# Zwitterionic Polypeptide-protein Conjugation for the Safe and Efficient Delivery of Therapeutic Enzymes

> **NIH NIH R21** · UNIVERSITY OF WASHINGTON · 2020 · $103,421

## Abstract

Zwitterionic Polypeptide-protein Conjugation
 for the Safe and Efficient Delivery of Therapeutic Enzymes
 PROJECT SUMMARY
One of the major obstacles that impede the wide application of therapeutic protein products is their potential
immunological response, especially for those obtained from non-human sources. Currently, the most
successful strategy to mitigate immune response induced by foreign proteins is “PEGylation”, i.e., to shield
the protein surface epitopes with polyethylene glycol (PEG). This surface conjugation strategy has been
shown to decrease to some extent immune responses to the underlying protein and more than ten PEGylated
protein products have been approved by the Food and Drug Administration (FDA). However, recent studies
both in animal models and clinical trials have demonstrated the presence of induced anti-PEG antibodies
after repeated administrations and pre-existing anti-PEG antibodies, which directly challenge the future of
this PEGylation technology. We believe there are two shortcomings for the current PEGylation technology:
1) the haptenic character of amphiphilic PEG leading to anti-PEG antibodies and 2) non-degradable character
of amphiphilic PEG leading to vacuolation of kidney and liver. Funded by one NIH R21 grant before, we
successfully developed a zwitterionic poly(carboxybetaine) (PCB) protected uricase, which was shown to be
capable of maintaining protein bioactivity, reducing the immunogenicity of encased proteins and extending
their circulation time without induced anti-polymer Abs. In the course of our study, we discovered zwitterionic
poly(EK) (PEK), a biodegradable polypeptide comprising of alternative lysine (K) and glutamic acid (E).
Extended from the zwitterionic concept, `highly water binding ability and zero net charge', zwitterionic PEK
has all properties of zwitterionic PCB. But, PEK is degradable to promote its elimination from the body while
PEG or PCB is not. A biodegradable zwitterionic polymer is highly desirable. Thus, PEK is a great alternative
beyond PEGylation, but has never been studied for its application to drug delivery. The purpose of this R21
proposal is to explore the potential of degradable zwitterionic poly(EK) (PEK)-protein conjugates. As a
degradable version of PCB, PEK is anticipated to provide similar benefits as PCB to its modified protein drugs
while possessing excellent biodegradability. In this proposal, uricase, a non-human enzyme with strong
immunogenicity, will be used as the protein drug. We hypothesize and will confirm though this study that
PEK-uricase conjugates will provide a safe and efficient strategy for enzyme delivery by greatly reducing
immunogenicity, improving pharmacokinetics (PK), and enhancing pharmacodynamics (PD). Since
PEGylation has been widely used in protein therapeutics, successful completion of this project will culminate
in a new approach as an alternative to or a replacement over the PEGylation technology, producing safer
and more effective enz...

## Key facts

- **NIH application ID:** 9942419
- **Project number:** 5R21EB027843-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** SHAOYI JIANG
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $103,421
- **Award type:** 5
- **Project period:** 2019-06-04 → 2020-06-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9942419

## Citation

> US National Institutes of Health, RePORTER application 9942419, Zwitterionic Polypeptide-protein Conjugation for the Safe and Efficient Delivery of Therapeutic Enzymes (5R21EB027843-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9942419. Licensed CC0.

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