Principal Investigators for Small Business: DiscoveryBioMed, Inc. (DBM) Project Summary Abstract The over-arching goal of this proposed SBIR-driven program is to create relevant DiscoveryBioMed (DBM) human cellular toxicity (HCT) platforms for the kidney grown in 3D and in 2D cell culture formats for a new ?gold standard? in lead therapeutic asset and materials in vitro testing and to reduce markedly the need for and the number of animals used in preclinical testing. Primary cultures of different human cell types from renal tissue will be utilized in these cellular toxicity platforms. Renal toxicity has arisen surprisingly late in preclinical development for several high profile biopharmaceutical drugs and biologics in recent efforts. It is apparent that the current methods and standards for preclinical toxicity testing require improvement. Recently, DBM launched a new Online Store and offers 2D tissue culture (TC) plastic-grown human cell platforms of kidney, lung, skin and the vasculature for HCT testing. To build upon these initial offerings, DBM seeks to design and establish 3D cell mono-culture and co-culture platforms for human kidney cells, so as to deepen the creativity and innovation of our Online Store offerings. In addition to preliminary data generated on 2D cell culture platforms, DBM has begun to establish and optimize 3D Biogel-based culture platforms where normal renal epithelial cells form tubule-like and duct-like structures, along with spherical fluid-filled cysts. Moreover, DBM has established 3D ?barrier? co-culture platforms where polarized human renal epithelial cell monolayers form on permeable filter supports and where vascular endothelial cells or other relevant cell types on grown immediately beneath the epithelium. Preliminary designs and results will be shared. In addition to the establishment of such 3D cell culture platforms, DBM wishes to test important hypotheses. First, do any FDA- approved drugs, known industry standard drugs, or drugs currently in clinical trials display cellular toxicity in DBM?s kidney HCT testing platforms? Second, does DBM?s HCT approach have more value when human cells are studied in 3D cell culture formats vs. 2D formats? DBM has been hesitant to pursue this line of research since defined HCT is not yet the ?gold standard? for lead therapeutic asset toxicity testing as mandated by the FDA or other regulatory agencies. It is DBM?s view that this needs to change, so as to save time, resources, and animal lives that are wantonly wasted on a drug or biologic that could be identified early as harmful with DBM?s HCT. Our milestones that DBM wishes to meet include: to offer existing 2D HCT testing platforms for kidney so as to begin to change the culture and methods used to ensure the safety of lead therapeutic assets; to design new 3D HCT testing platforms for kidney and renal vasculature; to optimize and test new 3D HCT testing platforms for kidney and renal vasculature versus existing 2D HCT testing platforms; and, finally, to explore microfluidics ?chip?-based 3D HCT testing platforms for kidney and renal vasculature. PHS 398/2590 (Rev. 09/04, re-issued 4/2006) Page Continuation Format Page
Principal Investigators for Small Business: DiscoveryBioMed, Inc. (DBM) Public Health Relevance Statement DiscoveryBioMed, Inc. (DBM) is establishing new paradigms for human cellular toxicity (HCT) testing so as to identify harmful lead therapeutics (small molecule drugs, biologics, antibody-drug conjugates, biosimilars, generic drugs), consumer products (over-the-counter formulations, personal care products, chemicals from the environment and from consumed goods), and materials (nanomaterials for drug formulation and delivery, etc.) at an early stage so as to save the enterprise and marketplace time, money and resources in both R&D and regulatory efforts and so as to protect the health of the public. Another important goal is to reduce the number of animals required for preclinical testing and the number of lead assets progressed to this inflection point by having a more relevant in vitro HCT ?filter? upstream in the process to capture/eliminate harmful test assets. This application is focused on the development of human kidney cell-based testing platforms in 2D and 3D formats. This program is designed as a prelude to entering into a U44 Cooperative Agreement as part of RFA- ES-15-016 ? ?NIEHS SBIR Phase IIB Awards for Validation and Commercialization of Approaches to Reduce Animal Use in Toxicology Testing.? PHS 398/2590 (Rev. 09/04, re-issued 4/2006) Page Continuation Format Page
