CN113842456B - 一种抗人4-1bb的单克隆抗体制剂及其用途 - Google Patents
一种抗人4-1bb的单克隆抗体制剂及其用途 Download PDFInfo
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Abstract
本发明涉及一种稳定的抗人4‑1BB抗体的药物制剂及其用途。所述药物制剂含有抗人4‑1BB的单克隆抗体、稳定剂、缓冲剂和表面活性剂。本发明的抗人4‑1BB抗体的药物制剂非常稳定,经长时间保存、强光、高温或者低温、冻融循环后仍能够符合药学使用要求,有着广泛的应用前景。
Description
技术领域
本发明属于抗体制剂领域,具体的涉及一种抗人4-1BB的单克隆抗体制剂及其用途。
背景技术
肿瘤免疫治疗作为目前肿瘤治疗领域中最具前景的研究方向之一,其通过增强机体抗肿瘤免疫功能来抑制和杀伤肿瘤细胞。T细胞的活性很大程度上受到抑制型和激活型“免疫检查”分子的调节,在肿瘤微环境中,抑制型免疫检查点分子的高表达,如CTLA-4和PD-1等,通过抗体来阻断这些抑制型免疫检查点分子受体-配体之间的相互作用,能够打破这种对T细胞的抑制性信号,使得肿瘤特异性T细胞恢复其肿瘤杀伤能力,进而达到治疗肿瘤的效果。除了抑制型免疫检查点,T细胞活性还受到激活型免疫检查点分子的调节,通过激活这类分子的信号,能够增强T细胞的抗肿瘤活性。4-1BB就是一种重要的激活型免疫检查点分子。
4-1BB又称为TNFRSF9或CD137,是肿瘤坏死因子(Tumor Necrosis Factor,TNF)受体超家族中的一种跨膜蛋白。4-1BB在活化的CD4+T淋巴细胞、活化的CD8+T淋巴细胞、活化的自然杀伤(NK)细胞、单核细胞、树突状细胞、B细胞、嗜中性粒细胞和肥大细胞上表达。
4-1BB激动剂疗法在先天性和适应性免疫上均引起不同的免疫效应应答。在临床前肿瘤模型中,4-1BB单一疗法和与其他免疫调节剂的组合疗法可建立持久的抗肿瘤T细胞记忆应答,这使得该受体成为癌症免疫治疗的有吸引力的靶标。
近20年来,针对4-1BB靶点的相关功能、作用机制进行了大量实验研究。目前,有近20家制药企业针对4-1BB靶点进行单抗药物布局,迄今为止还没有4-1BB靶点相关单抗药物上市。
虽然现有技术例如CN107921104A、CN110546166A、CN109963873A和CN110003332A等已经公开了若干4-1BB抗体,但追求临床效果更优的新抗体一直是肿瘤免疫领域的热点。同时抗体的制剂组成对抗体的治疗效果也有很大的影响,由于不同的4-1BB抗体的氨基酸序列组成不同,导致其理化性质和高级构象也存在差异,因此,现有技术已有的剂型组成难以适用于所有的4-1BB抗体。为了使得特定序列结构的4-1BB抗体能够适于临床应用,有必要针对特定的抗体进行制剂的开发研究。同时,还需要根据特定的4-1BB抗体制剂研究其与其他治疗剂组合进行联合用药的技术效果。
发明内容
为了追求更佳的临床效果,发明人首先获得了一个相较于Pfizer公司4-1BB抗体Utomilumab技术效果更优的抗人4-1BB的单克隆抗体,命名为MC03。在获得MC03抗体的基础上,进一步地对MC03的制剂处方进行了大量摸索和研究,最终获得了一种针对该MC03单抗最为适用的、且能稳定保存所述单抗的溶液制剂,该制剂能够充分防止单抗MC03蛋白聚集、降解、氧化或者变性等,从而保持其有效组分的生物学活性,适合于临床使用。进一步地,在得到单抗MC03制剂的基础上,对该制剂的药物学功能做了深入研究,发现该制剂具备良好的抗肿瘤活性,并且,该制剂与其他治疗剂联用,特别是与抗人PD-1抗体联用相较于单独使用该制剂具有更好的抗肿瘤效果。
发明详述
1、术语
本说明书中提及的所有公布、专利和专利申请都以引用的方式并入本文,所述引用的程度就如同已特定地和个别地指示将各个别公布、专利或专利申请以引用的方式并入本文。
在下文详细描述本发明前,应理解本发明不限于本文中描述的特定方法学、方案和试剂,因为这些可以变化。还应理解本文中使用的术语仅为了描述具体实施方案,而并不意图限制本发明的范围。除非另外定义,本文中使用的所有技术和科学术语与本发明所属领域中普通技术人员通常的理解具有相同的含义。
本文所公开的某些实施方案包含了数值范围,并且本发明的某些方面可采用范围的方式描述。除非另有说明,应当理解数值范围或者以范围描述的方式仅是出于简洁、便利的目的,并不应当认为是对本发明的范围的严格限定。因此,采用范围方式的描述应当被认为具体地公开了所有可能的子范围以及在该范围内的所有可能的具体数值点,正如这些子范围和数值点在本文中已经明确写出。不论所述数值的宽窄,上述原则均同等适用。当采用范围描述时,该范围包括范围的端点。
当涉及可测量值比如量、暂时持续时间等时,术语“约”是指包括指定值的±20%、或在某些情况下±10%、或在某些情况下±5%、或在某些情况下±1%、或在某些情况下±0.1%的变化。
本文所用氨基酸三字母代码和单字母代码如J.Biol.Chem,243,p3558(1968)中所述。
术语“抗人4-1BB”的抗体是指能够识别、结合来自于人的4-1BB分子的抗体。
本文所用的术语“抗体”,典型是指包含通过共价二硫键和非共价相互作用保持在一起的两条重(H)多肽链和两条轻(L)多肽链的Y型四聚蛋白。天然IgG抗体即具有这样的结构。每条轻链由一个可变结构域(VL)和一个恒定结构域(CL)组成。每条重链包含一个可变结构域(VH)和恒定区。
本领域已知五个主要类别的抗体:IgA,IgD,IgE,IgG和IgM,对应的重链恒定结构域分别被称为α,δ,ε,γ和μ,IgG和IgA可以进一步分为不同的亚类,例如IgG可分为IgG1,IgG2,IgG3,IgG4,IgA可分为IgA1和IgA2。来自任何脊椎动物物种的抗体的轻链基于其恒定结构域的氨基酸序列可以被分配到两种明显相异的类型之一,称为κ和λ。
在IgG、IgA和IgD抗体的情形中,该恒定区包含称为CH1、CH2和CH3的三个结构域(IgM和IgE具有第四结构域CH4)。在IgG、IgA和IgD类别中,CH1和CH2结构域被柔性铰链区分离,该铰链区是可变长度的富含脯氨酸和半胱氨酸的区段。每类抗体进一步包含由配对半胱氨酸残基形成的链间和链内二硫键。
术语“可变区”或“可变结构域”显示出从一种抗体到另一种抗体的氨基酸组成的显著变化,并且主要负责抗原识别和结合。每个轻链/重链对的可变区形成抗体结合位点,使得完整的IgG抗体具有两个结合位点(即它是二价的)。重链的可变区(VH)和轻链的可变区(VL)结构域各包含具有极端变异性的三个区域,被称为高变区(HVR),或更通常地,被称为互补决定区(CDR),VH和VL各有4个骨架区FR,分别用FR1,FR2,FR3,FR4表示。因此,CDR和FR序列通常出现在重链可变结构域(或轻链可变结构域)的以下序列中:FR1-HCDR1(LCDR1)-FR2-HCDR2(LCDR2)-FR3-HCDR3(LCDR3)-FR4。
术语“Fc”用于定义免疫球蛋白重链的C端区域,所述区域包含至少一部分的恒定区。该术语包括天然序列Fc区和变体Fc区。
如在此使用的,广义上的“抗体”的类型可包括如多克隆抗体(polyclonalantibodies)、单克隆抗体、嵌合抗体、人源化抗体及灵长类化抗体、CDR移植抗体(CDR-grafted antibody)、人类抗体(包括重组产生的人类抗体)、重组产生的抗体、胞内抗体、多特异性抗体、双特异性抗体、单价抗体、多价抗体、抗个体基因型抗体、合成抗体(包括突变蛋白及其变体)等等。
术语“单克隆抗体”(或称“单抗”)指由单一细胞克隆产生的基本均质、仅针对某一特定抗原表位的抗体。单克隆抗体可以使用本领域中已知的多种技术制备,包括杂交瘤技术、重组技术、噬菌体展示技术、转基因动物、合成技术或上述技术的组合等。
需说明的是,本发明的单克隆抗体可变区的CDR和FR的划分是根据Kabat定义确定的。而其他命名和编号系统,例如Chothia、IMGT或AHo等,也是本领域技术人员已知的。因此,以本发明的单抗序列为基础,包含任何命名系统衍生的一种或多种CDR的人源化抗体均明确地保持在本发明的范围内。
术语“抗体片段”包含完整抗体的至少一部分。如在此所使用,抗体分子的“片段”包括抗体的“抗原结合片段”,并且术语“抗原结合片段”是指免疫球蛋白或抗体中与所选抗原或其免疫原性决定部分特异性结合或反应的多肽片段,或由此片段进一步衍生的融合蛋白产物,例如单链抗体,嵌合抗原受体中的胞外结合区等。示例性的抗体片段或其抗原结合片段包括但不限于:可变轻链片段、可变重链片段、Fab片段、F(ab’)2片段、Fd片段、Fv片段、单结构域抗体、线性抗体、单链抗体(scFv)及由抗体片段形成的双特异性抗体或多特异性抗体等。
术语“抗原”是指被抗体或抗体结合片段识别并特异性结合的物质,广义上,抗原可以包括所选靶标的任何免疫原性片段或决定簇,包括单表位、多表位、单结构域、多结构域、完整的胞外结构域(ECD)或蛋白质。肽、蛋白质、糖蛋白、多糖和脂质,其部分及其组合均可构成抗原。非限制性示例性抗原包括肿瘤抗原或病原体抗原等。“抗原”也可以指引发免疫反应的分子。任何形式的抗原或含有该抗原的细胞或制剂都可以用于生成对抗原决定簇具有特异性的抗体。抗原可以是分离的全长蛋白质、细胞表面蛋白(例如,用在其表面上表达至少一部分抗原的细胞进行免疫的)、或可溶性蛋白质(例如,仅用该蛋白质的ECD部分进行免疫的)或蛋白质构建体(例如,Fc抗原)。该抗原可以在基因修饰的细胞中产生。前述任何抗原可以单独或与本领域已知的一种或多种免疫原性增强佐剂组合使用。编码该抗原的DNA可以是基因组的或非基因组的(例如,cDNA),并且可以编码足以引起免疫原性应答的至少一部分ECD。可以使用任何载体来转化其中表达抗原的细胞,所述载体包括但不限于腺病毒载体、慢病毒载体、质粒以及非病毒载体如阳离子脂质。
术语“表位”是指抗原上与免疫球蛋白或抗体特异性结合的位点。表位可以由相邻的氨基酸、或通过蛋白质的三级折叠而并列的不相邻的氨基酸形成。由相邻的氨基酸形成的表位通常在暴露于变性溶剂后保持,而通过三级折叠形成的表位通常在变性溶剂处理后丧失。表位通常以独特的空间构象存在并且包括至少3-15个氨基酸。由给定的抗体确定其结合的表位的方法是本领域熟知的,包括免疫印迹和免疫沉淀检测分析等。确定表位的空间构象的方法包括本领域中的技术,例如X射线晶体分析法和二维核磁共振等。
术语“亲和力”或“结合亲和力”指分子(例如抗体)的单一结合位点与其结合配偶体(例如抗原)之间全部非共价相互作用总和的强度。术语“KD”是指特定的抗体-抗原相互作用的解离常数。可以使用本领域已知的各种技术来确定结合亲和力,例如表面等离子体共振、生物层干涉法、双极化干涉法、静态光散射、动态光散射、等温滴定量热法、ELISA、分析超速离心和流式细胞术等。
术语“生物学活性”指抗体结合抗原并导致可测量的生物学反应的能力,所述生物学反应可以在体外或体内进行测量。
术语“药物制剂”或“制剂”或“制剂处方”,表示这样的制品:其存在形式允许活性成分的生物学活性有效,并且不含有对所述制剂要施用的受试者有毒的其他组分。
术语“溶液制剂”表示,在大气压下至少约2℃至约8℃的温度为液体的制剂。
术语“脱酰胺”表示,抗体中的一个或多个天冬酰胺残基已经被衍生成,例如,天冬氨酸或异-天冬氨酸。
术语“聚集”的抗体是这样一种抗体,其已经被发现与其它抗体分子一起聚集,特别是在冷冻和/或搅动之后。
术语“稳定的”制剂是这样的制剂,其中的蛋白质在保存后基本上保持其物理稳定性和/或化学稳定性和/或生物学活性。优选地,该制剂在保存后基本上保持其物理和化学稳定性,以及其生物学活性。一般基于制剂保质期来选择贮存期。用来测量蛋白质稳定性的各种分析技术是本领域已有的。可以在选定的温度下测量稳定性持续选定的时间。稳定性能够以许多不同的方式进行定性和/或定量地评估,包括评估聚集物形成(例如利用大小排阻层析,通过测量浊度,和/或通过肉眼观察);通过利用阳离子交换层析或毛细管分区电泳评估电荷异质性;氨基末端或羧基末端序列分析;质谱分析;SDS-PAGE分析以比较减小的和完整的抗体;肽图谱分析;评估生物学活性或抗体的抗原结合功能;等等。不稳定性可以包括下列的任一种或多种:聚集,脱酰胺作用(例如Asn脱酰胺作用),氧化作用(例如Met氧化作用),异构化作用(例如Asp异构化作用),剪切/水解/片段化(例如铰链区片段化),琥珀酰亚胺形成,未配对的半胱氨酸,N-末端延伸,C-末端加工,糖基化作用差异,等等。
术语“缓冲剂”或“缓冲液”表示稳定药物制剂pH的药学上可接受的赋形剂。合适的缓冲剂是本领域公知的,且可以在文献中找到的。优选的药学上可接受的缓冲液包括但不限于:组氨酸缓冲液、柠檬酸盐缓冲液、琥珀酸盐缓冲液、醋酸盐缓冲液、精氨酸缓冲液、磷酸盐缓冲液或其混合物等等。缓冲液用本领域已知的酸或碱进行pH调节,可以将pH调至在4.5-6.0范围内的值,特别是调至在4.5-5.5范围内的值,最特别地是调至pH5.1。
术语“稳定剂”表示药学可接受的赋形剂,其在制造,储存和应用过程中保护活性药物成分和/或制剂免受化学和/或物理降解。稳定剂包括但不限于糖,氨基酸,多元醇,环糊精等。
术语“表面活性剂”表示,用于保护蛋白制剂抵抗物理应力(如搅拌和剪切)的药学上可接受的赋形剂。药学上可接受的表面活性剂包括:聚氧乙烯脱水山梨糖醇脂肪酸酯(吐温)、聚氧乙烯烷基醚(例如在商标BrijTM下销售的那些)和聚氧乙烯-聚氧丙烯共聚物(泊洛沙姆,Pluronic)。聚氧乙烯脱水山梨糖醇-脂肪酸酯包括聚山梨酯20(在商标吐温20TM下销售)和聚山梨酯80(在商标吐温80TM下销售)。
术语“联合用药物”指包含各自具有活性成分的两种或两种以上药物制剂的组合,在施用于受试者时需要联合使用。活性成分可以混合在一起形成单一的给药单元,也可分别独立成为给药单元,分别使用。
术语“有效量”指本发明的抗体或片段的药物制剂的剂量,其以单一或多次剂量施用患者后,在治疗的患者中产生预期效果。有效量可以由作为本领域技术人员的主治医师通过考虑以下多种因素来容易地确定:诸如人种差异;体重、年龄和健康状况;涉及的具体疾病;疾病的严重程度;个体患者的应答;施用的具体抗体;施用模式;施用制剂的生物利用率特征;选择的给药方案;和任何伴随疗法的使用。
术语“药盒”包括有效量的一种或多种单位剂型的本发明的药物制剂或联合用药物。在一些实施方案中,药盒可含有治疗或预防性组合物的无菌容器;这样的容器可以是盒、安瓿、瓶、小瓶、管、袋、泡罩包装或本领域已知的其它合适的容器形式。这种容器可以由塑料、玻璃、层压纸、金属箔或其他适合于保持药物的材料制成。此外,药盒还包括将本发明的药物制剂或联合用药物给予个体的说明书。说明书中通常包含使用本发明的药物制剂或联合用药物来治疗或预防疾病的方法。
生产和纯化抗体和抗原结合片段的方法在现有技术中能够熟知和获得,如冷泉港的抗体实验技术指南,5-8章和15章。
本发明工程化的抗体或其抗原结合片段可用常规方法制备和纯化。比如,编码重链和轻链的cDNA序列,可以克隆并重组至表达载体。重组的免疫球蛋白表达载体可以稳定地转染CHO细胞。作为一种更推荐的现有技术,哺乳动物类表达系统会导致抗体的糖基化,特别是在Fc区的高度保守N端。通过表达与人源抗原特异性结合的抗体得到稳定的克隆。阳性的克隆在生物反应器的无血清培养基中扩大培养以生产抗体。分泌了抗体的培养液可以用常规技术纯化、收集。抗体可用常规方法进行过滤浓缩。可溶的混合物和多聚体,也可以用常规方法去除,比如分子筛、离子交换。
本文所用的术语“个体”或“受试者”是指任何动物,例如哺乳动物或有袋动物。本发明的个体包括但不限于人类、非人类灵长类动物(例如食蟹猴或恒河猴或其他类型的猕猴)、小鼠、猪、马、驴、牛、绵羊、大鼠和任何种类的家禽。
本文所用的术语“肿瘤”指的是一种以细胞或组织的病理性增生为特征的疾病,及其随后的迁移或侵袭其他组织或器官。肿瘤生长通常是不受控制的和进行性的,不诱导或抑制正常细胞增殖。肿瘤可影响多种细胞、组织或器官,包括但不限于选自膀胱、骨、脑、乳腺、软骨、神经胶质细胞、食管、输卵管、胆囊、心脏、肠、肾、肝、肺、淋巴结、神经组织、卵巢、胰腺、前列腺、骨骼肌、皮肤、脊髓、脾、胃、睾丸、胸腺、甲状腺、气管、尿道、输尿管、尿道、子宫、阴道器官,或组织或相应的细胞。肿瘤包括癌症,如肉瘤,癌,或浆细胞瘤(浆细胞的恶性肿瘤)。本发明所述的肿瘤,可包括,但不限于白血病(如急性白血病、急性淋巴细胞白血病、急性髓细胞性白血病,急性粒细胞白血病,急性早幼粒细胞白血病、急性粒-单核细胞白血病、急性单核细胞白血病、慢性白血病、慢性粒细胞白血病、慢性淋巴细胞白血病、真性红细胞增多症),淋巴瘤(霍奇金病、非霍奇金病)、原发性巨球蛋白血症,重链病,实体瘤如肉瘤和癌症(如纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、骨肉瘤、脊索瘤、内皮肉瘤、淋巴管肉瘤、血管肉瘤、淋巴管内皮肉瘤,间皮瘤,尤文氏瘤、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、癌、支气管癌、髓样癌、肾细胞癌、肝癌,尼罗河管癌,绒癌、精原细胞瘤、胚胎癌、肾母细胞瘤、宫颈癌、子宫癌、睾丸癌、肺癌、小细胞肺癌、膀胱癌、上皮癌、胶质瘤、星形细胞瘤、髓母细胞瘤,颅咽管瘤、室管膜瘤、松果体瘤、血管母细胞瘤,听神经瘤,少突胶质瘤、神经鞘瘤、脑膜瘤、黑色素瘤、神经母细胞瘤、视网膜母细胞瘤)、食管癌、胆囊癌、肾癌、多发性骨髓瘤。较佳地,所述的“肿瘤”包括但不限于:胰腺癌、肝癌、肺癌、胃癌、食管癌、头颈部鳞状细胞癌、前列腺癌、结肠癌、乳腺癌、淋巴瘤、胆囊癌、肾癌、白血病、多发性骨髓瘤、卵巢癌、宫颈癌和胶质瘤。
本文所用的术语“疾病”或“病症”或“紊乱”等是指任何损害或干扰细胞、组织或器官的正常功能的改变或失调。例如,所述的“疾病”包括但不限于:肿瘤、病原体感染、自身免疫性疾病、T细胞功能障碍性疾病、或免疫耐受能力缺陷(如移植排斥)。
本文所用的术语“治疗”是指在试图改变个人或处理细胞引起的的疾病过程中的临床干预,既可以进行预防也可以在临床病理过程干预。治疗效果包括但不限于,防止疾病的发生或复发、减轻症状、减少任何疾病直接或间接的病理后果、防止转移、减慢疾病的进展速度、改善或缓解病情、缓解或改善预后等。
2、发明内容
本发明的目的在于提供一种稳定的适用于特定的抗人4-1BB单克隆抗体的溶液制剂及其用途。
本发明的稳定的溶液制剂含有抗人4-1BB的单克隆抗体或其抗原结合片段和缓冲剂。所述溶液制剂还可以含有稳定剂和/或表面活性剂。
所述抗人4-1BB的单克隆抗体或其抗原结合片段的轻链可变区中的3个CDR序列依次为:SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:3;重链可变区中的3个CDR序列依次为:SEQID NO:4、SEQ ID NO:5和SEQ ID NO:6。
优选的,所述抗人4-1BB的单克隆抗体或其抗原结合片段的轻链可变区的序列如SEQ ID NO:7所示,重链可变区的序列如SEQ ID NO:8所示。
优选的,所述抗人4-1BB的单克隆抗体的轻链的序列如SEQ ID NO:9所示,重链的序列如SEQ ID NO:10所示。
优选的,所述的缓冲剂为醋酸钠、组氨酸醋酸或组氨酸盐酸。
优选的,制剂中还包含稳定剂。
优选的,制剂中还包含稳定剂,所述稳定剂为蔗糖或甘露醇或海藻糖,优选稳定剂为蔗糖。
优选的,制剂中还包含表面活性剂。
优选的,所述表面活性剂为聚山梨酯20或聚山梨酯80,优选聚山梨酯20。
优选的,所述溶液制剂的pH为4.5-5.5,优选为4.7-5.3。
优选的,所述制剂包含蔗糖、组氨酸-盐酸缓冲剂、聚山梨酯20中的任意两种或三种。
优选的,所述制剂包含20-30mg/ml的抗人4-1BB的单克隆抗体或其抗原结合片段。
优选的,所述制剂包含70-90mg/ml的蔗糖。
优选的,所述制剂包含5-20mM的组氨酸-盐酸缓冲剂。
优选的,所述制剂包含0.05-0.5mg/ml的聚山梨酯20。
优选的,所述制剂包含20-30mg/ml的抗人4-1BB的单克隆抗体或其抗原结合片段、70-90mg/ml的蔗糖、5-20mM的组氨酸-盐酸缓冲剂、0.05-0.5mg/ml的聚山梨酯20,溶液的pH为4.5-5.5。
优选的,包含25mg/ml抗人4-1BB的单克隆抗体或其抗原结合片段、80mg/ml蔗糖、10mM组氨酸-盐酸缓冲液和0.1mg/ml的聚山梨酯20,pH范围为4.5-5.5。
本发明还提供一种联合用药物,其包含抗人4-1BB的单克隆抗体或其抗原结合片段的溶液制剂和至少一种额外的治疗剂。
优选的,所述额外的治疗剂为针对下述靶点的抑制剂,包括:PD-1,A2AR,CTLA4,PD-L1,TIGIT,CCR4,CCR8,CSF1R,B7H3,B7H4,CD47,CD96,CD73,Claudin18.2,VEGF,VEGFR,EGFR,FGFR,Her2,IAP,LAG3,STING,TNF-a,VISTA,GITR,OX40,CD40,ICOS。
优选的,所述额外的治疗剂为IDO抑制剂、TDO抑制剂、IAP抑制剂。
本发明还提供一种药盒,包含抗人4-1BB的单克隆抗体或其抗原结合片段的溶液制剂或上述的联合用药物。
本发明还提供上述抗人4-1BB的单克隆抗体的溶液制剂或上述联合用药物或上述药盒在制备用于预防或治疗4-1BB介导的疾病或者肿瘤中的用途。
优选的,所述肿瘤为肺癌、胃癌、黑色素瘤、肾癌、乳腺癌、肠癌、肝癌、卵巢癌、宫颈癌、膀胱癌、食道癌、胰腺癌、头颈肿瘤。
本发明还提供一种治疗方法,其用于受试者中预防或治疗4-1BB介导的疾病或病症,所述的疾病优选为肿瘤;所述的肿瘤优选为肺癌、胃癌、黑色素瘤、肾癌、乳腺癌、肠癌、肝癌、卵巢癌、宫颈癌、膀胱癌、食道癌、胰腺癌、头颈肿瘤;所述方法包括给予受试者施用本发明所述的溶液制剂或所述联合用药物或所述药盒。
本发明所述的抗人4-1BB抗体的药物制剂,具有以下有益效果:该制剂非常稳定,经长时间保存、强光、高温或者低温、冻融循环后仍能够符合药学使用要求,有着广阔的应用前景。
附图说明
图1为MC03对4-1BB受体下游NF-κB信号通路活化曲线。
图2为MC03对活化人Pan T细胞IFN-γ释放的影响。
图3为MC03对活化人CD3+ T细胞和CD3+CD8+T细胞增殖的影响,其中图3A为MC03对活化人CD3+ T细胞增殖的影响,图3B为MC03对活化人CD3+CD8+T细胞增殖的影响。
图4为各组动物肿瘤生长趋势图。
图5为各组平均肿瘤重量。
具体实施方式
通过以下实施例进一步详细说明本发明。在本发明的基础上改变制剂组成成分的浓度或加入其它一些物质,但对MC03单克隆抗体的蛋白稳定性没有显著影响的改变,仍被视为本发明的一部分。
电荷异质性(iCIEF)
采用全柱成像毛细管等电聚焦电泳法来检测本品样品的电荷异质性和等电点。毛细管为100μm内径FC涂层熔融石英毛细管,有效分离长度5cm;样品处理时分别加入终浓度为2.0%的GE pharmalyte 3-10、2.0%的GE pharmalyte 5-8、0.35%的HPMC,样品终浓度0.3mg/ml;聚焦分离电压和时间为1.5kV-1min,3kV-9min。以峰面积百分比计算酸区、主峰与碱区含量,并以MarkerpI值计算目标峰的pI值。
分子排阻层析(SEC)
使用分子大小排阻层析来量化聚合体、单体和片段。这种测定利用WatersXbridge BEH SEC 200A,7.8×300mm柱并在Waters e2695-2489 HPLC系统上运行。流动相为100mM磷酸钾盐,250mM氯化钾缓冲液,pH5.8。用流动相稀释样品到1mg/mL,注射体积为20μL。以0.5mL/min的流速将蛋白质等度洗脱30min,于215nm检测洗脱物的吸光度。利用Empower 3软件进行积分处理。
毛细管电泳(CE-SDS)
通过非还原CE-SDS(nrCE)和还原CE-SDS(rCE)分别测定主峰和(LC+HC)纯度,将这一测定在BECKMAN COULTER PA800 plus毛细管电泳系统上以50μm I.D.非涂层石英毛细管进行,毛细管有效分离长度20cm(全长30.2cm),PDA220nm带宽10nm检测。
TR-FRET法测定结合活性
采用TR-FRET法测定本品与4-1BB的结合活性。TR-FRET技术结合了荧光共振能量转移(FRET,Fluorescence Resonance Energy Transfer)和时间分辨荧光(TRF,Time-Resolved Fluorescence)两种技术,利用可以与抗原结合的螯合标记物作为能量供体,另一可以与供试品结合的荧光标记物作为能量受体,当供试品和抗原相互作用导致两个荧光基团接近时,供体与受体间产生荧光共振能量转移,得到荧光信号,从而对抗原、抗体的结合力进行测定。首先将梯度稀释的本品与人4-1BB(带有His标签)等体积混合,加至96孔浅孔板中;再将能量供体(MAb Anti-6His Tb Cryptate Gold)与能量受体(PAb Anti-HumanIgG-XL665)按一定稀释比例等体积混合后,加至已加有抗原与样品的96孔浅孔板中;共同孵育一定时间后,测定荧光共振能量转移的信号值,计算本品与4-1BB抗原的结合活性。本品浓度越高,产生的荧光共振能量转移的信号值越强。试验数据采用SoftMax Pro或其他同类软件进行四参数拟合分析,并按下式自动分析结果:参考品(自制)浓度的对数值为X轴,吸光值为Y轴,软件将给出供试品和参考品的半数有效浓度(EC50),并绘制“S”形曲线。
以下列举具体实施例来阐明本发明,应理解这些例子仅仅是为了说明本发明,而非限制本发明的范围。
实施例1抗人4-1BB的单克隆抗体MC03的获得以及序列信息
根据PCT/US2020/012080中记载的内容获得抗人4-1BB的单克隆抗体MC03(对应于该专利中的huG28.21.G2.1.4),MC03的轻链可变区中的3个CDR序列依次为:SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:3;重链可变区中的3个CDR序列依次为:SEQ ID NO:4、SEQ IDNO:5和SEQ ID NO:6。轻链可变区的序列如SEQ ID NO:7所示,重链可变区的序列如SEQ IDNO:8所示。轻链的序列如SEQ ID NO:9所示,重链的序列如SEQ ID NO:10所示。
实施例2 MC03对4-1BB抗原的亲和力分析
采用捕获法将20ug/mL Protein A蛋白(Sino Biological,货号10600-P07E)通过氨基偶联的方式固定在CM5芯片(GE Healthcare,BR-1005-30)的实验通道和参比通道上,固定水平约为2500RU,然后将待测样品(3.0ug/mL)捕获在实验通道上,重组人4-1BB蛋白(ACRO,货号41B-H5227)经倍比稀释成系列浓度后(20nM-0.31nM)依次流过两通道表面发生结合,随后进行解离,从而得到各样品的结合解离曲线,最终利用BIAcore相关软件对其结果进行分析与评估。通过动力学分析,MC03对重组人4-1BB的亲和力KD值为0.918nM,具体分析结果见表1所示。
表1 MC03对重组人4-1BB蛋白的亲和力测定动力学拟合分析结果
在初步研究了MC03的亲和力的基础上,接下来将对MC03的制剂处方进行研究,以探索出适合MC03稳定性存在同时还能保持其良好药物学功能的制剂。
实施例3
首先筛选制剂最适合的pH值范围,处方设计如下:蔗糖作为稳定剂,浓度为70mg/mL;聚山梨酯20作为表面活性剂,浓度为0.1mg/mL;组氨酸醋酸作为缓冲溶液,浓度为10mmol/L;制剂处方如表2所示:
表2 MC03抗体不同pH的制剂处方
处方 | R1 | R2 | R3 | R4 | R5 | R6 | R7 | R8 |
pH | 4.0 | 4.5 | 4.7 | 5.0 | 5.2 | 5.5 | 5.7 | 6.0 |
对上述溶液进行了SEC、iCIEF、结合活性等分析。试验结果如下表3所示:
表3 MC03抗体制剂稳定性研究试验结果
注:NC代表未进行测试。
上述试验结果表明:处方样品R2~R6(pH4.5~pH5.5),SEC-HPLC主峰纯度随高温考察变化趋势一致,各处方间无明显差异,因此初步确定本品的pH值范围为4.5~5.5。进一步优选的,pH值范围为4.7~5.3。
实施例4
下一步进行缓冲体系的筛选,处方设计:蔗糖作为稳定剂,浓度为70mg/mL;采用不同缓冲体系进行考察,制剂处方如下表4:
表4 MC03抗体不同缓冲液的制剂处方
我们对上述溶液进行了SEC、iCIEF、结合活性等分析。试验结果如下表5所示:
表5 MC03抗体制剂稳定性研究试验结果
注:NC代表未进行测试。
从外观分析:各处方均为轻微乳光,无明显差异。高温试验30天,各处方样品SEC纯度略有下降,各处方样品下降趋势基本一致。高温30天,各处方样品iCIEF纯度下降明显,R3样品iCIEF纯度略优于其他处方。最终选择R3组氨酸盐酸体系。
实施例5
下一步进行稳定剂用量及剂型筛选,分别设计进行冻干剂型及水针剂型对比研究,并考察不同蔗糖含量对稳定性的影响。通过高温试验考查制剂的稳定性。
处方设计如下表6所示:
表6 MC03抗体不同制剂处方
编号 | 组氨酸-盐酸 | 蔗糖 | 聚山梨酯20 | 剂型 | pH |
R1 | 10mmol/L | 60mg/ml | 0.1mg/ml | 水针 | 5.0 |
R2 | 10mmol/L | 60mg/ml | 0.1mg/ml | 冻干 | 5.0 |
R3 | 10mmol/L | 80mg/ml | 0.1mg/ml | 水针 | 5.0 |
R4 | 10mmol/L | 80mg/ml | 0.1mg/ml | 冻干 | 5.0 |
对上述溶液进行SEC、iCIEF、结合活性等分析。试验结果如下表7所示:
表7 MC03抗体制剂稳定性研究试验结果
注:NC代表未进行测试。
高温放置14天后,R2及R4冻干粉针剂SEC-HPLC纯度、iCIEF纯度略优,但与注射液相比差异不大;相同剂型不同蔗糖浓度:R2与R4冻干粉针剂SEC-HPLC纯度、iCIEF纯度变化无明显差异,R1与R3注射液各项纯度变化无明显差异;
综合以上分析:采用6%蔗糖与8%蔗糖作为稳定剂无明显差异,进一步考虑到样品渗透压,优选接近人体正常渗透压的8%蔗糖含量作为制剂处方。
实施例6
根据上述实验结果,确定最优选制剂组成为25mg/ml MC03,80mg/ml蔗糖,0.1mg/ml聚山梨酯20,10mmol/L组氨酸-盐酸组氨酸缓冲液,pH值为5.1。对上述最优选制剂进行稳定性研究。包括:强制条件试验(高温试验、强光照射试验、冻融试验、振荡试验)、加速试验、长期试验。稳定性研究中样品放置方式为正置;长期、加速、高温、冻融及振荡试验样品均采用仿上市包装进行;光照试验样品除去外包装及瓶签进行。各考察条件如下表8所示:
表8 MC03抗体制剂各稳定性实验考察条件
上述各考察条件下的稳定性结果如下表9-表12所示:
表9 MC03抗体制剂长期试验(正置)结果(2~8℃)
表10 MC03抗体制剂加速试验(正置)结果(25℃±2℃)
表11 MC03抗体制剂高温试验结果(40℃±2℃)
表12 MC03抗体制剂光照、振荡、冻融试验结果
上述结果证明MC03抗体制剂在拟定保存条件(2~8℃)下是比较稳定的。
在获得了上述MC03抗体制剂组成的基础上,接下来的实施例将使用该制剂来研究该单抗的生物学功能,这对于今后的临床应用将具有更强的指导性意义。
实施例7 MC03制剂对4-1BB受体下游NF-κB信号通路活化作用评价
采用报告基因方法评价MC03对4-1BB受体下游NF-κB信号通路活化作用。该报告基因法包含两种细胞,分别为HEK293/Human4-1BB细胞和CHOK1/HuFcγR II A细胞。HEK293/Human4-1BB细胞是转染人4-1BB的HEK-DualTM TNF-α细胞(Invivogen),可以检测TNF-α诱导的NF-κB信号激活。CHOK1/HuFcγR II A细胞是稳转人FcγR II A的中国仓鼠卵巢细胞系,通过结合4-1BB抗体Fc段从而使4-1BB抗体交联(cross-linking)。取培养至对数生长期的HEK293/Human4-1BB细胞和CHOK1/HuFcγR II A细胞,以2×106个/mL的密度接种96孔圆底板,每孔50μL,两种细胞以1∶1比例混合均匀;然后对应孔中加入50μL不同浓度的同型阴性对照抗体HuIgG2(Biolegend,货号403602)或者MC03或者4-1BB-PF(三优生物,货号4-1BB-PF(Y0053),其氨基酸序列与Pfizer公司4-1BB抗体Utomilumab氨基酸序列相同,抗体Utomilumab的氨基酸序列参见“WHO Drug Information,Vol.30,No.2,2016年,第328页”),使其终浓度为10.0、3.33、1.11、0.370、0.123、0.0412、0.0137、4.57×10-3、1.52×10-3、5.08×10-4μg/mL,置37℃,5%CO2培养箱中共孵育18-22h;孵育结束后,吸取20μL细胞悬液到非透明96孔白色平底板中,加入50μL QUANTI-LucTM腔肠素荧光素酶底物稀释液(Invivogen,货号rep-qlc1),混合均匀;将板放入Synergy2型多功能酶标仪在460/40nm波长处检测发光值;利用GraphPad Prism6.0软件,以样品浓度梯度的Log值为横坐标,酶标仪检测发光值(RLU)为纵坐标做图,并对数据进行Nonlinear regression(curve fit)分析,计算各样品的EC50值。
结果如图1所示,同型阴性对照抗体HuIgG2不能引起4-1BB受体下游NF-κB信号通路活化,MC03能够剂量依赖性的激活HEK293/Human4-1BB细胞4-1BB受体下游NF-κB信号通路,EC50值为0.007694μg/mL,略强于对照抗体4-1BB-PF(EC50值为0.01778μg/mL)。
实施例8 MC03制剂对活化Pan T细胞IFN-γ释放的影响
抽取一名健康人外周血,利用Ficoll-PaqueTM Plus试剂(GE Healthcare,货号17-1440-02),通过密度梯度离心法分离获得PBMC;通过磁珠分选方法分离提取PanT细胞(EasySepTM Human Pan T Cell Isolation Kit,STEMCELL,货号17951),以2×106个/mL的密度接种96孔U底板,每孔50μL;收集培养至对数生长期的CHOK1/HuFcγR II A细胞以2×105个/mL的密度接种96孔U底板,每孔50μL;在对应孔中加入不同浓度的同型阴性对照抗体Dabi.hIgG2(QLSF Biotherapeutics转移)或者MC03或者PF2566.hIgG2(QLSFBiotherapeutics,氨基酸序列与Pfizer公司4-1BB抗体Utomilumab氨基酸序列相同,抗体Utomilumab的氨基酸序列参见“WHO Drug Information,Vol.30,No.2,2016年,第328页”),每孔50μL,使其终浓度分别为10.0、2.00、0.400、0.0800、0.0160、0.00320μg/mL;最后加入终浓度为250ng/mL的抗人CD3抗体(eBioscience,货号16-0037-85),每孔50μL,混合均匀;将培养板放入37℃,5%CO2培养箱中,共孵育48h;孵育结束后,收集细胞上清,利用HumanIFN-γFlex Set试剂盒(BD Bioscience,货号560111)检测细胞上清中IFN-γ含量。利用GraphPad Prism6.0软件,以样品浓度梯度为横坐标,IFN-γ含量为纵坐标作图。
结果如图2所示,在一定浓度范围内(0.0032-10μg/mL),与同型阴性对照抗体Dabi.hIgG2相比,MC03能明显促进活化的PamT细胞IFN-γ释放,与对照抗体PF2566.hIgG2相比作用相当或更强。
实施例9 MC03制剂对活化Pan T细胞增殖影响
抽取一名健康人外周血,利用Ficoll-PaqueTM Plus试剂(GE Healthcare,货号17-1440-02),通过密度梯度离心法分离获得PBMC;通过磁珠分选方法分离提取PanT细胞(EasySepTM Human Pan T Cell Isolation Kit,STEMCELL,货号17951);用Cell TraceTM-Violet荧光染料(Invitrogen,货号C34557)标记Pan T细胞;将标记后的Pan T细胞以2×106个/mL的密度接种96孔U底板,每孔50μL;收集培养至对数生长期的CHOK1/HuFcγR II A细胞以2×105个/mL的密度接种96孔U底板,每孔50μL;在对应孔中加入不同浓度的同型阴性对照抗体Dabi.hIgG2(QLSF Biotherapeutics转移)或者MC03或者PF2566.hIgG2(QLSFBiotherapeutics,氨基酸序列与Pfizer公司4-1BB抗体Utomilumab氨基酸序列相同),使其终浓度分别为10.0、2.00、0.400、0.0800、0.0160、0.00320μg/mL;最后加入终浓度为250ng/mL的抗人CD3抗体(eBioscience,货号16-0037-85)和10IU/mL的rhIL-2(SinoBiological,货号GMP-11848-HANE),每孔50μL,混合均匀;将培养板放入37℃,5%CO2培养箱中,共孵育5d;孵育结束后,收集细胞并标记带荧光标签的抗人CD3抗体(PerCP-Cy5.5anti-huCD3,eBioscience,货号45-0037-42)和抗人CD8抗体(PE anti-huCD8,BioLegend,货号300908),利用流式细胞术检测增殖Pan T细胞比例以及增殖CD3+CD8+T细胞比例;利用GraphPadPrism6.0软件,以样品浓度梯度为横坐标,增殖细胞比例为纵坐标作图。
实验结果表明:在一定浓度范围内(0.0032-10μg/mL),与同型阴性对照抗体Dabi.hIgG2相比,MC03能明显促进活化的Pan T细胞及CD3+CD8+T细胞增殖,与对照抗体PF2566.hIgG2相比作用相当或更强(如图3)。
实施例10 MC03制剂单用及联合ZMR01(抗人PD-1抗体)的药效研究
将HT-29细胞(ATCC)以4×106个/0.1mL接种于NOG小鼠(北京维通利华实验动物技术有限公司)的右侧腋窝皮下,同一天经尾静脉注射将PBMC(上海赛笠生物科技有限公司,批号190114)以5×106个/0.2mL接种于NOG小鼠,70只。当平均肿瘤体积达到50-100mm3时,挑选48只肿瘤体积适中的入组,按肿瘤体积随机分为6组:G1:HT-29细胞+PBMC+hIgG2(10mg/kg)+hIgG4(1mg/kg)组(北京义翘神州科技有限公司,hIgG2批号MA09OC3005,hIgG4批号MA11NO3010)、G2:HT-29细胞+PBMC+MC03(1mg/kg)组、G3:HT-29细胞+PBMC+MC03(3mg/kg)组、G4:HT-29细胞+PBMC+MC03(10mg/kg))组、G5:HT-29细胞+PBMC+ZMR01(1mg/kg)组和G6:HT-29细胞+PBMC+ZMR01(1mg/kg)组+MC03(1mg/kg)组,接种当天记为第0天。分组当天,G2-G6组经尾静脉给予相应抗体,G1组给予等量的hIgG2和hIgG4,每周2次,连续给药5次,末次给药第2天为试验终点,以安乐法处死动物。每周测量并记录肿瘤体积2次,其体积计算公式为:肿瘤体积=0.5×长径×短径2(图4)。试验期间观察各组小鼠出现的GVHD症状及其一般状态等。试验结束时,动物安乐死,计算肿瘤生长抑制率(TGI%),经GRAPHPAD PRISM作图对肿瘤体积进行t-test检验。试验终点剖取肿瘤并称重,计算肿瘤抑制率IR(%)=(1-给药组平均肿瘤重量/阴性对照组平均肿瘤重量)×100%(图5);
如图4所示,试验终点d19,G1-G6组动物的平均肿瘤体积分别为966.0mm3、685.1mm3、592.1mm3、527.5mm3、669.3mm3和513.9mm3,G2-G6给药组的TGI分别是31.5%、42.0%、49.1%、33.2%和50.7%,各给药组肿瘤体积与G1组相比均有显著差异(P<0.01),并且MC03(1mg/kg)+ZMR01(1mg/kg)联合用药组肿瘤体积(G6组)与相同剂量MC03单药组(G2)、ZMR01单药组(G5)相比均有显著差异(P<0.05)。如图5所示,试验终点d19,G1-G6的平均肿瘤重量分别为1.60g、1.29g、1.19g、0.99g、1.22g和0.89g,G2-G6给药组的瘤重抑制率分别是19.6%、25.7%、37.9%、23.0%和44.2%;MC03(10mg/kg)组(G4)瘤重、MC03(1mg/kg)+ZMR01(1mg/kg)联合用药组(G6组)瘤重与G1阴性对照组相比有显著差异(P<0.01),并且MC03(1mg/kg)+ZMR01(1mg/kg)联合用药组瘤重(G6组)与相同剂量MC03单药组(G2)、ZMR01单药组(G5)相比均有显著差异(P<0.05)。上述结果说明,供试品MC03(1、3、10mg/kg)可抑制HT-29皮下移植瘤的生长,在1-10mg/kg疗效呈剂量依赖性;MC03(1mg/kg)+ZMR01(1mg/kg)联用组的药效优于MC03(1mg/kg)或ZMR01(1mg/kg)单用。
所述ZMR01的重链序列如SEQ ID NO:11所示,轻链序列如SEQ ID NO:12所示。
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Claims (4)
1.一种抗人4-1BB的单克隆抗体的溶液制剂,其特征在于,所述制剂包含20-30mg/ml的抗人4-1BB的单克隆抗体或其抗原结合片段、70-90mg/ml的蔗糖、5-20mM的组氨酸-盐酸缓冲剂、0.05-0.5mg/ml的聚山梨酯20,溶液的pH为4.5-5.5,所述抗人4-1BB的单克隆抗体的轻链可变区的序列如SEQ ID NO:7所示,重链可变区的序列如SEQ ID NO:8所示。
2.如权利要求1所述的溶液制剂,其特征在于,包含25mg/ml抗人4-1BB的单克隆抗体或其抗原结合片段、80mg/ml蔗糖、10mM组氨酸-盐酸缓冲液和0.1mg/ml的聚山梨酯20,pH范围为4.5-5.5。
3.一种抗人4-1BB的单克隆抗体的溶液制剂,其特征在于,所述制剂包含20-30mg/ml的抗人4-1BB的单克隆抗体或其抗原结合片段、70-90mg/ml的蔗糖、5-20mM的组氨酸-盐酸缓冲剂、0.05-0.5mg/ml的聚山梨酯20,溶液的pH为4.5-5.5,所述抗人4-1BB的单克隆抗体的轻链的序列如SEQ ID NO:9所示,重链的序列如SEQ ID NO:10所示。
4.如权利要求3所述的溶液制剂,其特征在于,包含25mg/ml抗人4-1BB的单克隆抗体或其抗原结合片段、80mg/ml蔗糖、10mM组氨酸-盐酸缓冲液和0.1mg/ml的聚山梨酯20,pH范围为4.5-5.5。
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