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) 约占 PCa 死亡人数的 90%，并且 与骨骼转移有关。 CRPC 对患者的影响不同，使得这种疾病难以治疗 医生提供具有类似结果的标准化治疗。多西他赛可以延长总体寿命 转移性 CRPC 患者的生存率很高，但目前的疗法无法治愈。多西他赛非 选择性地针对快速分裂的细胞群，但也会引起全身毒性。 CRPC 细胞具有 增长速度相对缓慢。因此，开发针对增殖性较低、转移性 CRPC 的治疗方法至关重要 细胞以及标准化疗。为了解决这些问题，莫尔豪斯学院的研究人员 Medicine 和 JYANT Technologies, Inc. 已经确定了控制 PCa 细胞生长的关键途径， 转移和多西紫杉醇缓解率 – CCL25:CCR9 轴。我们最近发布的令人兴奋的 支持性数据表明 i) CCR9 在 PCa 细胞和肿瘤中高表达并介导 PCa ii) CCL25（CCR9 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着产生 CCL25，并且 iv) 阻断 CCL25- CCR9 轴使 PCa 细胞对多西紫杉醇敏感。重要的是，我们证明我们的鼠抗人 CCL25 候选抗体可缩小 SCID 小鼠股骨中建立的 CRPC 异种移植物。考虑到这些 研究结果显示，JYANT Technologies 寻求开发人源化抗人 CCL25 单克隆抗体（CCL25 HuMAB）用于治疗 CRPC。为了完成这些目标，我们将使用临床相关的小鼠 溶骨性和成骨性 CRPC 以及多西紫杉醇耐药异种移植模型，以进行以下操作 目标： Aim One 将使用初始 B6 小鼠确定 CCL25 HuMAB 的免疫原性以及 CCL25 HuMAB 的 PK/PD 特征， SCID 小鼠携带表达荧光素酶的溶骨 (PC3-luc) 和成骨细胞 (C4-2b-luc) 异种移植物 股骨。 目标二将确定 CCL25 HuMAB 的全身和免疫毒性以及抑制的功效 前列腺肿瘤生长和骨中多西紫杉醇耐药性，使用股骨受到去势攻击的 SCID 小鼠 耐药（PC3-luc 和 C4-2b-luc）和/或多西紫杉醇耐药（PC3R-luc 和 C4-2bR-luc）PCa 细胞系。