Anti-CCL25 mAb to treat castration resistant prostate cancer

抗 CCL25 mAb 用于治疗去势抵抗性前列腺癌

• 批准号: 9264953
• 负责人: Shailesh Singh
• 金额: $ 35万
• 依托单位: JYANT, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9264953
• 关键词: Address; Adjuvant; Adverse drug event; Affect; Antibodies; Antibody Response; Apoptosis; B-Lymphocyte Epitopes; Biological; Blood; Blood Chemical Analysis; Bone Marrow; Bone neoplasms; CCL25 gene; CCR9 gene; CD4 Positive T Lymphocytes; Caspase; Castration; Cell Line; Cells; Cessation of life; Clinical; Critical Pathways; Data; Disease; Dose; Engineering; Enzyme-Linked Immunosorbent Assay; Epithelium; Epitopes; Femur; Flow Cytometry; Frequencies; Growth; Helper-Inducer T-Lymphocyte; Hormones; Hour; Human; Immune; Immunofluorescence Immunologic; Implant; In Situ Nick-End Labeling; Inflammation; Injection of therapeutic agent; Intervention; Laboratories; Lead; Leukocytes; Ligands; Luciferases; Measures; Mediating; Metastatic Neoplasm to the Bone; Metastatic to; Methodology; Modeling; Monitor; Monoclonal Antibodies; Morehouse School of Medicine; Mus; Neoplasm Metastasis; Organ; Osteolytic; Outcome; PC3 cell line; PTK2 gene; Patients; Pharmaceutical Preparations; Phase; Phenotype; Phosphotransferases; Photons; Physicians; Play; Population; Process; Production; Prostate; Prostatic Neoplasms; Publications; Publishing; Race; Refractory; Reporting; Research; Research Personnel; Resistance; Role; SCID Mice; Saline; Sampling; Serum; Site; Small Business Technology Transfer Research; Staining method; Stains; Standardization; Stromal Cells; T-Lymphocyte; Technology; Testing; Time; Tissues; Toxic effect; Translating; Tumor Biology; Uncertainty; Validation; Whole Blood; Xenograft procedure; base; bone; castration resistant prostate cancer; cell growth; cell motility; chemokine; chemotherapy; clinically relevant; docetaxel; dosage; human monoclonal antibodies; imaging system; immunogenicity; improved; luminescence; mortality; mouse model; neoplastic cell; non-invasive monitor; novel therapeutics; overexpression; receptor; response; standard of care; systemic toxicity; therapy development; therapy outcome; trafficking; tumor; tumor growth

Metastatic castration resistant prostate cancer (CRPC; PCa) accounts for ~90% of PCa deaths and is associated with skeletal metastases. CRPC affects patients differently, making this disease difficult for physicians to provide standardized treatments with similar outcomes. Docetaxel can prolong the overall survival in patients with metastatic CRPC, but current therapies do not provide a cure. Docetaxel non- selectively targets rapidly dividing cell populations, but also causes systemic toxicities. CRPC cells have a relative slow growth rate. Hence, it is crucial to develop therapies to target less-proliferative, metastatic CRPC cells along with standard chemotherapies. To address these issues, investigators at Morehouse School of Medicine and JYANT Technologies, Inc. have identified a critical pathway that controls PCa cell growth, metastasis, and docetaxel response rates – the CCL25:CCR9 axis. Our recently published and exciting supportive data show that i) CCR9 is highly expressed by PCa cells and tumors and mediates PCa progression, ii) CCL25, the sole ligand for CCR9, is elevated in prostate tumors and PCa patient serum, iii) bone marrow stromal cells of tumor-bearing mice significantly produce CCL25, and iv) blockade of the CCL25- CCR9 axis sensitizes PCa cells to docetaxel. Importantly, we show that our murine anti-human CCL25 antibody candidate shrinks CRPC xenografts established in femurs of SCID mice. In consideration of these findings, JYANT Technologies seeks to develop a humanized anti-human CCL25 monoclonal antibody (CCL25 HuMAB) for the treatment of CRPC. To complete these objectives, we will use clinically relevant mouse models of osteolytic and osteoblastic CRPC as well as docetaxel-resistant xenografts to carryout the following aims: Aim One will ascertain the immunogenicity, using naïve B6 mice, and the PK/PD profile of CCL25 HuMAB, in SCID mice bearing luciferase-expressing osteolytic (PC3-luc) and osteoblastic (C4-2b-luc) xenografts in femurs. Aim Two will determine the systemic and immune toxicity as well as the efficacy of CCL25 HuMAB to inhibit prostate tumor growth and docetaxel-resistance in bone, using SCID mice challenged in femurs with castration resistant (PC3-luc and C4-2b-luc) and/or docetaxel-resistant (PC3R-luc and C4-2bR-luc) PCa cell lines.

转移性cast割抗性前列腺癌（CRPC; PCA）占PCA死亡的90％，IS 与骨骼转移有关。 CRPC对患者的影响有所不同，这使得这种疾病难以 医生提供具有相似结果的标准化治疗方法。多西他赛可以延长整体 转移性CRPC患者的生存期，但目前的疗法无法治愈。多西他赛非 - 有选择地靶向迅速分裂的细胞群体，但也会引起全身毒性。 CRPC细胞具有 相对缓慢的生长速率。因此，开发疗法以靶向靶向较低的转移性CRPC至关重要 细胞以及标准化学疗法。为了解决这些问题，Morehouse学校的调查人员 Medicine and Jyant Technologies，Inc。已经确定了控制PCA细胞生长的关键途径， 转移和多西他赛响应率 - CCL25：CCR9轴。我们最近出版和令人兴奋的 支持数据表明，i）CCR9由PCA细胞和肿瘤高度表达并介导PCA 进展，II）CCL25，CCR9的唯一配体，在前列腺肿瘤和PCA患者血清中升高，III） 含有肿瘤小鼠的骨髓基质细胞显着产生了CCL25，而IV）CCL25- CCR9轴将PCA细胞感应到多西他赛。重要的是，我们表明我们的鼠抗人CCL25 抗体候选者收缩在SCID小鼠股骨中建立的CRPC Xenographictics。考虑到这些 调查结果，Jyant Technologies试图开发人性化的抗人CCL25单克隆抗体（CCL25 HUMAB）用于治疗CRPC。为了完成这些目标，我们将使用临床上相关的鼠标 骨质和成骨细胞CRPC的模型以及抗多西他赛的异种移植物以携带以下 目标： AIM ONE将使用幼稚的B6小鼠确定免疫原性，以及CCL25 Humab的PK/PD轮廓 带有表达荧光素酶的溶性（PC3-LUC）和成骨细胞（C4-2B-LUC）异种移植的SCID小鼠 股骨。 目标两个将确定系统性和免疫毒性以及CCL25 Humab抑制的效率 使用在股骨上挑战的SCID小鼠，前列腺肿瘤的生长和多西他赛的抗性 抗性（PC3-LUC和C4-2B-LUC）和/或抗多西他赛（PC3R-LUC和C4-2BR-LUC）PCA细胞系。