Targeted Treatment of Recurrent Small Cell Lung Cancer with Anti-AbnV2 Antibodies

使用抗 AbnV2 抗体靶向治疗复发性小细胞肺癌

• 批准号: 8199575
• 负责人: Roy H.L. Pang
• 金额: $ 10万
• 依托单位: WOOMERA THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-07 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8199575
• 关键词: 90Y; Antibodies; Apoptosis; Apoptotic; Binding; Biological Assay; Breast; C-terminal; Cancer Cell Growth; Cell Line; Cells; Characteristics; DNA Sequence; Data; Detection; Development; Disease; Disease Marker; Effectiveness; Enzyme-Linked Immunosorbent Assay; Evaluation; Extracellular Domain; Flow Cytometry; Goals; Growth; Human; IgG1; Immunoglobulins; In Vitro; Investigation; Kidney; Label; Lead; Liver; Lung; Malignant Neoplasms; Methods; Modification; Monitor; Monoclonal Antibodies; Mus; Nature; Necrosis; Normal tissue morphology; Nude Mice; Patients; Phase; Preclinical Testing; Primary Neoplasm; Production; Proteins; Radio; Recurrence; Recurrent disease; Recurrent tumor; Refractory; Research; Residual Cancers; Residual Tumors; Reverse Transcriptase Polymerase Chain Reaction; Surface; Survival Rate; Testing; Therapeutic; Therapeutic Agents; Tumor-Derived; V2 Receptors; Variant; Vasopressins; antibody-dependent cell cytotoxicity; base; cancer cell; cell growth; cytotoxicity; design; effective therapy; extracellular; human tissue; improved; in vivo; innovation; lung small cell carcinoma; monoclonal antibody MOPC21; mouse model; new therapeutic target; phase 1 study; polyclonal antibody; prevent; receptor; therapeutic target; tumor; tumor growth; tumor xenograft; 90Y; Antibodies; Apoptosis; Apoptotic; Binding; Biological Assay; Breast; C-terminal; Cancer Cell Growth; Cell Line; Cells; Characteristics; DNA Sequence; Data; Detection; Development; Disease; Disease Marker; Effectiveness; Enzyme-Linked Immunosorbent Assay; Evaluation; Extracellular Domain; Flow Cytometry; Goals; Growth; Human; IgG1; Immunoglobulins; In Vitro; Investigation; Kidney; Label; Lead; Liver; Lung; Malignant Neoplasms; Methods; Modification; Monitor; Monoclonal Antibodies; Mus; Nature; Necrosis; Normal tissue morphology; Nude Mice; Patients; Phase; Preclinical Testing; Primary Neoplasm; Production; Proteins; Radio; Recurrence; Recurrent disease; Recurrent tumor; Refractory; Research; Residual Cancers; Residual Tumors; Reverse Transcriptase Polymerase Chain Reaction; Surface; Survival Rate; Testing; Therapeutic; Therapeutic Agents; Tumor-Derived; V2 Receptors; Variant; Vasopressins; antibody-dependent cell cytotoxicity; base; cancer cell; cell growth; cytotoxicity; design; effective therapy; extracellular; human tissue; improved; in vivo; innovation; lung small cell carcinoma; monoclonal antibody MOPC21; mouse model; new therapeutic target; phase 1 study; polyclonal antibody; prevent; receptor; therapeutic target; tumor; tumor growth; tumor xenograft

DESCRIPTION (provided by applicant): The objective of this Phase 1 project is to improve an effective treatment of recurrent small-cell lung cancer (rSCLC) by targeting a tumor-specific abnormal receptor, AbnV2 that is a surface-marker of the disease. Currently, there is no effective treatment for rSCLC. Our data show expression of this abnormal vasopressin V2 receptor (AbnV2 ) is a common feature of recurrent as well as primary cancers, and can be targeted by polyclonal and monoclonal antibodies recognizing unique features in a C-terminal extracellular domain. They are absent from normal tissues. Polyclonal Abs can inhibit in vitro the growth of cancer cells derived from recurrent as well as primary tumors. Expression of such receptors therefore not only raises the possibility to develop new and successful therapies for this disease, but also methods for detecting residual tumor and monitoring treatment. Such therapies should have particular relevance to recurrent disease. The hypothesis being tested is that the AbnV2 receptor will provide a sensitive and reliable target for effective treatment of recurrent rSCLC, and that monoclonal antibodies can serve as effective therapeutic targeting agents. Phase 1 goals are directed towards:(i) performing a 'proof of principle' evaluation of the effectiveness of unmodified and/or 90Y-labeled anti-AbnV2 monoAb to destroy/prevent growth of variant (and recurrent disease derived) NCI H82 and classical (and primary tumor-derived) NCI H345 SCLC cells grown in athymic mice; (ii) establishing the distribution and abundance in SCLC tumors of AbnV2 receptor protein and its unique expression by these tumors, and;(iii) determining the ability of anti-AbnV2 monoAb to inhibit the growth of SCLC cells in culture, and exploring mechanisms through which growth inhibition is accomplished. Treatment with forms of anti-AbnV2 monoAb will be compared with ubiquitous immunoglobulin (MOPC21). These investigations are designed to employ, tumor targeting in a mouse model, cytofluorographic and radiometric quantitation, antibody modification, tumor growth assessments, assessment of apoptotic and necrotic changes, IHC, ELISA, RIA, flow cytometry, RT-PCR, DNA sequencing, and Western analysis with densiometric quantitation. The approach employed is considered innovative because it represents the first treatment of form of recurrent SCLC cancer with an unmodified tumor-specific antibody. It is also provides the possibility that treatment progress can be monitored by use of radio-labeled fragments of the same antibody. A successful end-point of our Phase 1 studies would be the clear determination that unmodified, and/or 90Yttrium-labeled, anti-AbnV2 antibody can destroy or significantly curtail the growth of SCLC tumors in vivo, and that AbnV2 is a marker for >50% of SCLC tumors. Phase 2 would involve the preclinical testing of chimeric and humanized forms of anti-AbnV2 on SCLC. The proposed research is expected to rapidly lead to new and successful therapeutic approaches for managing recurrent small-cell lung cancer. rSCLC resists all current efforts at treatment. PUBLIC HEALTH RELEVANCE: This project will introduce a new targeted therapeutic approach for the treatment of recurrent small-cell lung cancer, a disease that is refractory to all current treatments. This refractoriness means < 10% expected 5 year survival rate for patients representing > 40,000 new cases of SCLC that arise in the USA each year. Our targeted approach is directed at a newly discovered abnormal receptor which seems to be a tumor-specific surface marker of recurrent small-cell lung cancer. Targeting will employ an available monoclonal antibody to treat this deadly disease. This antibody recognizes a unique extracellular portion of the marker. Currently patients with recurrent SCLC usually succumb to the disease in 3 to 6 months. The proposed research is expected to lead to new successful therapies for managing recurrent SCLC, thereby leading to a higher long- term survival rate for these patients.

描述（由申请人提供）：该阶段1项目的目的是通过靶向肿瘤特异性异常受体ABNV2，改善复发性小细胞肺癌（RSCLC）的有效治疗，这是该疾病的表面标志物。目前，RSCLC没有有效的治疗方法。我们的数据表明，这种异常加压素V2受体（ABNV2）的表达是复发和原发性癌症的常见特征，可以通过多克隆和单克隆抗体识别C-末端末端末端特征的靶向。它们不在正常组织中。多克隆ABS可以在体外抑制源自复发和原发性肿瘤的癌细胞的生长。因此，这种受体的表达不仅增加了为该疾病开发新的成功疗法的可能性，还可以检测残留肿瘤和监测治疗方法。这种疗法应与复发性疾病特别相关。正在检验的假设是，ABNV2受体将为有效治疗复发性RSCLC提供一个敏感且可靠的靶标，并且单克隆抗体可以用作有效的治疗靶向剂。第1阶段的目标是针对以下方面的：（i）对未修饰的和/或90y标记的抗ABNV2单支台进行“原则证明”评估，以破坏/防止变异（和经常性疾病衍生的）NCI H82和古典（以及原发性肿瘤）NCI H345 sclc Cellimic Cellimic shimicic Mice; （ii）确定ABNV2受体蛋白SCLC肿瘤的分布和丰度及其独特的表达，以及;（iii）确定抗ABNV2 MonoAb抑制SCLC细胞在培养中的生长的能力，并探索生长抑制的机制。将使用抗ABNV2单次单次单次单次的形式进行处理，将与普遍存在的免疫球蛋白（MOPC21）进行比较。这些研究旨在使用小鼠模型中的肿瘤靶向，细胞荧光和辐射定量，抗体修饰，肿瘤生长评估，凋亡和坏死变化的评估，IHC，ELISA，ELISA，RIA，流式细胞仪，RT-PCR，RT-PCR，DNA测序，DNA测序，DNA测序，以及使用量化量化的量化。所采用的方法被认为是创新的，因为它代表了具有未修饰的肿瘤特异性抗体的复发性SCLC癌的首次处理。还提供了可以通过使用同一抗体的无线电标记片段来监测治疗进展的可能性。我们1阶段研究的成功终点是明确的确定，即未修饰和/或90yttrium标记的抗ABNV2抗体可以破坏或显着减少体内SCLC肿瘤的生长，而ABNV2是SCLC肿瘤> 50％的标记物。第2阶段将涉及SCLC上抗ABNV2的嵌合和人源化形式的临床前测试。拟议的研究预计将迅速导致新的和成功的治疗方法来管理经常性的小细胞肺癌。 RSCLC拒绝当前的所有治疗努力。 公共卫生相关性：该项目将引入一种新的靶向治疗方法，用于治疗经常性的小细胞肺癌，这种疾病对所有当前治疗都具有难治性。这种折磨性意味着每年在美国出现的> 40,000例新的SCLC病例的患者预期5年生存率。我们的目标方法针对新发现的异常受体，该受体似乎是复发性小细胞肺癌的肿瘤特异性表面标记。靶向将采用可用的单克隆抗体来治疗这种致命疾病。该抗体识别标记的独特细胞外部分。目前，经常性SCLC的患者通常在3到6个月内屈服于该疾病。拟议的研究预计将导致用于管理经常性SCLC的新的成功疗法，从而导致这些患者的长期生存率更高。