Enzyme-mediated depletion of adenosine and/or methylthioadenosine

Abstract

Methods and compositions related to the engineering of a protein with MTA/ADO-degrading enzyme activity are described. For example, in certain aspects there may be disclosed an MTase capable of degrading MTA/ADO. Furthermore, certain aspects of the invention provide compositions and methods for the treatment of cancer or SCID with an MTase using the disclosed proteins or nucleic acids.

1 - 7 . (canceled) 
     
     
         8 . The formulation of  claim 21 , wherein the enzyme comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 1. 
     
     
         9 . The formulation of  claim 8 , wherein the enzyme comprises an amino acid sequence according to SEQ ID NO: 1. 
     
     
         10 - 14 . (canceled) 
     
     
         15 . The formulation of  claim 21 , wherein the enzyme is coupled to polyethylene glycol via one or more Lys or Cys residues. 
     
     
         16 - 20 . (canceled) 
     
     
         21 . A pharmaceutical formulation for treating cancer, the formulation comprising an enzyme capable of phosphorolysis of methylthioadenosine into methylthioribose-phosphate and adenine, wherein the enzyme is coupled to polyethylene glycol, wherein the enzyme comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 1. 
     
     
         22 . A method of treating a patient having a tumor comprising administering to the patient an effective amount of pharmaceutical formulation of  claim 21 . 
     
     
         23 - 25 . (canceled) 
     
     
         26 . The method of  claim 22 , wherein the enzyme comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 1. 
     
     
         27 . (canceled) 
     
     
         28 . The method of  claim 26 , wherein the enzyme comprises an amino acid sequence according to SEQ ID NO: 1. 
     
     
         29 . The method of  claim 22 , wherein the enzyme is coupled to polyethylene glycol (PEG). 
     
     
         30 . The method of  claim 29 , wherein the enzyme is coupled to PEG via one or more Lys or Cys residues. 
     
     
         31 - 35 . (canceled) 
     
     
         36 . The method of  claim 22 , wherein the tumor is a solid tumor. 
     
     
         37 . The method of  claim 22 , wherein the tumor is a hematological tumor. 
     
     
         38 . The method of  claim 22 , wherein the tumor is an osteosarcoma, a pancreatic cancer, a chordoma, a mesothelioma, a T-cell ALL, a glioma, a renal cell carcinoma, a melanoma, a squamous cell carcinoma, a gallbladder cancer, a gastric cancer, or a hepatocellular carcinoma. 
     
     
         39 . The method of  claim 22 , wherein the tumor has a decreased level of MTAP relative to a reference level. 
     
     
         40 . (canceled) 
     
     
         41 . The method of  claim 22 , wherein the tumor has an increased level of CD73, CD39, MTA, or ADO relative to a reference sample. 
     
     
         42 - 50 . (canceled) 
     
     
         51 . The method of  claim 22 , wherein the patient has previously failed to respond to the administration of an immune checkpoint inhibitor. 
     
     
         52 . The method of  claim 22 , further comprising administering at least a second anticancer therapy to the subject. 
     
     
         53 . The method of  claim 52 , wherein the second anticancer therapy is a surgical therapy, chemotherapy, radiation therapy, cryotherapy, hormone therapy, immunotherapy or cytokine therapy. 
     
     
         54 . The method of  claim 52 , wherein the second anticancer therapy comprises an adoptive T cell therapy, an anti-PD1 antibody, an anti-CTLA-4 antibody, and/or an anti-PD-L1 antibody. 
     
     
         55 - 57 . (canceled) 
     
     
         58 . The method of  claim 22 , further defined as a method of preventing metastasis. 
     
     
         59 - 98 . (canceled) 
     
     
         99 . A method of treating a patient having severe combined immunodeficiency (SCID), the method comprising administering to the subject an effective amount of a pharmaceutical formulation comprising an enzyme capable of phosphorolysis of methylthioadenosine into methylthioribose-phosphate and adenine, wherein the enzyme is coupled to polyethylene glycol, wherein the enzyme comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 1. 
     
     
         100 - 128 . (canceled)