CN116615458A - 抗cd73抗体的制剂 - Google Patents
抗cd73抗体的制剂 Download PDFInfo
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- CN116615458A CN116615458A CN202180079028.7A CN202180079028A CN116615458A CN 116615458 A CN116615458 A CN 116615458A CN 202180079028 A CN202180079028 A CN 202180079028A CN 116615458 A CN116615458 A CN 116615458A
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- histidine
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Abstract
本公开提供抗CD73抗体的稳定制剂,其包含5‑50mM组氨酸、2%‑20%(w/v)海藻糖和0.015%‑0.05%(w/v)聚山梨酯80(PS80),pH为5.6‑6.4。本公开还提供可以通过干燥含水制剂获得的冻干组合物和治疗疾病的方法。
Description
背景技术
目前正在开发抗CD73抗体用于治疗各种增殖性和炎性疾病。CD73(分化簇73)是用来将AMP转化为腺苷的酶。CD73催化胞外腺苷的形成,有助于免疫抑制的肿瘤环境。CD73在基质细胞和多种类型的肿瘤细胞以及Treg、M2和髓源性抑制细胞(MDSC)中过表达。
抑制CD73可以防止腺苷介导的淋巴细胞抑制,增加CD8+效应细胞的活性,并且减少MDSC和Treg。目前有一些抗CD73抗体正在被开发为潜在的抗癌药物,但尚未有批准用于临床。
通过注射递送一般是抗体或抗原结合片段进行癌症治疗的首选递送途径。然而,生物、化学和物理屏障,如较差的长期储存能力、渗透压、溶解度和稳定性使得通过注射向哺乳动物递送生物活性剂成为问题。因此,需要改进注射抗体制剂的稳定性和可溶性。
发明内容
本公开提供一种组合物,其包含抗CD73抗体、5-50mM组氨酸、2%-20%(w/v)海藻糖和0.015%-0.05%(w/v)聚山梨酯80(PS80),pH为5.6-6.4,其中所述抗体包含重链可变区(VH)和轻链可变区(VL),所述重链可变区(VH)包含CDR1、CDR2和CDR3,所述轻链可变区(VL)包含CDR1、CDR2和CDR3,并且其中VH CDR1、VH CDR2、VH CDR3、VL CDR1、VL CDR2和VLCDR3分别包含SEQ ID NO:1-6的氨基酸序列。
在一些实施方案中,所述组合物包含10-30mM组氨酸、5%-15%(w/v)海藻糖和0.015%-0.035%(w/v)PS80,pH为5.8-6.2。在一些实施方案中,所述组合物包含15-25mM组氨酸、6%-10%(w/v)海藻糖、0.015%-0.025%(w/v)PS80,pH为5.9-6.1。在一些实施方案中,所述组合物包含5-150mg/mL的抗体。
在一些实施方案中,VH包含SEQ ID NO:7的氨基酸序列,VL包含SEQ ID NO:8的氨基酸序列。在一些实施方案中,抗体包含重链和轻链,所述重链包含SEQ ID NO:9的氨基酸序列,所述轻链包含SEQ ID NO:10的氨基酸序列。
在一实施方案中,还提供一种冻干组合物,其通过冷冻干燥本公开的组合物可获得。还提供一种溶液(例如,水),其通过溶解冻干组合物可获得。
还提供使用所述组合物治疗癌症的用途和方法,如膀胱癌、乳腺癌、结肠直肠癌、子宫内膜癌、食道癌、头颈癌、肾癌、白血病、肝癌、肺癌、淋巴瘤、黑素瘤、胰腺癌、前列腺癌和甲状腺癌。
具体实施方式
I.定义
所有数字指代,例如,pH、温度、时间、浓度和分子量,包括范围,都是以0.1或10%的增量(+)或(-)变化的近似值。应当理解的是,尽管并不总是明确指出,所有数字指代前面都有术语“约”。还应当理解的是,尽管并不总是明确指出,本文描述的试剂只是示例性的,其等价物在本领域中是已知的。
“组合物”意指活性剂与另一种化合物或组合物的组合,惰性的(例如,可检测的药剂或标签)或活性的,如佐剂。
“药物组合物”旨在包括活性剂与惰性或活性载剂的组合,使所述组合物适合体外、体内或离体地诊断或治疗使用。
II.抗体制剂
为治疗性抗体开发合适的制剂通常有来自例如蛋白溶解度、稳定性和渗透压的矛盾要求。因此,能否平衡这些要求以产生可接受的制剂是具有挑战性和不可预测的。例如,如实施例2所证实的,当用本公开的抗CD73抗体测试不同缓冲液时,磷酸盐缓冲液看来比其他缓冲液产生更多的抗体片段(参见,例如,表4)。这会导致更明显的纯度降低(表5)。这些数据还表明高(pH 7.0)和低(pH 4.5)pH条件也可以对蛋白的纯度造成影响(另见表6)。
在所有这些测试的缓冲液和条件中,pH为6.0,20nM组氨酸的制剂F5看来能够支持蛋白稳定性。令人惊讶的是,这种缓冲条件还允许蛋白的高溶解度,至少可达80mg/mL和150mg/mL(表7)。
实施例3中测试了许多候选赋形剂,包括蔗糖、海藻糖、山梨醇、甘露醇和精氨酸。令人惊讶的是,在冻融试验后,即使在PS80(聚山梨酯80)存在的情况下,在含有甘露醇(蛋白制剂中最常用的赋形剂之一)的制剂中仍检测到了可见颗粒,PS80(聚山梨酯80)被认为在冻融循环中对蛋白稳定性发挥重要作用(表11-13)。此外,在含有蔗糖的制剂中抗体片段化最严重(表17)。另一种赋形剂精氨酸的使用也导致蛋白纯度相对大(1%)的下降(表18)。而另一种赋形剂山梨醇在10次冻融循环中未能充分支持蛋白稳定性(表23)。
有趣的是,候选赋形剂之一的海藻糖能够在所有这些测试条件下保持蛋白足够稳定。而且,具有海藻糖的制剂保持了抗体的抗原结合效力(表24)。然后,在实施例5中,测试了制剂的热动力学稳定性,发现在测试过程中至少需要0.02% PS80来保持蛋白稳定。因此,通过反复试验,本发明人能够开发出抗CD73抗体的合适制剂,该制剂pH为约6.0,包含组氨酸、海藻糖和PS80。
根据本公开的一个实施方案,提供一种组合物,其包含本公开的抗CD73抗体或抗原结合片段、组氨酸、海藻糖以及聚山梨酯80。在一些实施方案中,所述组合物是水溶液,溶液的pH为5.5-6.5。
在一些实施方案中,组氨酸(例如,组氨酸HCl)的浓度为约5-50mM。在一些实施方案中,组氨酸的浓度为至少约5mM、6mM、7mM、8mM、9mM、10mM、11mM、12mM、13mM、14mM、15mM、16mM、17mM、18mM、19mM、20mM、25mM、30mM、35mM、40mM或45mM。在一些实施方案中,组氨酸的浓度不高于约100mM、90mM、80mM、70mM、60mM、50mM、45mM、40mM、35mM、30mM、29mM、28mM、27mM、26mM、25mM、24mM、23mM、22mM、21mM、20mM、19mM、18mM、17mM、16mM或15mM。在一些实施方案中,组氨酸的浓度为约5-40mM、5-35mM、5-30mM、5-25mM、5-20mM、10-50mM、10-45mM、10-40mM、10-35mM、10-30mM、10-25mM、10-20mM、15-50mM、15-45mM、15-40mM、15-35mM、15-30mM、15-25mM、15-20mM、20-50mM、20-45mM、20-40mM、20-35mM、20-30mM或20-25mM。
在一些实施方案中,海藻糖(例如,海藻糖二水合物)以约2%-20%(w/v)的浓度存在。在一些实施方案中,海藻糖的浓度为至少约2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、15%、17%或18%(w/v)。在一些实施方案中,海藻糖的浓度不高于约20%、19%、18%、17%、16%、15%、14%、13%、12%、11%、10%、9%、8%、7%、6%、5%、4%或3%(w/v)。在一些实施方案中,海藻糖的浓度为约2%-20%、2%-19%、2%-18%、2%-17%、2%-16%、2%-15%、2%-14%、2%-13%、2%-12%、2%-11%、2%-10%、2%-9%、2%-8%、3%-20%、3%-19%、3%-18%、3%-17%、3%-16%、3%-15%、3%-14%、3%-13%、3%-13%、3%-11%、3%-10%、3%-9%、3%-8%、4%-20%、4%-19%、4%-18%、4%-17%、4%-16%、4%-15%、4%-14%、4%-13%、4%-14%、4%-11%、4%-10%、4%-9%、4%-8%、5%-20%、5%-19%、5%-18%、5%-17%、5%-16%、5%-15%、5%-14%、5%-13%、5%-15%、5%-11%、5%-10%、5%-9%、5%-8%、6%-20%、6%-19%、6%-18%、6%-17%、6%-16%、6%-16%、6%-14%、6%-13%、6%-16%、6%-11%、6%-10%、6%-9%、6%-8%、7%-20%、7%-19%、7%-18%、7%-17%、7%-17%、7%-17%、7%-14%、7%-13%、7%-17%、7%-11%、7%-10%、7%-9%、7%-8%、8%-20%、8%-19%、8%-18%、8%-18%、8%-18%、8%-18%、8%-14%、8%-13%、8%-18%、8%-11%、8%-10%、8%-9%、9%-20%、9%-19%、9%-18%、9%-19%、9%-19%、9%-19%、9%-14%、9%-13%、9%-19%、9%-11%、9%-10%、10%-20%、10%-19%、10%-18%、10%-110%、10%-110%、10%-110%、10%-14%、10%-13%、10%-110%或10%-11%(w/v)。
在一些实施方案中,聚山梨酯80(PS80)以约0.015%-0.05%(w/v)的浓度存在。在一些实施方案中,PS80以至少约0.015%、0.016%、0.017%、0.018%、0.019%、0.02%、0.021%、0.022%、0.023%、0.024%、0.025%、0.026%、0.027%、0.028%、0.029%或0.03%(w/v)的浓度存在。在一些实施方案中,PS80以不高于0.05%、0.049%、0.048%、0.047%、0.046%、0.045%、0.044%、0.043%、0.042%、0.041%、0.04%、0.039%、0.038%、0.037%、0.036%、0.035%、0.034%、0.033%、0.032%、0.031%、0.03%、0.029%、0.028%、0.027%、0.026%、0.025%、0.024%、0.023%、0.022%、0.021%或0.02%(w/v)的浓度存在。
在一些实施方案中,所述组合物的pH为5.6-6.4。在一些实施方案中,pH不低于5.6、5.7、5.8、5.85、5.9、5.95、6、6.05、6.1、6.15或6.2。在一些实施方案中,pH不高于6.4、6.3、6.2、6.15、6.1、6.05、6、5.95、5.9、5.85或5.8。在一些实施方案中,pH为约5.7-6.3、5.8-6.2、5.85-6.15、5.9-6.1、5.95-6.05,或者在约5.9、5.95、6、6.05或6.1。
在一些实施方案中,所述组合物进一步包含一种或多种膨松剂(bulking agent)。如本文所用,术语“膨松剂”是指为冻干制剂提供蓬松的成分。膨松剂的实例包括但不限于甘露醇、海藻糖、乳糖、蔗糖、聚乙烯吡咯烷酮、蔗糖、葡萄糖、甘氨酸、环糊精、葡聚糖、固体PEG以及它们的衍生物和混合物。在一实施方案中,本公开的制剂任选地包含膨松剂。
在一些实施方案中,所述组合物进一步包含一种或多种张度剂(tonicityagent)。如本文所用的术语“张度剂”表示用于调节制剂张度的药学可接受的药剂。等渗性一般与相对于溶液的渗透压有关,通常是相对于人血清的渗透压。制剂可以是低渗、等渗或高渗的。在一方面,所述制剂是等渗的。等渗制剂是液体或从固体形式重组的液体,例如从冻干形式,表示与比较的一些其他溶液(如生理盐溶液和血清)具有相同张度的溶液。合适的等渗剂包括但不限于氯化钠、氯化钾、甘油和如本文定义的氨基酸、糖的任何组分,以及它们的组合。
在一些实施方案中,所述组合物进一步包含一种或多种表面活性剂。如本文所用,术语“表面活性剂”是指具有两亲性结构的药学可接受的有机物质;即,它是由具有相反溶解性倾向的基团构成的,通常是油溶性碳氢链和水溶性离子基团。根据表面活性部分的电荷,表面活性剂可以分为阴离子、阳离子和非离子表面活性剂。表面活性剂常作为湿润剂、乳化剂、增溶剂和分散剂用于生物材料的各种药物组合物和制品。在本文所述药物制剂的一些实施方案中,表面活性剂的量描述为以重量/体积百分比(w/v%)表示的百分比。合适的药学可接受的表面活性剂包括但不限于聚氧乙烯山梨醇脂肪酸酯(Tween)、聚氧乙烯烷基醚(Brij)、烷基苯基聚氧乙烯醚(Triton-X)、聚氧乙烯-聚氧丙烯共聚物(Poloxamer,Pluronic)或十二烷基硫酸钠(SDS)。聚氧乙烯山梨醇-脂肪酸酯包括聚山梨酯20,(以商标Tween 20TM出售)和聚山梨酯80(以商标Tween 80TM出售)。聚乙烯-聚丙烯共聚物包括以名称F68或Poloxamer 188TM出售的那些。聚氧乙烯烷基醚包括以商标BrijTM出售的那些。烷基酚聚氧乙烯醚包括以商标Triton-X出售的那些。
在一些实施方案中,所述组合物进一步包含一种或多种冻干保护剂。“冻干保护剂”是指在冻干过程(在高真空中快速冷冻和干燥的过程)中稳定蛋白的药学可接受的物质。冻干保护剂的实例包括但不限于蔗糖、海藻糖或甘露醇。
在一些实施方案中,所述组合物进一步包含一种或多种抗氧化剂。“抗氧化剂”是指能够减缓或防止其他分子氧化的分子。氧化是将电子从一种物质转移至氧化剂的化学反应。氧化反应可以产生自由基,自由基启动链式反应,破坏蛋白治疗剂的稳定性,最终影响产品活性。抗氧化剂通过去除自由基中间体来终止这些链式反应,并且通过自身氧化来抑制其他氧化反应。因此,抗氧化剂通常是还原剂、螯合剂和氧清除剂,如柠檬酸盐、EDTA、DPTA、硫醇、抗坏血酸或多酚。抗氧化剂的非限制性实例包括抗坏血酸(AA,E300)、硫代硫酸盐、甲硫氨酸、生育酚(E306)、没食子酸丙酯(PG,E310)、叔丁基对苯二酚(TBHQ)、丁羟茴醚(BHA,E320)和丁羟甲苯(BHT,E321)。
在一些实施方案中,所述组合物进一步包含一种或多种防腐剂。“防腐剂”是一种天然或合成化学物质,添加到食品、药物、油漆、生物样品、木材等产品中,以防止因微生物生长或不期望的化学变化而分解。防腐添加剂可以单独使用或与其他防腐方法一起使用。防腐剂可以是抗微生物防腐剂,其抑制细菌和真菌的生长,或者抗氧化剂如脱氧剂,其抑制组分的氧化。常见的抗微生物防腐剂包括苯扎氯铵、苯甲酸、氯己定(cholorohexidine)、甘油、酚、山梨酸钾、硫柳汞、亚硫酸盐(二氧化硫、亚硫酸氢钠、亚硫酸氢钾等)和EDTA二钠。其他防腐剂包括常用于肠胃外蛋白的那些防腐剂,如苯甲醇、酚、间甲酚、氯代丁醇或对羟基苯甲酸甲酯。
如本文公开的,抗CD73抗体具有重链可变(VH)区和轻链可变(VL)区。VH包含三个互补决定区(CDR),CDR1、CDR2和CDR3,VL也包含三个CDR,CDR1、CDR2和CDR3。VH CDR1、CDR2和CDR3以及VL CDR1、CDR2和CDR3分别包含氨基酸序列SEQ ID NO:1-6。示例的VH和VL序列分别包含SEQ ID NO:7和8。所述抗体还可以包含重链和轻链恒定区。示例的重链和轻链序列分别包含SEQ ID NO:9和10。
在一些实施方案中,所述组合物包含5-150mg/mL本公开的抗CD73抗体或抗原结合片段、5-50mM组氨酸、2%-20%(w/v)海藻糖、0.015%-0.05%(w/v)PS80,pH为5.6-6.4。
在一些实施方案中,所述组合物包含10-120mg/mL本公开的抗CD73抗体或抗原结合片段、10-30mM组氨酸、5%-15%(w/v)海藻糖、0.015%-0.035%(w/v)PS80,pH为5.8-6.2。
在一些实施方案中,所述组合物包含10-120mg/mL本公开的抗CD73抗体或抗原结合片段、15-25mM组氨酸、6%-10%(w/v)海藻糖、0.015%-0.025%(w/v)PS80,pH为5.9-6.1。
在一些实施方案中,还提供一种冻干组合物,其可以通过冷冻干燥如本文公开的水溶液来制备。在一些实施方案中,还提供一种溶液,其可以通过将冻干组合物溶解在诸如水的溶剂中来制备。
III.使用制剂的方法
如本文所述,本公开的组合物可以用于某些治疗和诊断方法。本公开进一步涉及基于抗体的疗法,其包括向患者如动物、哺乳动物和人给药本公开的组合物,用于治疗本文所述的一种或多种病症或疾病状况。
本公开的组合物还可以用于治疗或抑制癌症。如上所述,CD73可以在肿瘤细胞中过表达。肿瘤衍生的CD73可以作为胞外酶产生细胞外腺苷,通过腺苷受体信号传导限制抗肿瘤T-细胞免疫来促进肿瘤生长。小鼠肿瘤模型中用靶向CD73的小分子抑制剂或单克隆抗体的结果表明,靶向CD73疗法是有效控制肿瘤生长的重要替代和现实方法。特别地,它通过增强适应性免疫应答机制来帮助基于T-细胞的疗法,这可能增加肿瘤浸润T淋巴细胞的功能,并且导致癌症患者的存活率提高。
因此,在一些实施方案中,提供在有此需要的患者中治疗癌症的方法。在一实施方案中,所述方法需要向患者给药有效量的本公开的组合物。在一些实施方案中,患者体内至少一种癌细胞(例如,基质细胞)过表达CD73。
癌症的非限制性实例包括膀胱癌、乳腺癌、结肠直肠癌、子宫内膜癌、食管癌、头颈癌、肾癌、白血病、肝癌、肺癌、淋巴瘤、黑素瘤、胰腺癌、前列腺癌和甲状腺癌。
可以用本公开的抗体或变体或者其衍生物治疗、预防、诊断和/或预后的与细胞存活率提高相关的其他疾病或疾病状况包括但不限于恶性肿瘤和相关病症的进展和/或转移,如白血病(包括急性白血病(例如,急性淋巴细胞白血病、急性髓细胞白血病(包括髓母细胞性、早幼粒细胞性(promyelocytic)、粒单核细胞性、单核细胞性和红白血病))和慢性白血病(例如,慢性髓细胞(粒细胞)白血病和慢性淋巴细胞白血病))、真性红细胞增多症、淋巴瘤(例如,霍奇金病和非霍奇金病)、多发性骨髓瘤、瓦尔登斯特伦巨球蛋白血症(Waldenstrom's macroglobulinemia)、重链病和实体瘤,包括但不限于肉瘤和癌,如纤维肉瘤、粘液肉瘤、脂肉瘤、软骨肉瘤、骨原性肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴管内皮肉瘤、滑膜瘤、间皮瘤、尤因瘤(Ewing's tumor)、平滑肌肉瘤、横纹肌肉瘤、结肠癌、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、胚胎癌、维耳姆斯瘤(Wilm's tumor)、宫颈癌、睾丸肿瘤、肺癌、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、室管膜细胞瘤、松果体瘤、血管母细胞瘤、听神经瘤、少突胶质细胞瘤、脑膜瘤、黑素瘤、神经母细胞瘤和视网膜母细胞瘤。
任何特定患者的具体剂量和治疗方案将取决于各种因素,包括使用的特定抗体、变体或其衍生物,患者的年龄、体重、一般健康状况、性别和饮食,以及给药时间、排泄率、药物组合和所治疗的特定疾病的严重程度。医疗护理人员对这类因素的判断在本领域的普通技术内。量还取决于待治疗的个体患者、给药途径、制剂类型、所用化合物的特征、疾病的严重程度和期望的效果。使用的量可以通过本领域公知的药理学和药代动力学原理来确定。
组合物的给药方法包括但不限于皮内、肌肉内、腹腔内、静脉内和皮下途径。组合物可以通过任何方便的途径给药,例如通过输注或推注,通过上皮或粘膜吸收(例如,口腔粘膜、直肠和肠粘膜等),并且可以与其他生物活性剂一起给药。因此,含有本公开的抗原结合多肽的药物组合物可以通过肠胃外、脑池内(intracistemally)、阴道内、腹腔内、局部(如通过粉末、软膏、滴剂或透皮贴剂)、含服或者作为口服或鼻喷雾的方式给药。
如本文所用的术语“肠胃外”是指给药方式,包括静脉内、肌肉内、腹腔内、胸骨内、皮下和关节内注射和输注。
给药可以是全身性的或局部的。此外,通过任何合适的途径将本公开的抗体引入中枢神经系统可能是可取的,包括脑室内和鞘内注射;脑室内注射可以通过脑室内导管来促进,例如,连接至储液器,如Ommaya储液器。也可以采用肺部给药,例如,通过使用吸入器或雾化器,以及具有雾化剂的制剂。
在治疗、抑制和预防炎性、免疫或恶性疾病、病症或疾病状况中有效的本公开的抗体的量可以通过标准临床技术确定。此外,体外测定可以任选地用来帮助鉴定最佳剂量范围。制剂中采用的精确剂量还取决于给药途径以及疾病、病症或疾病状况的严重性,并且应当根据执业医生的判断和每个患者的情况决定。有效剂量可以从源自体外或动物模型测试系统的剂量-反应曲线推断。
作为一般建议,向患者给药的本公开的抗原结合多肽的剂量通常是0.1mg/kg-100mg/kg患者体重,0.1mg/kg-20mg/kg患者体重,或1mg/kg-10mg/kg患者体重。一般来说,由于对外源多肽的免疫应答,人抗体在人体内的半衰期比来自其他物种的抗体半衰期长。因此,较低剂量的人抗体和较少的给药次数通常是可能的。此外,可以通过修饰如脂化增强抗体的摄取和组织渗透(例如,进入大脑),从而减少本公开的抗体的剂量和给药频率。
治疗传染性或恶性疾病、疾病状况或病症的方法,包括给药本公开的组合物,通常在体外测试,然后在可接受的动物模型中进行体内测试,以达到期望的治疗或预防活性,然后再用于人。合适的动物模型,包括转基因动物,是本领域普通技术人员公知的。例如,证明本文所述抗原结合多肽的治疗效用的体外测定包括抗原结合多肽对细胞系或患者组织样品的影响。抗原结合多肽对细胞系和/或组织样品的影响可以利用本领域技术人员已知的技术来确定,如本文其他地方公开的测定。根据本公开,可以用于确定是否需要给药特定抗原结合多肽的体外测定包括体外细胞培养测定,其中使患者组织样品在培养中生长,暴露于化合物或以其他方式给药化合物,观察这种化合物对组织样品的影响。
在另一实施方案中,本公开的组合物与抗肿瘤剂、抗病毒剂、抗细菌或抗生素剂或者抗真菌剂联合给药。本领域已知的这些药剂中的任何一种都可以在本公开的组合物中给药。
在另一实施方案中,本公开的组合物与化疗剂联合给药。可以与本公开的组合物一起给药的化疗剂包括但不限于抗生素衍生物(例如,多柔比星、博来霉素、柔红霉素和放线菌素D);抗雌激素(例如,他莫昔芬);抗代谢药(例如,氟尿嘧啶、5-FU、甲氨蝶呤、氟尿苷、干扰素α-2b、谷氨酸、普卡霉素、巯嘌呤和6-硫鸟嘌呤);细胞毒性剂(例如,卡莫司汀、BCNU、洛莫司汀、CCNU、阿糖胞苷、环磷酰胺、雌莫司汀、羟基脲、丙卡巴肼、丝裂霉素、白消安、顺铂和硫酸长春新碱);激素(例如,甲羟孕酮、雌莫司汀磷酸钠、炔雌醇、雌二醇、醋酸甲地孕酮、甲睾酮、己烯雌酚二磷酸酯、氯烯雌醚和睾内酯);氮芥衍生物(例如,美法仑(mephalen)、苯丁酸氮芥、二氯甲基二乙胺(mechlorethamine)(氮芥)和塞替派);类固醇及组合(例如,倍他米松磷酸钠);其他(例如,达卡巴嗪(dicarbazine)、天冬酰胺酶、米托坦、硫酸长春新碱、硫酸长春碱和依托泊苷)。
在另一实施方案中,本公开的组合物与细胞因子联合给药。可以与本公开的组合物一起给药的细胞因子包括但不限于IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-10、IL-12、IL-13、IL-15、抗CD40、CD40L和TNF-α。
在其他实施方案中,本公开的组合物与其他治疗或预防方案联合给药,例如,放射疗法。
实施例
参考以下实施例进一步理解本公开,这些实施例完全是对本公开的示例性说明。本公开的范围不受示例性实施方案的限制,这些实施方案仅作为本公开的单一方面的说明。任何在功能上等同的方法都在本公开的范围内。除了本文所述的那些修改,从上文的描述和附图,本公开的各种修改对于本领域技术人员是显而易见的。这类修改在所附权利要求的范围内。
实施例1.抗CD73抗体IM005的开发
开发了一种人源化抗CD73抗体(IM005),其在结合和抑制人CD73蛋白酶促活性方面表现出强活性。此外,如WO2018137598所证明的,该抗体有效诱导细胞表面CD73的内化。该抗体还可以完全逆转AMP以及肿瘤细胞介导的CD4+和CD8+T细胞应答的抑制,并且有效抑制肿瘤来源的CD73活性,从而抑制肿瘤生长。
结合分析显示IM005与CD73蛋白的C-末端结构域结合,不同于已知的与N-末端结构域结合的抗CD-73抗体。与已知抗体相比,IM005独特的结合性质有助于其优异的CD73抑制特性。例如,MEDI-9447(奥来鲁单抗(Oleclumab))是一种人抗CD73单克隆抗体,目前正在进行临床开发,用于治疗胰腺癌和结肠直肠癌以及其他癌症。MEDI-9447对CD73的抑制需要MEDI-9447全抗体上的两个结合位点都与CD73结合,而Hu101-28的单价结合是足够的。因此,MEDI-9447不能抑制可溶性CD73或者表达相对低水平CD73的细胞上的CD73。相比之下,IM005可以在表面表达不同水平CD73的细胞和可溶性CD73上实现CD73活性的完全抑制。
IM005具有以下VH/VL和CDR序列。
表1.抗CD73 CDR
为了制备IM005抗体,合成产生VH和VK基因,然后分别克隆至含有人γ1和人κ恒定结构域的载体中。
实施例2.缓冲液和pH选择
这个实施例是为了筛选出最能稳定蛋白的最佳pH/缓冲液条件,并且对蛋白溶解度进行研究,以支持IM005的后续制剂开发。
方法
蛋白浓度
蛋白浓度由Thermo UV分光光度计确定。在pH和缓冲液评价研究中使用的消光系数为1.660AU*mL*mg-1*cm-1,这应用于所有制剂开发研究。所有测量均重复两次,每次2.5μL样品,取平均值。
SEC-HPLC
使用Agilent HPLC系统,用TSKGel G3000SWXL柱(300×7.8mm,5μm)进行大小排阻色谱。流动相为50mM PB,300mM NaCl,pH 6.8±0.2,流速设置为1.0mL/min。每个样品进样100μg蛋白,检测器波长设置为280nm。
cIEF
在配备有FC包被的cIEF盒的ProteinSimple iCE分析仪上进行cIEF。cIEF方法用来分析IM005样品的等电点(pI)和电荷变体。上样混合物含有20μL浓度为1.0mg/mL的样品,35μL 1%甲基纤维素,1μL Pharmalyte 3-10和3μL Pharmalyte 8-10.5载体两性电解质,0.5μL低pI标志物6.61或6.14,0.5μL高pI标志物9.46或9.77,25μL 8mol/L尿素,以及15μL纯水以使最终上样体积为100μL。自动进样器的温度为5℃,样品进样时间为90秒。聚焦分两个阶段进行:在1500V下预聚焦1min,然后在3000V下聚焦8min。用全柱成像检测技术在280nm处检测信号。使用Chromperfect分析软件分析数据。
浊度(UV350)
通过分光光度计(Spectra Max)进行浊度测定。将150μL样品添加至96-孔板的孔中,还在相应的孔中添加150μL各自的缓冲液作为参考。然后在350nm处测试缓冲液和样品的吸收。通过减去相应的缓冲液获得蛋白的UV350值。
Caliper-SDS(还原和非还原)
通过Caliper-基于微芯片的测定进行Caliper-SDS。非还原:按20:1:0.7体积比混合样品缓冲液(来自试剂盒)、10% SDS和100mM N-乙基马来酰亚胺来制备变性溶液。将2μL样品和7μL变性溶液混合均匀,在70℃下孵育10min,然后离心下来。将H2O(35μL)添加至样品中,然后将42μL混合物转移至96-孔板中,在4000rpm下离心20min以去除气泡。将板装到仪器的板架上后,将样品吸出、染色、分离并在Microchip中检测,Microchip中装有脱色凝胶、荧光染料和标志物。用LabChip GX Reviewer分析数据。
还原:按20:1:0.7体积比混合样品缓冲液(来自试剂盒)、10% SDS和1M二硫苏糖醇来制备变性溶液,同时用MQ H2O将参考标准品或样品稀释至1mg/mL。将2微升样品和7μL变性溶液混合均匀,在70℃下孵育10min,然后离心下来。
将H2O(35μL)添加至样品中,然后将42μL混合物转移至96-孔板中,在4000rpm下离心20min以去除气泡。将板装到仪器的板架上后,将样品吸出、染色、分离并在Microchip中检测,Microchip中装有脱色凝胶、荧光染料和标志物。用LabChip GX Reviewer分析数据。
DSC
用GE DSC系统进行DSC分析。用参考缓冲液将样品稀释至1mg/mL。将400μL各自的参考缓冲液添加至96-孔板的奇数孔中,将400μL样品添加至同一板的偶数孔中。实验参数设置为扫描温度从10-110℃以200℃/h的速度递增。用MicroCal VP-Capillary DSC软件进行热谱图分析。
粘度
使用BROOKFIELD粘度计评价粘度,锥型为CPA-40Z。测试温度为25℃,需要0.5mL样品。
结果
首先将IM005(20.4mg/mL)换液至9种不同缓冲液中,如表1所示。将蛋白浓度调整至10mg/mL。
表1.缓冲液条件
每个制剂有4个2mL玻璃小瓶,装入1mL过滤的产品。灌装后立即将小瓶加塞并压盖。除压盖外,所有程序均在生物安全罩中进行。将小瓶放入40℃培养箱中,在不同时间点将小瓶从40℃条件下取出进行分析。
DSC
采用DSC检测每个制剂的热力学稳定性。蛋白的热诱导的解折叠的熔化温度(Tm)据认为是其构象稳定性的指标。
如表2所示,转变的起始温度的范围是46.18℃(F1:乙酸盐pH4.5)至57.25℃(F7:PB pH6.0)。Tm1的范围是54.53℃(F1乙酸盐pH4.5)至76.57℃(F3:乙酸盐pH5.5),Tm2的范围是77.27℃(F5:组氨酸pH6.0)至86.54℃(F9:PB pH7.0)(除了F3:乙酸盐pH5.5,F6:组氨酸pH6.5和F7:PB pH6.0)。在9种制剂的图谱中观察到不同的转变温度。
表2.pH/缓冲液筛选研究的DSC结果
pH/缓冲液 | TM起始(℃) | Tm1(℃) | Tm2(℃) |
F1:20mM乙酸盐,pH4.5 | 46.18 | 54.53 | 78.43 |
F2:20mM乙酸盐,pH5.0 | 49.15 | 60.27 | 78.05 |
F3:20mM乙酸盐,pH4.5 | 56.53 | 76.57 | NA |
F4:20mM组氨酸,pH5.5 | 49.58 | 59.61 | 77.96 |
F5:20mM组氨酸,pH4.5 | 52.80 | 63.36 | 77.27 |
F6:20mM组氨酸,pH4.5 | 56.33 | 75.78 | NA |
F7:20mM PB,pH6.0 | 57.25 | 74.47 | NA |
F8:20mM PB,pH6.5 | 56.80 | 72.37 | 86.26 |
F9:20mM PB,pH7.0 | 57.05 | 69.84 | 86.54 |
外观
外观评价结果如表3所示。在40℃条件下,2周后在F6(组氨酸pH6.5)、F7(PBpH6.0)、F8(PB pH6.5)和F9(PB pH 7.0)中观察到可见颗粒。4周后在F3(乙酸盐pH5.5)、F6(组氨酸pH6.5)、F7(PB pH6.0)、F8(PB pH6.5)和F9(PB pH7.0)中观察到可见颗粒。在40℃下孵育后,在F1(乙酸盐pH4.5)、F2(乙酸盐pH5.0)、F4(组氨酸pH5.5)和F5(组氨酸pH6.0)中未观察到可见颗粒。
pH
在所有采样点测量所有制剂的pH值。结果显示,在40℃孵育后pH值没有明显的变化。
蛋白浓度
在所有采样点测量所有制剂的蛋白浓度,使用nanodrop2000(UV280方法)。结果显示,在40℃条件下孵育后,在F9(PB pH7.0)中观察到蛋白浓度下降约10%,F1-F8的蛋白浓度没有明显的变化。
表3.pH/缓冲液筛选的外观、pH、UV280结果:40℃
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SEC-HPLC
40℃下的SEC结果如表4所示。在所有制剂中都观察到聚集,在一些缓冲液中观察到片段。来自所有9种制剂的%主峰随热处理时间的增加而减少。在F1(乙酸盐pH4.5)、F7(PB pH6.0)、F8(PB pH6.5)和F9(PB pH7.0)样品中观察到更明显的减少。这些结果与%LMW和%HMW物质一致。
基于SEC-HPLC结果,可以选择F2至F6作为候选制剂。
表4.pH/缓冲液筛选的SEC-HPLC结果:40℃
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Caliper-SDS(还原和非还原)
Caliper-SDS是一种基于CE的高通量分析,其能够以高灵敏度检测单克隆抗体的片段化。在Caliper-SDS实验中,在表5中观察到F1(乙酸盐pH4.5)、F7(PB pH6.0)、F8(PBpH6.5)和F9(PB pH7.0)非还原样品的%纯度更明显的下降。此外,%(LC+HC)下降在F1、F7、F8和F9样品中更快速。这些结果与SEC结果一致。
表5.pH/缓冲液筛选的Caliper-SDS(还原和非还原)结果(40℃)
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Caliper-SDS结果显示与其他测定结果相似的趋势,在低pH(pH4.5)和高pH(pH7.0)条件下纯度下降更多。
cIEF
在40℃下孵育4周后,获得cIEF数据并在表6中示出。结果显示与SEC-HPLC相似的趋势,%主峰降低在F1(乙酸盐pH4.5)、F7(PB pH6.0)、F8(PB pH6.5)和F9(PB pH7.0)样品中更明显。在每种缓冲液类型中,%碱性峰随pH升高而降低,但%酸性峰随pH升高而升高。
表6.pH/缓冲液筛选的cIEF结果:40℃
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这些结果表明在F9(PB pH7.0)中观察到最多的电荷变体变化,在F5(组氨酸pH6.0)中观察到最少的电荷变体变化。
总的来说,在pH/缓冲液筛选研究中,在40℃下孵育后,在F3(乙酸盐pH5.5)、F6(组氨酸pH6.5)、F7(PB pH6.0)、F8(PB pH6.5)和F9(PB pH7.0)中观察到可见颗粒。在40℃下,F1(乙酸盐,pH4.5)和F7、F8、F9(磷酸盐缓冲液)不仅在Caliper-SDS(还原和非还原)和SEC结果中表现出最显著的纯度下降,而且在cIEF中也表现出最多的电荷变体变化。在40℃下孵育后,观察到F9中浓度下降10%。
因此,这些结果表明IM005在磷酸盐缓冲液中稳定性较差,当缓冲液pH过低时该蛋白可能不稳定。对于F2、F4和F5,在40℃下孵育4周后,在Caliper-SDS还原结果中未观察到明显的变化,但是观察到Caliper-SDS非还原的%纯度下降。在Caliper-SDS非还原和SEC纯度结果中,F5的下降幅度均小于其他。因此选择F5(20mM组氨酸pH 6.0缓冲液)进行进一步开发。
实施例3.溶解度研究
这个实施例评估了IM005在所选缓冲系统中的溶解度。
将IM005换液至20mM组氨酸,pH 6.0缓冲液中,并且将浓度调整至80mg/mL和150mg/mL。将样品用0.22μm PVDF膜过滤器进行无菌过滤。对于每个浓度,在生物安全罩中用3个2-mL玻璃小瓶装1mL的DS。灌装后立即将小瓶加塞并压盖。
将总计6个小瓶放置在不同培养箱(2-8℃和25℃)中,每个条件取出1个小瓶用于分析。
在所有采样点测量外观、浓度(UV280)和浊度(UV350)(表7中的结果)。结果显示,在2~8℃和25℃下孵育48小时后,没有明显的变化。
表7.溶解度研究的外观、浓度和浊度结果:2-8℃和25℃
在20mM组氨酸,pH6.0缓冲液中,将IM005成功浓缩至目标浓度80mg/mL和150mg/mL。短期稳定性结果显示,在2~8℃和25℃下储存48小时后未观察到明显的变化。这表明IM005在20mM组氨酸,pH 6.0缓冲液中以80mg/mL或150mg/mL短期储存后是稳定的。
在压力条件(40℃)下,pH/缓冲液筛选研究考察了9种pH/缓冲液类型,结果显示IM005的稳定性与pH和缓冲液类型密切相关。在低pH、高pH条件和磷酸盐缓冲液下观察到较差的蛋白稳定性。所选缓冲液是20mM组氨酸,pH6.0缓冲液(F5)。
在溶解度研究中,在2~8℃和25℃下48小时没有明显变化,表明IM005在80mg/mL和150mg/mL浓度下短期内是稳定的。基于来自pH/缓冲液筛选研究和溶解度研究的结果,将20mM组氨酸、pH6.0缓冲液用于该产品的后续制剂开发研究。
实施例4.赋形剂的筛选
这个实施例考察了可以在20mM组氨酸,pH 6.0缓冲液系统中稳定IM005蛋白的候选赋形剂。
将IM005抗体储备溶液换液至20mM组氨酸pH 6.0缓冲液系统中。然后,将表8中列出的赋形剂分别添加至该溶液中。将蛋白浓度调整至50mg/mL。
表8.候选制剂配方
所有制剂样品最终用0.22μm PVDF膜过滤器过滤,装入2mL玻璃小瓶中(1mL/小瓶),在生物安全罩中塞好塞子并密封。除T0样品外,将小瓶放置在25℃、40℃培养箱和-40℃冰箱中,从这些条件取出小瓶进行分析。
Advanced 2020多样品渗透压力计用于6种制剂的渗透压测量。结果如表9所示。
表9.赋形剂筛选研究的渗透压结果:T0
编号 | 制剂组成 | 渗透压(mOsmol/kg) |
Fl | 20mM组氨酸,8%蔗糖,0.02%PS80,pH 6.0 | 334 |
F2 | 20mM组氨酸,8%海藻糖二水合物,0.02%PS80,pH 6.0 | 327 |
F3 | 20mM组氨酸,4%山梨醇,0.02%PS80,pH 6.0 | 327 |
F4 | 20mM组氨酸,4%甘露醇,0.02%PS80,pH 6.0 | 303 |
F5 | 20mM组氨酸,140mM精氨酸HCl,0:02%PS80,pH 6.0 | 344 |
F6 | 20mM组氨酸,8%蔗糖,pH 6.0 | 332 |
DSC
采用DSC检测每个制剂的热力学稳定性。诱导蛋白开始解折叠的温度熔化温度(Tm)据认为是其构象稳定性的指标。
如表10所示,转变的起始温度的范围是50.9℃(F5:精氨酸HCl,pH 6.0)至58.6℃(F2:海藻糖,pH 6.0)。Tm1的范围是59.3℃(F5:精氨酸HCl,pH 6.0)至65.2℃(Fl:蔗糖,pH6.0),Tm2的范围是76.7℃(F5:精氨酸HCl,pH 6.0)至78.5℃(Fl:蔗糖,pH 6.0)。6种制剂中Tm起始、Tm1和Tm2的最大差异值分别为7.7℃、5.8℃和1.9℃。
表10.赋形剂筛选研究的DSC结果
外观
如表11-13所示,在40℃下孵育2周和4周后,除F6(不含PS80)外,在所有制剂中均未观察到可见颗粒。而在25℃下孵育4周后,在所有6种制剂中均未观察到可见颗粒。在冻融(-40℃至RT)条件下,在10个冻融循环后,在F4(甘露醇,pH 6.0)中观察到可见颗粒,但是在其他5种制剂中没有。
pH
如表11-13所示在所有采样点测量6种制剂的pH值。结果显示在25℃、40℃下孵育4周或反复冻融5个循环/10个循环后,pH值没有明显的变化。
蛋白浓度(A280)
如表11-13所示在所有采样点测量6种制剂的蛋白浓度,使用nanodrop2000,一种UV280方法。如结果所示,在25℃、40℃下孵育4周或反复冻融5个循环/10个循环后,蛋白浓度没有明显的变化。
表11.赋形剂筛选研究的外观、pH、UV280结果:40℃
表12.赋形剂筛选研究的外观、pH、UV280结果:25℃
表13.赋形剂筛选研究的外观、pH、UV280结果:冻融
SEC-HPLC
40℃下的SEC-HPLC结果如表14所示。从F1到F6,%主峰分别下降3.3%、3.2%、3.4%、2.8%、2.7%和2.2%。%HMW分别上升2.3%、2.2%、2.5%、1.8%、1.7%和1.3%。同时,%LMW分别上升1.0%、0.9%、0.9%、1.0%、1.0%和1.0%。
表14.赋形剂筛选研究的SEC-HPLC结果:40℃
25℃下的SEC-HPLC结果如表15所示。这些结果表明,在25℃下孵育4周后,%主峰没有显著下降。
表15.赋形剂筛选研究的SEC-HPLC结果:25℃
冻融(-40℃至RT)条件下的SEC-HPLC如表16所示,显示在10个循环的冻融后这些制剂没有显著变化,除了F4(甘露醇,pH6.0),其%主峰下降4.4%,而%HMW上升4.4%。
表16.赋形剂筛选研究的SEC-HPLC结果:冻融
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Caliper-SDS(nr)
Caliper-SDS是一种基于CE的高通量分析方法,用于以高灵敏度检测单克隆抗体的片段化。40℃下的Caliper-SDS(nr)结果如表17所示。在所有6种制剂中均观察到%纯度降低。从F1到F6,%纯度分别降低5.8%、3.7%、4.4%、4.9%、4.8%和4.6%。其中,F2(海藻糖二水合物,pH 6.0)表现出最少的%纯度下降。
表17.赋形剂筛选研究的Caliper-SDS(nr)结果:40℃
25℃下的Caliper-SDS(nr)结果如表18所示。结果表明,除了F5(精氨酸HCl,pH6.0)的%纯度下降1%外,这些制剂在25℃下孵育4周后没有显著变化。
表18.赋形剂筛选研究的Caliper-SDS(nr)结果:25℃
冻融(-40℃至RT)条件下的Caliper-SDS(nr)结果如表19所示。结果表明,在10个循环的冻融后,所有6种制剂的%纯度均没有显著变化。
表19.赋形剂筛选研究的Caliper-SDS(nr)结果:冻融
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cIEF
40℃下的cIEF结果如表20所示。在所有6种制剂中均观察到酸性峰的增加和主峰的减少。从F1到F6,%主峰分别下降23.2%、22.2%、19.4%、21.6%、16.0%和19.8%。%酸性峰分别增加24.8%、21.6%、18.6%、21.0%、18.0%和18.0%。值得注意的是,%碱性峰没有明显变化。
表20.赋形剂筛选研究的cIEF结果:40℃
在25℃下孵育4周后,cIEF结果如表21所示。6种制剂的%酸性峰随着%主峰的减少而增加。从F1至F6,%主峰分别下降5.8%、5.4%、7.5%、5.4%、5.2%和4.3%;而%酸性峰分别增加6.8%、4.2%、7.3%、4.5%、5.8%和2.9%。
表21.赋形剂筛选研究的cIEF结果:25℃
表22示出冻融实验的cIEF结果。结果表明,在10个循环的冻融后,6种制剂的电荷没有显著变化。
表22.赋形剂筛选研究的cIEF结果:冻融
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MFI
如表23所示,使用MFI 5200流式显微镜检测每种制剂的亚可见颗粒。MFI结果显示,从F1至F5,T0时的颗粒数量(粒径≥2μm)处于相同水平。然而,在F6(不含PS80)中测试的颗粒数量(粒径≥2μm和粒径≥10μm)远远高于其他5种制剂。
10个循环的冻融后,F3(山梨醇,pH 6.0)中的颗粒数量(粒径≥2μm)从1043/mL增加至28428/mL,颗粒数量(粒径≥10μm)从61/mL增加至672/mL。除此以外,在其他制剂样品中未观察到显著变化。
表23.赋形剂筛选研究的MFI结果:冻融
结合抗原
结合抗原方法是一种基于ELISA的方法,用于检测单克隆抗体结合活性。结果如表24所示。在25℃和40℃下孵育4周后,F2(海藻糖二水合物,pH 6.0)的结合抗原活性没有明显下降。
表24.F2的赋形剂筛选研究的结合抗原结果
在这个赋形剂筛选研究中研究了6种制剂在40℃、25℃和冻融(-40℃至RT)条件下的稳定性。在40℃下孵育4周后,在F6(不含PS80)中观察到可见颗粒。此外,T0时在F6中测试的亚可见颗粒数量远远高于其他制剂,这表明PS80在抑制颗粒聚集方面起到关键作用。SEC-HPLC结果表明F3(山梨醇,pH 6.0)的%纯度下降幅度最大。此外,Caliper-SDS(非还原)结果表明,F1(蔗糖,pH 6.0)的%纯度下降最多,而F2(海藻糖,pH 6.0)的下降最少。如cIEF结果所示,在F1(蔗糖,pH 6.0)中观察到最大变化。
在25℃下孵育4周后,在所有6种制剂中均未观察到可见颗粒。SEC-HPLC结果显示在6种制剂中没有明显的纯度下降。Caliper-SDS(非还原)结果表明,除了FS(精氨酸HCl,pH6.0),这些制剂没有显著变化。cIEF结果显示F3(山梨醇,pH 6.0)的电荷变化最大。
在冻融(-40℃至RT)实验中,10个循环的冻融后在F4(甘露醇,pH 6.0)中观察到大量的可见颗粒,SEC-HPLC结果显示这种制剂的主峰下降4.4%。在所有这6种制剂中,Caliper-SDS(非还原)和clEF结果没有显著变化。MFI结果表明,在10个循环的冻融后,F3(山梨醇,pH 6.0)的亚可见颗粒数量增加。
基于上述结果,F1(蔗糖,pH 6.0)、F3(山梨醇,pH 6.0)和F4(甘露醇,pH 6.0)表现较差。Caliper-SDS(非还原)结果显示,在25℃下孵育4周后,F5(精氨酸HCl,pH6.0)的%纯度下降。DSC结果显示,F5的Tm起始(℃)值比其他制剂低至少5℃。总之,F2(海藻糖二水合物,pH 6.0)比其他制剂表现更好。因此,将F2(海藻糖二水合物,pH 6.0)用于后续的表面活性剂筛选研究。
实施例5.表面活性剂筛选
这个实施例筛选稳定IM005蛋白的PS80的最佳浓度。
将IM005抗体(20.4mg/mL)换液至20mM组氨酸,pH 6.0缓冲液中。将海藻糖二水合物的浓度用其储备溶液调整至8%。然后,添加10%的PS80储备溶液,使最终PS80浓度分别为0、0.01%、0.02%和0.03%,如表25所述。将蛋白的浓度调整至50mg/mL。
表25.表面活性剂筛选的制剂
将制备的制剂用0.22μm PVDF膜过滤器进行无菌过滤。对于每个制剂,将1mL样品装入2mL的玻璃小瓶中。灌装后立即将小瓶加塞并压盖。除压盖操作外,所有程序均在生物安全罩中进行。
然后将小瓶置于搅拌条件下(300rpm和25℃)。在指定的时间点对样品进行分析。
渗透压
使用渗透压力计(Advanced 2020多样品)确定T0时F1-F4的渗透压。渗透压数据如表26所示。
表26.表面活性剂筛选研究在T0时的渗透压结果
编号 | 制剂 | 渗透压(mOsmol/kg) |
F1 | 20mM组氨酸,8%海藻糖二水合物,pH 6.0 | 330 |
F2 | 20mM组氨酸,8%海藻糖二水合物,0.01%PS80,pH 6.0 | 328 |
F3 | 20mM组氨酸,8%海藻糖二水合物,0.02%PS80,pH 6.0 | 327 |
F4 | 20mM组氨酸,8%海藻糖二水合物,0.03%PS80,pH 6.0 | 329 |
DSC
采用DSC检测每个制剂(F1-F4)在T0时的热力学稳定性。如表27所示,所有制剂的起始转变温度的范围是56.30℃至57.39℃。Tm1值的范围是64.39℃至65.23℃,Tm2在78.60℃至78.90℃的范围中。4种制剂之间的热力学转变谱没有显著差异。
表27.表面活性剂筛选研究的DSC结果
外观、pH、蛋白浓度
目视检查结果如表28所示。搅拌(300rpm,25℃)1天和3天后,在F1(不含PS80)中观察到大量可见颗粒。相比之下,在相同的搅拌条件下,在F2(0.01% PS80)、F3(0.02%PS80)和F4(0.03% PS80)中未观察到可见颗粒。
在所有采样点检测F1-F4的pH值。如表28所示,在25℃下搅拌3天后,pH值没有显著变化。
使用nanodrop2000(UV280方法)在所有采样点测量F1-F4的蛋白浓度。如表28所示,在25℃下搅拌3天后,未检测到蛋白浓度的明显的变化。
表28.表面活性剂筛选研究的外观、pH和浓度结果:搅拌
SEC-HPLC
SEC-HPLC数据如表29所示。对于F1-F4,在25℃下搅拌3天后,未观察到%主峰的明显的变化。
表29.表面活性剂筛选研究的SEC-HPLC结果:搅拌
Caliper-SDS(nr)
Caliper-SDS是一种基于微芯片和CE的高通量分析方法,其能够以高灵敏度检测单克隆抗体片段。Caliper-SDS(nr)的结果如表30所示。对于所有制剂(F1-F4),在25℃下搅拌3天后,未观察到大幅度的%纯度降低。
表30.表面活性剂筛选研究的Caliper-SDS(nr)结果:搅拌
cIEF
cIEF数据如表31所示。对于所有制剂,在25℃下搅拌3天后,未观察到电荷变体的显著变化。
表31.表面活性剂筛选研究的cIEF结果:搅拌
MFI
使用MicroFlow Image(MFI5200)进行亚可见颗粒检测。MFI数据如表29所示。在T0的采样点,F1-F4中粒径≥25μm的颗粒数量处于相同水平。然而,Fl(不含PS80)中粒径≥10μm和≥25μm的颗粒数量比其他制剂(F2、F3和F4)高很多。
在25℃下搅拌3天后,对于F1(无PS80),粒径≥2μm的颗粒数量从715个颗粒/mL增加至2585个颗粒/mL,粒径≥10μm的颗粒数量从53个颗粒/mL增加至579个颗粒/mL,粒径≥25μm的颗粒数量从4个颗粒/mL增加至392个颗粒/mL。搅拌3天后,在F3(0.02% PS80)和F4(0.03% PS80)中未观察到显著差异。F2中粒径≥2μm的颗粒数量从112个颗粒/mL增加至1266个颗粒/mL,而粒径≥10μm和≥25μm的颗粒数量没有显著变化。
表32.表面活性剂筛选研究的MFI结果:搅拌
对于所有候选制剂(F1-F4),在300rpm和25℃下搅拌后,从SEC-HPLC、Caliper-SDS(非还原)和cIEF数据未观察到显著变化。然而,在搅拌1天和3天后,通过目视检查在F1(不含PS80)中观察到可见颗粒,而在F2-F4(有不同浓度的PS80)中未观察到可见颗粒。如MFI结果所示,F1(不含PS80)中的亚可见颗粒数量显著增加,F2(0.01% PS80)中粒径≥2μm的亚可见颗粒数量也有所增加,而在F3(0.02% PS80)和F4(0.03% PS80)中未检测到明显变化。
因此,结果表明在搅拌条件下,PS80在抑制颗粒产生中起到重要作用。然而,PS80在长期储存过程中可能降解,这可能降低蛋白产品的稳定性。因此,当PS80的蛋白保护能力得到保证时,建议较低的浓度。综上所述,0.02%是IM005的最终选择的PS80浓度。
表面活性剂筛选研究表明,PS80在抑制颗粒产生中起到重要作用,最终选择0.02% PS80。基于赋形剂和表面活性剂筛选研究的结果,在最终制剂确认研究中使用具有20mM组氨酸、8%海藻糖二水合物、0.02% PS80,pH 6.0的制剂。
通过在40℃、25℃和冻融条件下研究5种赋形剂,进行了赋形剂筛选研究。与其他4种赋形剂相比,具有海藻糖二水合物的制剂表现最好,因此,选择用于后续的表面活性剂筛选研究。
实施例6.制剂确认
该研究是为了确认实施例4中确定的IM005的先导制剂。先导制剂包含20mM组氨酸缓冲液、8%(w/v)海藻糖二水合物、0.02%(w/v)PS80,pH6.0。
将IM005样品(51.7mg/mL)用0.22-μm过滤器过滤,无菌装入8mL玻璃小瓶中,每瓶3.3mL IM005,在生物安全罩中加塞并压盖。
外观
表33总结了大多数样品的外观。所有样品都是淡黄色,略呈乳白色的液体,没有可见颗粒。仅在40℃-2W样品中,观察到一个颗粒,但是在40℃-4W样品中没有可见颗粒。
表33.制剂确认的外观评价
SO=略呈乳白色
亚可见颗粒(MFI)
表34中总结了每个样品中亚可见颗粒的计数,所有样品中的亚可见颗粒都在控制之中。而且,与T0样品相比,亚可见颗粒的计数没有明显变化。
表34.制剂确认的亚可见颗粒结果
单位=计数/mL
pH和蛋白浓度
表35-36中总结了pH和蛋白浓度结果。所有样品的pH和蛋白浓度都是稳定的。
表35.制剂确认的pH结果
表36.制剂确认的蛋白浓度结果
单位=mg/mL
SEC-HPLC
表37中总结了SEC结果。2-8℃样品的主峰没有明显下降。对于25℃样品,与T0相比,25℃-8W的主峰减少了1.0%,HMW增加了0.8%。对于40℃样品,与T0相比,40℃-4W的主峰减少了4.0%,HMW%增加了3.5%。这个趋势与以前的制剂筛选研究结果一致。
表37.制剂确认的SEC结果
CE-SDS(r&nr)
表38-39中总结了CE-SDS还原和非还原结果。对于CE-SDS还原结果,2-8°q样品的纯度没有明显下降。对于25℃样品,与T0相比,25℃-8W的纯度下降了0.6%。对于40℃样品,与T0相比,40℃-8W的纯度下降了2.3%。对于CE-SDS非还原结果,2-8℃样品的纯度没有明显下降。对于25℃样品,与T0相比,25℃-8W的纯度下降了2.3%。对于40℃样品,与T0相比,40℃-8W的纯度下降了5.6%。这个趋势与以前的制剂筛选研究结果一致。
表38.制剂确认的CE-SDS(还原)结果
表39.制剂确认的CE-SDS(非还原)结果
cIEF
表40中总结了cIEF结果。2-8℃样品的主峰没有明显下降。对于25℃样品,与T0相比,25℃-8W的主峰减少了6.4%,酸性峰增加了5.5%。对于40℃样品,与T0相比,40℃-4W的主峰减少了22.5%,酸性峰增加了16.4%。这个趋势与以前的制剂筛选研究结果一致。
表40.制剂确认的cIEF结果
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效力(基于细胞的测定)
表41中总结了通过基于细胞的测定测试的效力结果。在制剂确认过程中,所有测试样品的效力(基于细胞的测定)都没有明显变化。25℃和40℃样品的酸性峰的增加不影响效力。
表41.制剂确认的效力结果
在所有测试项目中,在任何2-8℃样品中都没有发现明显变化。对于加速条件25℃和压力条件40℃,样品的外观、亚可见颗粒、pH和蛋白浓度都可以保持一致和稳定。这些样品的SEC-HPLC、CE-SDS(r&nr)和cIEF都有一定程度的下降,但下降的趋势与以前的制剂开发研究一致。
因此确认了20mM组氨酸缓冲液、8%(w/v)海藻糖二水合物、0.02%(w/v)PS80,pH6.0的制剂。
***
本公开的范围不受所描述的具体实施方案的限制,这些实施方案旨在作为本公开的个别方面的单一说明,任何功能上等同的组合物或方法都在本公开的范围内。本领域技术人员会清楚在本公开的方法和组合物中可以进行各种修改和变化而不背离本公开的精神或范围。因此,本公开旨在涵盖本公开的修改和变化,只要它们属于所附权利要求及其等同物的范围。
本说明书中提到的所有出版物和专利申请援引加入本文,与具体并单独地表明每个单独的出版物或专利申请援引加入本文相同。
序列表
<110> 天境生物科技(上海)有限公司
<120> 抗CD73抗体的制剂
<130> P21404330WF
<150> PCT/CN2020/141601
<151> 2020-12-30
<160> 10
<170> PatentIn version 3.5
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Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Tyr Ser Ile Thr Ser Gly
20 25 30
Tyr Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Lys Leu Glu Trp
35 40 45
Met Gly Tyr Ile Asn Tyr Gly Gly Ser Asn Gly Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Ile Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Tyr Asp Ala Tyr Tyr Glu Ala Leu Asp Asp Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 8
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 8
Glu Ile Val Leu Ser Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Ser Arg Val Asn Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Arg Pro Trp Ile Ser
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu
65 70 75 80
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 9
<211> 450
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 9
Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Tyr Ser Ile Thr Ser Gly
20 25 30
Tyr Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Lys Leu Glu Trp
35 40 45
Met Gly Tyr Ile Asn Tyr Gly Gly Ser Asn Gly Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Ile Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Tyr Asp Ala Tyr Tyr Glu Ala Leu Asp Asp Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 10
<211> 213
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 10
Glu Ile Val Leu Ser Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Ser Arg Val Asn Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Arg Pro Trp Ile Ser
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu
65 70 75 80
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Pro 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
Claims (15)
1.一种组合物,其包含抗CD73抗体、5-50mM组氨酸、2%-20%(w/v)海藻糖和0.015%-0.05%(w/v)聚山梨酯80(PS80),pH为5.6-6.4,其中所述抗体包含重链可变区(VH)和轻链可变区(VL),所述重链可变区(VH)包含CDR1、CDR2和CDR3,所述轻链可变区(VL)包含CDR1、CDR2和CDR3,并且其中VH CDR1、VH CDR2、VH CDR3、VL CDR1、VL CDR2和VL CDR3分别包含SEQ ID NO:1-6的氨基酸序列。
2.权利要求1的组合物,其包含10-30mM组氨酸。
3.权利要求1或2的组合物,其包含5%-15%(w/v)海藻糖二水合物。
4.权利要求1-3中任一项的组合物,其包含0.015%-0.035%(w/v)PS80。
5.权利要求1的组合物,其包含10-30mM组氨酸、5%-15%(w/v)海藻糖和0.015%-0.035%(w/v)PS80,pH为5.8-6.2。
6.权利要求1的组合物,其包含15-25mM组氨酸、6%-10%(w/v)海藻糖、0.015%-0.025%(w/v)PS80,pH为5.9-6.1。
7.权利要求1-6中任一项的组合物,其包含5-150mg/mL的所述抗体。
8.权利要求1-7中任一项的组合物,其中所述VH包含SEQ ID NO:7的氨基酸序列,并且所述VL包含SEQ ID NO:8的氨基酸序列。
9.权利要求8的组合物,其中所述抗体包含重链和轻链,所述重链包含SEQ ID NO:9的氨基酸序列,所述轻链包含SEQ ID NO:10的氨基酸序列。
10.一种冻干组合物,其通过冷冻干燥权利要求1-9中任一项的组合物获得。
11.一种溶液,其通过将权利要求10的冻干组合物溶解在溶剂中获得。
12.权利要求11的溶液,其中所述溶剂是水。
13.权利要求1-9中任一项的组合物在制备用于治疗癌症的药物中的用途。
14.一种治疗有此需要的患者的癌症的方法,其包括向所述患者给药权利要求1-9中任一项的组合物。
15.权利要求13的用途或权利要求14的方法,其中所述癌症选自膀胱癌、乳腺癌、结肠直肠癌、子宫内膜癌、食道癌、头颈癌、肾癌、白血病、肝癌、肺癌、淋巴瘤、黑素瘤、胰腺癌、前列腺癌和甲状腺癌。
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US20230134160A1 (en) * | 2015-09-22 | 2023-05-04 | Pfizer Inc. | Method Of Preparing A Therapeutic Protein Formulation And Antibody Formulation Produced By Such A Method |
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UA126571C2 (uk) * | 2017-01-24 | 2022-11-02 | Ай-Маб Байофарма Юес Лімітед | Антитіло до cd73 та його застосування |
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