Saturday, December 21, 2024
12/21/2024
ABSTRACT eCD4-Ig is an antibody-like therapeutic for HIV that was constructed by fusing CD4 domains 1 and 2, and an HIV coreceptor-mimetic sulfopeptide, to the N- and C-termini of the constant Fc region of an antibody. eCD4-Ig will join an emerging class of long-acting therapeutics for treating and preventing HIV infection. As a consequence of being built from parts of HIV’s receptors, eCD4-Ig neutralizes 100% of HIV isolates, and even neutralizes simian immunodeficiency virus (SIV). Thus, eCD4-Ig presents fundamental barriers to escape. This grant will fund the work that is needed in between cell line development and IND-enabling studies to bring eCD4-Ig to the clinic. In Phase I, we will validate assays for critical quality attributes (CQAs) including the sulfotyrosine content of the coreceptor-mimetic sulfopeptide, and then show that the eCD4-Ig protein made by new cell lines meets pre-defined CQAs. In Phase II, we will optimize our upstream process, downstream process, formulation buffers, and generate a GLP lot of eCD4-Ig protein for IND-enabling studies. Features of the upstream process that will be optimized include media and feed selection, a temperature shift, and fed-batch versus perfusion culture. Our downstream process is based on convective chromatography, including for Protein A affinity chromatography, anion exchange (AEX) chromatography, and hydrophobic interaction (HIC) chromatography. These processes efficiently remove poorly sulfated eCD4-Ig, aggregates, and host cell protein (HCP). We will develop a formulation for intravenous injection, and a high-concentration formulation with acceptable viscosity for subcutaneous injection. Production of a GLP lot of protein for IND-enabling studies will be outsourced to a CMO after a technology transfer process. These are the essential next steps towards bringing eCD4-Ig to the clinic.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).