Therapeutic antibody for hyperemesis gravidarum

妊娠剧吐治疗性抗体 摘要 妊娠剧吐（HG）是一种涉及极度恶心和呕吐的妊娠综合征， 2%的孕妇。HG是妊娠期间住院的主要原因，与 产妇和胎儿发病率显著。没有有效的治疗方案。 遗传学研究支持遗传病因HG。生长分化因子15（GDF 15）的分析 过表达等位基因鉴定出与较高水平GDF 15相关的单核苷酸多态性， 在HG家族中与疾病分离。一项全基因组关联研究涉及GDF 15，也称为 HG中的MIC-1。血清GDF 15水平与孕中期呕吐和母体妊娠呈正相关。 止吐药的使用。GDF 15在脑干的化学感受器触发区的作用位点，连同其在脑干的化学感受器触发区的作用位点， 与HG的遗传关联，遗传和血清关联数据支持GDF 15的关键致病作用 并支持中和抗体的开发。 在癌症相关恶病质模型中，GDF 15介导的体重减轻被单克隆抗体逆转 GDF15 GDF 15敲除小鼠对化疗诱导的恶心具有抗性。GDF 15中和， 单克隆抗体改善了化疗诱导的厌食和体重减轻后小鼠的存活率， 减轻非人灵长类动物（NHP）的厌食和呕吐。这些结果支持临床前开发 GDF-15单克隆抗体，以确定妊娠期间使用的有效性和安全性， 治疗HG以改善孕产妇和新生儿结局。在第一阶段，我们将 我们的主要人源化抗GDF 15单克隆抗体的临床前毒性研究，并将评估该抗体 在HG相关动物模型中。

Therapeutic antibody for hyperemesis gravidarum Abstract Hyperemesis gravidarum (HG), a syndrome of pregnancy involving extreme nausea and vomiting, affects 0.3- 2% of pregnancies. HG is a major cause of hospital admissions during pregnancy and is associated with significant maternal and fetal morbidity. There are no effective treatment options. Genetic studies support a genetic etiology for HG. An analysis of growth differentiation factor 15 (GDF15) over-expression alleles identified single-nucleotide polymorphisms linked to higher levels of GDF15 which segregated with disease in HG families. A genome-wide association study implicated GDF15, also known as MIC-1 in HG. Serum GDF15 levels are positively associated with second trimester vomiting and maternal antiemetic use. GDF15’s site of action in the chemoreceptor trigger zone of the brainstem, together with its genetic association with HG, the genetic and serum association data support a key pathogenic role for GDF15 in HG and support development of a neutralizing antibody. In cancer-associated cachexia models, GDF15-mediated weight loss is reversed by a monoclonal antibody to GDF15. GDF15 knockout mice are resistant to chemotherapy-induced nausea. GDF15 neutralization with a monoclonal antibody improves survival of mice after chemotherapy-induced anorexia and weight loss and attenuates anorexia and emesis in non-human primates (NHP). These results support preclinical development of GDF-15 monoclonal antibodies to establish efficacy and safety for use during pregnancy as a potential therapeutic for HG to improve maternal and neonatal outcomes. During this Phase 1 project, we will conduct preclinical toxicity studies of our lead humanized anti-GDF15 monoclonal antibody and will evaluate the antibody in an animal model relevant to HG.