126、PD98059、TAK-733、PD318088、AS703026、BAY 869766)、烷基化剂(例如环磷酰胺、异环磷酰胺、苯丁酸氮芥、白消安、美法仑、双氯乙基甲胺、乌拉莫司汀、噻替派、亚硝基脲、氮芥(例如甲氯乙胺(mechloroethamine)、环磷酰胺、苯丁酸氮芥、美法仑(meiphalan))、乙烯亚胺和甲基蜜胺(例如六甲基蜜胺、噻替派)、烷基磺酸盐(例如白消安)、亚硝基脲(例如卡莫司汀、洛莫司汀、司莫司汀、链脲菌素)、三氮烯(达卡巴嗪))、抗代谢物(例如5-硫唑嘌呤、亚叶酸、卡培他滨、氟达拉滨、吉西他滨、培美曲塞、雷替曲塞、叶酸类似物(例如，甲氨蝶呤)或嘧啶类似物(例如氟尿嘧啶、氟尿苷、阿糖胞苷)、嘌呤类似物(例如巯嘌呤、硫鸟嘌呤、喷司他丁)等)、植物生物碱(例如长春新碱、长春碱、长春瑞滨、长春地辛、鬼臼毒素、紫杉醇、多西他赛等)、拓扑异构酶抑制剂(例如伊立替康、拓扑替康、安吖啶、依托泊苷(VP16)、磷酸依托泊苷、替尼泊苷等)、抗肿瘤抗生素(例如多柔比星、阿霉素、道诺霉素、表柔比星、放线菌素、博来霉素、丝裂霉素、米托蒽醌、普卡霉素等)、基于铂的化合物或含铂剂(例如顺铂、奥沙利铂、卡铂)、蒽二酮(例如米托蒽醌)、经取代的脲(例如羟基脲)、甲基肼衍生物(例如丙卡巴肼)、肾上腺皮质遏制剂(例如米托坦、氨鲁米特)、表鬼臼毒素(例如依托泊苷)、抗生素(例如道诺霉素、多柔比星、博来霉素)、酶(例如L-天冬酰胺酶)、丝裂原活化的蛋白激酶信号传导的抑制剂(例如U0126、PD98059、PD184352、PD0325901、ARRY-142886、SB239063、SP600125、BAY 43-9006、渥曼青霉素或LY294002、Syk抑制剂、mTOR抑制剂、棉子酚(gossyphol)、genasense、多元酚E、氯融合素、全反式维甲酸(ATRA)、苔藓抑素、肿瘤坏死因子相关的凋亡诱导配体(TRAIL)、5-氮杂-2’-脱氧胞苷、全反式维甲酸、多柔比星、长春新碱、依托泊苷、吉西他滨、伊马替尼(
)、格尔德霉素、17-N-烯丙基氨基-17-脱甲氧格尔德霉素(17-AAG)、夫拉平度、LY294002、硼替佐米、曲妥珠单抗、BAY 11-7082、PKC412、PD184352、20-epi-1、25二羟维生素D3；5-乙炔基尿嘧啶；阿比特龙；阿柔比星；酰基富稀；腺环戊醇；阿多来新；阿地白介素；ALL-TK拮抗剂；六甲蜜胺；氨莫司汀；阿米度(amidox)；氨磷汀；氨基乙酰丙酸；氨柔比星；安吖啶；阿那格雷；阿那曲唑；穿心莲内酯；血管生成抑制剂；拮抗剂D；拮抗剂G；安雷利克斯；抗背部化形态发生蛋白-1；抗雄激素、前列腺癌；抗雌激素；抗瘤酮；反义寡核苷酸；甘氨酸阿非迪霉素；凋亡基因调节剂；凋亡调节剂；无嘌呤核酸；ara-CDP-DL-PTBA；精氨酸脱氨酶；奥沙那宁；阿他美坦；阿莫司汀；阿新司坦汀1；阿新司坦汀2；阿新司坦汀3；阿扎司琼；阿扎托新；重氮酪氨酸；巴卡亭III衍生物；巴览醇；巴马司他；BCR/ABL拮抗剂；苯并二氢卟酚；苯甲酰基星形孢菌素；β内酰胺衍生物；β-阿立辛；β克拉霉素B；桦木酸；bFGF抑制剂；比卡鲁胺；比生群；二吖丙啶基精胺；双奈法德；双特拉汀A；比折来新；比锐来特；溴匹立明；布朵替坦；丁硫氨酸亚砜胺；钙泊三醇；卡弗他丁C；喜树碱衍生物；金丝雀痘IL-2；卡培他滨；甲酰胺-氨基-三唑；甲酰氨基三唑；CaRest M3；CARN 700；软骨来源的抑制剂；卡折来新；酪蛋白激酶抑制剂(ICOS)；粟树精胺；天蚕素B；西曲瑞克；二氢卟酚；氯喹喔啉磺胺；西卡前列素；顺式-卟啉；克拉屈滨；氯米芬类似物；克霉唑；克力霉素A；克力霉素B；康普瑞汀A4；康普瑞汀类似物；康瑞宁；克贝西定816；克雷斯托；念珠藻素8；念珠藻素A衍生物；卡拉新A；环戍蒽醌；环普兰姆；卷曲霉素；阿糖胞苷欧可弗斯特；细胞裂解因子；细胞抑素；达昔单抗；地西他滨；脱氢膜海鞘素B；德舍瑞林；地塞米松；右异环磷酰胺；右雷佐生；右维拉帕米；亚丝醌；膜海鞘素B；地多西；二乙基去甲精胺；二氢-5-氮杂胞苷；9-二氧霉素；二苯基螺莫司汀；二十二醇；多拉司琼；去氧氟尿苷；屈洛昔芬；卓那比醇；倍癌霉素SA；依布硒啉；依考莫司汀；依地福新；依决洛单抗；依洛尼塞；榄香烯；乙嘧替氟；表柔比星；爱普列特；雌莫司汀类似物；雌激素激动剂；雌激素拮抗剂；依他硝唑；磷酸依托泊苷；依西美坦；法倔唑；法扎拉滨；芬维A胺；非格司亭；非那雄胺；夫拉平度；氟卓斯汀；夫阿斯通；氟达拉滨；盐酸氟道诺霉素；福酚美克；福美司坦；福司曲星；福莫司汀；得克萨卟啉钆；硝酸镓；加洛他滨；加尼瑞克；明胶酶抑制剂；吉西他滨；谷胱甘肽抑制剂；贺沙芬；调节蛋白；六亚甲基二乙酰胺；金丝桃素；伊班膦酸；伊达比星；艾多昔芬；伊决孟酮；伊莫福新；伊洛马司他；咪唑并吖啶酮；咪喹莫特；免疫刺激肽；胰岛素样生长因子-1受体抑制剂；干扰素激动剂；干扰素；白介素；碘苄胍；碘代多柔比星；4-甘薯黑斑霉醇；伊罗普拉；伊索拉定；isobengazole；异质哈立康定(isohomohalicondrin)B；伊他司琼；jasplakinolide；卡哈拉德F；片螺素-N三乙酸盐；兰瑞肽；雷纳霉素；来格司亭；硫酸香菇多糖；立托斯坦汀；来曲唑；白血病抑制因子；白细胞α干扰素；亮丙瑞林+雌激素+黄体酮；亮丙瑞林；左旋咪唑；利阿唑；直链多胺类似物；亲脂性二糖肽；亲脂性铂化合物；利克酰胺7；络铂；蚯蚓磷脂；洛美曲索；氯尼达明；洛索蒽醌；洛伐他汀；洛索立宾；勒托替康；德卟啉镥；利索灵；裂解肽；美坦辛；抑甘露糖苷酶素A；马立马司他；马索罗酚；乳腺丝抑蛋白；基质溶解因子抑制剂；基质金属蛋白酶抑制剂；美诺立尔；美巴龙；美替瑞林；蛋氨酸酶；甲氧氯普胺；MIF抑制剂；米非司酮；米替福新；米立司亭；错配的双链RNA；米托胍腙；二溴卫矛醇；丝裂霉素类似物；米托萘胺；迈托毒素成纤维细胞生长因子-皂草素；米托蒽醌；莫法罗汀；莫拉司亭；人绒膜促性腺激素；单磷酰脂质A+分支杆菌细胞壁sk；莫哌达醇；多药抗性基因抑制剂；基于多重肿瘤抑制剂1的疗法；氮芥抗癌剂；印度洋海绵B；分枝杆菌细胞壁提取物；美瑞泡仁(myriaporone)；N-乙酰基地那林；N-取代的苯甲酰胺；那法瑞林；纳格瑞替；纳洛酮+喷他佐辛；纳帕因；纳福特平；那托司亭；奈达铂；奈莫柔比星；奈立膦酸；中性肽链内切酶；尼鲁米特；尼萨霉素；一氧化氮调节剂；硝基氧抗氧化剂；尼托林；O6-苄基鸟嘌呤；奥曲肽；奥克昔酮；寡核苷酸；奥那司酮；昂丹司琼；昂丹司琼；奥莱辛；口服细胞因子诱导剂；奥马铂；奥沙特隆；奥沙利铂；奥沙霉素；帕拉胺；棕榈酰利索新；帕米膦酸；人参炔三醇；帕诺米芬；副球菌素；泊泽尼普定；培门冬酶；培地新；戌聚糖多硫酸钠；喷司他丁；喷曲唑；全氟溴烷；培磷酰胺；紫苏醇；芬那霉素；乙酸苯酯；磷酸酶抑制剂；毕西巴尼；盐酸匹鲁卡品；吡柔比星；吡曲克辛；胎盘素A；胎盘素B；纤溶酶原活化物抑制剂；铂络合物；铂化合物；铂-三胺络合物；卟吩姆钠；泊非霉素；强的松；丙基双吖啶酮；前列腺素J2；蛋白酶体抑制剂；基于蛋白A的免疫调节剂；蛋白激酶C抑制剂；蛋白激酶C抑制剂、微藻(microalgal)；蛋白酪氨酸磷酸酶抑制剂；嘌呤核苷磷酸酶抑制剂；红紫素；吡唑啉吖啶；吡哆酰基化血红蛋白聚氧乙烯缀合物；raf拮抗剂；雷替曲塞；雷莫司琼；ras法呢基蛋白转移酶抑制剂；ras抑制剂；ras-GAP抑制剂；脱甲基化瑞替普汀；依替膦酸铼Re 186；利索新；核糖酶；RII维甲酰酚胺；罗谷亚胺；罗希吐碱；罗莫肽；罗喹美克；卢比基酮B1；卢比氧基(ruboxyl)；沙芬戈；散特平；SarCNU；沙卡弗托A；沙格司亭；Sdi 1模拟物；司莫司汀；衰老来源的抑制剂1；有义寡核苷酸；信号转导抑制剂；信号转导调节剂；单链抗原结合蛋白；西佐呋喃；索布佐生；硼卡钠；苯乙酸钠；索尔醇；生长调节素结合蛋白；索纳明；斯帕磷酸；司皮卡霉素D；螺莫司汀；斯耐潘定；海绵抑素1；角鲨胺；干细胞抑制剂；干细胞分裂抑制剂；斯蒂匹酰胺；溶基质素抑制剂；沙芬辛；强效血管活性肠肽拮抗剂；苏拉蒂斯塔；苏拉明；苦马豆素；合成的糖氨基聚糖；他莫司汀；他莫昔芬甲碘化物；牛磺莫司汀；他扎罗汀；替康兰钠；替加氟；特鲁拉吡喃鎓；端粒酶抑制剂；替莫卟吩；替莫唑胺；替尼泊苷；四氯十氧化物；四氮胺；沙力步拉司丁；噻考瑞林；促血小板生成素；促血小板生成素模拟物；胸腺法新；促胸腺生成素受体激动剂；胸腺曲南；甲状腺刺激激素；本红紫素乙基锡；替拉扎明；二氯二茂钛；特西汀；托瑞米芬；全能干细胞因子；翻译抑制剂；维甲酸；三乙酰尿苷；曲西立滨；三甲曲沙；曲普瑞林；托烷司琼；妥罗雄脲；酪氨酸激酶抑制剂；酪氨酸磷酸化抑制剂(tyrphostins)；UBC抑制剂；乌苯美司；泌尿生殖窦来源的生长抑制因子；尿激酶受体拮抗剂；伐普肽；法洛林B；载体系统，红细胞基因疗法；维拉雷琐；藜芦胺；维尔丁；维替泊芬；长春瑞滨；维萨汀；维他欣；伏氯唑；扎诺特隆；折尼铂；亚苄维；净司他丁苯马聚合物，阿霉素，放线菌素D，博来霉素，长春花碱，顺铂，阿西维辛；阿柔比星；盐酸阿考达唑；阿克罗宁；阿多来新；阿地白介素；六甲蜜胺；安波霉素；乙酸阿美蒽醌；氨鲁米特；安吖啶；阿那曲唑；氨茴霉素；天冬酰胺酶；曲林菌素；阿扎胞苷；阿扎替派；阿佐霉素；巴马司他；苄替哌；比卡鲁胺；盐酸比生群；二甲磺酸双奈法德；比折来新；硫酸博来霉素；布喹那钠；溴匹立明；白消安；放线菌素C；卡普睾酮；卡拉酰胺；卡贝替姆；卡铂；卡莫司汀；盐酸卡柔比星；卡折来新；西地芬戈；苯丁酸氮芥；西罗霉素；克拉屈滨；甲磺酸克雷斯托；环磷酰胺；阿糖胞苷；达卡巴嗪；盐酸道诺霉素；地西他滨；右奥马铂；地扎胍宁；甲磺酸地扎胍宁；亚丝醌；多柔比星；盐酸多柔比星；屈洛昔芬；柠檬酸屈洛昔芬；丙酸屈他雄酮；达佐霉素；依达曲沙；盐酸依洛尼塞；依沙芦星；恩洛铂；恩普氨酯；依匹哌啶；盐酸表柔比星；厄布洛唑；盐酸依索比星；雌莫司汀；雌莫司汀磷酸钠；依他硝唑；依托泊苷；磷酸依托泊苷；艾托卜宁；盐酸法倔唑；法扎拉滨；芬维A胺；氟尿苷；磷酸氟达拉滨；氟尿嘧啶；氟西他滨；磷喹酮；福司曲星钠；吉西他滨；盐酸吉西他滨；羟基脲；盐酸伊达比星；异环磷酰胺；伊莫福新；白介素I1(包括重组白介素II或rlL.sub.2)，干扰素α-2a；干扰素α-2b；干扰素α-n1；干扰素α-n3；干扰素β-1a；干扰素γ-1b；异丙铂；盐酸伊立替康；乙酸兰瑞肽；来曲唑；乙酸亮丙瑞林；盐酸利阿唑；洛美曲索钠；洛莫司汀；盐酸洛索蒽醌；马索罗酚；美登素；盐酸二氯甲基二乙胺；乙酸甲地孕酮；乙酸美仑孕酮；美法仑；美诺立尔；巯嘌呤；甲氨蝶呤；甲氨蝶呤钠；氯苯氨啶；美妥替哌；米丁度胺；米托卡西；米托罗明；米托洁林；米托马星；丝裂霉素；米托司培；米托坦；盐酸米托蒽醌；麦考酚酸；诺考达唑；诺加霉素；奥马铂；奥昔舒仑；培门冬酶；培利霉素；奈莫司汀；硫酸培洛霉素；培磷酰胺；哌泊溴烷；哌泊舒凡；盐酸吡罗蒽醌；普卡霉素；普洛美坦；卟吩姆钠；泊非霉素；泼尼莫司汀；盐酸丙卡巴肼；嘌呤霉素；盐酸嘌呤霉素；吡唑呋喃菌素；利波腺苷；罗谷亚胺；沙芬戈；盐酸沙芬戈；司莫司汀；辛曲秦；磷乙酰天冬氨酸钠；司帕霉素；盐酸锗螺胺；螺莫司汀；螺铂；链黑菌素；链脲菌素；磺氯苯脲；他利霉素；替康兰钠；替加氟；盐酸替洛蒽醌；替莫卟吩；替尼泊苷；替罗昔隆；睾内酯；硫咪嘌呤；硫鸟嘌呤；噻替派；噻唑呋林；替拉扎明；柠檬酸托瑞米芬；乙酸曲托龙；磷酸曲西立滨；三甲曲沙；葡糖醛酸三甲曲沙；曲普瑞林；盐酸妥布氯唑；乌拉莫司汀；乌瑞替派；伐普肽；维替泊芬；硫酸长春碱；硫酸长春新碱；长春地辛；硫酸长春地辛；硫酸长春匹定；硫酸长春甘酯；硫酸长春罗新；酒石酸长春瑞滨；硫酸长春罗定；硫酸长春利定；伏氯唑；折尼铂；净司他丁；盐酸佐柔比星，将细胞阻滞在G2-M期和/或调节微管的形成或稳定性的药剂(例如TaxolTM(即紫杉醇)、TaxotereTM，包含紫杉烷骨架的化合物、厄布洛唑(即R-55104)、尾海兔素10(即DLS-10和NSC-376128)、羟乙基磺酸米伏布尔(即作为CI-980)、长春新碱、NSC-639829、圆皮海绵内酯(即作为NVP-XX-A-296)、ABT-751(雅培，即E-7010)、阿托瑞亭(例如阿托瑞亭A和阿托瑞亭C)、海绵抑素(例如海绵抑素1、海绵抑素2、海绵抑素3、海绵抑素4、海绵抑素5、海绵抑素6、海绵抑素7、海绵抑素8和海绵抑素9)、盐酸西马多丁(即LU-103793和NSC-D-669356)、埃博霉素(例如埃博霉素A、埃博霉素B、埃博霉素C(即脱氧埃博霉素A或dEpoA)、埃博霉素D(即KOS-862、dEpoB和脱氧埃博霉素B)、埃博霉素E、埃博霉素F、埃博霉素BN-氧化物、埃博霉素A N-氧化物、16-氮杂-埃博霉素B、21-氨基埃博霉素B(即BMS-310705)、21-羟基埃博霉素D(即脱氧埃博霉素F和dEpoF)、26-氟埃博霉素、瑞奥西汀PE(即NSC-654663)、索利多丁(即TZT-1027)、LS-4559-P(法玛西亚，即LS-4577)、LS-4578(法玛西亚，即LS-477-P)、LS-4477(法玛西亚)、LS-4559(法玛西亚)、RPR-112378(安内特)、硫酸长春新碱、DZ-3358(第一三共)、FR-182877(藤泽，即WS-9885B)、GS-164(武田)、GS-198(武田)、KAR-2(匈牙利科学院)、BSF-223651(巴斯夫(BASF)，即ILX-651和LU-223651)、SAH-49960(礼来/诺华)、SDZ-268970(礼来/诺华)、AM-97(Armad/协和发酵)、AM-132(Armad)、AM-138(Armad/协和发酵)、IDN-5005(印第纳)、念珠藻素52(即LY-355703)、AC-7739(味之素，即AVE-8063A和CS-39.HCl)、AC-7700(味之素，即AVE-8062、AVE-8062A、CS-39-L-Ser.HCl和RPR-258062A)、维替乐福酰胺、微管菌素A、卡纳登索、矢车菊黄素(即NSC-106969)、T-138067(Tularik，即T-67、TL-138067和TI-138067)、COBRA-1(帕克休斯研究所，即DDE-261和WHI-261)、H10(堪萨斯州立大学)、H16(堪萨斯州立大学)、杀癌素A1(即BTO-956和DIME)、DDE-313(帕克休斯研究所)、福佳立德B、洛利玛内酯、SPA-2(帕克休斯研究所)、SPA-1(帕克休斯研究所，即SPIKET-P)、3-IAABU(细胞骨架/西奈山医学院，即MF-569)、那可辛(也被称为NSC-5366)、依那斯纳、D-24851(阿斯塔医药)、A-105972(雅培)、半阿司特林、3-BAABU(细胞骨架/西奈山医学院，即MF-191)、TMPN(亚利桑那州立大学)、乙酰丙酮酸瓦那多辛、T-138026(Tularik)、单星素、lnanocine(即NSC-698666)、3-IAABE(细胞骨架/西奈山医学院)、A-204197(雅培)、T-607(Tuiarik，即T-900607)、RPR-115781(安内特)、五加素(诸如去甲基五加素、去乙酰基五加素、异五加素A和Z-五加素)、卡利贝昔、卡巴林、软海绵素B、D-64131(阿斯塔医药)、D-68144(阿斯塔医药)、重氮酰胺A、A-293620(雅培)、NPI-2350(涅柔斯)、根薯酮内酯A、TUB-245(安内特)、A-259754(雅培)、戴佐斯他汀、(-)-苯基阿斯丁(即NSCL-96F037)、D-68838(阿斯塔医药)、D-68836(阿斯塔医药)、肌基质蛋白B、D-43411(赞塔里斯，即D-81862)、A-289099(雅培)、A-318315(雅培)、HTI-286(即SPA-110，三氟乙酸盐)(惠氏)、D-82317(赞塔里斯)、D-82318(赞塔里斯)、SC-12983(NCI)、瑞瓦斯汀磷酸钠、BPR-OY-007(国家卫生研究院)和SSR-250411(赛诺菲))、类固醇(例如地塞米松)、非那雄胺、芳香酶抑制剂、促性腺激素释放激素激动剂(GnRH)诸如戈舍瑞林或亮丙瑞林、肾上腺皮质类固醇(例如强的松)、孕酮(例如己酸羟孕酮、乙酸甲地孕酮、乙酸甲羟孕酮)、雌激素(例如己烯雌酚、乙炔雌二醇)、抗雌激素(例如他莫昔芬)、雄激素(例如丙酸睾酮、氟甲睾酮)、抗雄激素(例如氟他米特)、免疫刺激剂(例如卡介苗(BacillusCalmette-Guérin)(BCG)、左旋咪唑、白介素-2、α-干扰素等)、雷公藤甲素、高三尖杉酯碱、放线菌素D、多柔比星、表柔比星、拓扑替康、依曲康唑、长春地辛、西立伐他汀、长春新碱、脱氧腺苷、舍曲林、匹伐他汀、伊立替康、氯法齐明、5-壬基氧基色胺、维罗非尼、达拉菲尼、埃罗替尼、吉非替尼、EGFR抑制剂、表皮生长因子受体(EGFR)-靶向疗法或治疗剂(例如吉非替尼(IressaTM)埃罗替尼(TarcevaTM)西妥昔单抗(ErbituxTM)、拉帕替尼(TykerbTM)、帕尼单抗(VectibixTM)凡德他尼(CaprelsaTM)、阿法替尼/BIBW2992、CI-1033/卡奈替尼、来那替尼/HKI-272、CP-724714、TAK-285、AST-1306、ARRY334543、ARRY-380、AG-1478、达克替尼/PF299804、OSI-420/去甲基埃罗替尼、AZD8931、AEE788、培利替尼/EKB-569、CUDC-101、WZ8040、WZ4002、WZ3146、AG-490、XL647、PD153035、BMS-599626)、索拉非尼、伊马替尼、舒尼替尼、达沙替尼、激素疗法等。抗癌剂的施用途径、剂量和治疗方案的细节是本领域已知的，例如，如“Cancer Clinical Pharmacology”(2005)Jan H.M.Schellens,Howard L.McLeod和David R.Newell编辑,牛津大学出版社所述。
在一些其他实施方式中，所述另外的抗癌剂由不同于用于抑制癌症相关的免疫抑制的一种或多种Fc承载化合物的抗癌抗体组成。抗癌抗体涵盖了单克隆抗体(例如，抗CD20、抗HER2、抗CD52、抗HLA-DR和抗VEGF单克隆抗体)、免疫毒素(例如，抗CD33单克隆抗体-卡里奇霉素缀合物、抗CD22单克隆抗体-假单胞菌外毒素缀合物等)、放射免疫疗法(例如，缀合至111In、90Y或131I的抗CD20单克隆抗体等)。在一些实施方式中，这些抗癌抗体可以本身被糖工程化，诸如低岩藻糖基化。
抗癌剂还涵盖了已知活化或重新活化免疫系统的抗癌活性的药剂。活化或重新活化免疫系统抗癌活性的活化涵盖了以下那些：优选抑制抑制性免疫检查点的那些。这些剂可以在本文中称为“抑制性免疫检查点抑制剂”或“免疫检查点抑制剂”。如本领域已知，免疫检查点抑制剂由抑制抑制性免疫检查点蛋白的活性的药剂组成。
术语“免疫检查点蛋白”是本领域已知的。在该术语的已知含义内，本领域技术人员将清楚，在“免疫检查点蛋白”的水平上，免疫系统向其组分提供抑制性信号以平衡免疫反应。已知的免疫检查点蛋白包括CTLA-4、PD1及其配体PD-L1和PD-L2，并且此外LAG-3、BTLA、B7H3、B7H4、TIM3、KIR。涉及LAG3、BTLA、B7H3、B7H4、TIM3和KIR的途径在本领域中被认为构成类似于CTLA-4和PD-1依赖性途径的免疫检查点途径(参见例如Pardoll,2012.Nature Rev Cancer 12:252-264；Mellman等人,2011.Nature 480:480-489)。
在本发明中，免疫检查点蛋白抑制剂是抑制免疫检查点蛋白功能的任何化合物。抑制包括功能降低和完全阻滞。特别地，免疫检查点蛋白是人免疫检查点蛋白。因此，免疫检查点蛋白抑制剂优选是人免疫检查点蛋白的抑制剂。免疫检查点蛋白在本领域中已有描述(参见例如Pardoll,2012.Nature Rev.cancer12:252-264)。免疫检查点蛋白的命名包括通过在体外或体内抑制免疫检查点蛋白来刺激抗原-受体-触发的T淋巴细胞应答的实验证明，例如免疫检查点蛋白表达有缺陷的小鼠证明了增强的抗原特异性T淋巴细胞应答或自身免疫体征(诸如Waterhouse等人,1995.Science 270:985-988；Nishimura等人,1999.Immunity 11:141-151中公开)。它还可以包括由于在体外或体内故意刺激免疫检查点蛋白而引起的抗原-受体触发的CD4+或CD8+T细胞应答的抑制的证明(例如Zhu等人,2005.Nature Immunol.6:1245-1252)。优选的免疫检查点蛋白抑制剂是特异性识别免疫检查点蛋白的抗体。已知许多CTLA-4、PD1、PDL-1、PD-L2、LAG-3、BTLA、B7H3、B7H4、TIM3和KIR抑制剂，并且与这些已知的免疫检查点蛋白抑制剂类似，可替选的免疫检查点抑制剂可以在(不久的)将来被开发。例如伊匹单抗是目前以名称Yervoy(百时美施贵宝)出售的完全人CTLA-4阻断抗体。第二种CTLA-4抑制剂是替西木单抗(在Ribas等人,2013,J.Clin.Oncol.31:616-22中引用)。PD-1抑制剂的实例包括但不限于阻断人PD-1的人源化抗体，诸如兰洛珠单抗(例如在WO2008/156712；Hamid等人,N.Engl.J.Med.369:134-1442013中公开为hPD109A及其人源化衍生物h409All、h409A16和h409A17)或皮立珠单抗(于Rosenblatt等人,2011.J Immunother.34:409-18中公开)，以及完全人抗体诸如纳武单抗(之前称为MDX-1106或BMS-936558，Topalian等人,2012.N.Eng.J.Med.366:2443-2454，公开于US8008449中)。其他PD-1抑制剂可以包括可溶PD-1配体的表现形式，包括但不限于PD-L2 Fc融合蛋白(也被称为B7-DC-Ig或AMP-244)(公开于Mkrtichyan M,等人JImmunol.189:2338-47 2012)和目前正在研究和/或开发以用于疗法中的其他PD-1抑制剂。此外，免疫检查点抑制剂可以包括但不限于阻断PD-L1的人源化或完全人抗体，诸如MEDI-4736(在WO2011066389中公开)、MPDL328 OA(在US8217149中公开)和MIH1(经由eBioscience(16.5983.82)可获得的Affymetrix)和目前正在研究的其他PD-L1抑制剂。根据本发明，免疫检查点抑制剂优选选自CTLA-4、PD-1或PD-L1抑制剂，诸如选自以上提及的已知的CTLA-4、PD-1或PD-L1抑制剂(伊匹单抗、替西木单抗、拉立珠单抗、纳武单抗、皮立珠单抗、AMP-244、MEDI-4736、MPDL328 OA、MIH1)。因此，可以使用这些免疫检查点蛋白的已知抑制剂，或者可以使用类似物，特别是嵌合性、人源化或人形式的抗体。
如技术人员将知道的，可替选和/或等效的名称可以用于以上提及的某些抗体。在本发明的上下文中，此类可替选和/或等效的名称是可互换的。例如，已知兰洛珠单抗也以可替选和等效的名称MK-3475和帕博利珠单抗而闻名。
从PD1和PD-L1抑制剂(诸如以上提及的已知PD-1或PD-L1抑制剂)中选择免疫检查点抑制剂是更优选的，并且最优选从PD-1抑制剂(诸如以上提及的已知PD1抑制剂)中选择。在优选的实施方式中，PDl抑制剂是纳武单抗或帕博利珠单抗或另一种针对人PDl的拮抗剂抗体。
本发明还包括选择本领域已知刺激免疫应答的其他免疫检查点抑制剂。这包括直接或间接刺激或增强抗原特异性T淋巴细胞的抑制剂。这些其他免疫检查点抑制剂包括但不限于靶向免疫检查点蛋白的试剂和涉及PD-L2、LAG3、BTLA、B7H4和TIM3的途径。例如，本领域已知的人PD-L2抑制剂包括MIH18(公开于Pfistershammer等人,2006.Eur JImmunol.36:1104-13中)。另一个实例，本领域已知的LAG3抑制剂包括阻断人LAG3的可溶性LAG3(IMP321或LAG3-Ig，公开于WO2009044273中，并且公开于Brignon等人,2009.Clin.Cancer Res.15:6225-6231中)以及小鼠抗体或人源化抗体(例如IMP701，公开于并且来源于WO2008132601)，或阻断人LAG3的完全人抗体(诸如公开于EP 2320940中)。另一个实例通过使用针对BTLA的阻断剂来提供，包括但不限于阻断人BTLA与其配体的相互作用的抗体(诸如公开于WO2011014438中的4C7)。又一个实例通过使用中和B7H4的试剂包括但不限于针对以下的抗体来提供：人B7H4(在WO 2013025779Al和WO 2013067492中公开)或可溶重组形式的B7H4(诸如在US20120177645中公开或抗人B7H4克隆H74:eBiocience#14-5948)。又一个实例由中和B7-H3的试剂提供，包括但不限于中和人B7-H3的抗体(例如在US20120294796中公开为BRCA84D和衍生物的MGA271)。又一个实例由靶向TIM3的试剂提供，包括但不限于靶向人TIM3的抗体(例如WO 2013006490中公开或由Jones等人,J ExpMed.2008年11月24日；205(12):2763-79公开的抗人TIM3，阻断抗体F38-2E2)。免疫检查点蛋白的已知抑制剂可以以其已知形式使用，或可以使用类似物，特别地，嵌合形式的抗体，最优选人源化形式。
本发明还包括在本发明的各个方面中选择一种以上的选自CTLA-4、PD-1或PDL1抑制剂的免疫检查点抑制剂与糖工程化Fc片段承载化合物组合。例如，伊匹单抗(抗CTLA4)与纳武单抗(抗PD1)的同时疗法已证明临床活性似乎与单一疗法获得的不同(Wolchok等人,2013,N.Eng.J.Med.,369:122-33)。还包括了已显示提高检查点抑制剂的功效的药剂、诸如利鲁单抗(也被称为抗KIR、BMS-986015或IPH2102，如US8119775和Benson等人,Blood 120:4324-4333(2012)中所公开)与伊匹单抗(Rizvi等人,ASCO 2013和clinicaltrials.govNCT01750580)的组合或者与纳武单抗(Sanborn等人,ASCO 2013和clinicaltrials.govNCT01714739)的组合；靶向LAG3的药剂与抗PD-1(Woo等人,2012Cancer Res.72:917-27)或抗PD-L1(Butler Ns等人,Nat Immunol.2011 13:188-95)的组合，靶向ICOS的药剂与抗CTLA-4(Fu等人,Cancer Res.2011 72:917-27)的组合，或者靶向4-1BB的药剂与抗CTLA-4(Curran等人,PLoS One.2011 6(4)el 9499)的组合。
根据本发明，优选的靶向抑制性免疫检查点蛋白涵盖了选自包括以下的组的那些：PD-1、PD-L1、PD-L2、BTLA、CTLA-4、A2AR、B7-H3(CD276)、B7-H4(VTCN1)、IDO、KIR、LAG3、TIM-3和VISTA。
本文公开的感兴趣的抑制性免疫检查点蛋白的优选抑制剂由针对所述感兴趣的抑制性免疫检查点蛋白并且抑制所述感兴趣的抑制性免疫检查点蛋白的活性的抗体组成。
因此，在一些优选的实施方式中，可以根据本发明使用的抑制性免疫检查点蛋白的抑制剂涵盖了选自包括针对以下中的一者的抗体的组的那些：PD-1、PD-L1、PD-L2、BTLA、CTLA-4、A2AR、B7-H3(CD276)、B7-H4(VTCN1)、IDO、KIR、LAG3、TIM-3和VISTA。
本发明内的癌症包括但不限于白血病、急性淋巴细胞性白血病、急性髓细胞性白血病、成髓细胞早幼粒细胞、髓单核细胞性单核细胞性红白血病、慢性白血病、慢性髓细胞性(粒细胞性)白血病、慢性淋巴细胞性白血病、套细胞淋巴瘤、原发性中枢神经系统淋巴瘤、伯基特氏淋巴瘤和边缘带B细胞淋巴瘤、真性红细胞增多淋巴瘤、霍奇金氏病、非霍奇金氏病、多发性骨髓瘤、瓦尔登斯特伦氏巨球蛋白血症、重链病、实体瘤、肉瘤和癌、纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、成骨肉瘤、骨肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴管内皮细胞肉瘤、滑膜瘤、间皮瘤、尤文氏瘤、平滑肌肉瘤、横纹肌肉瘤、结肠肉瘤、结直肠癌、胰腺癌、乳腺癌、卵巢癌、前列腺癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊腺癌、髓样癌、支气管癌、肾细胞癌、肝癌、胆管癌、绒毛膜癌、精原细胞瘤、胚胎性癌、维尔姆氏瘤、子宫颈癌、子宫癌、睾丸瘤、肺癌、小细胞肺癌、非小细胞肺癌、膀胱癌、上皮癌、神经胶质瘤、星形细胞瘤、成神经管细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、成血管细胞瘤、听神经瘤、少突神经胶质瘤、脑膜瘤、黑素瘤、神经母细胞瘤、视网膜母细胞瘤、鼻咽癌、食管癌、基底细胞癌、胆管癌、膀胱癌、骨癌、脑和中枢神经系统(CNS)癌、子宫颈癌、绒毛膜癌、结直肠癌、结缔组织癌、消化系统癌、子宫内膜癌、食道癌、眼癌、头颈癌、胃癌、上皮内赘生物、肾癌、喉癌、肝癌、肺癌(小细胞、大细胞)、黑素瘤、神经母细胞瘤；口腔癌(例如唇、舌、口和咽)、卵巢癌、胰腺癌、视网膜母细胞瘤、横纹肌肉瘤、直肠癌；呼吸系统癌、肉瘤、皮肤癌、胃癌、睾丸癌、甲状腺癌、子宫癌和泌尿系统癌。
药物组合物和治疗性方法
如本说明书其他地方已经描述的，如本文定义的糖工程化Fc片段承载化合物可以有利地用于与一种或多种另外抗癌疗法的组合治疗过程中、特别是用于与一种或多种的抗癌剂组合治疗过程中，其包括在与一种或多种抑制性免疫检查点蛋白抑制剂的组合治疗过程中。
根据这些实施方式，所述糖工程化Fc片段承载化合物和所述另外的一种或多种抗癌剂“共施用”。
如本文所用的术语“共施用”是指至少两种不同物质的施用时间足够接近以调节免疫应答。优选地，共施用是指至少两种不同物质同时施用。
因此，“共施用”是指组合施用的两种或更多种组分，使得该组合的治疗或预防作用可以大于单独施用的任一种组分的治疗或预防作用。两种组分可以同时或依序共施用。可以在一种或多种药物组合物中同时提供共施用的组分。两种或多种组分的依序共施用包括其中施用组分以便每种组分可以同时出现在治疗位点的情况。可替选地，两种组分的依序共施用可以包括以下情况：至少一种组分已从治疗位点清除，但至少一种施用组分的细胞效应(例如，细胞因子产生、某些细胞群体的活化等)在治疗位点处持续直到向治疗位点施用一种或多种另外组分。因此，在某些情况下，共施用的组合可以包括在化学混合物中从未彼此一起存在的组分。
在一些实施方式中，所选的糖工程化Fc片段承载化合物和一种或多种另外的抗癌剂同时施用给待治疗的癌症个体，并且两种活性剂可以被包含在相同的药物组合物中或可替选地被包含在分开的药物组合物中。这两种分开的药物组合物可以在使用前混合在一起，然后施用给待治疗的癌症个体。在其他实施方式中，这两种分开的药物组合物可以在短时间间隔(例如在2至5分钟时间间隔内)施用给待治疗的癌症个体。
本发明还涉及包含(i)糖工程化Fc片段承载化合物和(ii)一种或多种不同的抗癌剂的药物组合物。
本发明涵盖了包含(i)糖工程化Fc片段承载化合物和(ii)一种或多种抑制性免疫检查点蛋白抑制剂的药物组合物。
在一些优选的实施方式中，所述糖工程化Fc片段承载化合物是针对肿瘤抗原的糖工程化抗体。
在一些实施方式中，肿瘤抗原选自由以下组成的组：HER2、HER3、HER4和AMHRII。
在一些实施方式中，所述糖工程化抗体选自由以下组成的组：糖工程化抗体称为3C23K或其变体9F7F11、H4B121和HE4B33，其在本说明书中其他地方详细公开。
在一些实施方式中，所述抑制性免疫检查点蛋白抑制剂选自由以下组成的组：PD-1的抑制剂、PD-L1的抑制剂、PD-L2的抑制剂、BTLA的抑制剂、CTLA-4的抑制剂、A2AR的抑制剂、B7-H3(CD276)的抑制剂、B7-H4(VTCN1)的抑制剂、IDO的抑制剂、KIR的抑制剂、LAG3的抑制剂、TIM-3的抑制剂和VISTA的抑制剂。
在一些实施方式中，所述抑制剂由针对所述抑制性免疫检查点蛋白的抗体或其抗原结合片段组成。
制备和施用糖工程化Fc承载化合物以及更通常的本公开的多肽给对象的方法是本领域技术人员众所周知的或容易确定的。本公开的多肽的施用途径可以是经口、肠胃外、通过输注或经局部。如本文所用的术语肠胃外包括静脉内、动脉内、腹膜内、肌内、皮下、经直肠或经阴道施用。尽管显然所有这些形式的施用均被认为在本公开的范围内，但是施用形式将是用于注射的溶液、特别是用于静脉内或动脉内注射或滴注的溶液。通常，适用于注射的药物组合物可以包含缓冲液(例如乙酸盐、磷酸盐或柠檬酸盐缓冲液)、表面活性剂(例如聚山梨醇酯)，任选地稳定剂(例如人白蛋白)等。然而，在与本文的教导相容的其他方法中，糖工程化Fc承载化合物可以直接递送至不良细胞群位点，从而增加患病组织对治疗剂的暴露。
用于肠胃外施用的制备物包括无菌水性或非水性溶液、混悬液和乳液。非水性溶剂的实例是丙二醇、聚乙二醇、植物油(诸如橄榄油)，以及可注射的有机酯(诸如油酸乙酯)。水性载体包括水、醇性/水性溶液、乳液或混悬液，包括盐水和缓冲介质。在本公开的组合物和方法中，药学上可接受的载体包括但不限于0.01-0.1M或0.05M磷酸盐缓冲液或0.8％盐水。其他常见的肠胃外媒介物包括磷酸钠溶液、林格氏右旋糖、右旋糖和氯化钠、乳酸林格氏液或不挥发性油。静脉内媒介物包括流体和营养补充剂、电解质补充剂，诸如基于林格氏右旋糖的那些。防腐剂和其他添加剂也可能存在，诸如例如抗微生物剂、抗氧化剂、螯合剂和惰性气体等。更特别地，适用于注射使用的药物组合物包括无菌水溶液(其中水可溶)或分散液，以及用于临时制备无菌注射溶液或分散液的无菌粉末。在此类情况下，组合物必须是无菌的，且应该是流体以达到容易注射的程度。在制造和储存条件下，它应该是稳定的，并且还应保存，以防微生物体(诸如细菌和真菌)的污染作用。载体可以是溶剂或分散介质，其含有例如水、乙醇、多元醇(例如，甘油、丙二醇和液体聚乙二醇等)及其适合的混合物。例如，通过使用诸如卵磷脂的包衣，在分散体的情况下通过保持所需的粒度，以及通过使用表面活性剂，可以保持适当的流动性。
在任何情况下，无菌注射溶液均可以通过在适当的溶剂中将所需量的活性化合物(例如，糖工程化Fc片段承载化合物本身或与其他活性剂组合)(按需要)与本文所列举的一种成分或成分组合掺入、然后进行过滤灭菌来制备。通常，分散液通过将活性化合物掺入含有基础分散介质和来自以上列举的那些的所需的其他成分的无菌媒介物中制备。在用于制备无菌注射溶液的无菌粉末的情况下，制备方法通常包括真空干燥和冷冻干燥，其从其先前的无菌过滤溶液中产生活性成分加任何另外的所期望成分的粉末。将用于注射的制备物根据本领域已知方法加工、装入容器(诸如安瓿、袋、瓶、注射器或小瓶)并在无菌条件下密封。此外，可以以试剂盒的形式包装和出售所述制备物，所述试剂盒诸如美国专利申请No.U.S.09/259,337和No.U.S.09/259,338中描述的那些，其中的每一个通过引用并入本文。
用于治疗上述疾患的本公开的组合物的有效剂量根据许多不同因素而改变，包括施用方式、靶位点、患者的生理状态、患者是人还是动物、施用的其他医药以及治疗是预防性还是治疗性的。通常，患者是人，但是也可以治疗非人哺乳动物，包括转基因哺乳动物。可以使用本领域技术人员已知的常规方法来滴定治疗剂量以优化安全性和功效。
本公开的糖工程化Fc片段承载化合物可以在多种情况下施用。单剂之间的间隔可以是每周、每月或每年。如通过测量患者中所述糖工程化Fc片段承载化合物的血液水平所指示的，间隔也可以是不规则的。在一些方法中，调节剂量以达到1μg/ml至1000μg/ml并且在一些方法中25μg/ml至300μg/ml的血浆糖工程化Fc片段承载化合物浓度、特别是糖工程化抗体浓度。可替选地，糖工程化Fc片段承载化合物可以作为持续释放制剂施用，在这种情况下需要较不频繁的施用。对于糖工程化抗体，剂量和频率根据患者体内抗体的半衰期而变化。通常人源化抗体显示了最长的半衰期，然后是嵌合性抗体和非人抗体。
根据本公开的药物组合物通常包含药学上可接受的无毒无菌载体，诸如生理盐水、无毒缓冲液、防腐剂等。出于本申请的目的，糖工程化Fc片段承载化合物的药学上有效量应保持为意指足以实现有效获得益处的量，例如减少或阻断在癌症患者中发生的免疫抑制状态。当然，可以以单剂量或多剂量施用本公开的药物组合物，以提供药学上有效量的糖工程化Fc片段承载化合物。
实施例
实施例1：合成糖工程化Fc片段承载化合物
A.材料和方法
克隆嵌合性12G4、人源化12G4和3C23K
如先前所述构建并表达了嵌合性12G4(ch12G4)(27)。简而言之，将VLDNA序列和VHDNA序列依序亚克隆至含有启动子、Kozak序列和人κ/IgG1恒定区序列的多顺反子CHK622-08载体中。
使用Genscript合成编码人源化12G4(h12G4)VL和VH的DNA序列，然后如上所述通过消化和连接将其克隆在CHK622-08中，得到HK622-18载体。通过噬菌体克隆3C23的定向诱变以引入VL E68K突变，获得了编码亲和力成熟的3C23K VL和3C23K VH的DNA序列。如上所述，通过使用h12G4的人源化可变区作为模板进行的PCR组装来添加信号肽，然后将其克隆在HK622-18中。表达人源化和亲和力成熟的3C23K抗体的所得载体被称为HK622-18 MAO3C23K。
产生和纯化ch12G4、h12G4和3C23K
如先前所述(Siberil等人,2006,Clin Immunol Orlando Fla,第118卷:170-179)，稳定地表达了不同的分子。CHO-S、HEK293或YB2/0细胞用适当的直链表达载体稳定转染。在YB2/0细胞中使用EMS(英杰)、5％超低IgG胎牛血清(FCS)(PAA)和0.5g/l G418产生Ch12G4、h12G4和3C23K抗体持续5至7天。在CHO-S细胞中使用ProCHO4(龙沙)、4mM谷氨酰胺和1g/l G418产生3C23K-CHO-S持续7天。
通过亲和色谱使用蛋白A琼脂糖凝胶(GE医疗保健)从培养上清液中纯化MAb。聚集物和内毒素的水平分别通过Superdex HR/200(GE医疗保健)上的凝胶过滤和LAL测试确定。通过SDS-PAGE和考马斯染色监测抗体质量和纯度。此外，通过高效毛细管电泳激光诱导的荧光(HPCE-Lif)确定每个纯化抗体的糖基化模式和核岩藻糖百分比(51)。
SPR分析
在25℃下在HBS-EP(GE医疗保健)中，在Bia3000或T200装置上进行SPR分析。对于亲和力测量，根据制造商的说明书(GE医疗保健)，使用EDC/NHS活化将MISRII共价固定(1000RU)在CM5传感器芯片上。在180秒内，将不同浓度(0.5nM至128nM)的12G4或3C23K注射至固定受体上。在运行缓冲液中解离400秒后，使用Gly-HCl pH 1.7再生传感器芯片。考虑到亲和力(affinity)和亲合性(avidity)，KD值使用朗格缪尔1:1拟合模型(BiaEvaluation3.2，GE医疗保健)计算。抗体-FcγR测量通过对以4000RU至5000RU水平共价固定的抗His(R&D系统)上捕获的FcγR(西格玛)在100μl/min下的单周期滴定来进行。在60秒内以20nM注射γ受体，并注射了五个增加的抗体浓度(注射时间＝60秒)。在运行缓冲液中进行解离步骤600秒后，使用5μl甘氨酸-HCl pH 1.7再生传感器表面。使用T200评价软件3.0(GE医疗保健)上的异质配体或稳态拟合模型从传感图中评价动力学参数。通过从对照参考表面(不含任何固定蛋白)和缓冲液空白注射液中减去低信号、之后进行拟合评价来校正所有传感图。
抗体
鼠抗MISRII MAb 12G4由Salhi等人和Kersual等人描述(17，22)。抗独特型因子VIII嵌合性IgG1 R565
Mab和抗CEA MAb 35A7(17)用作非相关的抗体。
结果
嵌合、人源化和亲和力成熟
3C23K人源化抗体最初来源于鼠12G4 Mab的可变区(Sahli等人,2004,Biochem J,第379卷:785-793)。人源化程序包括CDR移植(MAb h12G4)和亲和力成熟(通过随机诱变和噬菌体展示)，产生最终分子3C23K。
在第一步中，通过分别在IMGT/结构域GapAlign搜索程序(28)中输入VL结构域和VH结构域的序列并将搜索限制在IMGT/GENE-DB中的人序列(29)来鉴定用于CDR移植的候选人模板。最接近的人VH基因IGHV1-3*01与鼠对应物显示出67.34％的同一性。在将鼠12G4CDR-IMGT移植至人FR-IMGT中后，这同一性上升至92.85％。最接近的人VL基因IGK1-9*01与鼠对应物显示出62.76％的同一性。然而，IGKV1-5*01是优选的，因为IMGT/GeneFrequency工具(28)表明IGK1-9*01的表达不是很频繁。IGKV1-5*01具有58.51％的同一性，而12G4的VL在移植后增加至88.29％。
为了更好地定义结合特性，将克隆3C23K重新格式化为IgG1抗体，在YB2/0细胞中产生并通过表面等离子体共振(SPR)进行分析。3C23K抗体展现出比小鼠12G4(KD＝7.9x10-10M)更高的结合亲和力(KD＝5.5x10-11M)。该小鼠12G4值非常接近MAb 12G4的初始描述中公开的值(KD＝8.6x10-10M)(22)。通过使用COV434-MISRII细胞的流式细胞术也证实了结合亲和力增加。
YB2/0、CHO或HEK293细胞中的3C23K产生、糖基化分析和对结合至Fcγ受体的作用
YB2/0(
型；3C23K)(27)、CHO-S(3C23K-CHO)或HEK293(3C23K-HEK293)细胞(用作功能性测定的比较剂)中表达的3C23K的寡糖分析显示出两种显著不同的糖基化模式。对于3C23K，岩藻糖基化、半乳糖基化和二等分GlcNAc同工型的百分比分别为33.0％、57.2％和1.8％，并且对于3C23K-CHO分别为94.6％、54.4％和2.0％。通过SPR分析了这些糖基化差异对与FcγR结合的影响。岩藻糖减少后，对hFcγRIIIa和hFcγRIIIb的结合亲和力明显增加(分别地，对于3C23K为1nM至12nM和86.0nM，相较而言对于3C23K-HEK293为31nM至164nM和378nM)，但对于其他FcγR(hFcγRI、hFcγRIIa、hFcγRIIb)并非如此(还参见以下实施例2中的表2)。
然后，使用
技术在YB2/0细胞中表达3C23K，以增加与主要在NK细胞和巨噬细胞上表达的低/中亲和力Fc受体CD16的抗体相互作用(Siberil等人,2006,ClinImmunol Orlando Fla,第118卷:170-179)。与其他常用细胞系(诸如CHO细胞)相比，该性质与大鼠骨髓瘤YB2/0细胞中Fut8基因的较低表达有关((Siberil等人,2006,Clin ImmunolOrlando Fla,第118卷:170-179)。
如所预期，与高岩藻糖含量的3C23K相比，3C23K-YB2/0对CD16的结合亲和力更高。
实施例2：3C23K(GM102)抗体的聚糖分析
背景：
GM102是使用克隆18H2在YB2/0细胞(大鼠杂交瘤YB2/3HL)中产生的人源化单克隆抗体。
碳水化合物部分位于重链的ASN295处。
a)GM102的聚糖分析结果：-表2
b)PB01参考标准表征
在通过PNG酶F进行N-脱糖基化并标记释放的碳水化合物残基后，通过UPLC-HILIC-FD对这些碳水化合物残基进行分析，揭示了存在6个主要的碳水化合物部分：
1.非岩藻糖基化的(G0) 51.1％
2.岩藻糖基化的(G0F) 12.8％
3.单半乳糖基化的非岩藻糖基化的(G1) 10.2％
4.单半乳糖基化的岩藻糖基化的(G1F) 4.3％
5.非糖基化的非岩藻糖基化的(G0B) 9.9％
6.岩藻糖基化的，含二等分GlcNAc(G0FB) 3.4％
总岩藻糖基化残基是23％
表3：PB#01ref.和LC#02中主要N-糖基化形式的可比性
实施例3：糖工程化Fc片段承载化合物的Fc受体的高亲和力
A.材料和方法
表面等离子体共振(SPR)分析：
根据制造商的说明(GE医疗保健)，将抗组氨酸抗体(R&D系统)以10μl/min的流速在25℃下在HBS-EP中在T200装置上，使用EDC/NHS活化固定在CM5传感器芯片上。将它们以6900RU水平共价固定在流通池Fc2上，并使用相同的化学处理但在没有抗His抗体的情况下制备对照参考表面(流通池Fc1)。
Fc1和Fc2中的所有动力学测量均通过在HBS-EP中于25℃下在T200装置上以100μl/min的单周期滴定进行。在60s内将每个人γ受体(R&D系统)以20nM捕获在固定的抗His抗体上。注射了五种增加浓度的抗体(注射时间＝120s)。在运行缓冲液中进行解离步骤600s后，使用5μl甘氨酸-HCl pH1.7再生传感器表面。通过从对照参考表面和缓冲液空白注射中减去低信号来校正所有传感图。使用来自T200评价软件的异质配体或两个状态模型从传感图中评价动力学参数。
B.结果
下表4描绘了对人Fc受体的低岩藻糖基化抗AMHRII 3C23K抗体的亲和力常数(Kd)的测量结果。
表4
| 受体 | 人 |
| FcγRI/CD64 | 0.2-3.3** |
| FcγRII/CD32a | 120* |
| FcγRIIbc/CD32bc | 459* |
| FcγRIIIa/CD16a | 1.3-46** |
| FcγRIIIb/hCD16b | 49* |
| FcγRIV/mCD16-2 | - |
亲和力常数表示为KD，单位为nM。
*KD是使用异质配体拟合模型计算的。
**当拟合未遵守异质配体模型时，用两个状态反应模型确定KD值。
实施例4：减少的岩藻糖抗体阻断癌症中的肿瘤相关的巨噬细胞诱导的免疫抑制
A.材料和方法
体外免疫学测定：
T细胞增殖测定如下进行。简而言之，将CMFDA染色的COV434-AMHRII在4℃下用10μg/ml无关mAb R565或抗AMHRII FcKO或抗AMHRII 3C23K mAb处理1h，并与未染色的MDM2孵育4天，之后添加用CD3/CD28 Dynabeads以1:8的MDM2:T细胞比率预活化的CellTraceViolet(Molecular
Life TechnologiesTM)染色的T细胞。在4天另外的孵育期后，将细胞收集并用抗CD8 PerCP、CD11b PE-Cy7和CD4 AF647(BD
)染色，然后进行流式细胞术分析。通过Fixable Viability Dye
506(
)染色排除死细胞，然后抗体染色。通过测量对应于细胞分裂的CellTrace Violet稀释来在CD8+(CD11b-)T门控细胞上分析T细胞增殖。使用FlowJo(TreeStar，版本7.6.5)计算等于原始群体中细胞已经经历的平均细胞分裂数的分裂指数。计算等于原始群体中的细胞已经经历的平均细胞分裂数的分裂指数。
B.结果
清楚地确定了，肿瘤内的巨噬细胞抑制T细胞抗肿瘤活性。我们提出了这样的假设：巨噬细胞与3C23K抗AMHRII抗体的接合改变了其T细胞抑制功能。为了测试该假设，将COV434-AMHRII靶细胞用无关的mAb R565、抗AMHRII FcKO或抗AMHRII 3C23K mAb处理，并与MDM共培养4天，之后添加CD3/CD28预活化的PBT。通过流式细胞术分析了CD8+T细胞增殖。如所期望的，在存在对照mAb(无关同种型对照R565和FcKO抗AMHRII mAb)或不存在治疗的情况下，MDM严重损害了T细胞增殖。值得注意的是，当将共培养的肿瘤细胞用3C23K抗AMHRII mAb处理时，MDM介导的T细胞免疫抑制显著减少，如由CD8 T细胞的分裂指数的高增加显示的(图1A)。
肿瘤细胞数量的减少可以部分解释这种“免疫刺激”效应，因为已知肿瘤细胞直接发挥T细胞抑制功能。为了测试3C23K抗AMHRII mAb是否也可以作用于MDM从而赋予它们更低的免疫抑制性，我们设计了没有肿瘤细胞的实验。惰性
聚苯乙烯珠用作肿瘤靶细胞的替代物。在相同的肿瘤细胞环境中用mAb处理那些珠，即首先将MDM与mAb处理的珠共培养，然后与活化的PBT共培养。在这些条件下，当将MDM与3C23K包被的
聚苯乙烯珠共培养时，CD8+T细胞增殖得以部分恢复(图1B)。作为对照，我们检查了在没有MDM的情况下观察到的T细胞增殖不受3C23K的影响(图2)。这些实验强烈表明3C23K直接改变了MDM的T细胞抑制能力。
总之，这些结果表明，人源化糖工程化单克隆抗AMHRII抗体3C23K通过抗原结合位点有效靶向肿瘤细胞，并通过识别Fc结构域指导促肿瘤巨噬细胞针对肿瘤细胞。因此，mAb活化的巨噬细胞触发针对肿瘤细胞的ADCC和ADCP，并减少了它们对T细胞的免疫抑制行为。
结果讨论
ADCC/ADCP可能不是mAb治疗后巨噬细胞诱导的唯一机制。已经描述了肿瘤相关的巨噬细胞抑制T细胞活化‘Biswas等人,2010,Nat.Immunol.,第11卷(第10期):889-896)，并且我们的数据显示淋巴细胞与巨噬细胞之间的接触支持了两种细胞类型之间直接串扰的想法。通过使用体外测定，我们发现3C23K对FcR的接合减少了巨噬细胞的免疫抑制表型。在这种情况下，预活化的T细胞恢复了在没有3C23K的情况下被阻断的增殖能力。治疗性mAb可以接合先天性免疫细胞、也可以接合适应性免疫细胞的观点与先前的研究一致。在小鼠肿瘤模型中，已证明用抗肿瘤抗原Ab进行的治疗诱导了涉及T细胞的细胞免疫应答，这是长期存活所必需的(Montalvao等人,2013,J Clin Invest,第123卷:5098-5103；Gül等人,2014,J clin Invest,第124卷:812-823)。然而，在已经用抗肿瘤mAb治疗的癌症患者中诱导适应性免疫应答尚未得到广泛研究。
3C23K改变巨噬细胞表型从而减轻T细胞抑制的机制目前尚不清楚。然而，可以设想不同的假设。抗体与巨噬细胞表达的Fc受体的相互作用已显示出触发几个调节这些细胞功能的信号传导级联(Biswas等人,2010,Nat.Immunol.,第11卷(第10期):889-896)。我们的初步数据表明，经由FcR用3C23K活化的巨噬细胞产生包括IL-1β和IL-6的几种促炎性细胞因子，它们被描述为对T细胞发挥有益作用(Grugan等人,2012,J Immunol.,第189卷:5457-5466)。间接作用也是可能的。特别地，肿瘤细胞的死亡可以导致释放几种与危险相关的分子模式分子(DAMP)(诸如钙网蛋白)，这进而活化先天性免疫细胞和适应性免疫细胞(Yatim等人,2017,Nat Rev Immunol,第17卷(第4期):262-275)。树突状细胞在介导这种免疫原性细胞死亡中的作用已被充分描述。证据还表明，在细胞死亡期间释放的钙网蛋白活化巨噬细胞，这产生了易对T细胞发挥有益作用的IL-6和TNF-a(Duo等人,2014,Int J MolSci,第15卷(第2期):2916-2928)。
实施例5：糖工程化Fc承载化合物对TAM样巨噬细胞的活化
A.材料和方法
制备人单核细胞来源的巨噬细胞
外周血单核细胞(PBMC)获自健康血液供体
使用CD14+细胞的正向磁性选择，通过经典方法分离PBMC。将单核细胞在补充有10％胎牛血清的RPMI中于37℃5％CO2下培养，然后通过添加50ng/mL M-CSF在M2型巨噬细胞中分化4天。转化的M2型巨噬细胞的表型为CD14高CD163高IL10高IL12低。
由抗体体外活化巨噬细胞
将10μg/mL的抗体溶液(名为R18H2的低岩藻糖基化抗AMHRII或与Fcγ受体无任何结合的其FcKO对应物)通过在4℃下孵育24小时而吸附在24孔板上。这种实验条件模拟了抗体识别其抗原的情况。通过用PBS溶液洗涤来弃去未包被的抗体。然后将M2型巨噬细胞(106个细胞/mL培养基)在包被有抗体(或对于阴性对照没有包被有抗体)的孔中于37℃下孵育1至3天。
在由抗体活化后分析巨噬细胞
在分别通过qRT-PCR或流式细胞术进行分析之前，用100ng/mL LPS刺激与抗体孵育的巨噬细胞6或24小时。将PDGFα、VEGFβ、HGF、TGFβ、IDO1、IL10、Sepp1、Stab1、FOLR2、CD64a、CD64b和CD16a基因的转录定量并通过使用RPS18、B2M和EF1a基因作为参考进行归一化。
通过流式细胞术证实了巨噬细胞表达的膜蛋白以及通过用来自培养基的样品进行的典型ELISA测定证实了可溶因子(例如IL10、IL1β或TNFα)在蛋白水平上的表达变化。
B.结果
吸附在多孔板上的抗体根据其结合至巨噬细胞的Fcγ受体的潜能而差异地刺激M2型巨噬细胞。总体地，当在没有任何抗体的孔中培养M2型巨噬细胞时，没有观察到标记物的显著变化。在FcKO抗体的情况下，仅观察到微小变化，与那些蛋白质与巨噬细胞的非特异性结合相对应。相反，当巨噬细胞与低岩藻糖基化R18H2抗体相互作用时，M2型巨噬细胞的某些典型标记物(诸如Sepp1、Stab1、FOLFR2和CD163)明显减少，在3天孵育后减少，如图3A所示。这些变化强烈表明巨噬细胞的类型可能在低岩藻糖基化抗体的刺激下变化。这些变化伴随着与抗体结合并参与ADCC和吞噬作用的Fcg受体(例如CD16(图3B)和CD64(图3C))增加。
有趣的是，在用低岩藻糖基化R18H2抗体3天后，在M2巨噬细胞的培养基中检测到的细胞因子和可溶肽的概况揭示了，通常由M1巨噬细胞表达的促炎性因子明显增加，诸如TNFα、IL1β(图3D)或IL6(数据未显示)。此外，还观察到免疫抑制因子(如TGFβ、IDO1和IL10)(图3E，图3F，图3G)的减少以及促血管生成因子(如PDGFα、VEGFβ和HGF)的减少(图3H，图3I，图3J)。
此外，在用低岩藻糖基化R18H2抗体刺激后，M2巨噬细胞表面处PDL2表达减少(如图3K所示)连同IL10减少一起表明，这些表型修饰的巨噬细胞的免疫抑制活性更少的趋势。
总之，这些结果表明，低岩藻糖抗体与M2巨噬细胞的结合，导致在M2和M1之间转变为中间的巨噬细胞表型，并导致多种因素的变化，从而经由抑制血管生成并刺激免疫系统导致间接的抗肿瘤作用。
实施例6：3C23K抗体阻断免疫抑制，这导致免疫系统活化。
A.材料和方法
制备人单核细胞来源的巨噬细胞(MDM)
外周血单核细胞(PBMC)获自健康的献血者(法国血液机构(
Sang)，EFS)。
按照制造商的方案推荐，使用阴性选择单核细胞分离试剂盒II(Macs美天旎)从PBMC中分离人单核细胞。将单核细胞在补充有L-谷氨酰胺(英杰)和青霉素/链霉素(PS，英杰)的巨噬细胞-SFM(Gibco)中于37℃和5％CO2下培养。
通过用IFN-γ(Macs美天旎，100UI/ml)+LPS(100ng/ml，西格玛)或M-CSF(Macs美天旎，200UI/ml)+IL-10(Macs美天旎，50UI/ml)分别刺激，将经分离的单核细胞在三天内保持未分化(NS，未刺激)或分化为抗肿瘤(M1样)或促肿瘤巨噬细胞(TMA样)。
抗体依赖性细胞介导的细胞毒性(ADCC)测定
将SKOV-R2+细胞在4℃下用10μg/mL抗AMHRII抗体：GM102(也称为3C23K-YB20)、3C23K-CHO或3C23K-FcKO预处理。将靶SKOV-R2+细胞用BATDA(双-乙酰氧基甲基-2,2′:6′,2″-三联吡啶-6,6″-二羧酸酯)负载，再混悬于补充有L-谷氨酰胺、PS和10％热灭活的FCS的DMEM(Gibco)中，并于37℃下以1:1的比率添加在效应细胞(人巨噬细胞)中4h。
ADCC通过使用基于DELFIA EuTDA的细胞毒性测定(铂金埃尔默)进行测量。在靶细胞和效应细胞之间进行4h孵育后，将上清液与Eu3+溶液孵育，并测量荧光(Envision，铂金埃尔默)。将数据归一化至最大(靶细胞与Triton)和最小(仅效应细胞)裂解，并拟合至S形剂量响应模型。
通过流式细胞术评价巨噬细胞+抗体对卵巢癌肿瘤细胞系(SKOV-R2+细胞)的细胞
毒性作用
将SKOV-R2+细胞用CellTraceTM Violet细胞增殖试剂盒(Molecular ProbesTM，生命技术公司)染色、重混悬于补充有L-谷氨酰胺、PS和10％热灭活的胎牛血清(FCS，西格玛)的杜尔贝克氏改良的伊戈尔培养基(DMEM，Gibco)中，并在3种抗AMHRII抗体中的每一者的存在下以1:1的比率添加至每种类型的人巨噬细胞。
为了评价SKOV-R2+细胞数量和增殖，将预处理或未处理的人巨噬细胞用肿瘤细胞攻击3、4和5天。通过检测荧光标记的细胞来计算SKOV-R2+细胞数，并通过CellTrace稀释评价其增殖。
对每个数据点分析了10000个细胞的群。除通过使用Modfit软件分析的CellTrace稀释外，所有分析均在带有Diva软件的BD Fortessa流式细胞仪中进行。
通过检测人巨噬细胞上的受体表达来评价巨噬细胞分化
在(i)分化后和在(ii)分化的人巨噬细胞与SKOV-R2+肿瘤细胞(用不同的抗AMHRII抗体处理)之间共培养3天后，通过流式细胞术评价人巨噬细胞膜中的受体表达(CD11b、CD163、CD36、CD206、CD14、CD16、CD32、CD64、CD80、CD282)。
使用Cd11b-FITC、CD163-PE、CD36-PE、CD206-APC、CD16-VioBright 515、CD64-PerCP-Vio700、CD80-PE、CD32-PE-Vio770、CD282(TLR2)-APC、CD14-APC-Vio770(美天旎)检测受体，并将其与适当的同种型对照进行比较。
对每个数据点分析了10 000个细胞的群。在用存活力固定染料(美天旎)标记后，已从分析中去除了死细胞(阳性细胞)。对CD14或Cd11b阳性细胞进行了门控分析。所有分析均在带有Diva软件的BD Fortessa流式细胞仪中进行。
Th1/Th2 T-CD4极化和T-CD8活化
按照制造商的方案建议，使用阴性选择泛T细胞分离试剂盒(Macs美天旎)从PBMC中分离人T细胞。分离后，将细胞用CellTraceTM Violet细胞增殖试剂盒(MolecularProbesTM，生命科技公司)染色，重混悬于补充有L-谷氨酰胺、PS和10％热灭活的FCS的RPMI1640培养基(Gibco)中，并以1:8比率添加至人巨噬细胞+SKOV-R2+肿瘤细胞(用以上提及的不同抗AMHRII抗体处理)的共培养物中，持续4天。
为了评价Th1/Th2 T-CD4极化，用CD183(CD183(CXCR3)-APC，美天旎)标记T细胞，并对CD4阳性细胞(CD4-VioBright FITC，美天旎)进行门控分析。
为了评价T-CD8活化，用CD183(CD183(CXCR3)-APC，美天旎)和CD25(CD25-PE，美天旎)标记T细胞，并对CD8阳性细胞(CD8-PE-Vio770，美天旎)进行门控分析。
通过CellTrace稀释评价T-CD4和T-CD8细胞增殖，并在CD4阳性细胞或CD8阳性细胞上进行分析分析。
对于每个数据点分析了10000个细胞的群。除使用Modfit软件分析的CellTrace稀释外，所有分析均在带有Diva软件的BD Fortessa流式细胞仪中进行。
细胞因子和趋化因子的产生
细胞因子(IL-1β、IL-2、IL-6、IL-10、IL-12、IL-23、TNF-α和TGF-β)和趋化因子(CCL2、CCL4、CCL5、CXCL9和CXCL10)释放在(i)分化的人巨噬细胞的上清液中被定量，(ii)在分化的人巨噬细胞与SKOV-R2+肿瘤细胞(用不同的抗AMHRII抗体处理)共培养3天后在上清液中被定量，以及(iii)在该共培养物+T细胞另外4天后在上清液中被定量。
根据制造商的说明(ALisa试剂盒，铂金埃尔默)，通过ALisa免疫测定测量了细胞因子和趋化因子释放的定量。
B.结果
所有实验均使用来自三个不同且独立的健康供体的PBMC进行。发现与3C23K-CHO或3C23K-FcKO(用作无活性对照)相比，用3C23K-YB20低岩藻糖抗体，在存在TAM样未分化或分化的巨噬细胞(添加M-CSF和IL-10)的情况下测量的ADCC明显更高。图4A中显示了TAM样的数据。这种细胞裂解活性至少可以部分解释与TAM样巨噬细胞共孵育四天后肿瘤细胞减少。如图4B所示，使用3C23K YB20的减少也比使用3C23K-CHO的减少更高。
当将T细胞添加到TAM样巨噬细胞和肿瘤细胞的共培养物时，观察到记忆CD8+淋巴细胞的百分比增加(图4C)。在相同的实验条件下(图4D)，还发现Th1 CD4调节性T细胞增加的趋势，与Th2 CD4+T细胞减少同步。(图4E)所有这些调节根据长期T细胞介导的抗肿瘤活性的增加。用3C23K-YB20的所有这些变化都高于用3C23K-CHO和3C23K-FcKO。
有趣的是，在抗AMHRII 3C23K-YB20抗体的存在下，在TAM样+肿瘤细胞的共培养培养基中检测到的细胞因子和趋化因子的概况显示，CXCL9(图4F)和CXCL10(图4G)显著增加，这两种因子参与T细胞募集和CCL2(参与巨噬细胞募集的因子)，而该最后因子即CCL2的基础水平在每个供体中不同(图4H)。此外，当在这种共培养物中添加T细胞时，用3C23K-YB20检测到两种促炎性细胞因子IL6(图4I)和IL1b(图4J)和CCL5(图4K，与T细胞浸润相关的因子)的增加也高于用3C23K-CHO和3C23K-FcKO。
总之，这些结果表明，添加3C23K-YB20至肿瘤细胞+TAM样巨噬细胞的共培养物，然后+T细胞的共培养物，即将病理情况模拟到肿瘤中的条件导致直接肿瘤细胞裂解和抗肿瘤T细胞响应的活化。使用3C23K-YB20的所有这些观察都高于测试的其他抗AMHRII抗体。
有趣的是，3C23K-YB20的有利作用并不限于用TMA样巨噬细胞的条件。用与肿瘤细胞和抗体共培养的未刺激的(NS)巨噬细胞进行的类似实验允许显示促炎性因子(诸如IL12(图4L)、IL6(图4M)和IL1b(图4N))增加，与IL23(促肿瘤和促血管生成细胞因子)减少(图4O)同步。此外，如上用TAM样巨噬细胞所述，还观察到参与T细胞募集的两种抗血管生成趋化因子CXCL9(图4P)和CXCL10(图4Q)增加。在3C23K-YB20低岩藻糖抗体的情况下的所有这些变化比其他更为显著。这些结果强烈表明3C23K-YB20可以经由未分化的巨噬细胞以及经由TAM样巨噬细胞影响T细胞抗肿瘤活性。
实施例7：施用有糖工程化抗体的癌症患者的肿瘤组织中存在的巨噬细胞的活化
A.材料和方法
为了鉴定同一组织切片中的多个靶标，本研究使用了基于TSA的多重免疫荧光。酪酰胺信号方法(TSA)基于使用衍生的酪酰胺进行的专利催化报告子沉积(CARD)技术。在少量过氧化氢的存在下，固定化的HRP将标记的底物(酪酰胺)转化为寿命短、反应性极强的中间体。然后，经活化的底物分子非常迅速地与邻近蛋白质的富电子区反应并共价结合。活化的酪酰胺分子的这种结合仅紧接在与活化的HRP酶结合的位点处发生。在很短的时间内(通常在3至10分钟之内)发生标记的酪酰胺的多次沉积。随后检测标签产生有效的大型信号放大。该技术的优势在于可以在同一组织载玻片上检测到同一种中产生的多个一级抗体。当TSA荧光染料沉淀后，每个反应均停止。可以重复进行以达到5个靶标。在我们的实验室中，可以使用Ventana Discovery ULTRA自动载玻片染色机来使程序自动化。该仪器允许对FFPE组织载玻片进行高效、可重复的自动染色。
在多重应用中，使用下表5中公开的以下荧光团：
这些荧光团、二级抗体系统和一级抗体代表测定特异性试剂。用于进行染色的所有其他辅助试剂(预处理缓冲液、洗涤缓冲液和变性缓冲液)均被视为通用试剂。测定限值通过可用和使用的成像平台测定。所有的载玻片图像均使用3DHistech的P250 Panoramic扫描仪产生，该扫描仪装配有适合的滤光片以分离使用的荧光团(Rhodamin6G、RED610、DCC、FAM、Cy5)。然而，由于频谱特性，DAPI和DCC信号至今无法分离。因此，核复染色已被排除在外。
为了以下标记物/目的，要求多重免疫荧光显影：
-对于淋巴细胞的细胞角蛋白(CK)、CD3、CD4、CD8、FoxP3
-对于巨噬细胞的CK、CD14、HLADR、CD206和/或CD163
-对于树突细胞、多形核细胞、天然杀伤细胞的CK、CD56、CD15、颗粒酶、DC灯
-用于效应细胞对比免疫细胞的CK、CD45、CD16、CD32和CD64
这四个多重测定用以下依序标记验证：
1/抗CD3克隆2GV6、抗CD4克隆SP35、抗CD8克隆C8/144B、抗FoxP3克隆D2W8E和抗CK克隆混合物AE1/AE3
2/抗CD14克隆EPR3653、抗CD68克隆KP-1、抗CD163克隆MRQ-26、抗MHC-II克隆EPR11226和抗CK克隆混合物AE1/AE3
3/抗CD16克隆SP175、多克隆抗颗粒酶B、抗CD8克隆C8/144B和抗NKp46
4/抗CD15克隆MMA、抗CD64克隆3D3、多克隆抗CD206和抗LAMP3克隆13A205。
B.结果
在GM102的I期研究中，使用多重荧光染色和分析，研究了FFPE配对和基线卵巢癌活检组织上几种细胞类型的存在。多重染色覆盖了免疫浸润物和评价单核细胞/巨噬细胞分化和吞噬活性。在GM102之前7至15天对基线样品进行了活检，并且在1.5个月的治疗后进行了第二次活检。
由于仅研究了两个配对的活检组织，因此仅以描述性方式评价了GM102治疗的作用，而对观察到的现象没有统计学分析。初始基线样品的特征是免疫浸润物的可变存在。这项研究最突出的观察结果是GM102对单核细胞样CD16+细胞群(已经在基线处大量存在的细胞类型)的作用(图5A)。在GM102处理下，所研究患者的CD16+染色面积显著增加，然而其并未由CD16+细胞密度的增加反映出来，就好像GM102处理后CD16+细胞被CD16带电一样。该观察结果提示CD16+细胞的活化，CD16+细胞是参与GM102抗肿瘤活性的效应细胞(主要是巨噬细胞)。
此外，在GM102处理下观察到颗粒酶B表达增加(图5B)。颗粒酶B是专门储存在NK细胞或细胞毒性T细胞中的颗粒丝氨酸蛋白酶家族的29kDa成员。细胞裂解T淋巴细胞(CTL)和天然杀伤(NK)细胞共有识别、结合和裂解特定靶细胞的能力。认为它们可以通过裂解在其表面上携带'非自身'抗原(通常是细胞内病原体感染而产生的肽或蛋白质)的细胞来保护其宿主。颗粒酶B对于CTL在细胞介导的免疫应答中快速诱导靶细胞凋亡至关重要(Rousalova&Krepela,2010,Int.J.Oncol.37:1361-1378；Vaskoboinik等人,2015,Nat.rev.Immunol.15:388-400)。细胞毒性T淋巴细胞(CTL)和天然杀伤(NK)细胞是消除赘生性细胞和病毒感染细胞的主要因子。然而，在这些活检中，只能偶尔看到如通过NKp46观察到的天然杀伤细胞和CD8+淋巴细胞。该观察结果在临床样品中证实了GM102的治疗诱导了CD8+T淋巴细胞的细胞裂解活性。
实施例8：在施用有糖工程化抗体的癌症患者中活化NK细胞、单核细胞和ICOS+T细 胞
A.材料和方法
在GM102的I期研究中，为升级队列的每名患者计划在4个时间点采样5mL血液。时间点是在第一次GM102输注前第1天(命名为C1J1-SOI)和在第一次GM102输注结束时(命名为C1J1-EO1)，在第二次GM102输注前15天(C1J15-SOI)，并且处于稳定状态，即在第57天，第二个28天周期(C3J1-SOI)结束时。
为了科学探索的目的，在该研究的每个临床研究机构均监测了几种不同的标记物。
在古斯塔夫鲁西医院(Gustave Roussy)纳入了五名患者。LIO(肿瘤免疫监测实验室(Laboratoire d’Immunomonitoring en Oncologie))共接收了15个样品，如下表6详述。
表6
SOI：输注开始；EOI：输注结束
*样品于2017年2月9日在EOI时采集，并于次日在LIO时接收；
**样品于2017年5月29日在EOI时采集，并于次日在LIO时接收。
分析所有接收的样品。从所有样品中分离出PBMC，并将其储存在液氮罐中的专用于Gamamabs–GM102研究的盒中，只有经过授权的人员才能使用。下表7、表8和表9中详述了所有使用的材料：
表7
表8
| 材料 | 规格 | 目录No. | 供应商 |
| 50mL管 | 体积至多50mL，无菌，PP | 191050 | 达彻 |
| 15mL管 | 体积至多15mL，无菌，PP | 171015 | 达彻 |
| 移液管5mL | 血清学，移液体积1mL至5mL | 86.1253.001 | 莎斯特 |
| 移液管10mL | 血清学，移液体积1mL至10mL | 86.1254.001 | 莎斯特 |
| 移液管25mL | 血清学，移液体积2mL至25mL | 86.1685.001 | 莎斯特 |
| 移液管尖 | 过滤嘴，移液体积100mL至1000μL，无菌 | ||
| 移液管尖 | 过滤嘴，移液体积10μL，无菌 | ||
| 冷冻管 | 体积1.8ml | 479-6843 | VWR |
表9
根据以下程序分离PBMC：
1.用Anios擦拭血液管对其消毒。
2.取50mL预先装有15mL Ficoll的管，然后在Ficoll上慢慢层铺35mL稀释的血液，注意不要混合-应将两层清楚地分开。(对于其他体积，将稀释的血液:Ficoll的比率保持在2/3左右)。
3.将管牢固地关闭并在室温(RT)下以400g离心20分钟，中断。
4.用无菌的一次性使用的10mL移液管吸取单核细胞层(环)，并转移到新的50mL管中。(任选地：在吸取环之前，可以丢弃上相)。
5.添加PBS达到50mL并在15℃下以800RPM离心15min。
6.立即用移液管抽出上清液并在底部前3mL处停止。
7.轻弹以重悬沉淀。
8.在剩余的细胞沉淀上添加50ml PBS，并混合以彻底重悬。
9.在15℃下以300g离心10min。
10.翻转管，并添加1mL或2mL PBS以对细胞计数。
根据以下程序储存PBMC：
1.在96孔板中置入90μL Blue Hayem，并添加10μL先前重悬的沉淀，以仅对PBMC计数。
2.在96孔板中置入90μL台盼蓝，并添加10μL先前重悬的沉淀，以仅对活细胞计数。
3.对Malassez载玻片上的细胞计数，并在Hyclone中冷冻500至1000万个活细胞(每个冷冻管1mL)。
4.将冷冻管放在“Mr Freeze”盒中，并在-80℃下放置至少24小时，然后将其转移到Gamamabs–GM102盒内的氮气罐。
通过流式细胞术用以下程序和下表10至表17中描述的标记物进行血液免疫表型分析。
表10
表11
表12
表13：Duraclone面板：
| FITC | PE | ECD | PC5.5 | PC7 | APC | AA700 | AA750 | PB | Kro | |
| TSCM | CD95 | CD197 | HLA-DR | CD25 | CD45RA | CD278 | CD3 | CD127 | CD4 | CD8 |
表14：液体制剂面板：
| FITC | PE | ECD | PC5.5 | PC7 | APC | AA700 | AA750 | BV421 | KrO | |
| NK-NCR | CD335 | CD336 | HLA-DR | CD337 | CD137 | CD314 | CD3 | CD16 | CD56 | CD8 |
表15
| FITC | PE | ECD | PC5.5 | PC7 | APC | AA700 | AA750 | PB | BV510 | |
| FcγR-活化 | CD32 | CD54 | CD69 | CD244 | CD64 | CD163 | CD14 | CD16 | CD15 | CD56 |
表16
表17
B.结果
在治疗过程中对上面列出的每个标记进行了测量和分析。对于测试的5名患者，鉴定循环细胞的主要免疫群(N细胞、单核细胞、嗜中性粒细胞、嗜酸性粒细胞和T细胞CD4+、CD8+和Treg)没有显著变化。
一些标记物提示单核细胞和NK细胞的活化。在GM102注射期间减少后，在C1J1-EOI和C1J15之间在NK细胞上观察到CD16表达显著增加(图6A)。用单核细胞上的CD69表达还观察到增加的静态非显著趋势(图6B)。尽管CD69表达的免疫调节作用仍不清楚，但是已知CD69表达在免疫细胞活化后增加(Sancho等人,2005,Trends in Immunology,第26卷(3):137-140)。这些增加可以解释为单核细胞和NK细胞的活化的迹象。
有趣的是，主要和显著的变化是C1J1-EOI和C1J15之间在T细胞上ICOS表达增加(图6C)。ICOS是参与T细胞活化的受体(Yao等人,2013,Nature Reviews,第12卷:130-146；Mahoney等人,2015,Nature Reviews,第14卷:561-584)，并且其被称为伊匹单抗的药效动力学标记物(抗CTLA4抗体)，是免疫学检查点的抑制剂(Tang等人,2013,Americanassociation for cancer Reseatch Journal,第1卷(4):229-234)。因此，这种增加在患者中证实了GM102可以逆转免疫抑制。
实施例9：GM102对循环单核细胞的作用
A.材料和方法
在GM102的I期研究中，为升级队列的每名患者计划在4个时间点采样5mL血液。时间点是在第1天第一GM102输注前(命名为C1J1-SOI)和在第一GM102输注结束时(命名为C1J1-EO1)，在第15天第二GM102输注前(C1J15-SOI)，以及在稳定状态(即在第57天)，第二个28天周期结束时(C3J1-SOI)。
为了科学探索目的，在该研究的每个临床研究机构均监测了几种不同的标记物。
在Lymphoprep(Abcys)上通过密度梯度离心法从血液中分离人PBMC。对于淋巴细胞群输注及其活化，将PBMC用以下抗体标记：CD45-VioGreen、CD3-VioBlue、CD4-APCVio770、CD8-PerCP、CD25-PE、CD56-APC、CD19-PEVio770和CD69-FITC(美天旎生物技术)。
对于血液单核细胞，使用以下抗体评价了典型的、中间和非典型群体：CD45-VioGreen、CD16-PE和CD14-PerCPVio700(美天旎生物技术)。适当的荧光染料匹配的同种型抗体用于确定非特异性本底染色。所有染色均对100μL PBS-/-1％热灭活的胎牛血清进行。对于每个数据点分析了10.000个细胞的群体。所有分析均在带有Diva软件的BD Fortessa流式细胞仪中进行。
B.结果
在第一3C23K输注之前，发现T细胞、NK细胞和单核细胞的百分比在患者之间是可变的，表明患者之间有各种免疫能力。在处理时和之后，在T细胞和NK细胞群中未观察到明显的变化。相反，观察到单核细胞亚群的变化。
人血单核细胞是异质的，并且通常根据CD14和CD16表达分为三个亚群。在健康供体中，《典型单核细胞》(CD14高CD16-)占总单核细胞的90％-95％，而《非典型》(CD14低CD16+)和《中间》(CD14高CD16+)群体占较少(5％-10％)。
在四分之三的卵巢腺癌患者中，与健康患者相比，第一输注前患者中“典型单核细胞”比例大大降低(平均值＝37.5％)。通常在卵巢癌患者中观察到这种现象。因此，与健康供体相比，第一输注前卵巢腺癌患者中的中间单核细胞比例增加(平均值＝46.5％)。
有趣的是，用3C23K治疗时和之后的测量值百分比揭示了，患者中典型单核细胞亚群大量增加，伴随着中间单核细胞亚群的比例下降(平均值分别为54,6％和30.5％)，如图7中的患者04-06所例示。在波尔多研究所(Institut Bordet)在相同方案下研究的4名患者的血液样品中也观察到了单核细胞亚群的这种变化。这些变化是单核细胞表型修饰的迹象。最近描述了响应于免疫检查点抑制剂的单核细胞亚群的变化(Krieg C.,Nowicka M.,Guglietta S.,Schindler S.,Hartmann F.J.,Weber L.M.,等人.(2018).High-dimensional single-cell analysis predicts response to anti-PD-1immunotherapy.Nat Med.24,144–153)，从而导致淋巴细胞活化(通过阻断抑制信号)。我们的数据表明，没有与免疫检查点结合的3C23K也可以改变单核细胞亚群的比例，从而活化淋巴细胞。
表3：序列
SEQUENCE LISTING
<110> 加马玛布斯制药公司
国家健康与医学研究院（INSERM）
<120> 癌症相关的免疫抑制抑制剂
<130> PR80324
<150> EP17305619
<151> 2017-05-29
<160> 76
<170> BiSSAP 1.3.6
<210> 1
<211> 318
<212> DNA
<213> 人工序列
<220>
<223> 无前导序列的3C_23 VL
<220>
<223> 无前导序列的3C_23 VL
<220>
<221> CDS
<222> 1..318
<400> 1
gac atc cag atg aca cag tcc cca tct acc ctg tct gct tcc gtg gga 48
gat cgg gtg act atc acc tgc aga gca agc tcc tcc gtg agg tac atc 96
gct tgg tac cag cag aag cca gga aag gcc cca aag ctg ctg acc tac 144
cca acc tcc tcc ctg gaa tcc ggg gtg ccc agc aga ttc tca ggc agt 192
ggc tcc ggc acc gaa ttc acc ctg acc atc agc tca ctg cag cct gac 240
gac ttc gca acc tac tac tgt ctg cag tgg agt agc tac cct tgg aca 288
ttc ggc ggc ggc acc aag gtg gag atc aag 318
<210> 2
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 来自SEQ ID NO 1的[CDS]:1..318
<220>
<223> 来自SEQ ID NO 1的合成构建体[CDS]:1..318
<400> 2
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Arg Tyr Ile
20 25 30
Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Thr Tyr
35 40 45
Pro Thr Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Trp Ser Ser Tyr Pro Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 3
<211> 345
<212> DNA
<213> 人工序列
<220>
<223> 无前导序列的3C_23 VH
<220>
<223> 无前导序列的3C_23 VH
<220>
<221> CDS
<222> 1..345
<400> 3
cag gtg cgg ctg gtg cag agc ggg gcc gag gtg aag aag cct gga gcc 48
tca gtg aag gtg agt tgc aag gcc tcc ggt tac acc ttc acc agc tac 96
cac atc cac tgg gtc aga cag gct ccc ggc cag aga ctg gag tgg atg 144
ggc tgg atc tac cct gga gat gac tcc acc aag tac tcc cag aag ttc 192
cag ggt cgc gtg acc att acc agg gac acc agc gcc tcc act gcc tac 240
atg gag ctg tct tcc ctg aga tct gag gat acc gca gtc tac tac tgt 288
aca cgg ggg gac cgc ttt gct tac tgg ggg cag ggc act ctg gtg acc 336
gtc tcg agc 345
<210> 4
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 来自SEQ ID NO 3的[CDS]:1..345
<220>
<223> 来自SEQ ID NO 3的合成构建体[CDS]:1..345
<400> 4
Gln Val Arg 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
His Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Asp Ser Thr Lys Tyr Ser Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Arg 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
Thr Arg Gly Asp Arg Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 5
<211> 318
<212> DNA
<213> 人工序列
<220>
<223> 无前导序列的3C_23K VL
<220>
<223> 无前导序列的3C_23K VL
<220>
<221> CDS
<222> 1..318
<400> 5
gac atc cag atg aca cag tcc cca tct acc ctg tct gct tcc gtg gga 48
gat cgg gtg act atc acc tgc aga gca agc tcc tcc gtg agg tac atc 96
gct tgg tac cag cag aag cca gga aag gcc cca aag ctg ctg acc tac 144
cca acc tcc tcc ctg aaa tcc ggg gtg ccc agc aga ttc tca ggc agt 192
ggc tcc ggc acc gaa ttc acc ctg acc atc agc tca ctg cag cct gac 240
gac ttc gca acc tac tac tgt ctg cag tgg agt agc tac cct tgg aca 288
ttc ggc ggc ggc acc aag gtg gag atc aag 318
<210> 6
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 来自SEQ ID NO 5的[CDS]:1..318
<220>
<223> 来自SEQ ID NO 5的合成构建体[CDS]:1..318
<400> 6
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Arg Tyr Ile
20 25 30
Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Thr Tyr
35 40 45
Pro Thr Ser Ser Leu Lys Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Trp Ser Ser Tyr Pro Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 7
<211> 345
<212> DNA
<213> 人工序列
<220>
<223> 无前导序列的3C_23K VH
<220>
<223> 无前导序列的3C_23K VH
<220>
<221> CDS
<222> 1..345
<400> 7
cag gtg cgg ctg gtg cag agc ggg gcc gag gtg aag aag cct gga gcc 48
tca gtg aag gtg agt tgc aag gcc tcc ggt tac acc ttc acc agc tac 96
cac atc cac tgg gtc aga cag gct ccc ggc cag aga ctg gag tgg atg 144
ggc tgg atc tac cct gga gat gac tcc acc aag tac tcc cag aag ttc 192
cag ggt cgc gtg acc att acc agg gac acc agc gcc tcc act gcc tac 240
atg gag ctg tct tcc ctg aga tct gag gat acc gca gtc tac tac tgt 288
aca cgg ggg gac cgc ttt gct tac tgg ggg cag ggc act ctg gtg acc 336
gtc tcg agc 345
<210> 8
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 来自SEQ ID NO 7的[CDS]:1..345
<220>
<223> 来自SEQ ID NO 7的合成构建体[CDS]:1..345
<400> 8
Gln Val Arg 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
His Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Asp Ser Thr Lys Tyr Ser Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Arg 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
Thr Arg Gly Asp Arg Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 9
<211> 639
<212> DNA
<213> 人工序列
<220>
<223> 无前导序列的3C_23轻链
<220>
<223> 无前导序列的3C_23轻链
<220>
<221> CDS
<222> 1..639
<400> 9
gac atc cag atg aca cag tcc cca tct acc ctg tct gct tcc gtg gga 48
gat cgg gtg act atc acc tgc aga gca agc tcc tcc gtg agg tac atc 96
gct tgg tac cag cag aag cca gga aag gcc cca aag ctg ctg acc tac 144
cca acc tcc tcc ctg gaa tcc ggg gtg ccc agc aga ttc tca ggc agt 192
ggc tcc ggc acc gaa ttc acc ctg acc atc agc tca ctg cag cct gac 240
gac ttc gca acc tac tac tgt ctg cag tgg agt agc tac cct tgg aca 288
ttc ggc ggc ggc acc aag gtg gag atc aag cgg acc gtc gcc gca cca 336
agt gtc ttc atc ttc ccg cca tct gat gag cag ttg aaa tct gga act 384
gcc tct gtt gtg tgc ctg ctg aat aac ttc tat ccc aga gag gcc aaa 432
gta cag tgg aag gtg gat aac gcc ctc caa tcg ggt aac tcc cag gag 480
agt gtc aca gag cag gac agc aag gac agc acc tac agc ctc agc agc 528
acc ctg acg ctg agc aaa gca gac tac gag aaa cac aaa gtc tac gcc 576
tgc gaa gtc acc cat cag ggc ctg agc tcg ccc gtc aca aag agc ttc 624
aac agg gga gag tgt 639
<210> 10
<211> 213
<212> PRT
<213> 人工序列
<220>
<223> 来自SEQ ID NO 9的[CDS]:1..639
<220>
<223> 来自SEQ ID NO 9的合成构建体[CDS]:1..639
<400> 10
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Arg Tyr Ile
20 25 30
Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Thr Tyr
35 40 45
Pro Thr Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Trp Ser Ser Tyr Pro Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 11
<211> 1335
<212> DNA
<213> 人工序列
<220>
<223> 无前导序列的3C_23重链
<220>
<223> 无前导序列的3C_23重链
<220>
<221> CDS
<222> 1..1335
<400> 11
cag gtg cgg ctg gtg cag agc ggg gcc gag gtg aag aag cct gga gcc 48
tca gtg aag gtg agt tgc aag gcc tcc ggt tac acc ttc acc agc tac 96
cac atc cac tgg gtc aga cag gct ccc ggc cag aga ctg gag tgg atg 144
ggc tgg atc tac cct gga gat gac tcc acc aag tac tcc cag aag ttc 192
cag ggt cgc gtg acc att acc agg gac acc agc gcc tcc act gcc tac 240
atg gag ctg tct tcc ctg aga tct gag gat acc gca gtc tac tac tgt 288
aca cgg ggg gac cgc ttt gct tac tgg ggg cag ggc act ctg gtg acc 336
gtc tcg agc gcc agc acc aag ggc cca tcg gtc ttc ccc ctg gca ccc 384
tcc tcc aag agc acc tct ggg ggc aca gcg gcc ctg ggc tgc ctg gtc 432
aag gac tac ttc ccc gaa ccg gtg acg gtg tcg tgg aac tca ggc gcc 480
ctg acc agc ggc gtg cac acc ttc ccg gct gtc cta cag tcc tca gga 528
ctc tac tcc ctc agc agc gtg gtg acc gtg ccc tcc agc agc ttg ggc 576
acc cag acc tac atc tgc aac gtg aat cac aag ccc agc aac acc aag 624
gtg gac aag aaa gtt gag ccc aaa tct tgt gac aaa act cac aca tgc 672
cca ccg tgc cca gca cct gaa ctc ctg ggg gga ccg tca gtc ttc ctc 720
ttc ccc cca aaa ccc aag gac acc ctc atg atc tcc cgg acc cct gag 768
gtc aca tgc gtg gtg gtg gac gtg agc cac gaa gac cct gag gtc aag 816
ttc aac tgg tac gtg gac ggc gtg gag gtg cat aat gcc aag aca aag 864
ccg cgg gag gag cag tac aac agc acg tac cgt gtg gtc agc gtc ctc 912
acc gtc ctg cac cag gac tgg ctg aat ggc aag gag tac aag tgc aag 960
gtc tcc aac aaa gcc ctc cca gcc ccc atc gag aaa acc atc tcc aaa 1008
gcc aaa ggg cag ccc cga gaa cca cag gtg tac acc ctg ccc cca tcc 1056
cgg gat gag ctg acc aag aac cag gtc agc ctg acc tgc ctg gtc aaa 1104
ggc ttc tat ccc agc gac atc gcc gtg gag tgg gag agc aat ggg cag 1152
ccg gag aac aac tac aag acc acg cct ccc gtg ctg gac tcc gac ggc 1200
tcc ttc ttc ctc tac agc aag ctc acc gtg gac aag agc agg tgg cag 1248
cag ggg aac gtc ttc tca tgc tcc gtg atg cat gag gct ctg cac aac 1296
cac tac acg cag aag agc ctc tcc ctg tct ccg ggt aaa 1335
<210> 12
<211> 445
<212> PRT
<213> 人工序列
<220>
<223> 来自SEQ ID NO 11的[CDS]:1..1335
<220>
<223> 来自SEQ ID NO 11的合成构建体[CDS]:1..1335
<400> 12
Gln Val Arg 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
His Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Asp Ser Thr Lys Tyr Ser Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Arg 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
Thr Arg Gly Asp Arg Phe Ala 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 Pro
115 120 125
Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val
130 135 140
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
145 150 155 160
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
165 170 175
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
180 185 190
Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys
195 200 205
Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys
210 215 220
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
225 230 235 240
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
245 250 255
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
260 265 270
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
275 280 285
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
290 295 300
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
305 310 315 320
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
325 330 335
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
340 345 350
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
355 360 365
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
370 375 380
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
385 390 395 400
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
405 410 415
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
420 425 430
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 13
<211> 639
<212> DNA
<213> 人工序列
<220>
<223> 无前导序列的3C_23K轻链
<220>
<223> 无前导序列的3C_23K轻链
<220>
<221> CDS
<222> 1..639
<400> 13
gac atc cag atg aca cag tcc cca tct acc ctg tct gct tcc gtg gga 48
gat cgg gtg act atc acc tgc aga gca agc tcc tcc gtg agg tac atc 96
gct tgg tac cag cag aag cca gga aag gcc cca aag ctg ctg acc tac 144
cca acc tcc tcc ctg aaa tcc ggg gtg ccc agc aga ttc tca ggc agt 192
ggc tcc ggc acc gaa ttc acc ctg acc atc agc tca ctg cag cct gac 240
gac ttc gca acc tac tac tgt ctg cag tgg agt agc tac cct tgg aca 288
ttc ggc ggc ggc acc aag gtg gag atc aag cgg acc gtc gcc gca cca 336
agt gtc ttc atc ttc ccg cca tct gat gag cag ttg aaa tct gga act 384
gcc tct gtt gtg tgc ctg ctg aat aac ttc tat ccc aga gag gcc aaa 432
gta cag tgg aag gtg gat aac gcc ctc caa tcg ggt aac tcc cag gag 480
agt gtc aca gag cag gac agc aag gac agc acc tac agc ctc agc agc 528
acc ctg acg ctg agc aaa gca gac tac gag aaa cac aaa gtc tac gcc 576
tgc gaa gtc acc cat cag ggc ctg agc tcg ccc gtc aca aag agc ttc 624
aac agg gga gag tgt 639
<210> 14
<211> 213
<212> PRT
<213> 人工序列
<220>
<223> 来自SEQ ID NO 13的[CDS]:1..639
<220>
<223> 来自SEQ ID NO 13的合成构建体[CDS]:1..639
<400> 14
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Arg Tyr Ile
20 25 30
Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Thr Tyr
35 40 45
Pro Thr Ser Ser Leu Lys Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Trp Ser Ser Tyr Pro Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 15
<211> 1335
<212> DNA
<213> 人工序列
<220>
<223> 无前导序列的3C_23K重链
<220>
<223> 无前导序列的3C_23K重链
<220>
<221> CDS
<222> 1..1335
<400> 15
cag gtg cgg ctg gtg cag agc ggg gcc gag gtg aag aag cct gga gcc 48
tca gtg aag gtg agt tgc aag gcc tcc ggt tac acc ttc acc agc tac 96
cac atc cac tgg gtc aga cag gct ccc ggc cag aga ctg gag tgg atg 144
ggc tgg atc tac cct gga gat gac tcc acc aag tac tcc cag aag ttc 192
cag ggt cgc gtg acc att acc agg gac acc agc gcc tcc act gcc tac 240
atg gag ctg tct tcc ctg aga tct gag gat acc gca gtc tac tac tgt 288
aca cgg ggg gac cgc ttt gct tac tgg ggg cag ggc act ctg gtg acc 336
gtc tcg agc gcc agc acc aag ggc cca tcg gtc ttc ccc ctg gca ccc 384
tcc tcc aag agc acc tct ggg ggc aca gcg gcc ctg ggc tgc ctg gtc 432
aag gac tac ttc ccc gaa ccg gtg acg gtg tcg tgg aac tca ggc gcc 480
ctg acc agc ggc gtg cac acc ttc ccg gct gtc cta cag tcc tca gga 528
ctc tac tcc ctc agc agc gtg gtg acc gtg ccc tcc agc agc ttg ggc 576
acc cag acc tac atc tgc aac gtg aat cac aag ccc agc aac acc aag 624
gtg gac aag aaa gtt gag ccc aaa tct tgt gac aaa act cac aca tgc 672
cca ccg tgc cca gca cct gaa ctc ctg ggg gga ccg tca gtc ttc ctc 720
ttc ccc cca aaa ccc aag gac acc ctc atg atc tcc cgg acc cct gag 768
gtc aca tgc gtg gtg gtg gac gtg agc cac gaa gac cct gag gtc aag 816
ttc aac tgg tac gtg gac ggc gtg gag gtg cat aat gcc aag aca aag 864
ccg cgg gag gag cag tac aac agc acg tac cgt gtg gtc agc gtc ctc 912
acc gtc ctg cac cag gac tgg ctg aat ggc aag gag tac aag tgc aag 960
gtc tcc aac aaa gcc ctc cca gcc ccc atc gag aaa acc atc tcc aaa 1008
gcc aaa ggg cag ccc cga gaa cca cag gtg tac acc ctg ccc cca tcc 1056
cgg gat gag ctg acc aag aac cag gtc agc ctg acc tgc ctg gtc aaa 1104
ggc ttc tat ccc agc gac atc gcc gtg gag tgg gag agc aat ggg cag 1152
ccg gag aac aac tac aag acc acg cct ccc gtg ctg gac tcc gac ggc 1200
tcc ttc ttc ctc tac agc aag ctc acc gtg gac aag agc agg tgg cag 1248
cag ggg aac gtc ttc tca tgc tcc gtg atg cat gag gct ctg cac aac 1296
cac tac acg cag aag agc ctc tcc ctg tct ccg ggt aaa 1335
<210> 16
<211> 445
<212> PRT
<213> 人工序列
<220>
<223> 来自SEQ ID NO 15的[CDS]:1..1335
<220>
<223> 来自SEQ ID NO 15的合成构建体[CDS]:1..1335
<400> 16
Gln Val Arg 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
His Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Asp Ser Thr Lys Tyr Ser Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Arg 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
Thr Arg Gly Asp Arg Phe Ala 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 Pro
115 120 125
Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val
130 135 140
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
145 150 155 160
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
165 170 175
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
180 185 190
Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys
195 200 205
Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys
210 215 220
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
225 230 235 240
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
245 250 255
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
260 265 270
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
275 280 285
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
290 295 300
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
305 310 315 320
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
325 330 335
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
340 345 350
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
355 360 365
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
370 375 380
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
385 390 395 400
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
405 410 415
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
420 425 430
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 17
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 3C23K/3C23
<220>
<223> 3C23K/3C23
<400> 17
Gln Val Arg 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
His Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Asp Ser Thr Lys Tyr Ser Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Arg 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
Thr Arg Gly Asp Arg Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 18
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 3C23KR/6B78
<220>
<223> 3C23KR/6B78
<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 Ser Tyr
20 25 30
His Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Asp Ser Thr Lys Tyr Ser Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Arg 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
Thr Arg Gly Asp Arg Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 19
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 5B42
<220>
<223> 5B42
<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 Ser Tyr
20 25 30
His Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Asp Ser Thr Lys Tyr Ser Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Arg Asp Ala 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
Thr Arg Gly Asp Arg Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 20
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> K4D-24/6C59
<220>
<223> K4D-24/6C59
<400> 20
Arg Val Arg 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
His Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Asp Ser Thr Lys Tyr Ser Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Arg 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
Thr Arg Gly Asp Arg Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 21
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> K4D-20
<220>
<223> K4D-20
<400> 21
Gln Val Arg 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 Asn
20 25 30
His Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Asp Ser Thr Lys Tyr Ser Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Arg 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
Thr Arg Gly Asp Arg Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 22
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> K4A-12" <223> K4A-12
<220>
<223> K4A-12
<220>
<223> K4A-12
<400> 22
Gln Val Arg Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Thr
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
His Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Asp Ser Thr Lys Tyr Ser Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Arg 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
Thr Arg Gly Asp Arg Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 23
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> K5D05" <223> K5D05
<220>
<223> K5D05
<220>
<223> K5D05
<400> 23
Gln Val Arg 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 Gly Tyr
20 25 30
His Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Asp Ser Thr Lys Tyr Ser Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Arg 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
Thr Arg Gly Asp Arg Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 24
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> K5D-14" <223> K5D-14
<220>
<223> K5D-14
<220>
<223> K5D-14
<400> 24
Gln Val Arg 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 Ser Phe Thr Ser Tyr
20 25 30
His Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Asp Ser Thr Lys Tyr Ser Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Arg 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
Thr Arg Gly Asp Arg Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 25
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> K4D-123" <223> K4D-123
<220>
<223> K4D-123
<220>
<223> K4D-123
<400> 25
Gln Val Arg 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
His Ile His Trp Val Arg Gln Ala Pro Gly Gln Ser Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Asp Ser Thr Lys Tyr Ser Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Arg 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
Thr Arg Gly Asp Arg Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 26
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> K4D-127/6C07" <223> K4D-127/6C07
<220>
<223> K4D-127/6C07
<220>
<223> K4D-127/6C07
<400> 26
Gln Val Arg 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
His Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Asp Ser Thr Lys Tyr Ser Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Thr Thr Arg 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
Thr Arg Gly Asp Arg Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 27
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 5C14" <223> 5C14
<220>
<223> 5C14
<220>
<223> 5C14
<400> 27
Gln Val Arg 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
His Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Asp Ser Thr Lys Tyr Ser Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Phe Thr Arg 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
Thr Arg Gly Asp Arg Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 28
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 5C26" <223> 5C26
<220>
<223> 5C26
<220>
<223> 5C26
<400> 28
Gln Val Arg 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
His Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Asp Ser Thr Lys Tyr Ser Gln Lys Phe
50 55 60
Gln Gly Arg Met Thr Ile Thr Arg 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
Thr Arg Gly Asp Arg Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 29
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 5C27" <223> 5C27
<220>
<223> 5C27
<220>
<223> 5C27
<400> 29
Gln Val Arg 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
His Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Pro Glu Trp Met
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Asp Ser Thr Lys Tyr Ser Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Arg 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
Thr Arg Gly Asp Arg Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 30
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 5C60" <223> 5C60
<220>
<223> 5C60
<220>
<223> 5C60
<400> 30
Gln Val Arg Leu Val Gln Ser Gly Ala Lys Val Arg 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
His Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Asp Ser Thr Lys Tyr Ser Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Arg 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
Thr Arg Gly Asp Arg Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 31
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 6C13" <223> 6C13
<220>
<223> 6C13
<220>
<223> 6C13
<400> 31
Gln Val Arg 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
His Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Pro Glu Asp Asp Ser Thr Lys Tyr Ser Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Arg 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
Thr Arg Gly Asp Arg Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 32
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 6C18" <223> 6C18
<220>
<223> 6C18
<220>
<223> 6C18
<400> 32
Gln Val Arg 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
His Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Asp Ser Thr Lys Tyr Ser Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Arg 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 Asp Arg Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 33
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 6C54" <223> 6C54
<220>
<223> 6C54
<220>
<223> 6C54
<400> 33
Gln Val Arg 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
His Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Asp Ser Thr Lys Tyr Ser Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Gly Asp Arg Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 34
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 3C23K" <223> 3C23K
<220>
<223> 3C23K
<220>
<223> 3C23K
<400> 34
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Arg Tyr Ile
20 25 30
Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Thr Tyr
35 40 45
Pro Thr Ser Ser Leu Lys Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Trp Ser Ser Tyr Pro Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 35
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> L-K55E" <223> L-K55E
<220>
<223> L-K55E
<220>
<223> L-K55E
<400> 35
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Arg Tyr Ile
20 25 30
Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Thr Tyr
35 40 45
Pro Thr Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Trp Ser Ser Tyr Pro Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 36
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> L-T48I, L-P50S" <223> L-T48I, L-P50S
<220>
<223> L-T48I, L-P50S
<220>
<223> L-T48I, L-P50S
<400> 36
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Arg Tyr Ile
20 25 30
Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
35 40 45
Ser Thr Ser Ser Leu Lys Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Trp Ser Ser Tyr Pro Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 37
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> LT48I, L-K55E" <223> LT48I, L-K55E
<220>
<223> LT48I, L-K55E
<220>
<223> LT48I, L-K55E
<400> 37
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Arg Tyr Ile
20 25 30
Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
35 40 45
Pro Thr Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Trp Ser Ser Tyr Pro Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 38
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> LS27P, L-S28P" <223> LS27P, L-S28P
<220>
<223> LS27P, L-S28P
<220>
<223> LS27P, L-S28P
<400> 38
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Pro Pro Val Arg Tyr Ile
20 25 30
Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Thr Tyr
35 40 45
Pro Thr Ser Ser Leu Lys Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Trp Ser Ser Tyr Pro Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 39
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> L-M4L, L-T20A" <223> L-M4L, L-T20A
<220>
<223> L-M4L, L-T20A
<220>
<223> L-M4L, L-T20A
<400> 39
Asp Ile Gln Leu Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ala Ile Thr Cys Arg Ala Ser Ser Ser Val Arg Tyr Ile
20 25 30
Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Thr Tyr
35 40 45
Pro Thr Ser Ser Leu Lys Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Trp Ser Ser Tyr Pro Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 40
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> L-S27P" <223> L-S27P
<220>
<223> L-S27P
<220>
<223> L-S27P
<400> 40
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Pro Ser Val Arg Tyr Ile
20 25 30
Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Thr Tyr
35 40 45
Pro Thr Ser Ser Leu Lys Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Trp Ser Ser Tyr Pro Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 41
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> L-M4L, L-S9P, L-R31W" <223> L-M4L, L-S9P, L-R31W
<220>
<223> L-M4L, L-S9P, L-R31W
<220>
<223> L-M4L, L-S9P, L-R31W
<400> 41
Asp Ile Gln Leu Thr Gln Ser Pro Pro Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Trp Tyr Ile
20 25 30
Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Thr Tyr
35 40 45
Pro Thr Ser Ser Leu Lys Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Trp Ser Ser Tyr Pro Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 42
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> L-M4L" <223> L-M4L
<220>
<223> L-M4L
<220>
<223> L-M4L
<400> 42
Asp Ile Gln Leu Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Arg Tyr Ile
20 25 30
Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Thr Tyr
35 40 45
Pro Thr Ser Ser Leu Lys Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Trp Ser Ser Tyr Pro Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 43
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> L-I33T" <223> L-I33T
<220>
<223> L-I33T
<220>
<223> L-I33T
<400> 43
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Arg Tyr Thr
20 25 30
Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Thr Tyr
35 40 45
Pro Thr Ser Ser Leu Lys Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Trp Ser Ser Tyr Pro Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 44
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> L-M4L, L-K39E" <223> L-M4L, L-K39E
<220>
<223> L-M4L, L-K39E
<220>
<223> L-M4L, L-K39E
<400> 44
Asp Ile Gln Leu Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Arg Tyr Ile
20 25 30
Ala Trp Tyr Gln Gln Glu Pro Gly Lys Ala Pro Lys Leu Leu Thr Tyr
35 40 45
Pro Thr Ser Ser Leu Lys Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Trp Ser Ser Tyr Pro Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 45
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> L-T22P" <223> L-T22P
<220>
<223> L-T22P
<220>
<223> L-T22P
<400> 45
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Pro Cys Arg Ala Ser Ser Ser Val Arg Tyr Ile
20 25 30
Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Thr Tyr
35 40 45
Pro Thr Ser Ser Leu Lys Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Trp Ser Ser Tyr Pro Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 46
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> L-Y32D" <223> L-Y32D
<220>
<223> L-Y32D
<220>
<223> L-Y32D
<400> 46
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Arg Asp Ile
20 25 30
Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Thr Tyr
35 40 45
Pro Thr Ser Ser Leu Lys Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Trp Ser Ser Tyr Pro Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 47
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> L-Q37H" <223> L-Q37H
<220>
<223> L-Q37H
<220>
<223> L-Q37H
<400> 47
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Arg Tyr Ile
20 25 30
Ala Trp Tyr His Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Thr Tyr
35 40 45
Pro Thr Ser Ser Leu Lys Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Trp Ser Ser Tyr Pro Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 48
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> L-G97S" <223> L-G97S
<220>
<223> L-G97S
<220>
<223> L-G97S
<400> 48
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Arg Tyr Ile
20 25 30
Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Thr Tyr
35 40 45
Pro Thr Ser Ser Leu Lys Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Trp Ser Ser Tyr Pro Trp Thr
85 90 95
Phe Ser Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 49
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> L-S12P" <223> L-S12P
<220>
<223> L-S12P
<220>
<223> L-S12P
<400> 49
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Pro Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Arg Tyr Ile
20 25 30
Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Thr Tyr
35 40 45
Pro Thr Ser Ser Leu Lys Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Trp Ser Ser Tyr Pro Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 50
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> L-19A" <223> L-19A
<220>
<223> L-19A
<220>
<223> L-19A
<400> 50
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Ala Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Arg Tyr Ile
20 25 30
Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Thr Tyr
35 40 45
Pro Thr Ser Ser Leu Lys Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Trp Ser Ser Tyr Pro Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 51
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> L-T72A" <223> L-T72A
<220>
<223> L-T72A
<220>
<223> L-T72A
<400> 51
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Arg Tyr Ile
20 25 30
Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Thr Tyr
35 40 45
Pro Thr Ser Ser Leu Lys Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Glu Phe Ala Leu Thr Ile Ser Ser Leu Gln Pro Asp
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Trp Ser Ser Tyr Pro Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 52
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> L-R31W" <223> L-R31W
<220>
<223> L-R31W
<220>
<223> L-R31W
<400> 52
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Trp Tyr Ile
20 25 30
Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Thr Tyr
35 40 45
Pro Thr Ser Ser Leu Lys Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Trp Ser Ser Tyr Pro Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 53
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> L-M4L, L-M39K" <223> L-M4L, L-M39K
<220>
<223> L-M4L, L-M39K
<220>
<223> L-M4L, L-M39K
<400> 53
Asp Ile Gln Leu Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Arg Tyr Ile
20 25 30
Ala Trp Tyr Gln Gln Met Pro Gly Lys Ala Pro Lys Leu Leu Thr Tyr
35 40 45
Pro Thr Ser Ser Leu Lys Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Trp Ser Ser Tyr Pro Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 54
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> L-I2N" <223> L-I2N
<220>
<223> L-I2N
<220>
<223> L-I2N
<400> 54
Asp Asn Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Arg Tyr Ile
20 25 30
Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Thr Tyr
35 40 45
Pro Thr Ser Ser Leu Lys Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Trp Ser Ser Tyr Pro Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 55
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> L-G63C, L-W91C" <223> L-G63C, L-W91C
<220>
<223> L-G63C, L-W91C
<220>
<223> L-G63C, L-W91C
<400> 55
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Arg Tyr Ile
20 25 30
Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Thr Tyr
35 40 45
Pro Thr Ser Ser Leu Lys Ser Gly Val Pro Ser Arg Phe Ser Cys Ser
50 55 60
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Cys Ser Ser Tyr Pro Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 56
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> L-R31G" <223> L-R31G
<220>
<223> L-R31G
<220>
<223> L-R31G
<400> 56
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Gly Tyr Ile
20 25 30
Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Thr Tyr
35 40 45
Pro Thr Ser Ser Leu Lys Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Trp Ser Ser Tyr Pro Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 57
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> L-I75F" <223> L-I75F
<220>
<223> L-I75F
<220>
<223> L-I75F
<400> 57
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Arg Tyr Ile
20 25 30
Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Thr Tyr
35 40 45
Pro Thr Ser Ser Leu Lys Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Glu Phe Thr Leu Thr Phe Ser Ser Leu Gln Pro Asp
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Trp Ser Ser Tyr Pro Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 58
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> L-I2T" <223> L-I2T
<220>
<223> L-I2T
<220>
<223> L-I2T
<400> 58
Asp Thr Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Arg Tyr Ile
20 25 30
Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Thr Tyr
35 40 45
Pro Thr Ser Ser Leu Lys Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Trp Ser Ser Tyr Pro Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 59
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> L-I2T, L-K42R" <223> L-I2T, L-K42R
<220>
<223> L-I2T, L-K42R
<220>
<223> L-I2T, L-K42R
<400> 59
Asp Thr Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Arg Tyr Ile
20 25 30
Ala Trp Tyr Gln Gln Lys Pro Gly Arg Ala Pro Lys Leu Leu Thr Tyr
35 40 45
Pro Thr Ser Ser Leu Lys Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Trp Ser Ser Tyr Pro Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 60
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> L-Y49H" <223> L-Y49H
<220>
<223> L-Y49H
<220>
<223> L-Y49H
<400> 60
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Arg Tyr Ile
20 25 30
Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Thr His
35 40 45
Pro Thr Ser Ser Leu Lys Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Trp Ser Ser Tyr Pro Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 61
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> L-M4L, L-T20S, L-K39E" <223> L-M4L, L-T20S, L-K39E
<220>
<223> L-M4L, L-T20S, L-K39E
<220>
<223> L-M4L, L-T20S, L-K39E
<400> 61
Asp Ile Gln Leu Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Arg Ala Ser Ser Ser Val Arg Tyr Ile
20 25 30
Ala Trp Tyr Gln Gln Glu Pro Gly Lys Ala Pro Lys Leu Leu Thr Tyr
35 40 45
Pro Thr Ser Ser Leu Lys Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Trp Ser Ser Tyr Pro Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 62
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> L-T69P" <223> L-T69P
<220>
<223> L-T69P
<220>
<223> L-T69P
<400> 62
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Arg Tyr Ile
20 25 30
Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Thr Tyr
35 40 45
Pro Thr Ser Ser Leu Lys Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Pro Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Trp Ser Ser Tyr Pro Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 63
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 9F7F11_VH
<220>
<223> 9F7F11_VH
<400> 63
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Thr Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Asp Gly Gly Gly Val Thr Tyr Tyr Pro Asp Thr Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Tyr Gly Leu Phe Ala Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ala
115
<210> 64
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 9F7F11_VL
<220>
<223> 9F7F11_VL
<400> 64
Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Ile Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Met Gln Ser
65 70 75 80
Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Ser Asn Tyr Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 65
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> H4B121_VH
<220>
<223> H4B121_VH
<400> 65
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Gln Trp Pro Asn Tyr Gly Met Asp Val Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 66
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> H4B121_VL
<220>
<223> H4B121_VL
<400> 66
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln
1 5 10 15
Lys Val Thr Ile Ser Cys Pro Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Asp Asn Asn Glu Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Thr Ser Gly Thr Ser Ala Thr Leu Asp Ile Thr Asp Leu Gln
65 70 75 80
Ala Glu Asp Glu Ala Thr Tyr Tyr Cys Gly Ala Trp Asp Asn Thr Leu
85 90 95
Gly Val Tyr Val Leu Gly Thr Gly Thr Gln Leu Thr Val Leu
100 105 110
<210> 67
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> HE4B33_VH
<220>
<223> HE4B33_VH
<400> 67
Glu 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
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala 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 Phe Cys
85 90 95
Ala Arg Ser Arg Gly Tyr Tyr Asp Pro Phe Asp Val Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 68
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> HE4B33_VL
<220>
<223> HE4B33_VL
<400> 68
Gln Ser Val Val Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln
1 5 10 15
Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser
50 55 60
Ala Ser Lys Ser Gly Thr Ser Ala Thr Leu Asp Ile Thr Gly Leu Gln
65 70 75 80
Thr Gly Asp Glu Ala His Tyr Tyr Cys Gly Ala Trp Asp Ser Ser Leu
85 90 95
Ser Val Ala Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 69
<211> 990
<212> DNA
<213> 人工序列
<220>
<223> Fc片段 IGHG1
<220>
<223> Fc片段 IGHG1
<400> 69
gccagcacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 60
ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120
tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180
ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 240
tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agttgagccc 300
aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 360
ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420
gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 480
tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 540
agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600
gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 660
aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggatgag 720
ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 780
gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840
ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 900
cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960
cagaagagcc tctccctgtc tccgggtaaa 990
<210> 70
<211> 330
<212> PRT
<213> 人工序列
<220>
<223> Fc片段 IGHG1
<220>
<223> Fc片段 IGHG1
<220>
<221> 变体
<222> 97
<223> Xaa是指K或R
<220>
<221> 变体
<222> 239
<223> Xaa是指D或E
<220>
<221> 变体
<222> 241
<223> Xaa是指L或M
<400> 70
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
Xaa 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 Xaa Glu
225 230 235 240
Xaa 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 Lys
325 330
<210> 71
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 抗AMHRII抗体的CDRL-1
<220>
<221> 变体
<222> 4
<223> 位置4的Xaa是S或P
<220>
<221> 变体
<222> 5
<223> 位置5的Xaa是S或P
<220>
<221> 变体
<222> 7
<223> 位置7的Xaa是R或W或G
<220>
<221> 变体
<222> 8
<223> 位置8的Xaa是T或D
<220>
<221> 变体
<222> 9
<223> 位置9的Xaa是I或T
<400> 71
Arg Ala Ser Xaa Xaa Val Xaa Xaa Xaa Ala
1 5 10
<210> 72
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 抗AMHRII抗体的CDRL-2
<220>
<221> 变体
<222> 6
<223> 位置6的Xaa是K或E
<400> 72
Pro Thr Ser Ser Leu Xaa Ser
1 5
<210> 73
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 抗AMHRII抗体的CDRL-3
<400> 73
Leu Gln Trp Ser Ser Tyr Pro Trp Thr
1 5
<210> 74
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 抗AMHRII抗体的CDRH-1
<220>
<221> 变体
<222> 6
<223> 位置6的Xaa是S或T
<220>
<221> 变体
<222> 9
<223> 位置9的Xaa是S或G
<220>
<221> 变体
<222> 10
<223> 位置10的Xaa是Y或N
<400> 74
Lys Ala Ser Gly Tyr Xaa Phe Thr Xaa Xaa His Ile His
1 5 10
<210> 75
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 抗AMHRII抗体的CDRH-2
<220>
<221> 变体
<222> 5
<223> 位置5的Xaa是G或E
<400> 75
Trp Ile Tyr Pro Xaa Asp Asp Ser Thr Lys Tyr Ser Gln Lys Phe Gln
1 5 10 15
Gly
<210> 76
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 抗AMHRII抗体的CDRH-3
<400> 76
Gly Asp Arg Phe Ala Tyr
1 5
Claims (14)
1.一种糖工程化Fc片段承载化合物在治疗癌症相关的免疫抑制中作为免疫抑制抑制剂的用途。
2.根据权利要求1所述的糖工程化Fc片段承载化合物的用途，所述糖工程化Fc片段承载化合物由低岩藻糖基化Fc片段承载化合物组成。
3.根据权利要求1和2中的任一项所述的糖工程化Fc片段承载化合物的用途，所述糖工程化Fc片段承载化合物具有SEQ ID NO.70的两条氨基酸链。
4.根据权利要求1至3中的任一项所述的糖工程化Fc片段承载化合物的用途，所述糖工程化Fc片段承载化合物是糖工程化抗体。
5.根据权利要求4所述的糖工程化Fc片段承载化合物的用途，其中，所述糖工程化抗体针对肿瘤抗原。
6.根据权利要求5所述的糖工程化Fc片段承载化合物的用途，其中，所述肿瘤抗原选自由以下组成的组：HER2、HER3、HER4和AMHRII。
7.根据权利要求4至6中的任一项所述的糖工程化Fc片段承载化合物的用途，其中，所述糖工程化抗体选自由以下组成的组：
(i)糖工程化3C23K抗AMHRII抗体，其包含：
a)包含SEQ ID NO:2的轻链和包含SEQ ID NO:4的重链(无前导序列的3C23 VL序列和3C23 VH序列)；
b)包含SEQ ID NO:6的轻链和包含SEQ ID NO:8的重链(无前导序列的3C23K VL序列和3C23K VH序列)；
c)包含SEQ ID NO:10的轻链和包含SEQ ID NO:12的重链(无前导序列的3C23轻链和3C23重链)；
d)包含SEQ ID NO:14的轻链和包含SEQ ID NO:16的重链(无前导序列的3C23K轻链和3C23K重链)，
(ii)抗HER3 9F7F11糖工程化抗体，其包含(i)SEQ ID NO.63的重链可变区和(ii)SEQID NO.64的轻链可变区，
(iii)抗HER3 H4B121糖工程化抗体，其包含(i)SEQ ID NO.65的重链可变区和(ii)SEQID NO.66的轻链可变区，和
(iv)抗HER4 HE4B33糖工程化抗体，其包含(i)SEQ ID NO.67的重链可变区和(ii)SEQID NO.68的轻链可变区。
8.根据权利要求1至7中的任一项所述的糖工程化Fc片段承载化合物的用途，其中，所述癌症治疗还包括向所述个体施用抑制性免疫检查点蛋白抑制剂。
9.根据权利要求8所述的糖工程化Fc片段承载化合物的用途，其中，所述抑制性免疫检查点蛋白抑制剂选自由以下组成的组：PD-1的抑制剂、PD-L1的抑制剂、PD-L2的抑制剂、BTLA的抑制剂、CTLA-4的抑制剂、A2AR的抑制剂、B7-H3(CD276)的抑制剂、B7-H4(VTCN1)的抑制剂、IDO的抑制剂、KIR的抑制剂、LAG3的抑制剂、TIM-3的抑制剂和VISTA的抑制剂。
10.根据权利要求9所述的糖工程化Fc片段承载化合物的用途，其中，所述抑制剂由针对所述抑制性免疫检查点蛋白的抗体或其抗原结合片段组成。
11.一种药物组合物，其包含(i)如权利要求1至10中的任一项中所限定的糖工程化Fc片段承载化合物和(ii)抑制性免疫检查点蛋白抑制剂。
12.根据权利要求11所述的药物组合物，其中，所述糖工程化Fc片段承载化合物是如权利要求6和7中的任一项中所限定的针对肿瘤抗原的糖工程化抗体。
13.根据权利要求11和12中的任一项所述的药物组合物，其中，所述抑制性免疫检查点蛋白抑制剂选自由以下组成的组：PD-1的抑制剂、PD-L1的抑制剂、PD-L2的抑制剂、BTLA的抑制剂、CTLA-4的抑制剂、A2AR的抑制剂、B7-H3(CD276)的抑制剂、B7-H4(VTCN1)的抑制剂、IDO的抑制剂、KIR的抑制剂、LAG3的抑制剂、TIM-3的抑制剂和VISTA的抑制剂。
14.根据权利要求11至13中的任一项所述的药物组合物，其中，所述抑制性免疫检查点蛋白抑制剂由针对所述抑制性免疫检查点蛋白的抗体或其抗原结合片段组成。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP17305619 | 2017-05-29 | ||
| EP17305619.3 | 2017-05-29 | ||
| PCT/EP2018/064081 WO2018219956A1 (en) | 2017-05-29 | 2018-05-29 | Cancer-associated immunosuppression inhibitor |
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| Publication Number | Publication Date |
|---|---|
| CN111108123A true CN111108123A (zh) | 2020-05-05 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201880048764.4A Pending CN111108123A (zh) | 2017-05-29 | 2018-05-29 | 癌症相关的免疫抑制抑制剂 |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US20200148777A1 (zh) |
| EP (1) | EP3630826A1 (zh) |
| JP (2) | JP2020521780A (zh) |
| KR (1) | KR20200031571A (zh) |
| CN (1) | CN111108123A (zh) |
| BR (1) | BR112019025352A8 (zh) |
| CA (1) | CA3064333A1 (zh) |
| MX (1) | MX2019014192A (zh) |
| WO (1) | WO2018219956A1 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114716558A (zh) * | 2022-04-12 | 2022-07-08 | 广州明征生物科技有限公司 | 一种双特异性抗体及其治疗癌症的应用 |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL265800B2 (en) | 2016-10-11 | 2023-10-01 | Agenus Inc | Anti-LAG-3 antibodies and methods of using them |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103119059A (zh) * | 2010-05-12 | 2013-05-22 | Lfb生物技术公司 | 针对人抗苗勒管激素ii型受体的新的突变型人源化12g4抗体及其片段 |
| WO2015159253A1 (fr) * | 2014-04-16 | 2015-10-22 | Gamamabs Pharma | Anticorps humain anti-her4 |
| CN105849125A (zh) * | 2013-11-07 | 2016-08-10 | 国家医疗保健研究所 | 神经调节蛋白变构抗her3抗体 |
| CN106659774A (zh) * | 2014-05-16 | 2017-05-10 | 贝勒研究院 | 用于治疗自身免疫和炎性病症的方法和组合物 |
Family Cites Families (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE69942021D1 (de) | 1998-04-20 | 2010-04-01 | Glycart Biotechnology Ag | Glykosylierungs-engineering von antikörpern zur verbesserung der antikörperabhängigen zellvermittelten zytotoxizität |
| DK2270147T4 (da) | 1999-04-09 | 2020-08-31 | Kyowa Kirin Co Ltd | Fremgangsmåde til at kontrollere aktiviteten af immunologisk funktionelt molekyle |
| DK1297172T3 (da) | 2000-06-28 | 2006-02-13 | Glycofi Inc | Fremgangsmåder til frembringelse af modificerede glucoproteiner |
| US6946292B2 (en) | 2000-10-06 | 2005-09-20 | Kyowa Hakko Kogyo Co., Ltd. | Cells producing antibody compositions with increased antibody dependent cytotoxic activity |
| CN101613705A (zh) | 2002-03-19 | 2009-12-30 | 国际植物研究所 | 在植物中优化聚糖生成 |
| DK2287195T3 (da) | 2004-07-01 | 2019-08-19 | Innate Pharma | Pan-kir2dl nk-receptor-antistoffer og anvendelse heraf i diagnostik og terapi |
| US20070111281A1 (en) * | 2005-05-09 | 2007-05-17 | Glycart Biotechnology Ag | Antigen binding molecules having modified Fc regions and altered binding to Fc receptors |
| CN105315373B (zh) | 2005-05-09 | 2018-11-09 | 小野药品工业株式会社 | 程序性死亡-1(pd-1)的人单克隆抗体及使用抗pd-1抗体来治疗癌症的方法 |
| JP2008541770A (ja) * | 2005-06-03 | 2008-11-27 | ジェネンテック・インコーポレーテッド | 改変したフコシル化レベルを有する抗体の産生方法 |
| MX2008009220A (es) | 2006-01-17 | 2008-10-10 | Biolex Therapeutics Inc | Composiciones y metodos para la humanizacion y optimizacion de n-glicanos en plantas. |
| US7846724B2 (en) | 2006-04-11 | 2010-12-07 | Hoffmann-La Roche Inc. | Method for selecting CHO cell for production of glycosylated antibodies |
| EP1987839A1 (en) | 2007-04-30 | 2008-11-05 | I.N.S.E.R.M. Institut National de la Sante et de la Recherche Medicale | Cytotoxic anti-LAG-3 monoclonal antibody and its use in the treatment or prevention of organ transplant rejection and autoimmune disease |
| KR101562580B1 (ko) | 2007-06-18 | 2015-10-22 | 머크 샤프 앤 도메 비.브이. | 사람 프로그램된 사멸 수용체 ｐｄ-1에 대한 항체 |
| EP2044949A1 (en) | 2007-10-05 | 2009-04-08 | Immutep | Use of recombinant lag-3 or the derivatives thereof for eliciting monocyte immune response |
| AR072999A1 (es) | 2008-08-11 | 2010-10-06 | Medarex Inc | Anticuerpos humanos que se unen al gen 3 de activacion linfocitaria (lag-3) y los usos de estos |
| SG196798A1 (en) | 2008-12-09 | 2014-02-13 | Genentech Inc | Anti-pd-l1 antibodies and their use to enhance t-cell function |
| WO2011014438A1 (en) | 2009-07-31 | 2011-02-03 | N.V. Organon | Fully human antibodies to btla |
| AU2010286361A1 (en) | 2009-08-31 | 2012-03-15 | Amplimmune, Inc. | Methods and compositions for the inhibition of transplant rejection |
| CA2778714C (en) | 2009-11-24 | 2018-02-27 | Medimmune Limited | Targeted binding agents against b7-h1 |
| US8802091B2 (en) | 2010-03-04 | 2014-08-12 | Macrogenics, Inc. | Antibodies reactive with B7-H3 and uses thereof |
| WO2012156309A1 (en) * | 2011-05-13 | 2012-11-22 | Millegen | Antibodies against her3 |
| US8841418B2 (en) | 2011-07-01 | 2014-09-23 | Cellerant Therapeutics, Inc. | Antibodies that specifically bind to TIM3 |
| CA2845536A1 (en) | 2011-08-15 | 2013-02-21 | Amplimmune, Inc. | Anti-b7-h4 antibodies and their uses |
| WO2013067492A1 (en) | 2011-11-03 | 2013-05-10 | The Trustees Of The University Of Pennsylvania | Isolated b7-h4 specific compositions and methods of use thereof |
| FR2984750B1 (fr) * | 2011-12-23 | 2014-01-10 | Lfb Biotechnologies | Nouvelles compositions pharmaceutiques comprenant un anticorps liant le recepteur humain de l'hormone anti-mullerienne de type ii |
| WO2014173886A1 (en) * | 2013-04-22 | 2014-10-30 | Glycotope Gmbh | Anti-cancer treatments with anti-egfr antibodies having a low fucosylation |
| US10509035B2 (en) * | 2015-08-07 | 2019-12-17 | Gamamabs Pharma Sa | Antibodies, antibody drug conjugates and methods of use |
| US9630575B2 (en) | 2015-09-30 | 2017-04-25 | GM Global Technology Operations LLC | Panel assembly with noise attenuation system |
-
2018
- 2018-05-29 MX MX2019014192A patent/MX2019014192A/es unknown
- 2018-05-29 CA CA3064333A patent/CA3064333A1/en active Pending
- 2018-05-29 WO PCT/EP2018/064081 patent/WO2018219956A1/en active Application Filing
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- 2018-05-29 KR KR1020197038406A patent/KR20200031571A/ko not_active Application Discontinuation
-
2022
- 2022-09-26 JP JP2022153137A patent/JP2023073965A/ja active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103119059A (zh) * | 2010-05-12 | 2013-05-22 | Lfb生物技术公司 | 针对人抗苗勒管激素ii型受体的新的突变型人源化12g4抗体及其片段 |
| US20150232563A1 (en) * | 2010-05-12 | 2015-08-20 | Lfb Biotechnologies | Novel mutated humanized 12g4 antibodies and the fragments thereof against the human anti-mullerian hormone receptor type ii |
| CN105849125A (zh) * | 2013-11-07 | 2016-08-10 | 国家医疗保健研究所 | 神经调节蛋白变构抗her3抗体 |
| US20160319033A1 (en) * | 2013-11-07 | 2016-11-03 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Neuregulin Allosteric Anti-HER3 Antibody |
| WO2015159253A1 (fr) * | 2014-04-16 | 2015-10-22 | Gamamabs Pharma | Anticorps humain anti-her4 |
| CN106659774A (zh) * | 2014-05-16 | 2017-05-10 | 贝勒研究院 | 用于治疗自身免疫和炎性病症的方法和组合物 |
Non-Patent Citations (4)
| Title |
|---|
| GREGORY K PENNOCK等: "The Evolving Role of Immune Checkpoint Inhibitors in Cancer Treatment" * |
| IDA HUDE等: "The emerging role of immune checkpoint inhibition in malignant lymphoma" * |
| RINPEI NIWA等: "Enhancement of the antibody-dependent cellular cytotoxicity of low-fucose IgG1 Is independent of FcgammaRIIIa functional poIymorphism" * |
| TOYOHIDE SHINKAWA等: "The absence of fucose but not the presence of galactose or bisecting N-acetylglucosamine of human IgG1 complex-type oligosaccharides shows the critical role of enhancing antibody-dependent cellular cytotoxicity" * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114716558A (zh) * | 2022-04-12 | 2022-07-08 | 广州明征生物科技有限公司 | 一种双特异性抗体及其治疗癌症的应用 |
| CN114716558B (zh) * | 2022-04-12 | 2023-05-05 | 骏蓦(北京)生物科技有限公司 | 一种双特异性抗体及其治疗癌症的应用 |
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| JP2023073965A (ja) | 2023-05-26 |
| WO2018219956A1 (en) | 2018-12-06 |
| CA3064333A1 (en) | 2018-12-06 |
| BR112019025352A2 (pt) | 2020-08-18 |
| RU2019137534A (ru) | 2021-06-30 |
| US20200148777A1 (en) | 2020-05-14 |
| BR112019025352A8 (pt) | 2023-05-02 |
| MX2019014192A (es) | 2021-04-12 |
| JP2020521780A (ja) | 2020-07-27 |
| EP3630826A1 (en) | 2020-04-08 |
| RU2019137534A3 (zh) | 2021-11-01 |
| KR20200031571A (ko) | 2020-03-24 |
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