NBE-Therapeutics’ core technology, allowing the generation of site-specifically conjugated ADCs

Roger R. Beerli, PhD

Chief Scientific Officer at NBE-Therapeutics AG.

One of our valuable speakers on ANTIBODY DRUG CONJUGATE SUMMIT Roger Beerli has over 10 years of experience in discovery, engineering and preclinical development of therapeutic antibodies. Previously he has led R&D activities related to therapeutic antibody development at Cytos, Switzerland, and later at Intercell, Austria. Roger is a renowned expert in mammalian cell based antibody expression and display for the discovery of fully human therapeutic antibodies.

He specialized in phage display for protein and antibody engineering and was among the first to demonstrate artificial regulation of endogenous genes using engineered transcription factors. ?Roger Beerli has published widely in the areas of protein discovery, protein engineering and antibody development, and he is co-inventor on numerous patents and patent applications.

Dr. Roger Beerli and other employees (Tamara Hell, Anna S. Merkel, Ulf Grawunder) of NBE-Therapeutics AG. were presenting in article an enzymatic conjugation platform based on the S. aureus sortase A-mediated transpeptidation reaction, allowing the efficient generation of Antibody Drug Conjugates with toxins conjugated to pre-defined sites at pre-defined drug-to-antibody ratios.

For this, two modifications were introduced: first, immunoglobulin heavy (IgH) and light (IgL) chains were modified at their C-termini by addition of the sortase A recognition motif LPETG, and second, the small molecule tubulin polymerization inhibitors monomethylauristatin E (MMAE) and maytansine were modified by addition of a pentaglycine peptide, thus making them suitable substrates for sortase A-mediated transpeptidation.

They demonstrated efficient generation and characterization of the anti-CD30 ADC Ac10-vcPAB-MMAE, an enzymatically conjugated counterpart of brentuximab vedotin (Adcetris), as well as several anti-HER-2 ADCs including trastuzumab-maytansine, the counterpart of trastuzumab emtansine (Kadcyla). ADCs generated in this manner were found to display in vitro cell kill- ing activities indistinguishable from the classic conjugates. Further, when tested in vivo in a HER-2-overexpressing ovarian cancer xenograft mouse model, enzymatically generated trastuzumab-maytansine was found to lead to complete regression of established tumors, similar to Kadcyla.

In this article they present an enzymatic conjugation platform called SMAC-technology (sortase- mediated antibody conjugation technology) that allows efficient generation of homogenous ADCs involving full-length antibodies with pre-defined drug-to-antibody ratios. We describe the generation and functional characterization of several ADCs with different payloads and linker structures, including in vitro and in vivo tumor killing experiments in comparison to benchmark ADCs generated by classical chemical conjugation. We show that the SMAC-tech- nology is capable of producing homogeneous ADCs with in vitro and in vivo potencies similar to traditional ADCs used in the clinic.

Download full article here:  Sortase Enzyme-Mediated Generation of Site-Specifically Conjugated Antibody Drug Conjugates with High In Vitro and In Vivo Potency


Leave a comment