Catalytic Antibody Or Abzymes

1. Catalytic Antibody
Or
Abzymes
-Jayati Shrivastava

2. Catalytic Antibody
• Catalytic antibodies, also known as abzymes, are antibodies that
possess enzymatic activity. Unlike traditional enzymes, which are
proteins that catalyze chemical reactions, catalytic antibodies are
created by the immune system and can specifically recognize and
bind to target molecules.
• The discovery of catalytic antibodies has important implications
for the field of biotechnology and medicine. For example, catalytic
antibodies have the potential to be used as therapeutic agents for
a variety of diseases, including cancer and viral infections. They
can also be used in biocatalysis, where they can be used to
catalyze specific chemical reactions in a variety of industrial
applications.

3. History of Catalytic Antibody
• The concept of catalytic antibodies was first proposed in the early 1980s by
Geoffrey W. Joyce and Richard A. Lerner, who demonstrated that antibodies
could be engineered to catalyze chemical reactions. This was a groundbreaking
discovery because it challenged the prevailing view that enzymes were the only
biological catalysts capable of catalyzing chemical reactions with high specificity
and efficiency.
• In 1986, Richard A. Lerner and his team at The Scripps Research Institute in La
Jolla, California, published a landmark paper in Science describing the first
example of a catalytic antibody. The antibody, called 6D9, was able to catalyze
the hydrolysis of a specific phosphonate ester, which was previously thought to
be an impossible reaction for an antibody to catalyze. This discovery opened the
door to a new field of research that has since led to the development of a wide
range of catalytic antibodies.

4. • Since then, numerous studies have been conducted to understand
the mechanism of catalytic antibodies and to develop new
catalytic antibodies for a variety of applications. In 2001, Frances
Arnold and her team at the California Institute of Technology
demonstrated that directed evolution could be used to improve
the catalytic activity of antibodies. This approach involves creating
libraries of mutated antibodies and selecting for those that exhibit
the desired catalytic activity. This discovery has since
revolutionized the field of protein engineering and has led to the
development of many new and improved catalytic antibodies.
• Today, catalytic antibodies are recognized as a powerful tool for a
wide range of applications, from biotechnology to medicine to
environmental science. While much remains to be learned about
the fundamental mechanisms of catalytic antibodies, ongoing
research in this area is likely to continue to yield new and exciting
discoveries in the years to come.

5. Structure of catalytic antibody
• Catalytic antibodies have a structure similar to conventional
antibodies, which consist of four polypeptide chains - two
heavy chains and two light chains - that are linked together by
disulfide bonds. The heavy and light chains each contain
variable (V) and constant (C) regions, with the V regions being
responsible for antigen recognition and binding.
• The catalytic activity of a catalytic antibody is typically located
in the V region of one or both of the light chains. In some
cases, the catalytic activity may also involve residues in the
heavy chain or at the interface between the heavy and light
chains.

6. • The catalytic V region of a catalytic antibody typically
contains a reactive residue, such as a serine, cysteine, or
histidine, that is capable of forming a covalent bond with
the substrate. This reactive residue is usually located in the
complementarity-determining region (CDR) of the V region,
which is the part of the antibody that is responsible for
antigen recognition and binding.
• The three-dimensional structure of a catalytic antibody is
determined by X-ray crystallography or nuclear magnetic
resonance (NMR) spectroscopy. These techniques allow
researchers to determine the precise arrangement of
atoms in the antibody, which can provide insights into its
catalytic activity and specificity.

8. Production of Catalytic Antibody
• The principle of catalytic antibodies is based on the fact that
antibodies, which are proteins produced by the immune system,
can be engineered to exhibit enzymatic activity. Like traditional
enzymes, catalytic antibodies accelerate chemical reactions by
lowering the activation energy required for the reaction to occur.
• The catalytic activity of an antibody is determined by its variable
regions, which are responsible for binding to a specific target
molecule or antigen. In the case of a catalytic antibody, the target
molecule is not only recognized and bound by the antibody, but
also undergoes a chemical transformation within the antibody's
active site.

9. • The active site of a catalytic antibody is formed by the three-
dimensional arrangement of amino acid residues in the variable
regions of the antibody. This arrangement creates a pocket or cleft
that is complementary in shape and chemical properties to the
target molecule, allowing the target molecule to bind specifically to
the active site of the antibody.
• Once the target molecule is bound to the antibody, the chemical
transformation can occur, leading to the formation of a product. The
reaction can be driven forward by various means, including acid-base
catalysis, covalent catalysis, and transition state stabilization.
• The catalytic activity of an antibody is highly specific for its target
molecule, allowing for the selective transformation of a particular
substrate in the presence of other molecules. This specificity,
coupled with the high selectivity and versatility of antibodies, makes
them attractive candidates for use in biotechnology, biocatalysis, and
medicine.

10. • Overall, the principle of catalytic antibodies involves the
creation of antibodies that not only recognize and bind to a
specific molecule, but also catalyze a chemical reaction
involving that molecule within the antibody's active site

11. Stages of production : An overview

12. Methods for eliciting catalytic antibodies

13. Mechanism of action of catalytic antibody
• Recognition and binding: The antibody recognizes and
binds to a specific target molecule or antigen in a highly
specific manner through its variable regions.
• Transition state stabilization: Once the target molecule is
bound, the antibody stabilizes the transition state of the
chemical reaction. The transition state is the intermediate
state between the reactants and products and is highly
unstable and energetically unfavorable. By stabilizing the
transition state, the antibody lowers the activation energy
required for the reaction to occur.

14. • Covalent catalysis: In some cases, the antibody can also
catalyze the reaction through covalent catalysis. This involves
the formation of a covalent bond between the antibody and
the substrate, which stabilizes the transition state and lowers
the activation energy.
• Acid-base catalysis: In some cases, the antibody can also
catalyze the reaction through acid-base catalysis. This involves
the donation or acceptance of a proton by the antibody,
which can help to stabilize the transition state and lower the
activation energy.
• Product release: Once the reaction is complete, the product is
released from the active site of the antibody.

16. Examples of catalytic antibody
1.38C2 antibody, which was developed by Richard A. Lerner and
his team at The Scripps Research Institute. The 38C2 antibody is
capable of catalyzing the hydrolysis of a specific phosphate ester,
which is an important reaction in many biological processes. The
catalytic mechanism of the 38C2 antibody involves the
stabilization of the transition state of the reaction through the
formation of a covalent bond between the antibody and the
substrate.

17. 2.4D9 antibody, which was designed to
catalyze the Diels-Alder reaction, a
reaction that is commonly used in organic
chemistry to synthesize complex
molecules. The 4D9 antibody was
engineered to contain a catalytic triad
consisting of a histidine, a lysine, and a
tyrosine residue, which act in concert to
catalyze the reaction. The catalytic
mechanism of the 4D9 antibody involves
the coordination of the substrate to the
active site of the antibody, followed by
the activation of a carbonyl group in the
substrate by the catalytic triad.

18. Application of catalytic antibody
• Therapeutic agents: Catalytic antibodies can be used as
therapeutic agents to treat a variety of diseases, including cancer
and viral infections. For example, catalytic antibodies can be
designed to recognize and cleave specific proteins that are
involved in the development of cancer or viral infections, leading
to the destruction of cancer cells or the inhibition of viral
replication.
• Biocatalysis: Catalytic antibodies can be used in biocatalysis,
where they can catalyze specific chemical reactions in a variety of
industrial applications. For example, catalytic antibodies can be
used in the production of pharmaceuticals, fine chemicals, and
agrochemicals.

19. • Diagnostics: Catalytic antibodies can be used in diagnostic tests to
detect the presence of specific molecules in biological samples. For
example, catalytic antibodies can be used to detect the presence of
specific proteins or metabolites in blood or urine samples, which can be
used to diagnose diseases.
• Environmental remediation: Catalytic antibodies can be used in
environmental remediation to degrade or detoxify pollutants in soil or
water. For example, catalytic antibodies can be designed to recognize
and degrade specific pollutants, such as pesticides or heavy metals,
leading to the remediation of contaminated sites.
• Protein engineering: Catalytic antibodies can be used in protein
engineering to create new enzymes with specific catalytic activities. For
example, catalytic antibodies can be used as starting points for the
development of new enzymes that can catalyze specific chemical
reactions with high efficiency and selectivity

20. Challenges in the development of catalytic antibody
• Specificity: Catalytic antibodies need to be highly specific in
order to avoid unwanted side reactions. Achieving high
specificity can be difficult, particularly for complex reactions
that involve multiple substrates.
• Stability: Catalytic antibodies need to be stable under a
range of conditions in order to be practical for use in
industrial processes or as therapeutic agents. This can be
particularly challenging for antibodies that have been
engineered to have catalytic activity, as changes to the
structure of the antibody can affect its stability.

21. • Catalytic efficiency: Catalytic antibodies need to be efficient
in order to be practical for use in industrial processes.
Achieving high catalytic efficiency can be challenging,
particularly for reactions that involve complex substrates or
multiple reaction steps.
• Production: Producing catalytic antibodies in large quantities
can be challenging, particularly for antibodies that have been
engineered to have catalytic activity. The production process
must be scalable and cost-effective in order to be practical for
use in industrial processes or as therapeutic agents.
• Intellectual property: Developing catalytic antibodies can be
an expensive and time-consuming process, and there may be
challenges in protecting intellectual property related to the
development