Therapeutic antibody for hyperemesis gravidarum

Therapeutic antibody for hyperemesis gravidarum AbstractHyperemesis 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.