Evaluation of In Vitro Companion Diagnostic Monoclonal Antibodies for Use in a St

用于临床试验的体外伴随诊断单克隆抗体的评价

• 批准号: 8652703
• 负责人: Sunil S. Badve
• 金额: $ 14.98万
• 依托单位: INTICA BIOMEDICAL, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-25 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8652703
• 关键词: Animals; Anoikis; Apoptosis; Benefits and Risks; Biological Assay; Biopsy; Breast; Breast Cancer Cell; Cancer Diagnostics; Cancer Patient; Cancer cell line; Cell Line; Characteristics; Clinical; Companions; Contracts; Development; Devices; Diagnostic; Diagnostic tests; Disseminated Malignant Neoplasm; Dose; Drug Kinetics; Endothelin-1; Estrogens; Evaluation; Funding; Glioblastoma; Grant; Growth; Human; IgG1; In Vitro; Investigational New Drug Application; Malignant Neoplasms; Methods; Modeling; Monoclonal Antibodies; Neoplasm Metastasis; Neoplasms in Vascular Tissue; Oncologist; Organ; Pancreatic Adenocarcinoma; Pathologist; Pathway interactions; Patients; Pattern; Peptide Signal Sequences; Phase; Phase I Clinical Trials; Primary Neoplasm; Process; Production; Progesterone; Recurrence; Regimen; Research; Resistance; Scoring Method; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Staining method; Stains; Surveys; Survival Analysis; System; Testing; Therapeutic; Therapeutic Monoclonal Antibodies; Toxic effect; Tumor Cell Line; United States National Institutes of Health; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; Xenograft Model; Xenograft procedure; angiogenesis; antiangiogenesis therapy; base; cancer stem cell; cancer therapy; cell type; clinical practice; commercial application; design; in vivo; malignant breast neoplasm; neoplastic cell; novel; oncology; pre-clinical; prevent; programs; receptor; receptor expression; research and development; response; signal recognition particle receptor; therapeutic angiogenesis; triple-negative invasive breast carcinoma; tumor

DESCRIPTION (provided by applicant): This project is designed to allow independent experts in the development and/or application of in vitro breast cancer diagnostic tests, Drs. Badve (breast pathologist) and Sledge (breast oncologist), to evaluate INTICA's candidate anti-DEspR mAbs to develop the preliminary materials and methods for a commercially viable companion diagnostic test. DEspR, the dual endothelin-1 (ET-1)/vascular endothelial growth factor (VEGF) signal peptide (VEGFsp) receptor is a novel, alternate pro-angiogenic/pro-metastatic cancer target and pathway involved in cancer resistance to anti-angiogenesis therapies. DEspR is expressed on tumor vascular endothelial cells (TVECs), tumor cells (TCs) and cancer stem cells (CSCs) in "triple-negative" (TNBC; estrogen, progesterone and Her2 receptor-negative) breast cancer (BCa), pancreatic adenocarcinoma (PCa) and glioblastoma multiforme (GBM) primary tumors and respective cell lines (MDA- MB-468, Panc-1, U87). INTICA is developing INTI-1, an Anti-DEspR Therapeutic mAb for use against DEspR+ cancers, such as TNBC, PCa and GBM, where anti-angiogenic therapies are ineffective despite the presence of VEGFRs on TVECs and some TCs. Anti-DEspR therapy in vitro prevents HUVEC angiogenesis, TC invasiveness and CSC tumorsphere formation and promotes CSC anoikis (apoptosis), and in vivo inhibits DEspR+ spontaneous tumor and CSC xenograft growth. INTICA is also developing a Companion Diagnostic (CDx) mAb as a commercial in vitro CDx device to stratify DEspR+ tumors for patient response to INTI-1. The Specific Aims of this project are: 1) to manufacture candidate CDx mAbs; 2) to survey human primary BCa/TNBC tumors and tumor microarrays (TMAs) for DEspR by immunohistochemical staining (IHCS) with candidate CDx mAbs, to: a) develop IHCS methods, b) correlate DEspR expression on TVECs, TCs and CSCs with tumor characteristics (e.g., grade, malignancy, invasiveness, vascularity), c) correlate DEspR expression with Oncotype DX" recurrence scores and survival analysis, and d) select the preferred CDx mAb; 3) to design a preliminary CDx IHCS scoring system to stratify DEspR+ tumors and identify BCa/TNBC cancer patients likely to benefit (or not benefit) from anti- DEspR therapy with INTI-1; and 4) to use these CDx methods to select human TNBC cell lines with varying DEspR expression for use in xenograft models to test INTI-1. The resulting CDx test will be used in Phase 1 clinical trials of INTI-1. Key Words. Cancer, TNBC, DEspR, INTI-1, companion diagnostic, anti-angiogenic, anti-metastatic, cancer stem cells Brief Summary. The discovery of DEspR, a novel target on cancer stem cells, tumor cells and tumor blood vessels, and pathway involved in cancer metastasis, recurrence and angiogenesis, provides a new treatment paradigm. Combined use of anti-DEspR companion diagnostic and therapeutic mAbs has the potential to alter oncology clinical practice, particularly in BCa/TNBC, as an addition to or advantage over existing treatments.

描述（由申请人提供）：该项目旨在让独立专家能够开发和/或应用体外乳腺癌诊断测试，博士。 Badve（乳腺病理学家）和 Sledge（乳腺肿瘤学家）评估 INTICA 的候选抗 DEspR mAb，以开发商业上可行的伴随诊断测试的初步材料和方法。 DEspR 是双重内皮素-1 (ET-1)/血管内皮生长因子 (VEGF) 信号肽 (VEGFsp) 受体，是一种新型、替代的促血管生成/促转移癌症靶点和途径，涉及癌症对抗血管生成治疗的耐药性。 DEspR 在“三阴性”（TNBC；雌激素、孕激素和 Her2 受体阴性）乳腺癌 (BCa)、胰腺癌 (PCa) 和多形性胶质母细胞瘤 (GBM) 原发肿瘤和各自细胞系的肿瘤血管内皮细胞 (TVEC)、肿瘤细胞 (TC) 和癌症干细胞 (CSC) 上表达 (MDA-MB-468、Panc-1、U87)。 INTICA 正在开发 INTI-1，这是一种抗 DEspR 治疗性单克隆抗体，用于治疗 DEspR+ 癌症，例如 TNBC、PCa 和 GBM，在这些癌症中，尽管 TVEC 和一些 TC 上存在 VEGFR，但抗血管生成疗法仍无效。抗 DEspR 疗法在体外可防止 HUVEC 血管生成、TC 侵袭和 CSC 肿瘤球形成并促进 CSC 失巢凋亡（细胞凋亡），在体内抑制 DEspR+ 自发肿瘤和 CSC 异种移植物生长。 INTICA 还在开发一种伴随诊断 (CDx) mAb 作为商业体外 CDx 设备，用于对 DEspR+ 肿瘤进行分层，以确定患者对 INTI-1 的反应。该项目的具体目标是： 1) 生产候选 CDx mAb； 2) 通过使用候选 CDx mAb 进行免疫组织化学染色 (IHCS) 来调查人原发性 BCa/TNBC 肿瘤和肿瘤微阵列 (TMA) 中的 DEspR，目的是：a) 开发 IHCS 方法，b) 将 TVEC、TC 和 CSC 上的 DEspR 表达与肿瘤特征（例如分级、恶性、侵袭性、血管分布）相关联，c) 关联 使用 Oncotype DX 进行 DEspR 表达复发评分和生存分析，d) 选择首选 CDx mAb；3) 设计初步 CDx IHCS 评分系统，对 DEspR+ 肿瘤进行分层，并识别可能从 INTI-1 抗 DEspR 治疗中受益（或不受益）的 BCa/TNBC 癌症患者；4) 使用这些 CDx 方法来选择具有不同 DEspR 表达的人 TNBC 细胞系 在异种移植模型中测试 INTI-1。由此产生的 CDx 测试将用于 INTI-1 的 1 期临床试验。关键词。癌症、TNBC、DEspR、INTI-1、伴随诊断、抗血管生成、抗转移、癌症干细胞简要总结。发现癌症干细胞、肿瘤细胞和肿瘤血管的新靶点DEspR，以及参与癌症转移、复发和复发的通路 血管生成，提供了新的治疗范例。抗 DEspR 伴随诊断和治疗单克隆抗体的联合使用有可能改变肿瘤学临床实践，特别是在 BCa/TNBC 中，作为现有治疗的补充或优势。