Tumor Neovasculature Vector Targeting

描述(申请人提供)：拟议的黑色素瘤临床试验是基于开发的方案，并在人类小鼠异种移植模型上成功测试。 黑色素瘤。试验方案包括给黑色素瘤患者服用一种 由人凝血因子VII(Fvii)分子结合的免疫结合物 人免疫球蛋白的Fc区。免疫结合物结合于 对其天然受体组织因子的高亲和力和特异性 由肿瘤血管和肿瘤细胞表达。Fvii分子发生突变 以防止其与转铁蛋白结合后引发凝血。基因 编码免疫结合物由非复制腺病毒载体携带， 它被直接注射到黑色素瘤患者的皮肤肿瘤中。这个 腺病毒主要感染注射的肿瘤细胞，这些细胞合成 免疫结合物用于分泌到血液中，建立稳定的高血 几周内免疫结合物的滴度。血源性免疫结合物 结合肿瘤血管和整个患者的肿瘤细胞？S的身体， 从而诱导对原发疾病的强大的细胞免疫攻击 和播散性肿瘤。小鼠模型实验证明，小白鼠具有良好的抗炎作用。 免疫结合物导致人类黑色素瘤肿瘤的消退，与肿瘤血管的广泛破坏有关。无临床意义 在处理的小鼠中，检测到对正常组织的不良影响。安全 该方案在小鼠模型中的有效性表明，对于 拟议的临床试验。主要设计为剂量递增研究 瘤内注射腺病毒载体的安全性 编码fVII免疫结合物的试验也被设计为产生 功效数据。每位参加试验的黑色素瘤患者将获得 选择剂量的载体，间隔3天给药，共6次 剂量。毒性将在期间和之后通过一组测试进行监测 治疗，包括几种类型的血液和肝功能测试。功效 将通过测量注射的皮肤肿瘤和皮肤进行监测 未注射的肿瘤和内部肿瘤。因为协议应该 适用于广泛的人体实体瘤，对 黑色素瘤试验可能导致一种新的治疗方法，不仅治疗黑色素瘤，而且还 治疗其他类型的癌症。

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.