Schematic of the protection of therapeutic proteins using zwitterions.
Schematic of the protection of therapeutic proteins using zwitterions.

Researchers have found a promising way of protecting therapeutic proteins from the body’s immune system [S. Liu and S. Jiang, Nano Today (2016), doi: 10.1016/j.nantod.2016.05.006].

Proteins offer advantages over small-molecule drugs but can be readily identified by the body’s defense mechanisms and removed from circulation. Their inherent immunogenicity and short circulation time means that the efficacy of proteins can be low so higher doses are needed. The immune system can also become primed to recognize proteins after repeated use and eliminate them as a foreign substance more efficiently, leading to a reduction in circulation time.

To get around these limitations, it has become standard practice to protect proteins with a polymer such as poly(ethylene glycol) in process known as PEGylation. But although PEGylation is widely used in drug/gene delivery and diagnostics, it offers only an imperfect solution. The process can reduce the bioactivity of proteins and generate anti-PEG antibodies itself, leading to allergic reactions.

Instead, Sijun Liu and Shaoyi Jiang from the University of Washington used zwitterionic polymers – a unique type of molecule that contains an equal number of positively and negatively charged groups – to stabilize and protect an FDA-approved protein, uricase, which is used in the treatment of gout.

“We wanted to provide analternative polymer to PEG for protein conjugation, which could shield antigenic epitopes and increase blood residence time without generating polymer-specific antibody responses,” explains Jiang.

The researchers chemically conjugated the zwitterionic polymer poly(carboxybetaine), which contains naturally occurring glycine betaine derived from amino acids, to uricase and measured the antibody response in rats. The zwitterionic polymer stabilizes the protein and offers the same protection as PEG but withoutthenegative traits, Liu and Jiang found. The polymer does not generate polymer-specific antibodies, even though it is attached to the highly immunogenic uricase.

“We believe zwitterionic polymers may aid in the design of protein therapeutics that are exogeneous – in other words, those proteins to which our body is primed to mount immunological responses,” says Jiang.

The approach could decrease antibody response to protein therapeutics without sacrificing bioactivity, enabling increased efficacy and reduced dosage.

“Many therapies require multiple doses of the same drug, which would most likely induce antibody responses if the protein is immunogenic,” explains Jiang. “With our polymer as protection, we can avoid eliciting clearance mechanisms that is often seen in unprotected biologics or certain PEGylated ones.”

Jackie Yi-Ru Ying, executive director of the Institute of Bioengineering and Nanotechnology in Singapore, believes the advance is important.

“Jiang’s group has demonstrated the exciting potential of zwitterionic polymers as an alternative to PEG for preserving immunogenic enzyme bioactivity while reducing polymer-specific antibody response,” she says.

This article was originally published in Nano Today (2016), doi:10.1016/j.nantod.2016.06.003