Amino-Acid Depletion Therapies

Amino acid depletion has a long history in both clinical practice and experimental therapeutic settings. In addition to L-asparaginase therapy in ALL, other amino acid depletion approaches have been tried in leukemia and solid tumors, including methioninase for tumors with p16 deletions on chromosome 9p21 that also affect methylthioadenosine phosphorylase (MTAP) and arginine deiminase to target tumor initiating cells in lung cancer. Renewed interest in cancer cell metabolism and a better understanding of pathways connecting the Warburg effect, amino acid metabolism, and autophagy suggest that enzyme therapy that depletes essential cancer cell metabolites may be poised for a renaissance.

In each of these examples the enzyme that degrades the target amino acid comes from a bacterial source and, as such, these therapies have struggled to overcome neutralizing antibody responses to the enzyme. The most common approach to this problem is to conjugate polyethylene glycol (PEG) to the enzyme. However, while this approach can delay the formation of antibodies to enzyme, it does not completely eliminate the eventual production of neutralizing antibodies and it compromises enzyme activity while providing for extended circulation time. Furthermore, precisely defined and reproducible conjugation of PEG to proteins is a laborious and expensive process.

DevaCell solves the problem of neutralizing immune responses with a novel versatile nano-carrier platform called Synthetic Hollow Enzyme Loaded Shells (SHELS). SHELS are capable of hiding large biomolecular payloads from the immune system within the hollow core while allowing controlled interaction with the environment via pores on the surface. For enzyme payloads, the pore size can be tuned to allow the substrate to enter. This structure prevents antibodies from reaching the enzyme load, potentially eliminating or minimizing the effects of an immune response against the enzyme. Enzyme-loaded SHELS, administered IV or IM, systemically deplete an amino acid that tumor cells need to survive, such as asparagine or methionine, thereby creating a strong anti-cancer effect devoid of the immune responses against the enzyme that degrades the amino acid. SHELS may also be administered IT in order to deplete the amino-acid pool within the tumor microenvironment with minimal or no side effects. Amino-acid depletion also renders most solid tumors more sensitive to conventional chemotherapy, offering a platform of synergistic combination therapy modalities.

The synthesis method of SHELS is scalable and produces a high yield of mono-dispersed particles. DevaCell uses silica as the first generation material for SHELS. Silica is a biodegradable and biocompatible material suitable for in vivo application, and Generally Considered As Safe (GCAS) by the FDA . Silica is a fairly non-toxic material and silica nanoparticles were recently approved by the FDA for imaging. When given iv or im, silica nanoparticles of 80-110nm that have been coated with PEG have been found to be completely non-toxic in animals in the dose ranges we will use. SHELS particles are hollow and therefore contain much less silica than the corresponding solid sphere, depending on the actual shell thickness.