Anti-CCL25 mAb to treat castration resistant prostate cancer

转移性去势耐受前列腺癌(CRPC；PCA)占前列腺癌死亡的90%左右， 与骨骼转移有关。CRPC对患者的影响不同，使这种疾病难以 医生提供具有类似结果的标准化治疗。多西紫杉醇可延长整体 转移性CRPC患者的存活率，但目前的治疗方法并不能提供治愈。多西紫杉醇非- 选择性地针对快速分裂的细胞群体，但也会引起全身毒性。CRPC细胞有一个 增长速度相对较慢。因此，开发针对较少增殖、转移的CRPC的治疗方法是至关重要的。 细胞以及标准的化疗方法。为了解决这些问题，莫尔豪斯学院的调查人员 Medical和JYANT Technologies，Inc.已经确定了一条控制PCa细胞生长的关键途径， 转移和多西紫杉醇应答率-CCL25：CCR9轴。我们最近出版的令人兴奋的 支持数据表明：1)CCR9在PCa细胞和肿瘤中高表达，并介导PCa 进展，II)CCL25，CCR9的唯一配体，在前列腺癌和前列腺癌患者血清中升高，III) 荷瘤小鼠骨髓基质细胞显著产生CCL25，iv)阻断CCL25- CCR9轴使PCa细胞对多西紫杉醇增敏。重要的是，我们发现我们的鼠抗人CCL25 候选抗体缩小在SCID小鼠股骨中建立的CRPC异种移植。考虑到这些 JYANT Technologies寻求开发人源化抗人CCL25单抗(CCL25 HuMAB)治疗慢性前列腺癌。为了完成这些目标，我们将使用临床相关的鼠标 溶骨型和成骨型CRPC模型以及多西紫杉醇耐药异种移植模型 目标： 目的研究CCL25HuMAb在幼稚B6小鼠体内的免疫原性及PK/PD谱。 SCID小鼠携带表达荧光素酶的溶骨细胞(PC3-Luc)和成骨细胞(C4-2b-Luc)异种移植 大腿骨。 目的二测定CCL25HuMAb的全身毒性和免疫毒性以及抑制作用 去势激发股骨SCID小鼠的前列腺癌生长和骨中多西紫杉醇耐药性 耐药(PC3-LUC和C4-2b-LUC)和/或多西紫杉醇耐药(PC3R-LUC和C4-2BR-LUC)的PCa细胞株。

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.