4.5 Article

Development of disulfide-stabilized Fabs for targeting of antibody-directed nanotherapeutics

Journal

MABS
Volume 14, Issue 1, Pages -

Publisher

TAYLOR & FRANCIS INC
DOI: 10.1080/19420862.2022.2083466

Keywords

Antibody fragment; stability; manufacturability; liposome; antibody-drug conjugate; developability; antibody engineering

Ask authors/readers for more resources

Antibody-directed nanotherapeutics (ADNs) are a promising delivery platform for targeted drug delivery to disease sites. By engineering an alternative disulfide bond within the Fab antibody fragment, the conjugation process impurities can be eliminated while maintaining efficiency and stability. This technology has been successfully used for the delivery of ADNs to various targets and can be applied to nanoparticle encapsulated payloads.
Antibody-directed nanotherapeutics (ADNs) represent a promising delivery platform for selective delivery of an encapsulated drug payload to the site of disease that improves the therapeutic index. Although both single-chain Fv (scFv) and Fab antibody fragments have been used for targeting, no platform approach applicable to any target has emerged. scFv can suffer from intrinsic instability, and the Fabs are challenging to use due to native disulfide over-reduction and resulting impurities at the end of the conjugation process. This occurs because of the close proximity of the disulfide bond connecting the heavy and light chain to the free cysteine at the C-terminus, which is commonly used as the conjugation site. Here we show that by engineering an alternative heavy chain-light chain disulfide within the Fab, we can maintain efficient conjugation while eliminating the process impurities and retaining stability. We have demonstrated the utility of this technology for efficient ADN delivery and internalization for a series of targets, including EphA2, EGFR, and ErbB2. We expect that this technology will be broadly applicable for targeting of nanoparticle encapsulated payloads, including DNA, mRNA, and small molecules.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.5
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available