PMPC

Challenges in aptamer pharmacokinetics

One of the challenges in the pharmacokinetics of aptamers is their short half life in the blood due to their molecular size and are quickly excreted from the kidneys. Aptamer/PEG conjugates are currently widely used to prolong aptamer half life in the blood, but it is known that anti-PEG antibodies are produced, which may lead to reduced drug efficacy and anaphylactic shock.
To solve this problem, it is necessary to improve the half life of aptamers by using molecules other than PEG, which are not immunogenic and do not affect the activity of aptamers through binding.

PMPC［Poly(2-methacryloyloxyethyl phosphorylcholine)］

PMPC is a polymer whose building block is 2-methacryloyloxyethyl phosphorylcholine (MPC), which has the polar group of phosphatidylcholine in the cell membrane that makes up cells and is a molecularly designed polymer that mimics the cell membrane. It has a phospholipid-like structure that is easily absorbed by organisms and is used for surfaces of medical devices and artificial organs due to its low antigenicity. Using this PMPC, we collaborated with the University of Tokyo’s Sando Laboratory to study the effect of our aptamer Xenoligo® on the pharmacokinetics of the aptamers.

Xenoligo® ／PMPC complex

It was confirmed that there was no change in the activity of Xenoligo® due to PMPC binding and that the pharmacokinetics of Xenoligo® were equivalent to PEG. It was also confirmed that the blood retention of the aptamer can be controlled by changing the degree of polymerization of PMPC.
PMPC has low immunogenicity and improves half life without affecting the activity of Xenoligo®, indicating that it is a very useful molecule for controlling aptamer disposition.

The binding activity of Xenoligo® ／PMPC complex

TAGX-0003/PMPC complex was prepared by modifying PMPC to TAGX-0003, a Xenoligo® that binds to IFN-γ, and its activity was compared with that of TAGX-0003/PEG complex and TAGX-0003. The results showed that the inhibitory activity of the TAGX-0003/PEG complex was slightly lower than that of TAGX-0003, while the activity of the TAGX-0003/PMPC complex was not affected.

Pharmacokinetics of Xenoligo® ／PMPC complex

Xenoligo® (TAGX-0003)/PMPC complexes were synthesized using PMPC with degrees of polymerization of 50, 100, 200, and 400, and plasma concentration were measured after a single intravenous administration to rats and compared to TAGX-0003 and TAGX-0003/PEG complexes. The results showed that as the degree of polymerization of PMPC increased, its half life improved compared to that of TAGX-0003, and a complex of PMPC400 and TAGX-0003 showed similar plasma concentration trends as the TAGX-0003/PEG complex. PMPC is a useful molecule for PK control of Xenoligo® because it has low immunogenicity and improves blood half life without affecting the activity of the aptamer.