The pharmacokinetic profile of PEGylated steroidal liposomes demonstrates lack of accelerated blood clearance (ABC) phenomenon upon repeated injections: A case report

We developed a formulation of 80-nm PEGylated nano-liposomes (NSSL) remote loaded with the amphipathic weak acid, steroid prodrug methylprednisolone hemi-succinate( MPS) using trans-membrane calcium acetate gradient. NSSL-MPS was extensively evaluated in seven mice models of inflammatory diseases, demonstrating superior therapeutic efficacy as well as improvement in the inflamed tissue pathology, reduced level of pro-inflammatory cytokines and reduced toxicity, the latter, even following long-term (over 13 months) treatment [rev. in 1].

In a first in human study, NSSL-MPS was administrated to a patient suffering from intra-cardiac IgG4 sclerosing disease. The patient received escalating doses from 50 up to 300mg MPS once a week over two courses (5-week and 3-week long). PEGylated liposomes are known to elicit anti-PEG IgM antibodies that induce among others hypersensitivity reactions (HSR) and accelerated blood clearance (ABC), thereby reducing therapeutic efficacy. We studied the pharmacokinetics (PK) profile of NSSL-MPS in the patient upon repeated injections of escalating doses (50-300mg MPS). Blood samples were collected before, during and up to 5 days after administration. The PK profile was studied using LC/MS detector demonstrating prolonged circulation half-life and a dose-dependent serum levels. A significant level of the drug (>85% of the injected dose) was retained in plasma 24 hours at least after the 3^rd administration, proving the lack of ABC which is in good agreement with the lack of anti-PEG IgG and IgM (See abstract #172 by Yaelle Bavli et al.). Furthermore, NSSL-MPS demonstrated efficacy in the mass size reduction and a clear trend toward decrease in IgG levels (IgG1, IgG2, IgG3 and IgG4) with no sign of toxicity whatsoever (lack of HSR, no elicitation of anti-PEG antibodies, no complement activation).

Overall, the good tolerability of NSSL-MPS together with its beneficial therapeutic efficacy support further evaluation toward clinical development for treating inflammatory diseases.

[1] Turjeman K, Barenholz Y., Liposomal nano-drugs based on amphipathic weak acid steroid prodrugs for treatment of inflammatory diseases. J Drug Target. 2016 18:1-41.