L-asparaginase has been used to treat acute lymphoblastic leukemia (ALL) for over 40 years. However, despite evidence that adult leukemias are also sensitive to asparagine and other amino acid depletion, asparaginase therapy has not expanded beyond pediatric leukemia for several reasons. Foremost is the immunogenicity of L-asparaginase which can limit the duration of therapy and contribute to potential side effects such as hypersensitivity reactions and anaphylaxis. Other side effects, including pancreatitis and coagulopathy, may also limit the appeal of this form of therapy in Chronic Lymphocytic Leukemia (CLL) patients. The long term goal of this project is to develop a new platform for L-asparaginase therapy that overcomes both of these limitations. This platform has two components: a new recombinant L-asparaginase, developed by our collaborator Dr. Donald Durden, and a nanoparticle delivery vehicle that protects the enzyme from immune response and immune neutralization in vivo. This enzyme, derived from Wolinella succinogenes lacks glutaminase activity that contributes to the toxic side effects associated with the clinicall approved enzymes. However, since immune suppression is one of those side effects abrogated by our enzyme, the immunogenicity problem may be particularly acute if this enzyme is used without some form of shielding. We have developed a nanoparticle delivery system that we term silica hollow enzyme loaded spheres (SHELS). These SHELS are initially synthesized as "nano-wiffle balls" with large holes that allow them to be loaded with unmodified enzymes and subsequently sealed with a porous layer that allows diffusion of small enzyme substrates but is impermeable to large molecules and proteins, thus simultaneously encapsulating the enzyme and protecting it from antibody recognition. We have preliminary data that shows that primary human CLL cells are extremely sensitive to asparagine depletion. Our approach is divided into three general phases aligned with our specific aims. In the first, we will optimize the dosing of recombinant Wolinella succinogenes L-asparaginase loaded in SHELS (rWSasp-SHELS). In the second, we will evaluate the efficacy of rWSasp- SHELS in mice engrafted with either CLL cells alone or CLL cells co-administered with activated T cells to promote division. The former will allow for the testing of the particles in a model representative of the resting CLL population whereas the latter will model the impact of the particles on the proliferative compartment. In the final aim we will compare the toxicity profile of the rWSasp-SHELS with the current clinically used PEG- asparaginase.

Public Health Relevance

L-asparaginase is an enzyme that is currently successfully used to treat childhood leukemia but has not been used for chronic lymphocytic leukemia because it can lead to allergic type reactions and other severe side effects. We have developed a new version of the enzyme that does not have some of the side effects as well as a tiny nanometer sized wiffle ball like structure that we can put the enzyme in to shield it from the immune system so that there is not an allergic response.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA173330-01A1
Application #
8583809
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Fu, Yali
Project Start
2013-08-21
Project End
2015-07-31
Budget Start
2013-08-21
Budget End
2014-07-31
Support Year
1
Fiscal Year
2013
Total Cost
$168,563
Indirect Cost
$59,813
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093