Pre-existing anti-polyethylene glycol antibody reduces the therapeutic efficacy and pharmacokinetics of PEGylated liposomes

Rationale: Increasing frequency of human exposure to PEG-related products means that healthy people are likely to have pre-existing anti-PEG antibodies (pre-PEG Ab). However, the influence of pre-PEG Abs on the pharmacokinetics (PK) and therapeutic efficacy of LipoDox is unknown. Methods: We generated two pre-PEG Ab mouse models. First, nave mice were immunized with PEGylated protein to generate an endogenous PEG Ab titer (endo PEG). Second, monoclonal PEG Abs were passively transferred (PEG-PT) into nave mice to establish a PEG titer. The nave, endo PEG and PEG-PT mice were intravenously injected with 111 in-labeled LipoDox to evaluate its PK. Tumor-bearing nave, endo PEG and PEG-PT mice were intravenously injected with 111 in-labeled LipoDox to evaluate its biodistribution. The therapeutic efficacy of LipoDox was estimated in the tumor-bearing mice. Results: The areas under the curve (AUC)last of LipoDox in endo PEG and PEG-PT mice were 11.5-and 15.6-fold less, respectively, than that of the nave group. The biodistribution results suggested that pre-PEG Ab can significantly reduce tumor accumulation and accelerate blood clearance of 111 In-labeled LipoDox from the spleen. The tumor volumes of the tumor-bearing endo PEG and PEG-PT mice after treatment with LipoDox were significantly increased as compared with that of the tumor-bearing nave mice. Conclusions: Pre-PEG Abs were found to dramatically alter the PK and reduce the tumor accumulation and therapeutic efficacy of LipoDox. Pre-PEG may have potential as a marker to aid development of personalized therapy using LipoDox and achieve optimal therapeutic efficacy.