Currently, targeted protein degradation (TPD) drug discovery has been gaining increased attention in the industry. As an emerging TPD technology, antibody-based PROTACs are developed that overcome the limitations of classical PROTACs that can only target intracellular proteins.

BOC Sciences, as a leading contract service provider in drug discovery and research, has the capability and commitment to provide antibody PROTAC discovery. With our extensive expertise and advanced platform, we continue to pioneer new degradation technologies to meet the new drug discovery goals of our clients around the world.

Introduction

Proteins are the bearers of life activities and their structure determines their function, and changes in protein conformation often cause disease. The use of small molecules to selectively modulate protein function is fundamental to the treatment of many diseases, yet traditionally only a small number of proteins (around 20%) can be modulated by this mechanism, and around 80% of proteins associated with disease development, including folded proteins, transcription factors, and non-enzymatically catalyzed proteins, are difficult to drug, or commonly referred to as undruggable target proteins.

PROTAC uses the naturally occurring intracellular protein degradation system to degrade disease-associated proteins to achieve therapeutic effects. However, PROTAC technology mainly targets intracellular proteins, but not extracellular secreted proteins or membrane proteins. Therefore, new technologies have been developed to target antibody-based PROTAC for secretory and membrane proteins that are widely distributed in the body, many of which are closely related to the development of disease.

About AbTAC

Antibody-based PROTAC (AbTAC) differs dramatically from classical small molecule PROTAC. In terms of molecular composition, AbTAC is a fully recombinant bispecific antibody, representing a new prototype within the field of PROTAC, whereas classical PROTAC is a three-part small molecule. In terms of the degradation system, AbTAC targets membrane proteins and uses the lysosomal system to achieve degradation of the target protein. Rather than being a PROTAC derivative, AbTAC is more like a complementary approach to LYTAC in that both proteins are recruited for lysosomal degradation and no major cellular proteomic perturbations occur.

Specifically, AbTAC is a bispecific immunoglobulin G (IgG) that recognizes two distinct epitopes. An arm of AbTAC recruits E3 ligase (e.g., transmembrane E3 ligases ring finger 43, RNF43) and the other arm targets cell surface protein (e.g., programmed death-ligand 1, PD-L1), inducing the formation of E3 ligase-AbTAC-protein complex and subsequent degradation. AbTAC has been reported to induce internalization and lysosomal degradation of PD-L1 by recruiting the RNF43. AbTAC mediates protein degradation by harnessing the endosomal-lysosomal pathway, but its mechanism of action remains elusive, and it is unknown whether the intracellular region of POI is ubiquitinated prior to endocytosis.

Design of AbTAC

• The AbTAC is assembled separately expressed half IgG to form a bispecific IgG.
• Production of antibodies conjugated to E3 ligase and POI by phage display technology. After multiple rounds of selection, clones with high affinity are identified by sequencing and assessing the on-cell binding capacity.
• Heterodimerization is facilitated by creating a "knob" or a "hole" in each heavy chain by Knobs-into-holes (KIHs) technology, which prevents mismatch pairing of the light chain of anti-RNF43 and anti-POI half IgG.

Source: https://ptc.bocsci.com/solutions/abtac-degradation-technology-development.html