Therapeutic antibody for hyperemesis gravidarum 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 withsignificant 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 whichsegregated with disease in HG families. A genome-wide association study implicated GDF15, also known asMIC-1 in HG. Serum GDF15 levels are positively associated with second trimester vomiting and maternalantiemetic use. GDF15's site of action in the chemoreceptor trigger zone of the brainstem, together with itsgenetic association with HG, the genetic and serum association data support a key pathogenic role for GDF15in HG and support development of a neutralizing antibody. In cancer-associated cachexia models, GDF15-mediated weight loss is reversed by a monoclonal antibodyto GDF15. GDF15 knockout mice are resistant to chemotherapy-induced nausea. GDF15 neutralization with amonoclonal antibody improves survival of mice after chemotherapy-induced anorexia and weight loss andattenuates anorexia and emesis in non-human primates (NHP). These results support preclinical developmentof GDF-15 monoclonal antibodies to establish efficacy and safety for use during pregnancy as a potentialtherapeutic for HG to improve maternal and neonatal outcomes. During this Phase 1 project, we will conductpreclinical toxicity studies of our lead humanized anti-GDF15 monoclonal antibody and will evaluate the antibodyin an animal model relevant to HG.
Public Health Relevance Statement: Narrative
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. We describe a targeted
therapeutic antibody that will reverse nausea and vomiting, improving maternal quality of life and both maternal
and neonatal outcomes.
Project Terms: <7S Gamma Globulin><2nd trimester>
