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.

转移性去势抵抗性前列腺癌（CRPC; PCa）占PCa死亡的约90%， 与骨转移有关。CRPC对患者的影响不同，使这种疾病难以治疗。 医生提供标准化的治疗，具有类似的结果。多西他赛可以延长 转移性CRPC患者的生存率，但目前的治疗不能治愈。Docetonnon- 选择性靶向快速分裂的细胞群，但也会引起全身毒性。CRPC细胞具有 相对缓慢的增长速度。因此，开发针对增殖性较低、转移性CRPC的治疗方法至关重要 沿着标准化疗。为了解决这些问题，莫尔豪斯学院的研究人员 医药和JYANT Technologies，Inc.已经确定了控制PCa细胞生长的关键途径， 转移和多西他赛缓解率-CCL 25：CCR 9轴。我们最近出版的和令人兴奋的 支持性数据显示i）CCR 9由PCa细胞和肿瘤高度表达，并介导PCa ii）CCL 25，CCR 9的唯一配体，在前列腺肿瘤和PCa患者血清中升高，iii） 荷瘤小鼠的骨髓基质细胞显著产生CCL 25，和iv）阻断CCL 25- CCR 9轴使PCa细胞对多西他赛敏感。重要的是，我们发现我们的鼠抗人CCL 25 候选抗体使在SCID小鼠股骨中建立的CRPC异种移植物收缩。考虑到这些 JYANT Technologies寻求开发人源化抗人CCL 25单克隆抗体（CCL 25 HuMAB）用于治疗CRPC。为了完成这些目标，我们将使用临床相关的小鼠 溶骨性和成骨性CRPC以及紫杉醇耐药异种移植物模型，以进行以下研究 目的： 目的使用未处理B6小鼠确定免疫原性，并确定CCL 25 HuMAB的PK/PD特征， SCID小鼠中携带表达胰蛋白酶的溶骨性（PC 3-luc）和成骨细胞（C4-2b-luc）异种移植物， 股骨 目的探讨CCL 25 HuMAB的全身毒性和免疫毒性，以及CCL 25 HuMAB抑制人肝癌细胞增殖的有效性。 前列腺肿瘤生长和骨中的紫杉醇耐药性，使用去势后在股骨中激发的SCID小鼠 耐药（PC 3-luc和C4-2b-luc）和/或耐紫杉醇（PC 3R-luc和C4-2bR-luc）的PCa细胞系。