Site-Specific Antibody Drug Conjugates Using Streamlined Expressed Protein Ligation

Abstract

Antibody-Drug Conjugates (ADCs) have been shown to produce clinical benefit in cancer patient thanks to their ability to target highly cytotoxic small molecules to tumor cells. However, the development of these complex molecules faces significant challenges due to the need to combine a large biologic drug with a small molecule drug to generate the desired bioconjugate. We describe here the use of a protein ligation methodology, based on the native chemical ligation reaction to generate site-specific Antibody-Drug Conjugates, which does not require the incorporation of unnatural modifications into the antibody. Fully native antibodies, with only the desired cytotoxic molecules attached, can be generated, thus minimizing the risk that additional modifications required for the site-specific conjugation pose a risk to the antibody activity. We demonstrate that our approach can be used to generate site-specifically modified ADCs, with potent in vitro and in vivo antitumor activity in a breast cancer tumor model.

Nanoparticle-based drug delivery in the inner ear: current challenges, limitations and opportunities

“…The surface of NPs can be modified to target specific structures by conjugating ligands to the surface using bioconjugation techniques. Some newer methods include expressed protein ligation (EPL) and click chemistry [36,37]. In EPL, a site-specific chemical ligation is made between a recombinant protein with a C-terminal thioester and a peptide or protein with an N-terminal cysteine.…”

The Use of Antibody-Antibiotic Conjugates to Fight Bacterial Infections

“…It presents high selectivity, lower time reactions, high yields, and high purity. So far, there are some examples reporting the success of streamlined-expressed protein ligation ( Shimamoto et al, 2012 ; Cavaco et al, 2018 , 2021b ; Frutos et al, 2018 ); however, it is expected an increase use of such technique to conjugate peptides/peptidomimetics to antibodies, which might lead to better therapeutic options in order to eliminate bacterial infections.…”

Nanocarriers for Inner Ear Disease Therapy

“…Moreover, a specific surface modification could further enable the nanoparticle-based drug delivery systems with target properties to reach a specific type of cell, which is ideal for inner ear therapies to deliver the drugs to a specific type of inner ear cell. Ligands have a specific interaction with certain cells and, thus, could be used for cell-specific targeting of nanoparticles for inner ear disease therapy (Frutos et al, 2018 ; Valero et al, 2018 ). For example, in an in vitro model prepared from the mouse cochleae, peptide-based nanoparticles could interact with spiral ganglion cells through tyrosine kinase and p75 neurotrophin receptors (Roy et al, 2010 ).…”