CELLIVERY

PIPELINE

CV-01

PIPELINE | CV-01
TSDT Platform

Advanced Macromolecule Transduction Domain (aMTD)-enabled Therapeuticmolecule Systemic Delivery Technology (TSDT), a powerful platform technology for the discovery and development of the new medicinal drug, is enabled with hydrophobic cell-penetrating peptides (CPPs) that provide cell-permeability of therapeuticmolecules in-vivo.

Previous generations of hydrophobic CPPs were derived from the hydrophobic signal peptides of secreted proteins and used to deliver biologically active peptides and proteins systemically in animals. However, many efforts to develop cell-permeable therapeutic proteins by using previous generations of hydrophobic CPP sequences for further clinical development and applications have been hampered by poor solubility of the recombinant proteins in physiological buffer condition and relatively low cell-permeability. To develop improved hydrophobic CPPs, Cellivery analyzed sequences from all 1st and 2nd generation hydrophobic CPP sequences and identified 6 ‘critical factors’ associated with efficient protein translocation across the plasma membrane. 136 synthetic peptides were developed that incorporated different permutations of the 6 CFs and have been designated advanced macromolecule transduction domains

Compared to the previous generations of CPPs, proteins containing aMTDs displayed an average of 13±1.1-folds greater cell-penetrating ability.

aMTD-mediated therapeuticmolecule uptake involves direct penetration of the plasma membrane. In particular, uptake did not require ATP, cell surface proteins or microtubule function. The uptake, however, was abolished in the presence of calcium chelator and also blocked in temperature at 4°Csuggesting the requirements of aMTD-mediated uptake aremembrane integrity and fluidity.

Finally, aMTD-enabled TSDT platform is able to internalize the therapeutic moleculeinto cells and tissues systemically via cell-to-cell delivery.

However, because macromoleculeshave high target specificity with the binding partner, it makes mechanism specific-targeted therapy possible. In general, having entered the cell, CP-Proteins spread everywhere in a similar way as small molecule drugs. However, unlike small molecule drugs, aMTD/SD-fused recombinant protein does not function without binding to its correct target because CP-Proteins possess the ability of interact with its targets specifically. In this case, affinity plays a role of target receptor in the distribution of cells. Moreover, affinity controls the selectivity and defines the specificity. Ultimately, CP-Proteins will produce fewer off-target effects than small molecule drugs by virtue of their grater specificity.

aMTD-enabled TSDT platform can be applied to many moieties of therapeuticmolecules across different disease areas. Therapeutic moleculeswith proven biological activities can easily be developed into cell-permeable medicinal candidate by simplyfusing aMTD empirically. TSDT enabled by aMTD can efficiently and cost-effectively be used as platform technology for discovery/development of protein-based biotherapeutics.