My project is to prolong the half life of immunotoxin (antibody + toxin), so that they can be more potent in treating cancer.
The strategy that I used is pegylation at different locations. When I treated the mice that were pre-implanted with KLM1 tumor at the dosage of 10ug/mouse (mouse average weight 25g), 3x a week, mice started to lose significant weight, and some were found dead.
Does anyone have a strategy for reducing the toxicity of pegylated protein?
Based on what I found, PEG itself is none toxic, and my original protein without PEG can not kill the mice at such a low dosage, so this has to be unique to the pegylation itself.
Dear Zeliang Zheng
Please check "Role of PEGylation in passive and active targeting of drugs" in this paper hope it could be some inspiration for you:
Article PEGylation in anti-cancer therapy: An overview
PEGylation increasing permeation and retention of your complex mAb+toxin but could change stability in vivo too. It should be checked. In some cases thermal stability could be affected after PEGylation: Article Effects of PEG size on structure, function and stability of ...
Toxicity of PEGs is discussed in details in paper by Claudia Fruijtier-Polloth https://pdfs.semanticscholar.org/0823/e31852418da589797c46fd5a4dd253325658.pdf and Guoqiang Liu and coworkers:https://pubs.rsc.org/en/content/articlepdf/2017/ra/c7ra00861a
Based on current knowledge about PEGylated drugs I would like suggest rethink some ideas:
1) In general after PEGylation activity (efficacy) of your molecule should be much higher than before so question is how dose was calculated and what range of dose response studies should be performed before final proof of concept study with KLM1 tumors.
2) It should be confirmed that your PEGylated drug have affinity only for targets in KLM1 tumors, if not then taking into account increasing permeability your molecules can go through compartments not available for Non pegylated formulation in huge amount and then give some effects (not in tumor tissue). So question is are you sure that PEGylated drug have no any other targets outside tumor tissue.
3) It should be excluded that pre-existing anti-polyethylene glycol (PEG) antibodies could initiate the complement activation Article Understanding the Role of Anti-PEG Antibodies in the Complem...
4) Are you sure that your PEGylated drug is stable in blood plasma, serum, whole blood and in final formulation (not drug substance but drug product).
5) Are you sure that your PEGylated and Not pegylated drug have the same affinity and binding profile in vitro (SPR for example).
6) Possible impact of by-products and impurities of PEG.
Hope some ideas will be helpful for you ....
Best regards
Tomasz
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