The presence of anti-
polyethylene glycol (PEG)
antibodies in the systemic circulation might have potential implications for the therapeutic activity of PEGylated products in vivo in the clinic. In order to study the effect of pre-existing anti-PEG
antibodies on the in vivo fate and the therapeutic efficiency of PEGylated
therapeutics, we developed a BALB/c mouse model by virtue of the intraperitoneal (i.p.) inoculation of hybridoma cells (HIK-M09 and HIK-M11), secreting monoclonal anti-PEG
IgM, mimicking the presence of pre-existing anti-PEG
antibodies in the blood. In the model, the titers of anti-PEG
IgM in the blood increased as a function of hybridoma cells numbers and time after i.p. inoculation. The in vivo levels of anti-PEG
IgM decreased in a dose-dependent manner, following i.v. administration of empty PEGylated
liposomes. C26
tumor-bearing mice with measurable levels of anti-PEG
IgM, receiving i.v. injection of DiR-labeled empty PEGylated
liposomes, showed lower levels of liposomal
tumor accumulation and higher levels of liver and spleen accumulation, compared to C26
tumor-bearing mice without measurable anti-PEG
IgM. This specifies that the presence of anti-PEG
IgM in the murine circulation induced accelerated blood clearance of PEGylated
liposomes and reduced their
tumor accumulation. The biodistribution and antitumor efficacy of commercially available
doxorubicin (DXR)-containing PEGylated
liposomes, Doxil®, were scrutinized in the anti-PEG
IgM mouse model. In C26
tumor-bearing mice having circulating anti-PEG
IgM, at 24 h after injection almost no DXR was observed in blood and
tumor, and increased DXR accumulation was observed in spleen and liver, compared to
tumor-bearing mice with no circulating anti-PEG
IgM. The antitumor efficacy of Doxil® was significantly compromised in the C26
tumor-bearing mice in the presence of anti-PEG
IgM. These results demonstrate that the anti-PEG
IgM mouse model could be a useful prognostic
indicator for the therapeutic effectiveness of different formulations of PEGylated
therapeutics in pre-clinical studies.