ASPAREC® is a proprietary PEGylated recombinant Erwinia chrysantemi-derived L-asparaginase that has significant potential to become a key product for the treatment of acute lymphoblastic leukemia (ALL) in patients with hypersensitivity to E. coli-derived L-asparaginase.
Preclinical data indicate that ASPAREC® is both longer acting and less immunogenic than the currently available Erwinia chrysanthemi derived L-asparaginase product. ASPAREC® is currently in Phase I development and partnered with EUSA Pharma (now Jazz Pharmaceuticals). It is protected by a patent filed internationally, and by orphan drug designations granted both in the US and Europe.
The medical need
Acute Lymphoblastic Leukemia is a rare and severe disease characterized by a malignant proliferation of immature lymphoid cells in the bone marrow. ALL has an overall incidence of 1 to 1.5/100,000 persons and accounts for 80% of acute leukemias of childhood and 20% of all adult leukemias.
L-asparaginase has been used successfully for many years and remains a standard and vital component of the anti-leukemia armamentarium during the early phases of the therapy, including the remission/induction and intensification/consolidation phases. It is believed that the anti-tumor activity of L-asparaginase is a result of the depletion of exogenous L-asparagine, an important amino acid required for the production of most proteins, and the failure of the leukemia cells to generate endogenous L-asparagine.
There are currently three asparaginase preparations available: 1) native Escherichia coli (e.g., Kidrolase®, Elspar®); 2) L-asparaginase from E. coli, covalently linked to units of PolyEthylene Glycol (Oncaspar®); and 3) L-asparaginase derived from Erwinia chrysanthemi (Erwinase®), also known as crisantaspase. These preparations present several limitations:
- They are strongly immunogenic, inducing hypersensitivity reactions and production of serum antibodies that neutralize the therapeutic effect of the preparation. Treatment protocols use L-asparaginase derived from E. coli as front line therapy and Erwinia chrysanthemi asparaginase as second line therapy when signs of hypersensitivity occur to the E. coli products. Symptoms are observed in up to 50% of patients with the native forms and up to 30% with Oncaspar®. Despite the availability of a second line product, hypersensitivity reactions and neutralizing antibodies are still observed in up to 50% of patients treated with Erwinase.
- They are extracted from bacterial sources, using non-optimal production processes. Manufacturing difficulties have led in the past to several periods of shortage.
- Native forms have short half-lives, necessitating several administrations a week.
All of these limitations underline a clear medical need and warrant the development of new L-asparaginase preparations with reduced immunogenicity, improved PK/PD properties, and produced using robust manufacturing processes.
The Alizé response : Asparec ®
Using recombinant and state-of-the-art PEGylation technologies, Alizé has designed a new Erwinia chrysanthemi L-asparaginase (crisantaspase). Pharmacological studies have indicated that PEGylation of this recombinant crisantaspase resulted in a significantly improved potency and a reduced immunogenicity, as compared to Erwinase® (1, 2).
ASPAREC® is produced using recombinant DNA technology to express the Erwinia chrysanthemi L-asparaginase, also known as crisantaspase. After extraction and purification, this material is further modified by covalent addition of 5 kDa methoxy PEG molecules. ASPAREC® is being developed as a ready to use solution for intravenous injection.
Figure 1: Plasma L- asparagine levels following a single intravenous administration of ASPAREC® or Erwinase® in mice. A) Only high doses of Erwinase® were able to deplete serum L-asparagine levels while B) ASPAREC® was shown to deplete L-asparagine levels for at least 48 h at any dose tested, suggesting that PEGylation improved potency by at least 50 times when compared to Erwinase® (1).
Figure 2: Anti-crisantaspase antibodies following repeated intravenous administration of ASPAREC® or Erwinase® in mice. High titers of antibodies were observed following treatment with Erwinase® while no relevant antibody titers were observed for ASPAREC®, indicating that PEGylation significantly reduced immunogenicity of r-crisantaspase(2).
An international PCT patent application was filed in 2010, with the objective of giving ASPAREC® a long patent protection.
(1) Allas S et al. “Pharmacokinetics and pharmacodynamics in mice of a PEGylated recombinant Erwiniachrysanthemi-derived L-asparaginase”. Abstract #2033. 51st ASH annual meeting, December 5-8, 2009 (New-Orleans, LA). 2009.
(2) Allas S et al. “Immunogenicity profile in mice of a PEGylated recombinant Erwiniachrysanthemi-derived L-asparaginase”. Abstract #2034. 51st ASH annual meeting, December 5-8, 2009 (New-Orleans, LA). 2009.