The resistin-like molecule (RELM) family of proteins comprises pleiotropic cytokines critically involved in the vascular remodeling and cardiac dysfunction seen in animal and human pulmonary arterial hypertension (PH). Our rodent and human work and the work of others strongly suggests that human resistin (hResistin) and human RELM? (hRELM?) are mechanistically important to the etiology of human PH and associated right ventricular dysfunction (RVD) and serve as potential biomarkers and therapeutic targets for this disease. IN the CADET I we accomplished target validation and developed a series of human antibodies against hResistin and against hRELM? including some that recognized both targets.
The first aim (UH2) will identify an optimal lead antibody through biophysical and antigen-antibody interaction studies, antibody inhibition of target effects in cell based assays, and clinical efficacy studies of antibodies in our humanized overexpressing resistin and RELM? mouse models of PH. It will also include antibody affinity maturation and optimization as needed and initial GLP cell line selection and optimization.
This aim will further assess the selectivity, functionality and """"""""drugability"""""""" of our lead candidates.
The second aim (UH3) will evaluate the in vivo pharmacokinetics and pharmacodynamics of our lead candidate(s), perform toxicology, immunogenicity and bioavailability studies in animal models, further optimize cell production efficiency of the lead antibody, and manufacture and scale-up GMP production of the lead antibody(ies). It will include pre-formulation development and clinical formulation development. It will end with creation and filing of our IND application with the FDA.
The third aim (UH2, UH3) will explore and develop the biomarker potential of human resistin and RELM? to assess severity and progression of PH and to predict response to therapy, by studying the functional role of genetic polymorphisms, PBMC gene expression, and serum levels for these proteins, and integrating and correlating these findings with the demographic, hemodynamic, clinical, genetic and genomic data already obtained in our recent SCCOR grant on pulmonary arterial hypertension, with a primary focus on PH and cardiac function.
Our prior research found a novel family of proteins to be related to the cause of high blood pressure in the lungs, an often fatal disease with no curative treatment. In this proposal, we aim to develop antibodies against these proteins as a novel therapy for pulmonary hypertension.
|Liu, Qun; Li, Diandian; Berger, Alan E et al. (2017) Survival and prognostic factors in hypertrophic cardiomyopathy: a meta-analysis. Sci Rep 7:11957|
|Johns, Roger A; Takimoto, Eiki; Meuchel, Lucas W et al. (2016) Hypoxia-Inducible Factor 1? Is a Critical Downstream Mediator for Hypoxia-Induced Mitogenic Factor (FIZZ1/RELM?)-Induced Pulmonary Hypertension. Arterioscler Thromb Vasc Biol 36:134-44|