Tumor Neovasculature Vector Targeting

描述（由申请方提供）：拟定的黑色素瘤临床试验是基于在人的小鼠异种移植模型中成功开发和测试的方案 黑素瘤该试验方案涉及向黑色素瘤患者施用 由人因子VII（fVII）分子偶联至 人IgG1免疫球蛋白的Fc区。免疫缀合物结合 与其天然受体组织因子（TF）具有高亲和力和特异性， 由肿瘤血管和肿瘤细胞表达。fVII分子发生了突变 以防止其与TF结合后引发血液凝固。基因 编码免疫偶联物的基因由非复制型腺病毒载体携带， 其被直接注射到黑素瘤患者的皮肤肿瘤中。的 腺病毒主要感染注射的肿瘤细胞，这些细胞合成腺病毒。 免疫缀合物用于分泌到血液中，建立稳定的高血 免疫缀合物的滴度持续数周。所述血源性免疫缀合物 与患者体内的肿瘤血管和肿瘤细胞结合的身体， 导致诱导针对原发性肿瘤的强有力的溶细胞免疫攻击， 和扩散性肿瘤。小鼠模型实验表明， 免疫缀合物引起人黑素瘤肿瘤的消退，与肿瘤脉管系统的广泛破坏相关。无临床显著 在处理的小鼠中检测到对正常组织的副作用。安全 该方案在小鼠模型中的效果表明， 拟议的临床试验。主要设计为剂量递增研究， 肿瘤内注射腺病毒载体的安全性 编码fVII免疫缀合物，该试验还被设计为产生 功效数据。参加试验的每名黑色素瘤患者将接受 以3天的间隔施用选定剂量的载体，总共6次 剂量毒性将通过一组测试进行监测期间和之后 治疗，包括几种类型的血液和肝功能检查。疗效 将通过测量注射的皮肤肿瘤以及皮肤 未注射的肿瘤和内部肿瘤。因为协议应该 适用于广泛的人类实体肿瘤，对于 黑色素瘤试验可能会导致一种新的治疗方法，不仅对黑色素瘤， 其他类型的癌症。

DESCRIPTION (provided by applicant): The proposed clinical trial for melanoma is based on the protocol developed and tested successfully in a mouse xenograft model of human melanoma. The trial protocol involves administering to melanoma patients an immunoconjugate composed of a human factor VII (fVII) molecule conjugated to the Fc region of a human IgG1 immunoglobulin. The immunoconjugate binds with high affinity and specificity to its natural receptor tissue factor (TF) expressed by tumor blood vessels and tumor cells. The fVII molecule is mutated to prevent initiation of blood coagulation after it binds to TF. The gene encoding the immunoconjugate is carried by a non-replicating adenoviral vector, which is injected directly into skin tumors of a melanoma patient. The adenovirus infects mainly the cells of the injected tumor, which synthesize the immunoconjugate for secretion into the blood, establishing a steady high blood titer of the immunoconjugate for several weeks. The blood-borne immunoconjugate binds to tumor blood vessels and tumor cells throughout a patient?s body, resulting in induction of a powerful cytolytic immune attack against primary and disseminated tumors. The mouse model experiments demonstrated that the immunoconjugate causes regression of human melanoma tumors, associated with extensive destruction of the tumor vasculature. No clinically significant adverse effects on normal tissues were detected in the treated mice. The safety and efficacy of the protocol in the mouse model suggest a similar outcome for the proposed clinical trial. Designed primarily as a dose escalation study of the safety of administering intratumoral injections of an adenoviral vector encoding the fVII immunoconjugate, the trial is also designed to generate efficacy data. Each melanoma patient enrolled in the trial will receive a selected dose of the vector administered at 3-day intervals for a total of 6 doses. Toxicity will be monitored by a panel of tests during and after treatment, including several types of blood and liver function tests. Efficacy will be monitored by measurements of injected skin tumors, and also of skin tumors and internal tumors that were not injected. Because the protocol should be applicable to a broad range of human solid tumors, a favorable outcome for the melanoma trial could lead to a new treatment not only for melanoma but also for other types of cancer.