Novel Protein Degradation Technologies: LYTACs and AbTACs

    1. TPD (targeted protein degradation)

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


    Scientists have developed methods to degrade disease-associated proteins using naturally occurring intracellular protein degradation systems, such as autophagy-targeting chimera (AUTAC) and autophagosome-tethering compound (ATTEC), as well as the more recent proteolysis-targeting chimera (PROTAC) and molecular gel.


    However, these protein degradation technologies primarily target intracellular proteins and are inapplicable to extracellular secretory proteins and membrane proteins, which are widely distributed in the human body, accounting for approximately 40% of the total, and many of which are linked to disease development, so scientists have developed new technologies: lysosome targeting chimeras (LYTACs) and antibody-based PROTACs (AbTACs).


    1. LYTAC

    LYTAC is a bifunctional compound that binds both external protein and cell surface lysosomal targeting receptor (LTR) to form a ternary complex, resulting in protein that can be internalized via lattice-protein mediated endocytosis. It was first proposed by Prof. Bertozzi in 2020. Following engulfment, the complex passes through early endosomes (EE) and late endosomes (LE), after which POI enters the lysosome for degradation, and LTR is recycled into the cell membrane via recycled endosomes (RE).


    A bispecific antibody (bsAb) is an antibody that recognizes two distinct epitopes or antigens. AbTAC is a completely recombinant bispecific immunoglobulin G (IgG) that can attract both cell membrane E3 ligase RNF43 and cell surface proteins, inducing internalization of the RNF43-AbTAC-protein complex and subsequent degradation by lysosomes.


    1. Development of LYTAC and AbTAC

    The development of LYTAC is divided into two parts: the fragment that binds LTR, of which there are currently two main types, M6Pn and Tri-GalNAC, and the extracellular protein binding ligand (POI-binding ligand), of which there are currently three main types, antibodies, small molecules, and peptides.


    The design and development of LYTAC requires a combination of factors due to the following imitations.

    * Antibodies against extracellular protein-bound ligands are highly specific but inherently unstable.

    * Small molecules have strong stability and good permeability, but are less suitable for non-druggable proteins.

    * While peptides are easy to synthesize with low cost, they are also relatively unstable and have weak cell permeability.


    AbTAC recruits cell membrane E3 ligase RNF43 because it is extensively expressed in a range of cancer cells, including MDA-MB-231, HCC827, and T24, suggesting its potential for universal protein degradation.


    Advances in clinical research

    So far, it has been reported that LYTAC and AbTAC technologies can successfully degrade the secreted protein apolipoprotein E4 (ApoE4) as well as the membrane proteins epidermal growth factor receptor (EGFR), CD71, and programmed death-ligand 1 (PD-L1).


    Lilly announced a collaboration with Lycia (co-founded by Carolyn R. Bertozzi, the discoverer of the LYTAC technology) on August 25, 2021, in which Lilly will use Lycia's proprietary LYTAC protein degradation technology for the development and commercialization of novel targeted therapies for autoimmune and pain relief treatments. If the targeted degradation of extracellular and membrane proteins is effectively brought to the clinic and market, it would surely benefit humanity and lead to the treatment of numerous diseases.