Dosing of recombinant l-asparaginase

Abstract

The present invention provides compositions and methods for treating a disease treatable by asparagine depletion in a human subject comprising dosing a human subject with L-asparaginase.

1 - 15 . (canceled) 
     
     
         16 . A method of substituting a treatment of a human subject for acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL), wherein the human subject is in need thereof, said method comprising:
 administering intramuscularly to the human subject, as a substitute for each dose of a long-acting  E - coli .-derived asparaginase, a series of six doses of an L-asparaginase,   wherein   four of the six doses are about 25 mg/m2,   two of the six doses are about 50 mg/m2,   the time between administration of the two doses that are about 50 mg/m2 is seven days,   the time between administration of a dose in the series that is about 25 mg/m2 and a next dose is two days, and   the time between administration of a dose in the series that is about 50 mg/m2 and a next dose is three days,   wherein the L-asparaginase is not a long-acting  E - coli .-derived asparaginase.   
     
     
         17 . The method of  claim 16 , wherein each respective dose of the long-acting E- coli .-derived asparaginase in a plurality of doses of the long-acting  E - coli .-derived asparaginase is separately substituted with an instance of the series of six doses of the L-asparaginase. 
     
     
         18 . The method of  claim 17 , wherein the long-acting  E - coli .-derived asparaginase is pegasparaginase. 
     
     
         19 . The method of  claim 17 , wherein the L-asparaginase is a tetramer, and wherein each monomer of the tetramer comprises SEQ ID NO: 1. 
     
     
         20 . The method of  claim 17 , wherein the L-asparaginase is a tetramer, and wherein each monomer of the tetramer has a sequence identity of at least 95 percent to SEQ ID NO: 1. 
     
     
         21 . The method of  claim 17 , wherein the human subject exhibited hypersensitivity to the  E - coli .-derived asparaginase. 
     
     
         22 . The method of  claim 17 , wherein the human subject has terminated  E - coli .-derived asparaginase therapy. 
     
     
         23 . The method of  claim 17 , wherein the human subject is an adult. 
     
     
         24 . The method of  claim 17 , wherein the human subject is pediatric. 
     
     
         25 . The method of  claim 17 , wherein the L-asparaginase demonstrates less than 6% aggregation. 
     
     
         26 . (canceled) 
     
     
         27 . The method of  claim 17 , wherein the L-asparaginase is non-lyophilized. 
     
     
         28 . The method of  claim 17 , wherein the L-asparaginase is recombinantly produced in  Pseudomonas fluorescens.    
     
     
         29 . The method of  claim 17 , wherein a nadir serum asparaginase activity (NSAA) assay as measured from a serum sample from the human subject equals or exceeds 0.1 IU/mL after administration after treatment with the L-asparaginase. 
     
     
         30 . The method of  claim 17 , wherein the L-asparaginase is co-administered with one or more other chemotherapeutic agents as part of a multi-agent chemotherapeutic regimen. 
     
     
         31 . A method of treating Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LBL) in a human subject in need thereof, said method comprising:
 administering intramuscularly to the human subject L-asparaginase, other than an  E - coli .-derived asparaginase, as a set of time-ordered doses; wherein   the set of time-ordered doses comprises a first dose followed by a second dose,   the first dose is one of (i) about 50 mg/m2 and (ii) about 25 mg/m2 of L-asparaginase,   the second dose is the other of (i) about 50 mg/m2 and (ii) about 25 mg/m2 L-asparaginase,   the time period between administration of the first dose and the second dose to the human subject is three days when the first dose is about 50 mg/m2,   the time period between administration of the first dose and the second dose to the human subject is two days when the first dose is about 25 mg/m2,   no further L-asparaginase is administered to the subject for three days when the second dose is 50 mg/m2, and   no further L-asparaginase is administered to the subject for two days when the second dose is 25 mg/m2.   
     
     
         32 . The method of  claim 31 , wherein
 the first dose is about 50 mg/m2,   the second dose is about 25 mg/m2,   the set of time-ordered doses further comprises a third dose after the second dose,   the third dose is about 25 mg/m2, and   wherein the time period between administration of the second dose and the third dose to the human subject is two days.   
     
     
         33 . The method of  claim 32 , wherein the first dose is administered on a Friday and the second dose is administered on a Monday. 
     
     
         34 . The method of  claim 32 , wherein the first dose is administered on a Friday, the second dose is administered on a Monday, and the third dose is administered on a Wednesday. 
     
     
         35 . The method of  claim 31 , wherein
 the first dose is about 25 mg/m2,   the second dose is about 50 mg/m2,   the set of time-ordered doses further comprises a third dose after the second dose,   the third dose is about 25 mg/m2, and   the time period between administration of the second dose and the third dose to the human subject is three days.   
     
     
         36 . (canceled) 
     
     
         37 . (canceled) 
     
     
         38 . The method of  claim 31 , wherein
 the first dose is about 25 mg/m2,   the second dose is about 50 mg/m2,   the set of time-ordered doses further comprises a third dose before the first dose,   the third dose is about 25 mg/m2, and   the third dose is administered to the human subject two days before the first dose.   
     
     
         39 . (canceled) 
     
     
         40 . (canceled) 
     
     
         41 . The method of  claim 31 , the method further comprising intramuscularly administering to the human subject a plurality of instances of the set of time-ordered doses of the L-asparaginase, wherein each respective instance of the set of time-ordered doses of the recombinant L-asparaginase is administered to the subject upon completion of a prior instance of the set of time-ordered doses in the plurality of instances of the set of time-ordered doses. 
     
     
         42 . The method of  claim 41 , wherein the plurality of instances of the set of time-ordered doses of the L-asparaginase is between two and one hundred. 
     
     
         43 . The method of  claim 41 , wherein the plurality of instances of the set of time-ordered doses of the L-asparaginase is between two and fifteen. 
     
     
         44 . The method of  claim 31 , wherein the  E - coli .-derived asparaginase is native. 
     
     
         45 . The method of  claim 31 , wherein the  E - coli .-derived asparaginase is long-acting. 
     
     
         46 . The method of  claim 45 , wherein the long-acting  E - coli .-derived asparaginase is pegasparaginase. 
     
     
         47 . The method of  claim 31 , wherein the L-asparaginase is a tetramer, and wherein each monomer of the tetramer comprises SEQ ID NO: 1. 
     
     
         48 . The method according to  claim 31 , wherein the L-asparaginase is a tetramer, and wherein each monomer of the tetramer has a sequence identity of at least 95 percent to SEQ ID NO: 1. 
     
     
         49 . The method of  claim 31 , wherein the human subject exhibited hypersensitivity to the  E - coli .-derived asparaginase. 
     
     
         50 . (canceled) 
     
     
         51 . (canceled) 
     
     
         52 . (canceled) 
     
     
         53 . (canceled) 
     
     
         54 . (canceled) 
     
     
         55 . (canceled) 
     
     
         56 . (canceled) 
     
     
         57 . The method of  claim 31 , wherein the L-asparaginase is co-administered with one or more other chemotherapeutic agents as part of a multi-agent chemotherapeutic regimen.