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

基本信息

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
项目类别：
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

项目摘要

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%，并且与骨骼转移相关的 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可以延长总体疗效。转移性 CRPC 患者的生存率较高，但目前的疗法无法提供非多西紫杉醇治疗。选择性地靶向快速分裂的细胞群，同时也会导致 CRPC 细胞产生全身毒性。因此，开发针对增殖性较低的转移性 CRPC 的治疗方法至关重要。为了解决这些问题，莫尔豪斯学院的研究人员进行了研究。 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——我们最近发表的令人兴奋的 CCL25:CCR9 轴。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，我们证明了我们的鼠抗人 CCL25。考虑到这些，候选抗体可缩小 SCID 小鼠股骨中建立的 CRPC 异种移植物。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。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The TLK1-Nek1 axis promotes prostate cancer progression.

TLK1-Nek1 轴促进前列腺癌进展。

DOI：
发表时间：
2019
期刊：
影响因子：
9.7
作者：
Singh, Vibha;Jaiswal, Praveen Kumar;Ghosh, Ishita;Koul, Hari K;Yu, Xiuping;De Benedetti, Arrigo
通讯作者：
De Benedetti, Arrigo

Targeting the deubiquitinase STAMBPL1 triggers apoptosis in prostate cancer cells by promoting XIAP degradation.

靶向去泛素酶 STAMBPL1 通过促进 XIAP 降解来触发前列腺癌细胞凋亡。