Treatment of IgG4-related sclerosing disease by PEGylated nano-liposomal methylprednisolone succinate (MPS), a case report

The high occurrence of hypersensitive reactions (HSR) to a wide number of PEGylated nanomedicines underlies the importance of early and reliable detection for immune responses. The HSR symptoms are usually manageable, but in rare cases they can be fatal, even with premedication. HSRs have been linked to complement (C) activation and to pre-existing or elicited anti-PEG antibodies. These antibodies may also lead to ABC (Accelerated Blood Clearance), which results in fast plasmatic clearance of the liposomes at later administrations. These adverse responses may reduce the therapeutic efficacy of PEGylated nanodrugs. In the following case study, we focus on the major side effects of PEGylated nanodrugs: anti-PEG antibodies and CARPA.

We developed a formulation of PEGylated nano-liposomes, remotely loaded with the steroid prodrug methylprednisolone hemi-succinate (MPS), referred to as NSSL-MPS (or LC200). It was administered weekly under a compassionate approval to a patient suffering from intra-cardiac IgG4 sclerosing disease over 2 courses (5-week and 3-week long) with escalated doses up to 300mg MPS. The patient received pre-medication aimed to reduce HSR. Blood was tested for C activation by collecting plasma samples during the drug infusion, and quantifying the proteins SC5b-9, Bb, C3a and iC3b by ELISA. Anti-PEG IgM and IgG were measured in serum just before each treatment and every 2-3 days thereafter using chimeric humanized anti-PEG IgG and IgM antibody standards in ELISA as described by Roffler and coworkers^[1].

NSSL-MPS demonstrated good clinical results, namely a decrease in the disease markers and in the mass size. No clinical signs of HSR were observed, and plasma analysis showed no C activation during the infusion. The patient had no pre-existing anti-PEG antibodies (pre-infusion) and anti-drug antibodies (ADA) were not generated during or after the treatment.

These results, together with Turjeman et al. (poster no.159) on the lack of ABC, clearly demonstrate that NSSL-MPS exhibit therapeutic efficacy concomitant with good tolerability and lack of the unique pegylated assemblies’ toxicities (HSR, CARPA, ABC), supporting further clinical development of NSSL-MPS for the treatment of diseases which involves inflammation.

^[1]Chen, B.-M., et al., Measurement of Pre-Existing IgG and IgM Antibodies against Polyethylene Glycol in Healthy Individuals. Analytical Chemistry, 2016.