We're engaging targets previously considered inaccessible and undruggable
Using our proprietary Endosomal Escape Vehicle (EEV™) platform, we aim to develop intracellular therapeutics with the potential to fundamentally improve the standard of care across a wide range of diseases.
Intracellular therapeutics have the potential to alter the treatment landscape for patients suffering from devastating diseases by targeting and engaging the underlying drivers of disease. Despite significant advances in understanding disease drivers, obstacles to effective treatment remain, in part because approximately 75% of all disease-causing targets are located inside of cells. Small molecules can permeate cell membranes but tend to be rapidly cleared by the body before they reach the intended tissue and can be associated with off-target effects.
On the other hand, biological therapeutics are highly targeted and potent but are limited in their ability to reach intracellular targets of interest. These limitations often necessitate high therapeutic doses and can be associated with less-than-optimal therapeutic activity.
We believe our EEV™ platform will enable specific and potent therapeutics to enter cells for treatment using intracellular target engagement, broad biodistribution, deep tissue penetration and a broad potential therapeutic index. Our intracellular therapeutics pass through the phospholipid bilayer, allowing the cell to fold around the therapy and internalize it. They also have the ability to access multiple cell and tissue types including previously difficult to access tissues. By accessing these tissues, we have observed that therapies can be effectively delivered to the cytosol and multiple organelles within cells.
Entrada has developed a patented library of EEVs that enable the intracellular engagement of therapeutics against previously inaccessible and undruggable disease-causing targets.
Endosomal Escape Vehicle
Even when a therapeutic is successful in penetrating a cell, only less than 2% of the drug will escape the early endosome to reach its intended intracellular target. As a result, high doses of drug product are often needed to produce a therapeutic effect, which could potentially cause systemic dose-related toxicity. To effectively capitalize on both known biology and future discoveries, a better way of targeted intracellular delivery of therapeutics is needed.
We believe we have discovered a potential solution.
Entrada's EEV™ platform harnesses the inherent endocytic mechanism of cells. We have observed that our approach enables higher intracellular target engagement, lower drug concentrations and reduced or minimal toxicity compared to alternative approaches. Importantly, our EEV™ platform may solve a fundamental problem related to intracellular target engagement which is independent of cellular uptake – the efficient escape from the early endosome.
In our preclinical studies, we have observed that greater than 90% of EEV-conjugated material is taken up by the tissues of the body. Once inside the cell, these studies indicate that the EEV-conjugated material rapidly and efficiently escapes from the early endosome. Because of the low-pH conditions in the early endosome, the binding affinity of the EEV to the inner endosome wall increases, resulting in the successful formation and budding of unstable vesicles which then collapse and release therapeutic contents into the cell cytosol. In our preclinical studies, we observed that approximately 50% of the EEV-conjugated material escaped the endosome to reach the intracellular disease target, indicating a potentially significant improvement over the less than 2% observed in current biologics.
Given the flexibility and modular nature of the EEV™ platform, we are able to design and develop therapeutics with adequate exposure to intracellular compartments of target cells and tissues at reasonable doses.
Broad Therapeutic Potential
Our EEV™ platform is designed to enable the development of intracellular therapeutics that either modulate, inhibit, degrade or replace an intracellular target to correct the underlying disease pathophysiology. It is a simple and scalable construct designed to translate from preclinical to clinical development across our therapeutic programs.
Ultimately, we believe that the significant increase in intracellular target exposure enabled by EEV conjugation has the potential to translate into substantial improvements to the efficacy, safety, tolerability, manufacturability and cost of future medicines.