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: 8554292
• 负责人: Roy H.L. Pang
• 金额: $ 47.6万
• 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 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8554292
• 关键词: Affinity; Animals; Antibodies; Antibody Specificity; Binding; Chimera organism; Clinical; Cloning; Confocal Microscopy; Cyclophosphamide; DNA; DNA Sequence; Data; Development; Disease; Dose; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Generations; Genes; Goals; Growth; Human; Human Cell Line; IgG1; Immunoglobulin Constant Region; Immunoglobulin Variable Region; Immunohistochemistry; In Vitro; Investigation; Label; Lead; Ligation; Malignant Neoplasms; Medical center; Membrane Proteins; Modeling; Modification; Monoclonal Antibodies; Mus; Normal tissue morphology; Organ; Patients; Phase; Process; Protocols documentation; Reaction; Recurrence; Refractory; Research; Reverse Transcriptase Polymerase Chain Reaction; Specific qualifier value; Specificity; Surface; Survival Rate; Testing; Therapeutic; Time; Tumor Cell Line; Tumor-Derived; V2 Receptors; Variant; Vasopressins; Whole-Body Scintigraphy; Xenograft procedure; cancer cell; cell growth; clinical application; cytotoxicity; design; effective therapy; extracellular; in vivo; killings; lung small cell carcinoma; meetings; neoplastic cell; new therapeutic target; phase 1 study; phase 2 study; prevent; programs; protein aminoacid sequence; radioligand; receptor; receptor expression; tumor; tumor growth; tumor xenograft

DESCRIPTION (provided by applicant): There is currently no effective treatment for recurrent small-cell lung cancer (rSCLC). The objective of this project is to utilize a monoclonal antibody, Abner, to develop new, rational, and successful treatment of rSCLC. The hypothesis being tested is that an abnormal vasopressin type 2 receptor (AbnV2R) present on these tumors will provide a sensitive, tumor-specific, and reliable target for the effective treatment by Abner antibodies. The data from the studies of Phase 1 of the project clearly show that treatment of variant SCLC tumor xenografts, with native and 90Yttrium-labelled mouse Abner significantly slows growth, but this growth is completely impaired when antibody treatment follows cyclophosphamide. Our data indicate AbnV2R expression is a feature common to all, or most, SCLC and that AbnV2R is a surface protein. Phase 2 is directed at advancing treatment of rSCLC with Abner by developing a human chimeric form (cAbner) of the mouse monoclonal antibody, and then a humanized form (hAbner) as potential clinical candidates. The ability of cAbner and hAbner to target and prevent growth of human variant SCLC xenografts in mice will then be tested. Phase 2 goals are directed towards (i) generating a chimeric form (cAbner) of mouse Abner with the constant regions of human IgG1; (ii) establishing that the targeting, recognition, and treatment profiles of mAbner are retained by cAbner; (iii) modeling a humanized form (hAbner) of Abner from the cAbner with genetically grafting CDRs from the VH and VL regions of mMAG-1 into the DNA framework of a human antibody; (iv) establishing that the targeting, recognition, and treatment profiles of mAbner are retained by hAbner. These investigations will employ, RT-PCR, ligation, and cloning, DNA recombinance, DNA sequencing, immunohistochemistry, antibody modification, Northern and Western analysis with densiometric quantitation, ELISA, RIA, tumor-directed targeting, whole-body scintigraphy for 99mTechnetium, cytofluorographic and radiometric quantitation, confocal microscopy, radioligand binding, flow cytometry, and cell and tumor growth assessments with mechanism analysis in vitro and for nu/nu mice. A successful end-point of our Phase 2 studies would be the generation of cAbner and/or hAbner forms of our antibody that show a similar binding affinity as mAbner, recognize all or most recurrent (and primary) cancers, do not react with normal tissues, and can reduce the size of tumors, and/or prevent their growth in vivo. The proposed research is expected to rapidly lead to new and successful therapeutic approaches for managing recurrent small-cell lung cancer.

描述（由申请人提供）：目前尚无对复发小细胞肺癌（RSCLC）的有效治疗方法。该项目的目的是利用单克隆抗体Abner开发RSCLC的新，理性和成功治疗。测试的假设是，这些肿瘤上存在的异常加压素2型受体（ABNV2R）将为Abner抗体有效治疗提供一个敏感，肿瘤特异性且可靠的靶标。来自该项目第一阶段研究的数据清楚地表明，具有天然和90塔标记的小鼠abner的变异SCLC肿瘤异种移植物的处理显着减慢了生长，但是当抗体治疗遵循环磷酰胺时，这种生长完全受损。我们的数据表明ABNV2R表达是所有人或大多数SCLC共有的特征，并且ABNV2R是表面蛋白。第2阶段是通过开发小鼠单克隆抗体的人类嵌合形式（CABNER），然后将人源化形式（HABNER）作为潜在的临床候选者来推进RSCLC的治疗。然后，将测试Cabner和Habner靶向和防止人类变体SCLC异种移植物在小鼠中的生长的能力。第2阶段目标是针对（i）产生小鼠abner的嵌合形式（CABNER），该形式具有人IgG1的恒定区域； （ii）确定马布纳的靶向，识别和治疗概况由卡伯纳保留； （iii）对Cabner的Abner的人性化形式（HABNER）对MMAG-1的VH和VL区域进行了遗传接枝的CDR，以将CDR植入人类抗体的DNA框架中； （iv）确定马布纳（Habner）保留了马布纳（Mabner）的靶向，识别和治疗谱。 These investigations will employ, RT-PCR, ligation, and cloning, DNA recombinance, DNA sequencing, immunohistochemistry, antibody modification, Northern and Western analysis with densiometric quantitation, ELISA, RIA, tumor-directed targeting, whole-body scintigraphy for 99mTechnetium, cytofluorographic and radiometric quantitation, confocal microscopy,通过体外和NU/NU小鼠的机制分析，放射性结合，流式细胞仪以及细胞和肿瘤生长评估。我们2阶段研究的成功终点是我们的抗体的Cabner和/或Habner形式的产生，它们表现出与Mabner相似的结合亲和力，识别全部或大多数复发性（和原发性）癌症，不会与正常组织反应，并且可以减少肿瘤的大小和/或在体内预防其生长。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。