optimized Human Apyrase for Bone Cancer Pain Treatment

描述（申请人提供）：骨转移在晚期乳腺癌、前列腺癌和肺癌患者中很常见，因为这些肿瘤具有显著的骨转移能力。三分之二的转移性骨癌患者经历严重的疼痛，通常描述为特征迟钝，表现不变，并且随着时间的推移逐渐增加强度。骨癌疼痛是所有持续性疼痛中最难控制的疼痛之一，因为转移通常不局限于单一部位，骨癌疼痛与独特的病理生理有关。非甾体抗炎药（NSAIDs）和阿片类药物是最常用的镇痛药，但它们有明显的副作用，如胃出血和神经精神症状。APT102是CD39家族的专有、优化的人类酶。APT102选择性地清除过量的促炎和致痛ATP和促转移ADP为AMP，从而减轻血管炎症，防止转移，减轻疼痛。无处不在的CD73进一步将AMP代谢为腺苷，这已被证明可以减轻人类的神经性疼痛。因此，APT102的镇痛作用来自ATP的消除和腺苷的产生。在拟议的研究中，我们将评估APT102在溶骨性骨癌疼痛模型中的剂量反应。该模型是通过胫骨注射同源MRMT-1大鼠乳腺癌细胞驱动的，与人类的情况密切相关。我们还将在健康大鼠的旋转体和功能观察电池（FOB）试验中确定APT102的潜在副作用。长期目标是开发APT102作为一种安全有效的镇痛疗法。每周或每两周给药将为骨癌疼痛患者提供持续的疼痛缓解，没有明显的副作用或成瘾性。

DESCRIPTION (provided by applicant): Bone metastasis is common in patients with advanced breast, prostate, and lung cancers as these tumors have a remarkable ability to metastasize to bone. Two-thirds of patients with metastatic bone cancer experience severe pain which is usually described as dull in character, constant in presentation, and gradually increasing in intensity with time. Bone cancer pain is one of the most difficult of all persistent pains to control because the metastases are generally not limited to a single site and bone cancer pain is associated with unique pathophysiology. Nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids are the most commonly used an- algesics, but are limited by significant adverse side effects, such as gastric bleeding and neuropsychiatric symptoms. APT102 is a proprietary, optimized human apyrase of the CD39 family. APT102 selectively scav- enges excess pro-inflammatory and algogenic ATP and pro-metastatic ADP to AMP, thereby attenuating vas- cular inflammation, preventing metastasis, and reducing pain. Ubiquitous CD73 further metabolizes AMP to adenosine, which has been shown to reduce neuropathic pain in humans. Hence, the analgesic effect of APT102 results both from the elimination of ATP and from the production of adenosine. In the proposed studies, we will evaluate the dose-response of APT102 in a model of osteolytic bone cancer pain. This model is driven by in- tra-tibial injections of syngeneic MRMT-1 rat mammary gland carcinoma cells and closely mirrors the human condition. We also will determine the potential side effects of APT102 in the rotarod and Functional Observa- tional Battery (FOB) assays in healthy rats. The long-term goal is to develop APT102 as a safe and effective analgesic therapy. Weekly or bi-weekly dosing will provide sustained pain relief for bone cancer pain patients without significant side effects or addiction.