The technology describes engineered methylthioadenosine (MTA) and adenosine (ADO)-degrading enzymes from either prokaryotic or mammalian sources to be used in pharmaceutical formulations to treat cancer or severe combined immunodeficiency (SCID) by enhancing pharmacological properties like serum stability and reducing immunogenicity.
The accumulation of methylthioadenosine (MTA) and adenosine (ADO) due to the deletion or repression of the methylthioadenosine phosphorylase (MTAP) gene is a significant issue in various cancers, including osteosarcomas, pancreatic cancers, and gliomas. MTAP is responsible for degrading MTA into adenine and methylthioribose-1-phosphate, which are then recycled into essential metabolic pathways. The loss of MTAP leads to elevated MTA levels, which have been shown to promote tumorigenesis and immunosuppression by inhibiting T-cell proliferation and activation. Additionally, high levels of extracellular ADO, produced by ectonucleotidases like CD39 and CD73, contribute to an immunosuppressive tumor microenvironment, further complicating cancer treatment. Current therapeutic approaches, such as enzyme replacement therapies and gene therapies, face challenges including poor enzyme stability, immunogenicity, and limited efficacy in degrading MTA and ADO in the tumor microenvironment. Therefore, there is a critical need for more effective methods to deplete these metabolites to enhance cancer treatment outcomes.
The technology involves an engineered protein with MTA/ADO-degrading enzyme activity, specifically an MTase, capable of degrading MTA/ADO. This MTase can be derived from either prokaryotic or mammalian sources, such as Salmonella enterica MTAN or Homo sapiens MTAP. The invention includes methods for treating cancer or SCID by administering the engineered MTase proteins or nucleic acids encoding these proteins. The MTase enzymes may be modified to enhance their pharmacological properties, such as increased serum stability or reduced immunogenicity, via techniques like PEGylation or fusion with heterologous peptide segments. It also encompasses the use of these engineered enzymes in pharmaceutical formulations for therapeutic applications.
This technology is differentiated by its ability to specifically target and degrade MTA/ADO, which are compounds associated with aggressive cancer phenotypes and immunosuppressive tumor microenvironments. By engineering MTase enzymes from both prokaryotic and mammalian sources, the technology offers flexibility and potential for high efficacy in different therapeutic contexts. The modifications to enhance pharmacological properties, such as PEGylation, ensure that the enzymes have increased stability and reduced immunogenicity, making them more suitable for clinical use. Furthermore, the inclusion of these enzymes in pharmaceutical formulations provides a novel approach to treating cancers with MTAP deletions or high levels of CD73, as well as SCID patients with mutations in the adenosine deaminase gene, addressing significant unmet medical needs.
Issued patent US 11,118,167