Vascular targeted therapy with anti-prostate-specific membrane antigen monoclonal antibody J591 in advanced solid tumors
Vascular targeted therapy with anti-prostate-specific membrane antigen monoclonal antibody J591 in advanced solid tumors
复制标题
DOI：
10.1200/jco.2006.07.8097
复制
发表时间：
2007-02-10
影响因子：
45.3
通讯作者：
Bander, Neil H.
中科院分区：
文献类型：
--
作者：
Milowsky, Matthew I.;Nanus, David M.;Bander, Neil H.
目的：基于前列腺特异性膜抗原（PSMA）在实体肿瘤血管中的表达，我们在晚期实体肿瘤患者中开展了针对PSMA细胞外结构域的抗体J591的I期临床试验。这是PSMA作为潜在新血管靶点的原则性评估。主要终点是靶向性、毒性、最大耐受剂量、药代动力学（PK）和人抗人抗体（HAHA）反应。患者和方法患者患有晚期实体瘤，先前显示在新生血管上表达PSMA。他们接受了（111）铟((111)ln)-J591进行闪烁和PK测量，随后在2周后接受了J591和少量的In-111进行额外的PK测量。J591剂量水平分别为5、10、20、40和80 mg。对议定书进行了修订，每周给药6次未螯合的J591。有反应或病情稳定的患者有资格再治疗。免疫组化检测PSMA在肿瘤组织中的表达。结果27例患者接受单克隆抗体J591治疗。治疗耐受性良好。27例患者中有20例（74%）至少有一个已知的in -111- j591靶向转移性疾病区域，在肾癌、膀胱癌、肺癌、乳腺癌、结直肠癌、胰腺癌和黑色素瘤患者中可见阳性成像。用于肿瘤相关血管中PSMA表达免疫组化评估的10例患者标本中有7例显示PSMA染色。没有看到哈哈的反应。病情稳定的27例患者中有3例再次接受治疗。结论抗psma抗体J591在多种实体瘤类型患者中具有良好的毒性和对已知转移部位的良好靶向性，这突出了抗psma抗体J591作为血管靶向药物的潜在作用。
PurposeBased on prostate-specific membrane antigen ( PSMA) expression on the vasculature of solid tumors, we performed a phase I trial of antibody J591, targeting the extracellular domain of PSMA, in patients with advanced solid tumor malignancies. This was a proof-of-principle evaluation of PSMA as a potential neovascular target. The primary end points were targeting, toxicity, maximum-tolerated dose, pharmacokinetics (PK), and human antihuman antibody ( HAHA) response.Patients and MethodsPatients had advanced solid tumors previously shown to express PSMA on the neovasculature. They received (111)Indium ((111)ln)-J591 for scintigraphy and PK, followed 2 weeks later by J591 with a reduced amount of In-111 for additional PK measurements. J591 dose levels were 5, 10, 20, 40, and 80 mg. The protocol was amended for six weekly administrations of unchelated J591. Patients with a response or stable disease were eligible for re-treatment. Immunohistochemistry assessed PSMA expression in tumor tissues.ResultsTwenty-seven patients received monoclonal antibody (mAb) J591. Treatment was well tolerated. Twenty (74%) of 27 patients had at least one area of known metastatic disease targeted by In-111-J591, with positive imaging seen in patients with kidney, bladder, lung, breast, colorectal, and pancreatic cancers, and melanoma. Seven of 10 patient specimens available for immunohistochemical assessment of PSMA expression in tumor-associated vasculature demonstrated PSMA staining. No HAHA response was seen. Three patients of 27 with stable disease received re-treatment.ConclusionAcceptable toxicity and excellent targeting of known sites of metastases were demonstrated in patients with multiple solid tumor types, highlighting a potential role for the anti-PSMA antibody J591 as a vascular-targeting agent.