Site-Specific Modification of Large Peptides and Proteins Creating More Homogenous Biologics

Northeastern University Background
Antibodies are a predominant class of macromolecules with wide-spread use throughout the scientific community including laboratory assays, imaging techniques, and medical treatments. Antibodies can be costly and challenging to properly manufacture or engineer whilst maintaining initial structural integrity and function of the antibody itself. Non-specific chemical methods are widely used to construct protein conjugates for a myriad of applications. These techniques have several shortcomings including the lack of site-specificity resulting in heterogenous products prone to side reactions. Additionally, non-specific modifications at or near the functional domains of proteins may significantly alter and/or reduce their activity and specificity.
Technology Overview
Northeastern spinout, Alycorn Bio, has developed a new method for modification of peptides, antibodies and their related fragments via a chemoenzymatic process. These site-specific methods using transglutaminase (TGase) produce homogenous, reproducible products. Alycorn has developed a method to trim native or engineered glycans on antibodies to render antibody glutamine residues accessible for conjugation by TGase. This newly developed process maintains the antibody’s core glycan without generating charged intermediary side residues as seen with current methods. This initial remodeling can be followed up to conjugate native or engineered glutamine residues with amine containing reagents or other suitable substitutions (i.e., fluorophores, reactive side chains enabling click chemistry, PEGs, modified Fc regions reducing ADCC, photocleavable conjugates). The final engineered product is homogenous with a single glycoform and more likely to have reduced immunogenicity than previous PNGaseF hydrolysis methods. These specific alterations can not only change an antibody’s biological form and function, but abolishment of effector function can result in better imaging agents by decreasing non-specific binding. This method overcomes several limitations in antibody engineering and demonstrates a useful strategy in generating biologics for therapeutics, imaging, and analysis.
Alycorn Bio has also developed a novel method for photocaging that addresses current limitations, by replacing existing chemical methods with a chemo-enzymatic site-specific approach. This method can be used to photocage large and complicated proteins and peptides, and allows for greater control of reaction conditions, including pH, time, and temperature. The site-specificity afforded by using an enzyme to incorporate photolabile groups has not been previously attainable. This method can be used for controlled release of protein therapeutics, as well as biological probes.

No generation of charge variants (i.e., aspartic acid) compared to previous methods of complete removal of glycan and concomitant conversion of the asparaginyl amide to aspartyl carboxylic acid.
Enables glycoengineering of the macromolecules, e.g., modulation of effector functions such as antibody-dependent cellular cytotoxicity (ADCC).
Multi-functionalized macromolecules can be readily produced via two sites: i.e., glycan and glutamine residues.


Antibody drug conjugates
PEGylated drugs
Bioconjugation Protein drugs


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