Prolactin monoclonal antibodies (PRL-mAbs) for the treatment of female-predominant pain syndromes

摘要：女性受到功能性疼痛综合征（FPS）的严重影响， 由缺乏明确病因或组织损伤定义的疼痛状况。这些综合征具有高 女性：男性患病率比，包括但不限于颞下颌关节和肌肉疾病 （TMJD）（9：1比率）、纤维肌痛（9：1比率）、肠易激综合征（IBS）（3：1比率）和偏头痛（3：1比率）， 以及痛经、子宫内膜异位症、外阴痛等女性专属FPS。 FPS中性二态患病率的原因仍不确定，但新出现的证据表明， 催乳素（PRL）增强女性伤害感受器的敏感性。催乳素选择性地促进痛觉过敏和疼痛， 雌性小鼠对雄性动物的影响最小。PRL信号通过相互抑制的长和短形式 在雌性伤害感受器中以较高水平表达的PRL受体（PRLR）亚型。雌性动物和 人类比男性具有更高的循环PRL。循环PRL的作用通过预防 卡麦角林（一种多巴胺能D2激动剂， 抑制垂体释放催乳素。同样，与PRL分泌肿瘤相关的偏头痛也可以治疗， D2激动剂。总的来说，这些数据支持PRL选择性地促进女性痛觉过敏。 我们的团队现在希望将这些突破性的发现转化为新的和变革性的治疗方法， 女性普遍的疼痛状况。我们建议开发PRL单克隆抗体（PRL-mAbs）作为第一批 类治疗女性FPS，针对偏头痛作为主要适应症。 该SBIR第一阶段应用的具体目标是（i）评估该计划的技术可行性（即， 中和PRL-mAb先导物的鉴定）和（ii）验证工作假设（即，示威 全身给予中和性PRL-mAb选择性地预防PRL诱导的雌性痛觉过敏， 偏头痛相关模型）。 影响和

ABSTRACT: Women are disproportionally impacted by functional pain syndromes (FPS), a large subgroup of pain conditions defined by the absence of a clear etiology or tissue injury. These syndromes have a high female:male prevalence ratio and include, but are not limited to, temporomandibular joint and muscle disorders (TMJD) (9:1 ratio), fibromyalgia (9:1 ratio), irritable bowel syndrome (IBS) (3:1 ratio), and migraine (3:1 ratio), as well as female exclusive FPS such as dysmenorrhea, endometriosis and vulvodynia. Reasons for the sexually dimorphic prevalence in FPS remain uncertain but emerging evidence suggests that prolactin (PRL) elicits sensitization of female nociceptors. PRL selectively promotes hyperalgesia and pain in female mice with minimal effects in male animals. PRL signals through mutually inhibitory long- and short-form PRL receptor (PRLR) isoforms that are expressed at higher levels in female nociceptors. Female animals and humans have higher circulating PRL than males. A role for circulating PRL was demonstrated by prevention of opioid-induced hyperalgesia (OIH) selectively in female mice by cabergoline, a dopaminergic D2 agonist which inhibits PRL release from the pituitary. Similarly, migraines associated with PRL-secreting tumors are treated with D2 agonists. Collectively, these data support that PRL selectively promotes female hyperalgesia. Our team now wishes to translate these breakthrough findings into novel and transformative therapeutics for female-prevalent pain conditions. We propose to develop PRL monoclonal antibodies (PRL-mAbs) as first-in- class therapeutics for female FPS, targeting migraine as the primary indication. The specific goals of this SBIR Phase I application are to (i) assess the technical feasibility of the program (i.e., identification of neutralizing PRL-mAb leads) and (ii) validate the working hypothesis (i.e., demonstration that systemic administration of a neutralizing PRL-mAb selectively prevents PRL-induced female hyperalgesia in a migraine relevant model). Impact and