Polynorbornene-based bioconjugates by aqueous grafting-from ring-opening metathesis polymerization reduce protein immunogenicity

Church, Derek C.; Davis, Elizabathe; Caparco, Adam A.; Takiguchi, Lauren; Chung, Young Hun; Steinmetz, Nicole F.; Pokorski, Jonathan K.

doi:10.1016/j.xcrp.2022.101067

Cited by 5 publications

(11 citation statements)

References 65 publications

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“…Recent studies from our lab demonstrated the effectiveness of PNBbased polymers in reducing immune recognition of proteinpolymer conjugates. [58][59][60] In our current study, protein bioconjugates using PONBs of both a model protein, Lyz, and the therapeutically relevant UO enzyme were successfully synthesized. The conjugates retained significant bioactivity of 62%-94% for Lyz-PONB and 33%-65% for UO-PONB.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies from our lab have demonstrated a reduction in protein immunogenicity as a result of polymer conjugations. [6,[58][59][60]87] The polymers conjugated to the pro-teins form a protective corona making the protein antigenic sites inaccessible to antibodies and preventing aggregation and uptake of the proteins into macrophages and other clearance cells. [88] To quantify the reduction in immunogenicity of UO after bioconjugation, ELISA was performed utilizing anti-UO antibodies on each UO conjugate (Figure 7A).…”

Section: Immunogenicity Of Uo Conjugates and Anti-peg Antibody Recogn...mentioning

confidence: 99%

“…Recent studies from our lab demonstrated improved immune shielding of proteins by PNB-based polymers in proteinpolymer conjugates. [58][59][60] Herein, we describe the advantages of poly(oxanorbornene) (PONB) based water-soluble polymers as PEG alternatives for protein conjugation and demonstrate potential utility in a therapeutic protein. PONB polymers offer a unique solution relative to PNB, since the backbone oxygen increases polarity and may impact polymer conformation and solubility.…”

Section: Introductionmentioning

confidence: 99%

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Poly(Oxanorbornene)‐Protein Conjugates Prepared by Grafting‐to ROMP as Alternatives for PEG

Davis,

Caparco,

Steinmetz

et al. 2023

Macromolecular Bioscience

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PEGylation is the gold standard in protein‐polymer conjugation, improving circulation half‐life of biologics while mitigating the immune response to a foreign substance. However, preexisting anti‐PEG antibodies in healthy humans are becoming increasingly prevalent and elicitation of anti‐PEG antibodies when patients are administered with PEGylated therapeutics challenges their safety profile. In the current study, two distinct amine‐reactive poly(oxanorbornene) (PONB) imide‐based water‐soluble block co‐polymers are synthesized using ring‐opening metathesis polymerization (ROMP). The synthesized block‐copolymers include PEG‐based PONB‐PEG and sulfobetaine‐based PONB‐Zwit. The polymers are then covalently conjugated to amine residues of lysozyme (Lyz) and urate oxidase (UO) using a grafting‐to bioconjugation technique. Both Lyz‐PONB and UO‐PONB conjugates retained significant bioactivities after bioconjugation. Immune recognition studies of UO‐PONB conjugates indicated a comparable lowering of protein immunogenicity when compared to PEGylated UO. PEG‐specific immune recognition is negligible for UO‐PONB‐Zwit conjugates, as expected. These polymers provide a new alternative for PEG‐based systems that retain high levels of activity for the biologic while showing improved immune recognition profiles.

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Section: Discussionmentioning

confidence: 99%

Section: Immunogenicity Of Uo Conjugates and Anti-peg Antibody Recogn...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Poly(Oxanorbornene)‐Protein Conjugates Prepared by Grafting‐to ROMP as Alternatives for PEG

Davis,

Caparco,

Steinmetz

et al. 2023

Macromolecular Bioscience

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“…As an example, they used a commercially available, water-soluble Hoveyda–Grubbs type catalyst called AquaMet to carry out the ROMP of norbornene introduced with lysozyme and Bacteriophage Qβ (Qubevirus durum) in buffer solution, followed by block copolymerisation with PEG- or sulfobetaine-modified monomers to synthesise protein–polymer conjugates (PPCs) 226 (Fig. 26).…”

Section: Polymers From Bicyclic Alkenesmentioning

confidence: 99%

“…Pokorski et al have also reported on the synthesis and application of peptide-modified polymers utilising ROMP. [221][222][223][224][225][226] Their synthesised polymer consists of a hydrophilic segment that is modified with PEG sidechains and a 5-norbornene-2,3-dicarboxylic acid anhydride segment that facilitates binding with peptides. Peptide modification of the anhydride segment can be carried out either at the monomer synthesis step or post ROMP.…”

Section: Amino Acids and Peptidesmentioning

confidence: 99%

Design of biomaterials through direct ring-opening metathesis polymerisation of functionalised cyclic alkenes

Kobayashi

Tanaka

2023

Mol. Syst. Des. Eng.

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Mechanochemical Synthesis of Ionic Polymers: Solid-State Ball-Milling Polymerization for Unrestricted Solubility Enabling Copolymerization of Immiscible Monomers

Lee,

Kim

et al. 2024

Macromolecules

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This study demonstrates the facile synthesis of ionic polymers using a solid-state mechanochemical ball milling method, which offers a straightforward, ecofriendly, and broad scope compared to conventional solution polymerization techniques. Unlike solution polymerization, which is limited by solvent selection and often results in poor efficiency, direct ball-milling polymerization enables the production of the desired product polymers from a broader range of ionic monomers without solubility and miscibility constraints. We employed free-radical polymerization of styrene and (meth)acrylic ionic monomers, as well as Ruinitiated ring-opening metathesis polymerization of norbornenyl ionic monomers, to demonstrate the effectiveness of the mechanochemical approach. Additionally, the study explored the mechanochemical copolymerization of immiscible monomer pairs such as sodium carboxylate/pyrene and ammonium sulfone betaine/porphyrin moieties, producing water-soluble porphyrin and pyrene polymers. Overall, this research showcases mechanochemistry's versatility and efficiency in synthesizing ionic polymers, anticipating its use in various applications.

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Polynorbornene-based bioconjugates by aqueous grafting-from ring-opening metathesis polymerization reduce protein immunogenicity

Cited by 5 publications

References 65 publications

Poly(Oxanorbornene)‐Protein Conjugates Prepared by Grafting‐to ROMP as Alternatives for PEG

Poly(Oxanorbornene)‐Protein Conjugates Prepared by Grafting‐to ROMP as Alternatives for PEG

Design of biomaterials through direct ring-opening metathesis polymerisation of functionalised cyclic alkenes

Mechanochemical Synthesis of Ionic Polymers: Solid-State Ball-Milling Polymerization for Unrestricted Solubility Enabling Copolymerization of Immiscible Monomers

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