MONOCLONAL ANTIBODY-BASED STRATEGIES FOR TREATMENT OF BREAST CANCER

我们的目标是开发有效的放射免疫治疗转移性和/或复发性乳腺癌使用人源化单克隆抗体。 我们建议评估和克服两个障碍：通过这种方法单独提供杀肿瘤辐射剂量的有限能力和免疫缀合物的免疫原性。 我们使用了一种新的人源化BrE-3单克隆抗体，针对400-kD乳腺上皮粘蛋白抗原，并用111铟（111 In）MX-DTPA金属螯合剂对其进行标记。 我们在12/15例患者中检测到了72个已知病变中的86%。 所有患者的肿瘤均表达BrE-3抗原，通过对先前获得的组织进行免疫组织化学染色进行评估。 在所有患者中，通过HPLC测量的血清中放射性标记抗体的生物半衰期平均为56125.4小时。 毒性轻微且可预测;然而，在7/15例患者中，在治疗后检测到人抗小鼠IgG抗体。 我们假设，人源化BrE-3单克隆抗体与90钇（90 Y）复合将是一种有效的治疗转移性乳腺癌，并结合这种治疗与拓扑替康将提高疗效。 拓扑异构酶I抑制剂的连续输注，在纽约大学进行了广泛的研究，在I期试验中显示出对乳腺癌的活性，毒性最小。 在小鼠模型中，这两种药物的新组合提供了优于单独使用每种药物的显著治疗功效。我们的具体目标如下：1）使用分次剂量方案和90 Y MX-DTPA人源化抗BrE-3开发乳腺癌的有效放射免疫治疗; 2）在I期剂量递增试验中使用联合剂量分次90 Y MX-DTPA人源化BrE-3抗体和持续输注拓扑替康确定最大耐受剂量（MTD）;和3）在转移性或复发性乳腺癌患者中进行的II期临床试验中，评估90 Y MX-DTPA人源化BrE-3和托泊替康联合给药（MTD）的潜在疗效。

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 radioimmuno- therapy 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.