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The Complete Guide to Site-directed Conjugation in Antibody-drug Conjugates

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Antibody drugs have become the mainstay of modern biopharmaceutical development with high specificity, high stability and low toxicity. In recent years, antibody-drug conjugates (ADC), the combination of antibodies and small molecule drugs, have made a breakthrough, and it is very likely to grow into a new generation of heavy drugs in antibody tumor therapy. – PowerPoint PPT presentation

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Title: The Complete Guide to Site-directed Conjugation in Antibody-drug Conjugates


1
The Complete Guide to Site-directed Conjugation
in Antibody-drug Conjugates
https//www.creative-biolabs.com/adc/
Creative Biolabs
2
1
Introduction of reactive cysteine
CONTENTS
2
Introduction of non-natural amino acids
3
Through the enzymatic method
4
Through the disulfide bond modification
3
Antibody drugs have become the mainstay of modern
biopharmaceutical development with high
specificity, high stability and low toxicity. In
recent years, antibody-drug conjugates (ADC), the
combination of antibodies and small molecule
drugs, have made a breakthrough, and it is very
likely to grow into a new generation of heavy
drugs in antibody tumor therapy. The ADC drug
connAntibody drugs have become the mainstay of
modern biopharmaceutical development with high
specificity, high stability and low toxicity. In
recent years, antibody-drug conjugates (ADC), the
combination of antibodies and small molecule
drugs, have made a breakthrough, and it is very
likely to grow into a new generation of heavy
drugs in antibody tumor therapy. The ADC drug
connects the cytotoxic drug to the monoclonal
antibody through a small molecule linker, and
relies on the unique site-directed conjugation of
the monoclonal antibody to bind the drug and kill
the cancer cell, making up for the side effects
of the cytotoxic drug and the weak effect of the
monoclonal antibody. There are four different
site-conjugation methods below.ects the cytotoxic
drug to the monoclonal antibody through a small
molecule linker, and relies on the unique
site-directed conjugation of the monoclonal
antibody to bind the drug and kill the cancer
cell, making up for the side effects of the
cytotoxic drug and the weak effect of the
monoclonal antibody. There are four different
site-conjugation methods below.
Background
Antibody drugs have become the mainstay of modern
biopharmaceutical development with high
specificity, high stability and low toxicity. In
recent years, antibody-drug conjugates (ADC), the
combination of antibodies and small molecule
drugs, have made a breakthrough, and it is very
likely to grow into a new generation of heavy
drugs in antibody tumor therapy. The ADC drug
connects the cytotoxic drug to the monoclonal
antibody through a small molecule linker, and
relies on the unique site-directed conjugation of
the monoclonal antibody to bind the drug and kill
the cancer cell, making up for the side effects
of the cytotoxic drug and the weak effect of the
monoclonal antibody. There are four different
site-conjugation methods below.
4
01
Introduction of reactive cysteine
5
Antibody drugs have become the mainstay of modern
biopharmaceutical development with high
specificity, high stability and low toxicity. In
recent years, antibody-drug conjugates (ADC), the
combination of antibodies and small molecule
drugs, have made a breakthrough, and it is very
likely to grow into a new generation of heavy
drugs in antibody tumor therapy. The ADC drug
connAntibody drugs have become the mainstay of
modern biopharmaceutical development with high
specificity, high stability and low toxicity. In
recent years, antibody-drug conjugates (ADC), the
combination of antibodies and small molecule
drugs, have made a breakthrough, and it is very
likely to grow into a new generation of heavy
drugs in antibody tumor therapy. The ADC drug
connects the cytotoxic drug to the monoclonal
antibody through a small molecule linker, and
relies on the unique site-directed conjugation of
the monoclonal antibody to bind the drug and kill
the cancer cell, making up for the side effects
of the cytotoxic drug and the weak effect of the
monoclonal antibody. There are four different
site-conjugation methods below.ects the cytotoxic
drug to the monoclonal antibody through a small
molecule linker, and relies on the unique
site-directed conjugation of the monoclonal
antibody to bind the drug and kill the cancer
cell, making up for the side effects of the
cytotoxic drug and the weak effect of the
monoclonal antibody. There are four different
site-conjugation methods below.
01
The study found that by mutating an amino acid
residue in an antibody molecule into cysteine,
and then using it to specifically conjugate with
a drug to synthesize an ADC, the effect of
interchain disulfide bond destruction can be
eliminated. However, if the design of the
mutation site is inappropriate, a wrong
intrachain or interchain disulfide bond will be
formed. Junutula et al. developed the PHESELECTOR
(Phage ELISA for Selection of Reactive Thiols)
technique, which first selects some amino acids
that are completely or partially exposed to the
surface of the antibody such as Val, Ala, Ser,
etc., which are mutated to Cys and then the Fab
fragment mutant is displayed on the surface of
the phage by phage display technology and reacts
with Biotin. Then, a mutant can be screened,
which can stably bind to the biotin and conjugate
with streptavidin by the introduced Cys residue
by an ELISA method.
6
02
Introduction of non-natural amino acids
7
Antibody drugs have become the mainstay of modern
biopharmaceutical development with high
specificity, high stability and low toxicity. In
recent years, antibody-drug conjugates (ADC), the
combination of antibodies and small molecule
drugs, have made a breakthrough, and it is very
likely to grow into a new generation of heavy
drugs in antibody tumor therapy. The ADC drug
connAntibody drugs have become the mainstay of
modern biopharmaceutical development with high
specificity, high stability and low toxicity. In
recent years, antibody-drug conjugates (ADC), the
combination of antibodies and small molecule
drugs, have made a breakthrough, and it is very
likely to grow into a new generation of heavy
drugs in antibody tumor therapy. The ADC drug
connects the cytotoxic drug to the monoclonal
antibody through a small molecule linker, and
relies on the unique site-directed conjugation of
the monoclonal antibody to bind the drug and kill
the cancer cell, making up for the side effects
of the cytotoxic drug and the weak effect of the
monoclonal antibody. There are four different
site-conjugation methods below.ects the cytotoxic
drug to the monoclonal antibody through a small
molecule linker, and relies on the unique
site-directed conjugation of the monoclonal
antibody to bind the drug and kill the cancer
cell, making up for the side effects of the
cytotoxic drug and the weak effect of the
monoclonal antibody. There are four different
site-conjugation methods below.
02
Some researchers have used the genetic code
extension technology to synthesize a tRNA that
recognizes the termination codon and designed an
aminoacyl tRNA synthetase that catalyzes the
attachment of unnatural amino acids to the tRNA
to form an amino acid tRNA synthetase/tRNA
orthogonal pair. Then, an amino acid codon in the
DNA sequence of the antibody is mutated to a
termination codon, and the orthogonal pair is
used to synthesize an antibody containing an
unnatural amino acid in or out of the cell. Since
the introduced non-natural amino acid contains
some special functional groups such as an azide
group, a ketone group, an alkynyl group and the
like, the drug and the antibody can more easily
achieve site-directed conjugation.
8
03
Through the enzymatic method
9
Antibody drugs have become the mainstay of modern
biopharmaceutical development with high
specificity, high stability and low toxicity. In
recent years, antibody-drug conjugates (ADC), the
combination of antibodies and small molecule
drugs, have made a breakthrough, and it is very
likely to grow into a new generation of heavy
drugs in antibody tumor therapy. The ADC drug
connAntibody drugs have become the mainstay of
modern biopharmaceutical development with high
specificity, high stability and low toxicity. In
recent years, antibody-drug conjugates (ADC), the
combination of antibodies and small molecule
drugs, have made a breakthrough, and it is very
likely to grow into a new generation of heavy
drugs in antibody tumor therapy. The ADC drug
connects the cytotoxic drug to the monoclonal
antibody through a small molecule linker, and
relies on the unique site-directed conjugation of
the monoclonal antibody to bind the drug and kill
the cancer cell, making up for the side effects
of the cytotoxic drug and the weak effect of the
monoclonal antibody. There are four different
site-conjugation methods below.ects the cytotoxic
drug to the monoclonal antibody through a small
molecule linker, and relies on the unique
site-directed conjugation of the monoclonal
antibody to bind the drug and kill the cancer
cell, making up for the side effects of the
cytotoxic drug and the weak effect of the
monoclonal antibody. There are four different
site-conjugation methods below.
03
The method refers to artificially causing the
related amino acid sequence which can be
recognized by some enzymes in the antibody by
genetic engineering technology, and then
utilizing the specificity of the enzyme to the
substrate to modify the specific amino acid
residue, thereby achieving site-conjugation.
Formylglycine-generating enzyme (FGE) recognizes
a pentapeptide sequence CXPXR, and oxidize Cys to
formylglycine (fGly), and the resulting formyl
group can form a stable CC bond with the drug
through the HIPS reaction. Transglutaminase (TG)
recognizes the LLQGA pentapeptide sequence and
can catalyze Glns ?-amide group forms a
heteropeptide chain with a compound containing a
primary amine.
10
04
Through the disulfide bond modification
11
Antibody drugs have become the mainstay of modern
biopharmaceutical development with high
specificity, high stability and low toxicity. In
recent years, antibody-drug conjugates (ADC), the
combination of antibodies and small molecule
drugs, have made a breakthrough, and it is very
likely to grow into a new generation of heavy
drugs in antibody tumor therapy. The ADC drug
connAntibody drugs have become the mainstay of
modern biopharmaceutical development with high
specificity, high stability and low toxicity. In
recent years, antibody-drug conjugates (ADC), the
combination of antibodies and small molecule
drugs, have made a breakthrough, and it is very
likely to grow into a new generation of heavy
drugs in antibody tumor therapy. The ADC drug
connects the cytotoxic drug to the monoclonal
antibody through a small molecule linker, and
relies on the unique site-directed conjugation of
the monoclonal antibody to bind the drug and kill
the cancer cell, making up for the side effects
of the cytotoxic drug and the weak effect of the
monoclonal antibody. There are four different
site-conjugation methods below.ects the cytotoxic
drug to the monoclonal antibody through a small
molecule linker, and relies on the unique
site-directed conjugation of the monoclonal
antibody to bind the drug and kill the cancer
cell, making up for the side effects of the
cytotoxic drug and the weak effect of the
monoclonal antibody. There are four different
site-conjugation methods below.
04
When the interchain disulfide bond of the
antibody is opened, the reduced Cys can be
rejoined by reacting with the bireactive reagent
to replace the traditional interchain disulfide
bond with the bireactive reagent. Accordingly,
the drug can be positioned at the disulfide bond
site of the antibody to form an ADC using a
drug-conjugated bireactive reagent. Moreover, the
molecular weight of the dual reactive reagent is
small enough to affect the spatial structure of
the antibody molecule.
12
Thanks
https//www.creative-biolabs.com/adc/
Creative Biolabs
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