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Investigational New Drugs
Published in: Investigational New Drugs 5/2014

01-10-2014 | PRECLINICAL STUDIES

Pharmacology, immunogenicity, and efficacy of a novel pegylated recombinant Erwinia chrysanthemi-derived L-asparaginase

Authors: Wei-Wen Chien, Soraya Allas, Nicolas Rachinel, Pierre Sahakian, Michel Julien, Céline Le Beux, Claire-Emmanuelle Lacroix, Thierry Abribat, Gilles Salles

Published in: Investigational New Drugs | Issue 5/2014

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Summary

Bacterial L-asparaginase (ASNase), hydrolyzing L-asparagine (Asn), is an indispensable component used in the treatment of acute lymphoblastic leukemia (ALL) and certain lymphoma entities. Native Erwinia chrysanthemi-derived ASNase (n-crisantaspase) has been approved as a second-line drug for treating patients exhibiting allergy syndromes to native and pegylated Escherichia coli-derived ASNase (EC-ASNase). However, it still induces hypersensitivity in at least 17 % of treated patients. In the present study, we investigated the pharmacological activity, immunogenicity and anti-leukemic activity of a new pegylated recombinant crisantaspase (PEG-r-crisantaspase). The results demonstrate that when compared to n-crisantaspase in vivo, PEG-r-crisantaspase maintains a complete depletion of plasma Asn for up to 72 h with a 50-fold lower dose. In mice receiving PEG-r-crisantaspase, specific antibodies against the enzyme were undetectable, indicating a lower immunogenicity of the pegylated enzyme. In vitro, PEG-r-crisantaspase exhibits similar cytotoxic effects (EC50 < 5 × 10−4 U/mL for the most sensitive cell lines) to n-crisantaspase on various leukemia and lymphoma cells and was shown to be more efficient than EC-ASNase. Three repeated PEG-r-crisantaspase injections (2–20 U/Kg) prevented leukemia development in leukemia-bearing mice for 17 days and significantly prolonged animal survival to 7–12 days. Therefore, PEG-r-crisantaspase appears to be a promising drug candidate for ALL treatment and should be further explored in experimental and clinical trials.
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Literature
1.
Pieters R, Hunger SP, Boos J, Rizzari C, Silverman L, Baruchel A, Goekbuget N, Schrappe M, Pui CH (2011) L-asparaginase treatment in acute lymphoblastic leukemia: a focus on Erwinia asparaginase. Cancer 117(2):238–249PubMedCentralCrossRefPubMed
2.
Asselin BL (1999) The three asparaginases. Comparative pharmacology and optimal use in childhood leukemia. Adv Exp Med Biol 457:621–629CrossRefPubMed
3.
4.
Avramis VI (2011) Asparaginases: a successful class of drugs against leukemias and lymphomas. J Pediatr Hematol Oncol 33(8):573–579CrossRefPubMed
5.
Kidd JG (1953) Regression of transplanted lymphomas induced in vivo by means of normal guinea pig serum. I. Course of transplanted cancers of various kinds in mice and rats given guinea pig serum, horse serum, or rabbit serum. J Exp Med 98(6):565–582PubMedCentralCrossRefPubMed
6.
Broome JD (1963) Evidence that the L-asparaginase of guinea pig serum is responsible for its antilymphoma effects. II. Lymphoma 6C3HED cells cultured in a medium devoid of L-asparagine lose their susceptibility to the effects of guinea pig serum in vivo. J Exp Med 118:121–148PubMedCentralCrossRefPubMed
7.
Mashburn LT, Wriston JC Jr (1964) Tumor inhibitory effect of L-asparaginase from escherichia coli. Arch Biochem Biophys 105:450–452CrossRefPubMed
8.
Jaffe N, Traggis D, Das L, Kim BS, Won H, Hann L, Moloney WC, Dohlwitz A (1972) Comparison of daily and twice-weekly schedule of L-asparaginase in childhood leukemia. Pediatrics 49(4):590–595PubMed
9.
Tallal L, Tan C, Oettgen H, Wollner N, McCarthy M, Helson L, Burchenal J, Karnofsky D, Murphy ML (1970) E. coli L-asparaginase in the treatment of leukemia and solid tumors in 131 children. Cancer 25(2):306–320CrossRefPubMed
10.
Ertel IJ, Nesbit ME, Hammond D, Weiner J, Sather H (1979) Effective dose of L-asparaginase for induction of remission in previously treated children with acute lymphocytic leukemia: a report from Childrens Cancer Study Group. Cancer Res 39(10):3893–3896PubMed
11.
Haskell CM, Canellos GP (1969) l-asparaginase resistance in human leukemia–asparagine synthetase. Biochem Pharmacol 18(10):2578–2580CrossRefPubMed
12.
Hutson RG, Kitoh T, Moraga Amador DA, Cosic S, Schuster SM, Kilberg MS (1997) Amino acid control of asparagine synthetase: relation to asparaginase resistance in human leukemia cells. Am J Physiol 272(5 Pt 1):C1691–C1699PubMed
13.
Aslanian AM, Fletcher BS, Kilberg MS (2001) Asparagine synthetase expression alone is sufficient to induce l-asparaginase resistance in MOLT-4 human leukaemia cells. Biochem J 357(Pt 1):321–328PubMedCentralCrossRefPubMed
14.
15.
Yong W, Zheng W, Zhang Y, Zhu J, Wei Y, Zhu D, Li J (2003) L-asparaginase-based regimen in the treatment of refractory midline nasal/nasal-type T/NK-cell lymphoma. Int J Hematol 78(2):163–167CrossRefPubMed
16.
Yamaguchi M, Suzuki R, Kwong YL, Kim WS, Hasegawa Y, Izutsu K, Suzumiya J, Okamura T, Nakamura S, Kawa K, Oshimi K (2008) Phase I study of dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy for advanced-stage, relapsed or refractory extranodal natural killer (NK)/T-cell lymphoma and leukemia. Cancer Sci 99(5):1016–1020. doi:10.​1111/​j.​1349-7006.​2008.​00768.​x CrossRefPubMed
17.
Jaccard A, Petit B, Girault S, Suarez F, Gressin R, Zini JM, Coiteux V, Larroche C, Devidas A, Thieblemont C, Gaulard P, Marin B, Gachard N, Bordessoule D, Hermine O (2009) L-asparaginase-based treatment of 15 western patients with extranodal NK/T-cell lymphoma and leukemia and a review of the literature. Ann Oncol Off J Eur Soc Med Oncol ESMO 20(1):110–116. doi:10.​1093/​annonc/​mdn542 CrossRef
18.
Molineux G (2003) Pegylation: engineering improved biopharmaceuticals for oncology. Pharmacotherapy 23(8 Pt 2):3S–8SCrossRefPubMed
19.
Avramis VI, Sencer S, Periclou AP, Sather H, Bostrom BC, Cohen LJ, Ettinger AG, Ettinger LJ, Franklin J, Gaynon PS, Hilden JM, Lange B, Majlessipour F, Mathew P, Needle M, Neglia J, Reaman G, Holcenberg JS, Stork L (2002) A randomized comparison of native Escherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children’s Cancer Group study. Blood 99(6):1986–1994CrossRefPubMed
20.
Wang B, Relling MV, Storm MC, Woo MH, Ribeiro R, Pui CH, Hak LJ (2003) Evaluation of immunologic crossreaction of antiasparaginase antibodies in acute lymphoblastic leukemia (ALL) and lymphoma patients. Leukemia 17(8):1583–1588CrossRefPubMed
21.
Shinnick SE, Browning ML, Koontz SE (2013) Managing hypersensitivity to asparaginase in pediatrics, adolescents, and young adults. J Pediatr Oncol Nurs Off J Assoc Pediatr Oncol Nurs 30(2):63–77. doi:10.​1177/​1043454212471728​ CrossRef
22.
Panosyan EH, Seibel NL, Martin-Aragon S, Gaynon PS, Avramis IA, Sather H, Franklin J, Nachman J, Ettinger LJ, La M, Steinherz P, Cohen LJ, Siegel SE, Avramis VI (2004) Asparaginase antibody and asparaginase activity in children with higher-risk acute lymphoblastic leukemia: Children’s Cancer Group Study CCG-1961. J Pediatr Hematol Oncol 26(4):217–226CrossRefPubMed
23.
Jaccard A, Gachard N, Marin B, Rogez S, Audrain M, Suarez F, Tilly H, Morschhauser F, Thieblemont C, Ysebaert L, Devidas A, Petit B, de Leval L, Gaulard P, Feuillard J, Bordessoule D, Hermine O (2011) Efficacy of L-asparaginase with methotrexate and dexamethasone (AspaMetDex regimen) in patients with refractory or relapsing extranodal NK/T-cell lymphoma, a phase 2 study. Blood 117(6):1834–1839. doi:10.​1182/​blood-2010-09-307454 CrossRefPubMed
24.
25.
26.
Vrooman LM, Supko JG, Neuberg DS, Asselin BL, Athale UH, Clavell L, Kelly KM, Laverdiere C, Michon B, Schorin M, Cohen HJ, Sallan SE, Silverman LB (2010) Erwinia asparaginase after allergy to E. coli asparaginase in children with acute lymphoblastic leukemia. Pediatr Blood Cancer 54(2):199–205PubMedCentralPubMed
27.
Roberts J, Holcenberg JS, Dolowy WC (1972) Isolation, crystallization, and properties of Achromobacteraceae glutaminase-asparaginase with antitumor activity. J Biol Chem 247(1):84–90PubMed
28.
Wehner A, Harms E, Jennings MP, Beacham IR, Derst C, Bast P, Rohm KH (1992) Site-specific mutagenesis of Escherichia coli asparaginase II. None of the three histidine residues is required for catalysis. Eur J Biochem/FEBS 208(2):475–480CrossRef
29.
Rajasekariah GH, Ryan JR, Hillier SR, Yi LP, Stiteler JM, Cui L, Smithyman AM, Martin SK (2001) Optimisation of an ELISA for the serodiagnosis of visceral leishmaniasis using in vitro derived promastigote antigens. J Immunol Methods 252(1–2):105–119CrossRefPubMed
30.
Miller HK, Balis ME (1969) Glutaminase activity of L-asparagine amidohydrolase. Biochem Pharmacol 18(9):2225–2232CrossRefPubMed
31.
Avramis VI, Panosyan EH (2005) Pharmacokinetic/pharmacodynamic relationships of asparaginase formulations: the past, the present and recommendations for the future. Clin Pharmacokinet 44(4):367–393CrossRefPubMed
32.
Tardito S, Uggeri J, Bozzetti C, Bianchi MG, Rotoli BM, Franchi-Gazzola R, Gazzola GC, Gatti R, Bussolati O (2007) The inhibition of glutamine synthetase sensitizes human sarcoma cells to L-asparaginase. Cancer Chemother Pharmacol 60(5):751–758CrossRefPubMed
33.
Fishburn CS (2007) The pharmacology of PEGylation: balancing PD with PK to generate novel therapeutics. J Pharm Sci 97(10):4167–4183CrossRef
34.
Soares AL, Guimaraes GM, Polakiewicz B, de Moraes Pitombo RN, Abrahao-Neto J (2002) Effects of polyethylene glycol attachment on physicochemical and biological stability of E. coli L-asparaginase. Int J Pharm 237(1–2):163–170CrossRefPubMed
35.
Fine BM, Kaspers GJ, Ho M, Loonen AH, Boxer LM (2005) A genome-wide view of the in vitro response to l-asparaginase in acute lymphoblastic leukemia. Cancer Res 65(1):291–299PubMed
36.
Papageorgiou AC, Posypanova GA, Andersson CS, Sokolov NN, Krasotkina J (2008) Structural and functional insights into Erwinia carotovora L-asparaginase. Febs J 275(17):4306–4316CrossRefPubMed
37.
Patel N, Krishnan S, Offman MN, Krol M, Moss CX, Leighton C, van Delft FW, Holland M, Liu J, Alexander S, Dempsey C, Ariffin H, Essink M, Eden TO, Watts C, Bates PA, Saha V (2009) A dyad of lymphoblastic lysosomal cysteine proteases degrades the antileukemic drug L-asparaginase. J Clin Invest 119(7):1964–1973. doi:10.​1172/​JCI37977 PubMedCentralPubMed
38.
Ollenschlager G, Roth E, Linkesch W, Jansen S, Simmel A, Modder B (1988) Asparaginase-induced derangements of glutamine metabolism: the pathogenetic basis for some drug-related side-effects. Eur J Clin Invest 18(5):512–516CrossRefPubMed
39.
Durden DL, Salazar AM, Distasio JA (1983) Kinetic analysis of hepatotoxicity associated with antineoplastic asparaginases. Cancer Res 43(4):1602–1605PubMed
40.
Durden DL, Distasio JA (1980) Comparison of the immunosuppressive effects of asparaginases from Escherichia coli and Vibrio succinogenes. Cancer Res 40(4):1125–1129PubMed
41.
Storti E, Quaglino D (1970) Dysmetabolic and neurological complications in leukemia patients treated with L-asparaginase. Recent Results Cancer Res 33:344–349CrossRefPubMed
42.
Distasio JA, Salazar AM, Nadji M, Durden DL (1982) Glutaminase-free asparaginase from vibrio succinogenes: an antilymphoma enzyme lacking hepatotoxicity. Int J Cancer 30(3):343–347CrossRefPubMed
43.
44.
Derst C, Henseling J, Rohm KH (2000) Engineering the substrate specificity of Escherichia coli asparaginase. II. Selective reduction of glutaminase activity by amino acid replacements at position 248. Protein Sci Publ Protein Soc 9(10):2009–2017. doi:10.​1110/​ps.​9.​10.​2009 CrossRef
45.
46.
Riley V, Spackman D, Fitzmaurice MA, Roberts J, Holcenberg JS, Dolowy WC (1974) Therapeutic properties of a new glutaminase-asparaginase preparation and the influence of the lactate dehydrogenase-elevating virus. Cancer Res 34(2):429–438PubMed
47.
Panosyan EH, Grigoryan RS, Avramis IA, Seibel NL, Gaynon PS, Siegel SE, Fingert HJ, Avramis VI (2004) Deamination of glutamine is a prerequisite for optimal asparagine deamination by asparaginases in vivo (CCG-1961). Anticancer Res 24(2C):1121–1125PubMed
48.
Rotoli BM, Uggeri J, Dall’Asta V, Visigalli R, Barilli A, Gatti R, Orlandini G, Gazzola GC, Bussolati O (2005) Inhibition of glutamine synthetase triggers apoptosis in asparaginase-resistant cells. Cell Physiol Biochem 15(6):281–292CrossRefPubMed
49.
Metadata
Title
Pharmacology, immunogenicity, and efficacy of a novel pegylated recombinant Erwinia chrysanthemi-derived L-asparaginase
Authors
Wei-Wen Chien
Soraya Allas
Nicolas Rachinel
Pierre Sahakian
Michel Julien
Céline Le Beux
Claire-Emmanuelle Lacroix
Thierry Abribat
Gilles Salles
Publication date
01-10-2014
Publisher
Springer US
Published in
Investigational New Drugs / Issue 5/2014
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-014-0102-9

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