AbTAC Degradation Technology Development

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AbTAC Degradation Technology Development Currentl
y, targeted protein degradation (TPD) drug
discovery has been gaining increased attention
the industry. As an emerging TPD technology,
antibody PROTAC 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-based 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 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.
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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. Heterodim
erization 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. Our Advantages Innovative
AbTAC technology development Experienced experts
team and extensive expertise Short turn-around
time and competitive price Data analysis,
detailed report with results and discussion
Highly reliable and reproducible result Our
Services As a leading CRO, BOC Sciences provides
AbTAC design and evaluation services. We have the
capability to perform design and production of
bispecific antibodies as well as in vitro and in
vivo evaluation of antibody-based drug molecules.