贝伐珠单抗生物类似药质量相似性评价探讨*

贝伐珠单抗是研发热度最高的生物类似药之一,在梳理国内23家贝伐珠单抗生物类似药厂家研发数据和原研厂家研究数据的基础上,结合目前国内外生物类似药相关指导原则的理念以及相关文献,从生物类似药相似性评价一般原则、贝伐珠单抗关键质量属性识别和相似性评价几个方面,对贝伐珠单抗生物类似药质量相似性的技术评价要点进行初步探讨。     

贝伐珠单抗联合化疗二线及以上治疗晚期非鳞型非小细胞肺癌的临床观察

目的：考察贝伐珠单抗联合化疗二线及以上治疗晚期非鳞型非小细胞肺癌的疗效和安全性。方法：28 例经病理组织学或细胞学证实的晚期非鳞型非小细胞肺癌患者接受贝伐珠单抗联合化疗的二线及以上治疗,其间,贝伐珠单抗所用剂量为7.5 mg ? kg -1,在化疗第1 d 静滴给予;化疗方案包括培美曲塞加或不加铂类、白蛋白结合型紫杉醇加或不加铂类及替吉奥以及吉西他滨/ 紫杉醇/ 多西紫杉醇加或不加铂类。各治疗方案每3 周为1 个周期,持续4 个周期,然后维持治疗,直至受试者不能耐受或疾病进展。按RECIST 1.1 版评价疗效,按NCI-CTC 4.0版评价不良反应。结果：28 例受试者中,无完全缓解病例,部分缓解11 例(39.3％ ),稳定16 例（57.1％ ),进展1 例(3.6％ );客观缓解率为39.3％ (11/28),疾病控制率为96.4％ (27/28);中位无进展生存期为5 个月,中位总生存期为10 个月。亚组数据分析可见,贝伐珠单抗联合化疗各方案亚组中,培美曲塞方案受试者的中位无进展生存期为6 个月,疗效最好,较其他各方案亚组有统计学差异（P=0.028）。安全性数据分析显示,与贝伐珠单抗相关的主要不良反应有Ⅰ ~ Ⅲ度高血压以及Ⅰ / Ⅱ度蛋白尿/ 出血/ 发热。结论：贝伐珠单抗联合化疗用于二线及以上治疗晚期非鳞型非小细胞肺癌的疗效较单纯化疗有一定改善,且毒副反应可耐受,对经济上可以接受的患者值得推荐使用。     

贝伐珠单抗的疗效预测研究现状

抗血管生成的贝伐珠单抗已被广泛应用于多种恶性肿瘤的治疗。但因其受益人群有限及逐渐出现的获得性耐药,也限制了其对患者总生存的改善。迫切需要寻找有效的预测贝伐珠单抗疗效的预测因子指导临床应用。人们在生物标记物、影像学方面进行了大量探索,但目前尚没有一个公认的普遍适用的临床预测指标,仍需要从多角度出发,进行进一步的基础研究及临床研究去发现和验证有效的疗效预测指标。     

LC-MS对奥马珠单抗与其生物类似物CMAB007的分析与结构特征

哮喘是当今世界威胁公共健康的最主要的慢性肺部疾病,作为治疗中重度和难治性哮喘的特效药奥马珠单抗治疗费用相对昂贵,生物类似药CMAB007的研制可以降低治疗费用。本研究用质谱分析一种奥马珠单抗生物类似药CMAB007与原研药的一致性,分别从氨基酸分析、肽图、N/C端序列,还原质谱,寡糖含量,N糖分析等层面对CMAB007和奥马珠单抗进行了系统的比对研究,为进一步临床研究打下基础。结果表明CMAB007和奥马珠单抗氨基酸序列一致,赖氨酸剪切也基本一致,带唾液酸修饰糖形和带核心岩藻糖形比例相近,高甘露糖形比例差异不大,CMAB007略低于奥马珠单抗。因此CMAB007满足生物类似药在结构比对上一致性的要求,有望成为国内首先上市的重组抗人Ig E单克隆抗体药物。     

贝伐珠单抗在肿瘤治疗中的应用研究进展

贝伐珠单抗是一种重组人源化免疫球蛋白 G1 单克隆抗体,可通过抑制血管内皮生长因子活性及抗血管生成,达到抑制肿瘤生长 的目的,目前已广泛用于结直肠癌、肺癌、卵巢癌等多种肿瘤的治疗,尤其是通过与基础化疗结合,能显著提高治疗的有效率以及延长 肿瘤患者的无进展生存期和总生存期。综述贝伐珠单抗的抗肿瘤作用机制、在不同肿瘤治疗中的应用、用于肿瘤治疗时机与疗效差异以 及不良反应和防治。     

贝伐珠单抗联合化疗治疗晚期非鳞非小细胞肺癌的临床观察

目的:观察贝伐珠单抗联合化疗对晚期非小细胞肺癌患者的疗效、安全性及影像学改变。方法:对2007年至2014年于我院治疗的晚期NSNSCLC(非鳞非小细胞肺癌non-squamous non-small cell lung cancer)患者,给予贝伐珠单抗(15 mg/kg或7.5mg/kg)联合化疗(紫杉醇175 mg/m~2,d1,卡铂AUC=5或6,d1,q3 w)6周期及贝伐珠单抗维持治疗(15 mg/kg或7.5 mg/kg,d1,q3w)。观察疗效、不良反应、肺部病灶空洞改变的情况、恶性胸腔积液的治疗效果及部分患者EGFR、KRAS基因突变状况。结果:共观察26例患者,均接受贝伐珠单抗联合化疗,17例行贝伐珠单抗维持治疗。部分缓解(partial response,PR)、疾病稳定(stable disease,SD)、疾病进展(disease progression,PD)率分别为53.8%、42.3%、3.8%。中位无进展生存期(progression free survival,PFS)为11.0个月,中位总生存期(overall survival,OS)达25.8个月。26例患者中15.4%治疗后病变发生空洞改变,空洞组的2年、3年生存率略高于无空洞组,但无统计学差异(P值分别为0.586、0.509)。13例患者伴有恶性胸腔积液,胸腔积液的疾病控制率为100%。11例患者标本可进行EGFR基因检测,敏感突变占36.4%,未突变占63.6%。对10例患者标本行KRAS基因检测,均为突变阴性。不良反应包括骨髓抑制、消化道反应、鼻衄、咯血、高血压、蛋白尿等。大多数不良反应程度较轻,可控制。结论:贝伐珠单抗联合化疗治疗晚期NSNSCLC患者疗效确切,副反应可耐受,控制恶性胸腔积液效果较好。肺部病灶空洞改变的临床意义有待进一步研究。     

西妥昔单抗和贝伐珠单抗治疗晚期结直肠癌的有效性和安全性比较

目的:比较西妥昔单抗和贝伐珠单抗治疗晚期结直肠癌的有效性和安全性。方法:选取2014年1月～2017年8月我院收治的晚期结直肠癌患者100例,根据患者入院先后顺序随机分为两组,所有患者均给予FOLFIRI方案进行化疗,A组在化疗的基础上给予贝伐珠单抗进行治疗,B组在化疗的基础上给予西妥昔单抗进行治疗。比较两组患者临床治疗的缓解率、控制率及不良反应的发生情况,对所有患者随访1年,记录并比较两组患者的无进展生存期。结果:两组患者的缓解率、控制率、恶心呕吐、头晕、延迟性腹泻、肝肾损伤、白细胞减少、血小板减少和尿蛋白的发生率相比均无统计学差异(P0.05),但B组患者骨髓抑制和皮疹的发生率显著高于A组(P0.05);两组患者的无进展生存期相比无统计学差异(P0.05)。结论:西妥昔单抗和贝伐珠单抗治疗晚期结直肠癌的临床效果相当,且不良反应较轻,以Ⅰ～Ⅱ度为主,患者均可耐受,对症治疗后均有所缓解。西妥昔单抗易引发骨髓抑制和皮疹,在临床应用过程中需注意并进行有效预防和积极处理。     

血清VEGF水平与贝伐珠单抗联合化疗治疗转移性结直肠癌患者疗效的关系研究

目的:研究血清血管内皮生长因子(VEGF)水平与贝伐珠单抗联合化疗治疗转移性结直肠癌患者疗效的关系。方法:选取2015年2月至2016年2月间我院收治的转移性结直肠癌患者80例,按照数字随机表法将患者随机分为观察组(n=40)和对照组(n=40)。对照组给予氟尿嘧啶/奥沙利铂(FOLFOX-6)方案治疗,观察组则在此基础上加用贝伐珠单抗5 mg/kg治疗,d1,两组均进行4个化疗周期,比较两组患者临床疗效及治疗前、治疗后血清VEGF水平,并分析血清VEGF与疗效的相关性。结果:观察组有效率(RR)为52.50%(21/40),高于对照组的30.00%(12/40)(P0.05)。治疗前两组患者血清VEGF水平差异无统计学意义(P0.05),治疗后两组患者血清VEGF水平均较治疗前显著降低,观察组患者血清VEGF水平显著低于对照组患者,观察组VEGF下降幅度显著高于对照组(均P0.05)。经秩相关分析显示,结直肠癌患者治疗后VEGF下降幅度与治疗疗效呈显著正相关(r=0.683,P=0.000)。结论:贝伐珠单抗联合化疗治疗转移性结直肠癌可显著降低患者血清VEGF水平,疗效更佳。     

贝伐珠单抗联合紫杉醇/卡铂方案治疗晚期非小细胞肺癌的临床疗效分析

目的:探讨贝伐珠单抗联合紫杉醇/卡铂方案治疗晚期非小细胞肺癌的临床疗效和安全性.方法:选择本研究中心入组SAiL (MO19390)研究的13例患者为研究对象,给予贝伐珠单抗15 mg/kg,化疗d1静点,以后每3周重复;联合化疗方案为175mg/m2紫杉醇,d1,卡铂AUC=6,d1,每3周重复.化疗4-6周期,贝伐珠单抗每3周应用一次直至病情进展.评价患者的不良反应、客观有效率(objective response rate,ORR)、中位无进展生存期(progression free survival,PFS)和总生存期(overall survival,OS).同时,对可取得肿瘤组织标本的患者进行回顾性EGFR和KRAS突变检测.结果:13例患者中,发生5级肺动脉栓塞1例,4级脑梗塞1例,4级蛋白尿2例,3级鼻出血1例,最常见的不良反应为鼻出血(69.2％)、蛋白尿(46.2％)、高血压(38.5％)、咯血(30.8％)、流涕(30.8％)、头晕(23.1％),大多程度较轻可以耐受.部分缓解(partial response,PR)7例(53.8％),疾病稳定(stable disease,SD)6例(46.2),总有效率53.8％,疾病控制率100％,中位PFS 7.7个月,中位OS 16.1个月.6例可进行EGFR和KRAS突变检测的患者中,1例存在EGFR 19外显子缺失突变,1例存在21外显子L858R点突变,4例未检测到EGFR敏感突变,6例患者KRAS突变均为阴性.结论:贝伐珠单抗联合紫杉醇/卡铂方案治疗中国晚期非小细胞肺癌可延长PFS和OS,患者的耐受性良好.     

贝伐珠单抗联合化疗治疗晚期结直肠癌的临床疗效

目的:探讨晚期结直肠癌采用贝伐珠单抗联合化疗的临床疗效,为临床治疗提供参考。方法:按照随机数字表法将2010年2月~2013年2月我院收治的50例晚期结直肠癌患者分为两组,观察组采用贝伐珠单抗联合奥沙利铂,卡培他滨化疗,对照组单用奥沙利铂,卡培他滨进行化疗,比较两组的临床疗效、血清肿瘤标志物浓度变化及不良反应。结果:化疗4个周期后观察组有效率为56.00%高于对照组的24.00%,差异有统计学意义(P0.01),观察组疾病控制率为84.00%高于对照组的60.00%,差异有统计学意义(P0.05);观察组治疗后的CEA、CA242、CA19-9浓度均低于对照组,差异有统计学意义(P0.01);化疗后两组不良反应主要有恶心、呕吐、食欲减低等胃肠道反应,乏力,肝功能损害,骨髓抑制,脱发,贫血以及中性粒细胞下降等,其中观察组乏力,肝功能损害发生率低于对照组,差异有统计学意义(P0.05),其余不良反应两组差异无统计学意义(P0.05)。结论:结直肠癌采用贝伐珠单抗联合化疗治疗具有近期疗效好,安全性高等特点,临床有重要参考价值。     

Recent advances in the study of Kaposi's sarcoma-associated herpesvirus replication and pathogenesis

It has now been over twenty years since a novel herpesviral genome was identified in Kaposi's sarcoma biopsies. Since then, the cumulative research effort by molecular biologists, virologists, clinicians, and epidemiologists alike has led to the extensive characterization of this tumor virus, Kaposi's sarcoma-associated herpesvirus(KSHV; also known as human herpesvirus 8(HHV-8)), and its associated diseases. Here we review the current knowledge of KSHV biology and pathogenesis, with a particular emphasis on new and exciting advances in the field of epigenetics. We also discuss the development and practicality of various cell culture and animal model systems to study KSHV replication and pathogenesis.     

A Unique Protease Cleavage Site Predicted in the Spike Protein of the Novel Pneumonia Coronavirus (2019-nCoV) Potentially Related to Viral Transmissibility

正Dear Editor,In December 2019, a novel human coronavirus caused an epidemic of severe pneumonia(Coronavirus Disease 2019,COVID-19) in Wuhan, Hubei, China(Wu et al. 2020; Zhu et al. 2020). So far, this virus has spread to all areas of China and even to other countries. The epidemic has caused 67,102 confirmed infections with 1526 fatal cases     

Curcuminoids as inhibitors of thioredoxin reductase: A receptor based pharmacophore study with distance mapping of the active site

Curcumin is the yellow pigment of turmeric that interacts irreversibly forming an adduct with thioredoxin reductase (TrxR), an enzyme responsible for redox control of cell and defence against oxidative stress. Docking at both the active sites of TrxR was performed to compare the potency of three naturally occurring curcuminoids, namely curcumin, demethoxy curcumin and bis-demethoxy curcumin. Results show that active sites of TrxR occur at the junction of E and F chains. Volume and area of both cavities is predicted. It has been concluded by distance mapping of the most active conformations that Se atom of catalytic residue SeCYS498, is at a distance of 3.56 from C13 of demethoxy curcumin at the E chain active site, whereas C13 carbon atom forms adduct with Se atom of SeCys 498. We report that at least one methoxy group in curcuminoids is necessary for interation with catalytic residues of thioredoxin. Pharmacophore of both active sites of the TrxR receptor for curcumin and demethoxy curcumin molecules has been drawn and proposed for design and synthesis of most probable potent antiproliferative synthetic drugs.     

The structure, reproduction and taxonomy of Vidalia and Osmundaria (Rhodophyta, Rhodomelaceae)

Comprises species occurring mostly in subtidal habitats in tropical, subtropical and warm-temperate areas of the world. An analysis of the type species, V. spiralis (Sonder) Lamouroux ex J. Agardh, a species from Australia, establishes basic characters for distinguishing species in the genus. These characters are (1) branching patterns of thalli, (2) flat blades that may be spiralled on their axis, (3) width of the blade, (4) primary or secondary derivation of sterile and fertile branchlets and (5) position of sterile and fertile branchlets on the thalli. Application of the latter two characters provides an important basic method for separation of species into three major groups. Osmundaria , a genus known only in southern Australia, was studied in relation to Vidalia , and its separation from the Vidalia assemblage is not accepted. Species of Vidalia therefore are transferred to the older genus name, Osmundaria. Two new species, Osmundaria papenfussii and Osmundaria oliveae are described from Natal. Confusion in the usage of the epithet, Vidalia fimbriala Brown ex Turner has been clarified, and Vidalia gregaria Falkenberg, described as an epiphyte on Osmundaria pro/ifera Lamouroux, is revealed to be young branches of the host, Osmundaria prolifera.     

New or rare chromosome counts in Artemisia L. (Asteraceae, Anthemideae) and related genera from Kazakhstan

Fifteen chromosome counts of six Artemisia taxa and one species of each of the genera Brachanthemum, Hippolytia, Kaschgaria, Lepidolopsis and Turaniphytum are reported from Kazakhstan. Three of them are new reports, two are not consistent with previous counts and the remainder are confirmations of very scarce (one to four) earlier records. All the populations studied have the same basic chromosome number, x = 9, with ploidy levels ranging from 2x to 6x. Some correlations between ploidy level, morphological characters and distribution are noted.