Therapeutic antibody for hyperemesis gravidarum

妊娠期剧吐治疗性抗体 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，影响0.3- 2%的怀孕。HG是怀孕期间住院的主要原因，并与 严重的孕产妇和胎儿发病率。目前还没有有效的治疗选择。 遗传学研究支持HG的遗传病因学。生长分化因子15的分析 过度表达的等位基因发现了与更高水平的GDF15相关的单核苷酸多态 在HG家系中以疾病隔离。一项全基因组关联研究表明，GDF15也被称为 HG中的麦克风-1。血清GDF15水平与妊娠中期呕吐和孕妇 止吐用法。GDF15‘S在脑干化学感受器触发区的作用部位及其 与HG的遗传关联，遗传和血清关联数据支持GDF15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，GDF15介导的体重减轻可被单抗逆转 至GDF15。GDF15基因敲除小鼠对化疗引起的恶心具有抵抗力。GDF15中和 单抗可改善化疗引起的厌食和体重减轻小鼠的存活率 减轻非人类灵长类(NHP)的厌食和呕吐。这些结果支持临床前发展。 GDF-15单抗作为潜在的妊娠期应用的有效性和安全性 治疗HG以改善孕产妇和新生儿的结局。在这一期工程中，我们将进行 我们的铅人源化抗GDF15单抗的临床前毒性研究并将对该抗体进行评价 在与HG相关的动物模型中。

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.