An urchin-like helical polypeptide-asparaginase conjugate with mitigated immunogenicity.

Abstract

The use of asparaginase (ASNase), a first line drug for lymphoma treatment, is impaired by short circulation and notoriously high immunogenicity. Although PEGylation can prolong the circulating half-life of ASNase, however, it also induces anti-PEG antibodies that lead to accelerated blood clearance (ABC) and hypersensitivity reactions. Here, we create an urchin-like polypeptide-ASNase conjugate P(CB-EG3Glu)-ASNase, in which the surface of ASNase is sufficiently shielded by an array of zwitterionic helical polypeptides through the labeling of the ε-amine of lysine. The conjugate is fully characterized with size exclusion chromatography, SDS-PAGE, dynamic light scattering, and circular dichroism. In vitro, P(CB-EG3Glu)-ASNase retains full activity based on the enzymatic assay using the Nessler's reagent and cell viability assay. In vivo, examination of the enzyme activity in serum indicates that P(CB-EG3Glu)-ASNase prolongs the circulating half-life of ASNase for ~20 fold. Moreover, P(CB-EG3Glu)-ASNase significantly inhibits tumor growth in a xenografted mouse model using human NKYS cells. Importantly, P(CB-EG3Glu)-ASNase elicits almost no antidrug or antipolymer antibodies without inducing ABC effect, which is in sharp contrast with a similarly produced PEG-ASNase conjugate that develops both antidrug/antipolymer antibodies and profound ABC phenomenon. Our results demonstrate that urchin-like conjugates are outstanding candidates for reducing immunogenicity of therapeutic proteins, and P(CB-EG3Glu)-ASNase holds great promises for the treatment of various lymphoma diseases.

• Authors: Yali Hu, Dedao Wang, Hao Wang, Ruichi Zhao, Yaoyi Wang, Yunfei Shi, Jun Zhu, Yan Xie, Yu-Qin Song, Hua Lu
• Journal: Biomaterials (Biomaterials) Vol. 268 Pg. 120606 (01 2021) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 33360506 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Ltd. All rights reserved.

Chemical References

• Antibodies
• Antineoplastic Agents
• Peptides
• Asparaginase

Topics

• Animals
• Antibodies (pharmacology)
• Antineoplastic Agents (pharmacology, therapeutic use)
• Asparaginase (pharmacology, therapeutic use)
• Cell Survival
• Mice
• Peptides (pharmacology)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy)