Lactate oxidase/vSIRPα conjugates efficiently consume tumor-produced lactates and locally produce tumor-necrotic H 2 O 2 to suppress tumor growth

• Published in: International journal of biological macromolecules Vol. 231; p. 123577
• Main Authors: Kang, Yujin, Yeo, Mirae, Choi, Hyukjun, Jun, Heejin, Eom, Soomin, Park, Seong Guk, Yoon, Haejin, Kim, Eunhee, Kang, Sebyung
• Format: Journal Article
• Language: English
• Published: Netherlands 15-03-2023
• Subjects: Animals; Hydrogen Peroxide - metabolism; Lactic Acid; Ligands; Mice; Necrosis; Neoplasms; Tumor Microenvironment; Lactate oxidase; Lactate; HO; vSIRPα; Necrosis
• ISSN: 1879-0003

Aggressive tumor formation often leads to excessive anaerobic glycolysis and massive production and accumulation of lactate in the tumor microenvironment (TME). To significantly curb lactate accumulation in TME, in this study, lactate oxidase (LOX) was used as a potential therapeutic enzyme and signal regulatory protein α variant (vSIRPα) as a tumor cell targeting ligand. SpyCatcher protein and SpyTag peptide were genetically fused to LOX and vSIRPα, respectively, to form SC-LOX and ST-vSIRPα and tumor-targeting LOX/vSIRPα conjugates were constructed via a SpyCatcher/SpyTag protein ligation system. LOX/vSIRPα conjugates selectively bound to the CD47-overexpressing mouse melanoma B16-F10 cells and effectively consumed lactate produced by the B16-F10 cells, generating adequate amounts of hydrogen peroxide (H
O
), which induces drastic necrotic tumor cell death. Local treatments of B16-F10 tumor-bearing mice with LOX/vSIRPα conjugates significantly suppressed B16-F10 tumor growth in vivo without any severe side effects. Tumor-targeting vSIRPα may allow longer retention of LOX in tumor sites, effectively consuming surrounding lactate in TME and locally generating adequate amounts of cytotoxic H
O
to suppress tumor growth. The approach restraining the local lactate concentration and H
O
in TME using LOX and vSIRPα could offer new opportunities for developing enzyme/targeting ligand conjugate-based therapeutic tools for tumor treatment.