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

摘要：女性不成比例地受到功能性疼痛综合征(FPS)的影响，FPS是功能性疼痛综合征的一个大亚群 没有明确的病因或组织损伤的疼痛状况。这些症状有很高的 女性：男性患病率，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)，AS 以及女性独有的FPS，如痛经、子宫内膜异位症和外阴疼痛。 FPS中性二型性流行的原因尚不清楚，但新出现的证据表明 催乳素(PRL)可引起女性伤害性感受器的敏化。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。长短波相互抑制的PRL信号 PRL受体(PRLR)亚型在雌性伤害性感受器中表达水平较高。雌性动物和 人类的血液中催乳素水平高于男性。循环催乳素的作用被证明是通过预防 卡麦角林选择性地诱导雌性小鼠阿片样痛敏(OIH)，卡麦角林是多巴胺能D2激动剂， 抑制垂体腺分泌催乳素。同样，与催乳素分泌肿瘤相关的偏头痛也得到了治疗 使用D2激动剂。总而言之，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疗法 女性--普遍的疼痛状况。我们建议开发PRL单抗(PRL-mAbs)作为第一个用于... 女性FPS的类疗法，以偏头痛为主要适应症。 该SBIR阶段I应用的具体目标是(I)评估该计划的技术可行性(即， 中和性PRL-mAb导联的鉴定)和(Ii)验证工作假设(即，证明 全身给予中和性PRL-mAb选择性地预防PRL诱导的雌性小鼠痛敏 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