An Integrated Method to Evaluate the Treatment Efficacy and Immunogenicity of B-Cell Acute Lymphoblastic Leukemia...

Acute Lymphoblastic Leukemia (ALL) accounts for over 25% of pediatric cancers. It affects lymphoid progenitor cells, leading to overproduction of immature B- or T-cells. ALL cells rely on asparagine for survival. Therefore, the addition of l-asparaginase (ASNase), an enzyme that depletes asparagine, to the ALL chemotherapy backbone has dramatically improved treatment outcomes. However, marketed formulations of l-ASNase, all derived from bacteria, with or without polyethylene glycol (PEG) modification, cause allergic reactions to the enzyme or to PEG, impacting treatment efficacy. Herein, existing procedures are capitalized on to propose an integrated set of improved methods to evaluate the efficacy of ASNase formulations against B-cell ALL in mice, comprising the establishment of an ALL murine model not requiring humanization, an amino acid depletion study, and an assessment of antibody production. It is shown that unmodified ASNase results in short-lived asparagine depletion and a strong immune response. PEG-ASNase produces longer-lasting asparagine depletion, reduces ALL cell counts, and minimizes anti-ASNase immunogenicity but induces an increased immune response to PEG and is not curative without the chemotherapy backbone. With the increasing use of PEG-modified drugs, these tools offer a framework for assessing pharmacokinetics and immunogenicity of new enzyme-based therapeutics or nanoparticles.