One-step strategy for synthesizing LacNAc-based substrates and site-specific antibody-drug conjugates

Graphical abstraction. Credit: DOI: 10.1016 / j.apsb.2021.12.013

The antibody drug conjugate (ADC), a complex that covalently binds potent cytotoxins to antibodies, is of great interest as a new biotherapeutic approach. Site-specific binding of strong payloads can improve the therapeutic index of ADCs compared to random binding. Glycosite-specific ADCs (gsADCs) that utilize Asn297N-glycans of IgGFc as the binding site of the drug payload typically require multiple steps for IgG glycan engineering with two or more enzymes, and thus of the substrate. It limits diversification and complicates the preparation process.

To solve these problems, a research team led by Huang Wei of the Shanghai Materia Medica Institute of the Chinese Academy of Sciences has developed a simple and efficient method for synthesizing gsADC using disaccharides in one step. did. substrate..The study was recently published Acta Pharmaceutica Sinica B..

Researchers first screened a range of glycan substrates and ENGase by one-step IgG glycan engineering. They can transfer N-acetyllactosamine (LacNAc) to the N-glycosylation site of native trussumab in one step without hydrolysis, and derived LacNAc substrates with various functional groups and small molecules also have excellent glycosylation activity. Found to show. Glycoengineered trastuzumab with bioorthogonal groups has been further applied for Fc receptor binding determination, fluorescent labeling, and click chemistry-induced glycan elongation.

Boosted by robust LacNAc-based IgG glycan engineering, researchers applied this method to one- or two-step synthesis of glycosite-specific ADCs. First, the resulting LacNAc-based trastuzumab with azide tag reacts easily with the cyclooctyne-tagged payload to generate gsADC in two steps via click chemistry. More importantly, researchers prepared the MMAE-LacNAc substrate and found that the complex could be recognized by Endo-S2 and transferred to the glycosylation site within 1 hour to generate the corresponding gsADC in one step. discovered. The gsADC containing the resulting sugar chain LacNAc showed excellent uniformity, stability, and improved antitumor activity.

This study presents a new strategy for highly efficient synthesis of gsADC by reprogramming multi-step IgG glycan engineering into a one-step process using LacNAc-based substrates. This strategy is also compatible with other antibody types such as bispecific antibodies and Nanobodies with Fc domains.

Recent advances in site-specific binding of antibody-drug conjugates

For more information:
Wei Shi et al, One-step synthesis of site-specific antibody-drug conjugates by reprogramming IgG glycan engineering with LacNAc-based substrates, Acta Pharmaceutica Sinica B (2021). DOI: 10.1016 / j.apsb.2021.12.013

Quote: Https: // substrate (February 8, 2022) and site-specific antibody drug obtained on February 8, 2022. One-step strategy for synthesizing conjugates site-specific-antibody-drug-conjugates.html

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One-step strategy for synthesizing LacNAc-based substrates and site-specific antibody-drug conjugates

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