CN1933851A - 使用抗-α5β1抗体抑制癌细胞增殖 - Google Patents
使用抗-α5β1抗体抑制癌细胞增殖 Download PDFInfo
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Abstract
Description
肿瘤类型(#样品) | 肿瘤血管 | 肿瘤上皮 | ||||||||
阴性 | 1+ | 2+ | 3+ | 4+ | 阴性 | 1+ | 2+ | 3+ | 4+ | |
肾癌(n=39) | 2 | 2 | 13 | 18 | 4 | 27 | 8 | 4 | 0 | 0 |
胰腺癌(n=32) | 0 | 1 | 17 | 12 | 2 | 15 | 2 | 7 | 7 | 1 |
肺癌(n=39) | 0 | 1 | 0 | 28 | 1 | 19 | 14 | 3 | 2 | 1 |
结肠癌(n=21) | 2 | 2 | 3 | 8 | 6 | 19 | 0 | 1 | 1 | 0 |
黑色素瘤(n=19) | 3 | 0 | 2 | 13 | 1 | 13 | 5 | 1 | 0 | 0 |
卵巢网膜转移性癌(n=4) | 0 | 0 | 1 | 3 | 0 | 2 | 2 | 0 | 0 | 0 |
膀胱癌(n=8) | 0 | 0 | 4 | 3 | 1 | 5 | 2 | 1 | 0 | 0 |
细胞株 | 来源癌症 | α5β1表面表达(MFI) | 生长抑制百分比 | |
-血清 | +血清 | |||
A549 | 肺癌 | 71.41 | 40 | 0 |
H460 | 肺癌 | 87.5 | 40 | 0 |
SW839 | 肾癌 | 65.8 | 30 | 0 |
MIA PACA-2 | 胰腺癌 | 61.9 | 20 | 0 |
HCT-116 | 结肠癌 | 42.5 | 15 | 0 |
786-0 | 肾癌 | 144.4 | 10 | 0 |
EKVX | 肺癌 | 36.7 | 10 | 0 |
SW1990 | 脾脏癌 | nd1 | 10 | 0 |
SN12C | 肾癌 | 129.1 | 5 | 0 |
A498 | 肾癌 | 67.1 | 5 | 0 |
A375 | 黑色素瘤 | 156.1 | 5 | 0 |
A2058 | 黑色素瘤 | 36.2 | 0 | 0 |
CHL-1 | 黑色素瘤 | 6.8 | 0 | 0 |
TK-10 | 肾癌 | 36.6 | 0 | 0 |
COLO357 | 胰腺癌 | 7.8 | 0 | 0 |
HT144 | 黑色素瘤 | 102.1 | 0 | 0 |
C8161 | 黑色素瘤 | 122 | 0 | 0 |
HT1376 | 膀胱癌 | 111.9 | 0 | 0 |
DU145 | 前列腺癌 | 87.5 | 0 | 0 |
UACC-62 | 黑色素瘤 | 88.5 | 0 | 0 |
HT1080 | 纤维肉瘤 | 421.7 | 0 | 0 |
ES-2 | 卵巢癌 | 132.8 | 0 | 0 |
CAPAN-1 | 胰腺癌 | nd1 | 0 | 0 |
CAPAN-2 | 胰腺癌 | nd1 | 0 | 0 |
ASPC-1 | 胰腺癌 | nd1 | 0 | 0 |
C32 | 黑色素瘤 | 5.7 | 0 | 0 |
LOX | 黑色素瘤 | 261.6 | 402 | 35 |
NW231 | 乳腺癌 | 132.2 | 102 | 35 |
水平 | 剂量(mg/kg) | PK值a | 剂量编号 | ||||
1 | 2 | 3 | 4 | 5 | |||
1 | 0.5 | Cmax | 11 | 11 | 12 | 13 | 13 |
Cminb | 1.5 | 1.6 | 2 | 2.1 | 2.2 | ||
2 | 1.0 | Cmax | 22 | 22 | 25 | 26 | 26 |
Cmin | 3 | 3 | 4 | 5 | 5 | ||
3 | 2.5 | Cmax | 54 | 57 | 64 | 67 | 68 |
Cmin | 9 | 10 | 13 | 14 | 15 | ||
4 | 5.0 | Cmax | 108 | 114 | 132 | 141 | 147 |
Cmin | 20 | 24 | 33 | 39 | 43 | ||
5 | 10.0 | Cmax | 216 | 236 | 282 | 317 | 346 |
Cmin | 51 | 66 | 101 | 131 | 156 | ||
6 | 15.0 | Cmax | 324 | 366 | 450 | 524 | 592 |
Cmin | 91 | 126 | 200 | 268 | 332 | ||
Cmax范围(54-140%) | 175-453 | 197-512 | 243-629 | 283-733 | 320-829 |
0.5mg/kg | 1.0mg/kg | 2.5mg/kg | 5.0mg/kg | 10.0mg/kg | 15.0mg/kg |
CRC(PD) | HCC(SD) | CRC(PD) | HCC(SD) | CRC(SD) | EC(PD) |
PC(SD) | NSCLC(SD) | EC(PD) | CRC(SD) | RCC(SD) | |
MEL眼(PD) | THY(PD) | PARO(SD) | PRO(PD) | ||
BC(SD) | MEL(PD) | ||||
RCC(SD) | MEL(SD) | ||||
MEL(PD) | RCC(PD) |
剂量组(患者数;肿瘤类型) | 最佳响应结果 | 进程时间*(天) |
2.5mg/kg(1;NSCLC) | SD | 129 |
5mg/kg(1;HCC) | SD | 122 |
10mg/kg(1;CRC) | PD | 70 |
10mg/kg(1;PARO) | SD | 143 |
15mg/kg(1;RCC) | PR | 214 |
15mg/kg(1;MEL) | SD | 172+(研究中) |
研究人群: | 患有透明细胞组织特征的转移性RCC的至少18岁的男性和女性 |
关键的患者准入/排除标准: | 准入:接受0-2次现有转移性疾病治疗方案的患有基本透明的细胞组织特征的转移性RCC的至少18岁的男性和女性;可根据实体瘤的响应标准(RECIST)测定的疾病;东部协作癌症小组(ECOG)性能状态≤1;妊娠试验阴性(仅对可能怀孕的妇女);符合特定标准的治疗前实验室水平;签署知情同意书,包括允许使用保护的健康信息(PHI)。排除:任何以下RCC组织特征:乳头、难染、收集导管或未分类;已知对鼠蛋白质或嵌合抗体或产品的其它组分过敏;筛选前4周内使用任何研究药物或在使用研究药物的5个半衰期内(以较长的为准);给予M2004周内进行全身化疗、免疫治疗放疗或单克隆抗体治疗;记录有CNS肿瘤或CNS转移;过去一年内有血栓形成和出血障碍的病史;出血可加剧的医学状态 |
样本大小: | 招募多达40位患者。20位患者进入阶段1。如果4个月(16周)内能够观察到一例证实的完全响应(CR)或部分响应(PR)或4个月时观察到一例稳定疾病(SD),则另外招募20位患者(阶段2)。 |
剂型与强度/制剂 | M200为无菌、无色、澄清-稍呈乳光、不含防腐剂的静脉注射用液体。充满各10-mL单次使用管,以递送10毫升10mg/mL的M200。各管的组成为10mg/mL M200、25mM柠檬酸盐、150mM氯化钠和0.05%聚山梨酯(TWEEN)80,pH6.5。 |
储存与过滤 | 将完整的小管储存在2-8℃(36-46°F)的冰箱里。不要冻结或振荡。如果在室温下(25℃)储存,必须6小时内给予M200, |
冰箱内(2-8℃)则必须48小时内给予。超过上述时间,应丢弃制备的溶液。 | |
给予方案/给药途径 | 30分钟内,所有符合条件的患者静脉内(IV)输注给予10mg/kg的M200,每隔1周一次,持续52周或直到疾病进展,以先发生的为准。通过患者体重(kg)乘以剂量水平(10kg/mg)计算给予患者的M200的剂量。采用试验第0天给药前患者体重计算整个试验过程的中的剂量,只要体重变化不超过10%。除去适当体积的10mg/mL M200制剂,用0.9%氯化钠稀释至最终体积120mL,30分钟内静脉输注入患者。 |
治疗持续时间与随访 | 所有患者每隔一周静脉内给予M200(10mg/kg)一次,持续52周或直到疾病进展,以先发生的为准。最后一次给药后45天或患者不能返回而导致提早结束时,该研究退出随访。最后一次给药后3个月进行随访。如果随访不可行,也可电话随访。最后一次给药后6个月进行长期电话随访。 |
终点: | 本研究的初步终点为研究期间的任何时间具有证实的肿瘤响应的患者比例。第二终点为:(1)至疾病进展时间;(2)肿瘤响应持续时间;(3)M200的PK;和(4)免疫原性。研究终点为测定到血清和血浆中可检测的生物标记。 |
效力测定: | 采用一维RECIST,每8周(2个月)进行疾病导向的放射成像,以评价肿瘤响应。筛选时,进行头部、胸部、腹部和骨盆的CT或MRI。每8周,对筛选中呈现的所有病灶以及所有疾病导向的解剖学病灶进行一次完整身体检查和成像扫描。对于任何PR或CR,PR或CR后一个月(28-35天)重复进行证实性放射成像。所有可测定病灶中,作为所有涉及器官的代表,每个器官最多5个病灶,共10个病灶被鉴定为靶病灶,在基线处记录和测定。可测定的病灶定义如下:采用常规CT/MRI在一个维度上为2.0厘米,采用螺旋状CT的在一个维度上为1.0厘米。计算所有靶病灶的最长直径(LD)之和,记录为基线总 |
LD。使用基线总LD作为参照,鉴定目标肿瘤响应。 | |
安全性测定: | 监测以下安全性测定:副作用(AE);严重的副作用(SAE);身体检查数据;生命指征;异常的实验值 |
药动学测定: | 给药前(给药前15分钟内)或给药后(输液结束后1小时)对所有患者进行药动学(PK)测定:第0天、第2、4和6周,每隔一月一次(第8、16、24、32、40、48周)、第52周、研究退出随访、以及3-个月随访(如果可能)。如果合适,使用PK的样品进行抗-Ab分析。 |
免疫原性: | 第0天、第8周、研究退出随访和3个月随访(如果可能)时,给药前15分钟内对所有患者进行抗-Ab测定。如果合适,使用PK的样品进行抗-Ab分析。 |
其它测定: | 探索性分析将评价血清和血浆中生物标记的存在。分析中包括以下癌症标记:CEA、CA 19-9、Syndecan、IGFBP-2和LFL2。包括以下细胞因子/生长因子:MIA、IL-6、TNF-α、PGF、VEGF、EGF和bFGF。 |
统计学方法: | 本研究设计检测总响应率≥20%、显示稳定疾病(SD)的响应者高达20%的能力至少为79.5%。为二歧终点提供总结的统计学结果和95%置信区间。采用Kaplan-Meier方法总结临时变量。 |
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US55642104P | 2004-03-24 | 2004-03-24 | |
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US62504904P | 2004-11-03 | 2004-11-03 | |
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US65109805P | 2005-02-07 | 2005-02-07 | |
US60/651,098 | 2005-02-07 | ||
US65751405P | 2005-02-28 | 2005-02-28 | |
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PCT/US2005/009939 WO2005092073A2 (en) | 2004-03-24 | 2005-03-24 | Use of anti-alpha5beta1 antibodies to inhibit cancer cell proliferation |
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CN1933851B CN1933851B (zh) | 2011-09-14 |
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CN103180737A (zh) * | 2010-07-19 | 2013-06-26 | 霍夫曼-拉罗奇有限公司 | 鉴定响应抗癌疗法的可能性升高的患者的方法 |
CN104159596A (zh) * | 2011-12-22 | 2014-11-19 | 北加州大学药学院 | 用于抗血管生成和癌症治疗的α5β1的拮抗剂的给药 |
WO2020108497A1 (zh) * | 2018-11-29 | 2020-06-04 | 和铂医药(香港)有限公司 | 一种抗pd-l1抗体制剂 |
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US6852318B1 (en) * | 1998-05-08 | 2005-02-08 | The Regents Of The University Of California | Methods for detecting and inhibiting angiogenesis |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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CN103180737A (zh) * | 2010-07-19 | 2013-06-26 | 霍夫曼-拉罗奇有限公司 | 鉴定响应抗癌疗法的可能性升高的患者的方法 |
CN104159596A (zh) * | 2011-12-22 | 2014-11-19 | 北加州大学药学院 | 用于抗血管生成和癌症治疗的α5β1的拮抗剂的给药 |
CN104159596B (zh) * | 2011-12-22 | 2017-03-08 | 北加州大学药学院 | 用于抗血管生成和癌症治疗的α5β1的拮抗剂的给药 |
WO2020108497A1 (zh) * | 2018-11-29 | 2020-06-04 | 和铂医药(香港)有限公司 | 一种抗pd-l1抗体制剂 |
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UA88294C2 (ru) | 2009-10-12 |
ZA200607849B (en) | 2007-12-27 |
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