MONOCLONAL ANTIBODY-BASED STRATEGIES FOR TREATMENT OF BREAST CANCER

基于单克隆抗体的乳腺癌治疗策略

• 批准号: 6277057
• 负责人: ELISSA KRAMER
• 金额: $ 2.03万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-01 至 1998-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6277057
• 关键词: antitumor antibody; breast neoplasms; clinical research; clinical trial phase I; combination cancer therapy; human subject; human therapy evaluation; immunoconjugates; metastasis; monoclonal antibody; neoplasm /cancer chemotherapy; neoplasm /cancer immunotherapy; neoplasm /cancer radionuclide therapy; neoplasm /cancer relapse /recurrence; radionuclides; topotecan; yttrium

Our goal is to develop effective radioimmunotherapy using humanized monoclonal antibodies for metastatic and/or recurrent breast cancer. We propose to evaluate and overcome two obstacles: the limited ability to deliver tumoricidal radiation doses by this method alone and the immunogenicity of the immunoconjugates. We have utilized a new, humanized BrE-3 monoclonal antibody directed against a 400-kD breast epithelial mucin antigen and labeled it with a 111Indium (111In) MX- DTPA metal chelator. We detected 86% of 72 known lesions in 12/15 patients. All the patientsU tumors expressed the BrE-3 antigen, as assessed by immunohistochemical staining of previously obtained tissue. Biological half-life of radiolabeled antibody in serum measured by HPLC averaged 56125.4 hours across all patients. Toxicity was mild and predictable; however, human anti-mouse IgG antibody was detected after treatment in 7/15 patients. We hypothesize that humanized BrE-3 monoclonal antibody complexed with 90Yttrium (90Y) will be an effective therapy against metastatic breast carcinoma and that combining this therapy with topotecan will enhance efficacy. Continuous infusion of a topoisomerase I inhibitor, explored extensively at NYU, has shown activity in breast cancer in phase-I trials with minimal toxicity. In the mouse model, the novel combination of these two agents provides significant therapeutic efficacy over each agent alone. Our specific aims are as follows: 1) to develop effective radioimmunotherapy of breast cancer using a fractionated dose regimen and 90Y MX-DTPA humanized anti-BrE-3; 2) to determine the maximum tolerated dose (MTD) using combined dose-fractionated 90Y MX-DTPA humanized BrE-3 antibody and continuous infusion topotecan in a phase-I dose-escalation trial; and 3) to assess the potential efficacy of combined 90Y MX-DTPA humanized BrE-3 and topotecan at MTD in a phase-II clinical trial in patients with metastatic or recurrent breast cancer.

我们的目标是开发有效的放射免疫疗法， 用于转移性和/或复发性乳腺癌的单克隆抗体。 我们建议评估和克服两个障碍：有限的能力 仅通过这种方法来递送杀肿瘤的辐射剂量， 免疫缀合物的免疫原性。 我们使用了一种新的， 针对400 kD乳腺癌的人源化BrE-3单克隆抗体 上皮粘蛋白抗原，并用111铟（111 In）MX- DTPA金属螯合剂。 在12/15例患者中，我们发现了72个已知病变中的86%。 患者 所有患者的肿瘤均表达BrE-3抗原， 通过先前获得的组织的免疫组织化学染色来评估。 HPLC法测定血清中放射性标记抗体的生物半衰期 所有患者的平均时间为56125.4小时。 毒性轻微， 可预测;然而，人抗小鼠IgG抗体检测后 治疗7/15例患者。我们假设人源化BrE-3 与90钇（90 Y）复合的单克隆抗体将是有效的 针对转移性乳腺癌的治疗以及将其组合 用托泊替康治疗将增强功效。 持续输注 一种拓扑异构酶I抑制剂，在纽约大学进行了广泛的研究， 在乳腺癌的I期试验中具有最小的毒性。 在 在小鼠模型中，这两种药物的新组合提供了 与单独的每种药剂相比具有显著的治疗功效。 我们的具体 目的：1）开发有效的放射免疫治疗方法， 使用分次剂量方案和90 Y MX-DTPA治疗乳腺癌 人源化抗BrE-3; 2）确定最大耐受剂量（MTD） 使用组合的剂量分级的90 Y MX-DTPA人源化BrE-3抗体 和连续输注拓扑替康的I期剂量递增试验; 和3）评估联合90 Y MX-DTPA的潜在疗效 人源化BrE-3和托泊替康在MTD下的II期临床试验， 转移性或复发性乳腺癌患者。