Reduction of non-specific toxicity of immunotoxin by intein mediated reconstitution on target cells.

Abstract:

:Recombinant immunotoxins are chimeric proteins composed of a targeting peptide that binds to a specific tumor antigen and a toxin protein killing target cells. Recombinant immunotoxin exhibits potent cancer inhibiting effects both in vivo and in vitro. However, the non-specific toxicity causes severe syndromes limiting their clinical application. To reduce toxicity caused by recombinant immunotoxins in general, we divided an immunotoxin into two nontoxic segments that may restore toxic bioactivity on tumor cell surface based on the intein mediated trans-splicing reaction. Both split and reconstituted immunotoxins were tested for their biological activities. We found that the reconstituted immunotoxin retained antigen specificity and affinity toward cancer cells overexpressing HER2/neu. After being internalized into HER2/neu positive cells, the reconstituted immunotoxin showed comparable cytotoxicity as the original immunotoxin, while the split immunotoxin fragments showed no toxic activity to cells with or without HER2/neu expression. This approach can potentially be used under clinical settings to reduce non-specific toxicity by administering patients with inactive immunotoxin fragments. Cytotoxic effect only occurs at tumor sites where the inactive fragments bind, trans-splice and become active toxin.

journal_name

Int Immunopharmacol

authors

Wang J,Han L,Chen J,Xie Y,Jiang H,Zhu J

doi

10.1016/j.intimp.2018.11.039

subject

Has Abstract

pub_date

2019-01-01 00:00:00

pages

288-295

eissn

1567-5769

issn

1878-1705

pii

S1567-5769(18)30890-7

journal_volume

66

pub_type

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