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Therapeutic antibody for hyperemesis gravidarum

妊娠剧吐治疗性抗体

基本信息

批准号：
10601709
负责人：
JAMES W LARRICK
金额：
$ 30.08万
依托单位：
LARIX BIOSCIENCE, LLC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-19 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10601709
关键词：
Affect Alleles Animal Model Anorexia Antibodies Antiemetics Attenuated Behavior Body Weight decreased Brain Stem Chemoreceptors Data Development Disease Drug Kinetics Emetics Exhibits Family Ferrets Funding GDF15 gene Genetic Genetic Predisposition to Disease Genetic study Hospitalization Human Hyperemesis Gravidarum IgG2 IgG4 Immunoglobulin G Knockout Mice Lead Link Mediating Modeling Monoclonal Antibodies Morbidity - disease rate Mus Nausea Nausea and Vomiting Outcome Pathogenicity Phase Pica Disease Pregnancy Quality of life Rattus Reporting Resistance Role Safety Second Pregnancy Trimester Secure Serum Shrews Single Nucleotide Polymorphism Site Syndrome Testing Therapeutic Therapeutic Uses Therapeutic antibodies Time Toxicology Twin Studies Vomiting Work cancer cachexia chemotherapy developmental toxicity effective therapy experimental study family support fetal first-in-human genetic association genome wide association study humanized antibody immunogenicity improved in vivo maternal outcome neonatal outcome neutralizing antibody nonhuman primate overexpression placental transfer preclinical development preclinical toxicity pregnant response targeted treatment

项目摘要

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.

妊娠剧吐治疗抗体