BISPECIFIC ANTIBODY THERAPY OF HER2/NEU POSITIVE CANCERS

描述：(申请人摘要)双特异性抗体(BsAb)是 用两株亲本单抗构建的杂合抗体 (单抗)：一个专用于肿瘤细胞，另一个专用于免疫 效应细胞。当特定的“触发”时，肿瘤细胞可以被杀死 单核细胞表面包括CD64(FcgRl)在内的分子，单核细胞来源 巨噬细胞(MAK)和IFNG激活的中性粒细胞与BsAb结合 在效应细胞与肿瘤细胞相互作用的过程中。效应器 BsAb靶向细胞可克服自然和病理障碍 用单抗进行免疫治疗。申请人研制出抗FcgRl的BsAb X-抗HER-2/neu(MDX-210)有效靶向人单核细胞MAK 中性粒细胞吞噬并杀死过度表达的肿瘤细胞 原癌基因-HER-2neu。HER-2/neu在许多地方过度表达 癌症包括大约30%的乳腺癌。第一阶段试验 证明MDX-210具有良好的耐受性和免疫学特性 激活。观察肿瘤消退情况。最优生物剂量 (OBD)，最大耐受量(MTD)为7~10 mg/m2。这个 抗FcgRl单抗22已人源化，命名为MDX-H210的单抗 建造的。MDX-210和MDX H210在以下方面几乎相同 临床前测试。申请人预计MDX-H210将 与MDX-210相比，诱导的人抗鼠抗体更少。在这 申请申请人建议进行MDX的第一阶段试验- H210加IFNG。之所以选择这种组合，是因为IFNG有多个 作用包括增加FcgR1的表达和激活 可提高MDX治疗效果的效应细胞- H210。患者将在第1天和第3天接受IFNG 0.1 mg/m2治疗， 使用MDX-H210，第2天。每周重复治疗。剂量为 MDX-H210将增加用于3名患者的队列，直到MTD 下定决心。MDX-H210的免疫效力将通过以下方式进行评估 测定：1)MDX-H210与单核细胞、中性粒细胞和肿瘤的结合 体内细胞；2)刺激T细胞和B细胞对 HER-2/neu；3)血浆细胞因子(肿瘤坏死因子、IL-1、 IL-6、G-CSF、新喋呤)；4)效应细胞对肿瘤的侵袭。 他预计，MTD和OBD将是相同的。第二阶段试验 然后将进行检查以确定MDX-H210的治疗效果 再加上在这个最佳剂量下给予IFNG治疗乳腺癌。 MDX-210具有很强的免疫活性和良好的临床应用前景。 单独给药时在I期测试中的有效性。IFNG的组合 而MDX-H210可能通过以下方式提高这种有前途的BsAb的疗效 增强效应细胞活性。

DESCRIPTION: (Applicant's Abstract) Bispecific antibodies (BsAb) are hybrid antibodies constructed from two parent monoclonal antibodies (mAbs): one specific for tumor cells and the other specific for immune effector cells. Tumor cells can be killed when specific "trigger molecules" including CD64 (FcgRl) on monocytes, monocyte-derived macrophages (MAK) and IFNg-activated neutrophils are engaged by BsAb during the interaction of an effector cell with a tumor cell. Effector cell targeting with BsAb may overcome natural and pathological barriers to immunotherapy with mAbs. The applicant developed a BsAb anti-FcgRl x anti-HER-2/neu (MDX-210) that effectively targets human monocytes, MAK and neutrophils to phagocytose and kill tumor cells that over express the proto-oncogene-HER-2neu. HER-2/neu is over expressed in many cancers including approximately 30% of breast cancers. A phase 1 trial demonstrated that MDX-210 is well tolerated and is immunologically active. Tumor regressions were observed. The optimal biological dose (OBD) and maximum tolerated dose (MTD) was between 7 and 10mg/m2. The anti-FcgRl mAb 22 has been humanized and a BsAb designated MDX-H210 was constructed. MDX-210 and MDX H210 are virtually identical in preclinical testing. The applicant anticipates that MDX-H210 will induce less human anti-mouse antibodies than did MDX-210. In this application the applicant proposes to perform a phase I trial of MDX- H210 plus IFNg. This combination was chosen because IFNg has multiple actions including increased expression of FcgRl and activation of effector cells that may increase effectiveness of treatment with MDX- H210. Patients will be treated with IFNg 0.1 mg/m2 on days 1 and 3 and with MDX-H210 on day 2. Treatment is repeated weekly. The dose of MDX-H210 will be increased for cohorts of 3 patients until the MTD is determined. The immunological efficacy of MDX-H210 will be assessed by determining: 1) binding of MDX-H210 to monocytes and PMNs and to tumor cells in vivo; 2) stimulation of T cell and B cell responses to HER-2/neu; 3) changes in plasma concentration of cytokines (TNF, Il-1, Il-6, G-CSF, neopterin); and 4) tumor infiltration by effector cells. He anticipates that the MTD and OBD will be identical. A phase II trial will then be performed to determine the therapeutic efficacy of MDX-H210 plus IFNg given at this optimal dose for treatment of breast cancer. MDX-210 has shown potent immunological activity and promising clinical efficacy in phase I testing when given alone. The combination of IFNg and MDX-H210 may increase the efficacy of this promising BsAb by enhancing effector cell activity.