The plasma membrane acts as an impermeable barrier, controlling the flow of proteins and other macromolecules in and out of cells.
However, Cellivery’s proprietary Therapeuticmolecule Systemic Delivery Technology (TSDT) allows functionally active macromolecules to rapidly transverse cellular membranes. The process utilizes specialized Cell-Penetrating Peptides (CPPs) that can be engineered into peptides, whole proteins, DNA fragments, and other bioactive substances, such as, drugs. With additional subcellular trafficking signals, transduced macromolecules can be guided to specific cellular locations, providing an effective way to influence intracellular protein function.
Indeed, TSDT platform has attracted vast interest and commentary by individuals outside of the Company for its potential use in a variety of applications. We anticipate that many activities throughout the biotechnology industry will involve licensing of Cellivery’s TSDT platform.
A series of papers published by Dr. Daewoong Jo and his colleagues have described a process, termed TSDT, to deliver biologically active proteins into mammalian cells and tissues. The technology provides a way to control biochemical processes in living cells quantitatively and under non-steady conditions. This sets the stage for the development of a new generation of protein-based therapeutics.
Since proteins function with specificity in the context of cellular biochemical pathways, protein-based therapies are expected to produce fewer side-effects than conventional small molecule-based drugs. TSDT exploits the ability of hydrophobic sequences termed macromolecule transduction domains (MTDs) to promote the uptake of peptides and proteins into mammalian cells. Consequently, MTD-fused recombinant proteins are said to be “cell-permeable (CP)”.
TSDT has proven to be superior to other protein transduction technologies. In particular, the use of HIV Tat and other basic sequences that promote unidirectional protein uptake via fluid-phase and adsorptive endocytosis. This sequesters most proteins in intracellular vesicles, which traps the protein cargo inside the cell, limiting cytoplasmic delivery, resulting in low bioavailability.
Finally, proteins modified with MTD sequences had significantly prolonged clearance times as compared to the identical proteins without an MTD sequence.