Antibody Soon after its release and use in

Antibody Drug Conjugates:

One quality synonymous with good
antibodies is their specificity. Some of the best monoclonal antibodies (mAbs)
used in scientific research and disease therapy go through rounds of stringent
selection to ensure that they are highly selective and specific to the target
they bind. Good monoclonal antibodies can be thought of as homing devices, that
will find a target and then specifically bind to that target only, to deliver
the desired therapeutic action.

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Imagine combining the specificity
of an antibody with the cytotoxic effect of a cancer drug and what you get is
an Antibody Drug Conjugate (ADC).

ADCs have also been called
“empowered antibodies” or “homing missiles” as they designed to harness the
targeting ability of antibodies while packing a solid punch with delivering
cytotoxic effects through the conjugated drug. Because in ADCs antibodies are
usually conjugated to cytotoxic drugs, they have mostly been used as
anti-cancer drugs.

Though theoretically ADCs sound
like the ideal candidate to target specific cancer cells, their development and
approval has been fraught with technical challenges. To date, only four ADCs
have been approved as biopharmaceutical drugs while several others are in the
clinical trial pipeline. The very first ADC, Gemtuzuman ozogamicin (Mylotarg),
was developed and marketed by Wyeth in 2001. Mylotarg was a combination of a
monoclonal antibody against CD33 linked to a cytotoxic agent from the class of
calicheamicins. CD33 is expressed in high levels on leukemic cells but it’s
expression is also retained on normal hematopoietic cells albeit at a lower
level and it further decreases as the hematopoietic cells mature. As most of
the leukemic blast cells retain undifferentiated characteristics with higher
expression of CD33 as compared to maturing hematopoetic cells, CD33 was deemed
fit as a candidate to target these leukemic cancer cells.

In United States, Mylotarg was
approved by the FDA in 2001 for use in patients over the age of 60 who are not
considered candidates for standard chemotherapy and/or who had suffered a
relapse with their acute myelogenous leukemia (AML) treatment. Soon after its release
and use in leukemic patients, concerns about Gemtuzumab (mylotarg) increasing
the risk of veno-occlusive disease (VOD) started surfacing. Wyeth, the parent
company, decided to launch a phase 3 randomized clinical trial in 2004, just
short 3 years after the drug’s launch. The clinical trial was itself stopped
prior to completion due to worrisome outcomes. It took about 6 more years for
Mylotarg to be removed from the market in 2010. However, in 2017 Mylotarg was
approved and launched again in the US and Europe based on a meta-analysis
showing no fatal side-effects of the drug. Regardless of its controversial
history, Mylotarg is now an FDA approved drug and more importantly, it’s
conception and launch has inspired the design and inception of similar ADC
drugs like Brentuximab vedotin, Trastuzumab emtansine, and the newest Inotuzumab
ozogamicin.

So, what are these armed antibodies
made of? Like mentioned earlier, they consist of a highly specific monoclonal antibody against a specific
antigen which is highly expressed on a target cancer cell type. The antibodies
used for ADC design have to meet very stringent specificity criteria and
undergo rounds of selection. Once, a candidate antibody is chosen, the next
step is identification of the second key component of an ADC, the cytotoxic agent. The
cytotoxic agent is the component that will result in cell death, once it’s
fully internalized by the target cell. The antibody can hence be thought of as
a car, taking the cytotoxic agent, a soldier, to the destination of operation.

The cytotoxic agents used in ADC design are also subjected to rounds of
selection, and a key feature they share is activation
after release. These cytotoxic agents are “deactivated” until they are
bound to the antibody and are only activated once they are separated from the
antibody, after the antibody is internalized by the cell. This is key to
protect other cells who come in proximity with the cytotoxic agent on the
antibody. Even at that close proximity, due to the cytotoxic agent being
deactivated, the non-targeted cells do not come in harm’s way. This brings us
to the third and final component of an ADC, a linker. As the name suggests, the linker links the
antibody and the cytotoxic agent together and is usually chemically labile, i.e
prone to be chemically removed once inside a cell.

The mechanism of action (MOA) of
ADC is really quite simple. Once administered to a patient, ADCs traverse the
system till the antibody takes them to the target cancer cells. Once the
antibody binds to the target cell, the whole ADC complex (antibody with the
linker attaching it to the cytotoxic agent) is internalized by the cell.

Post-internalization, the internalized vesicle fuses with lysosomal vesicles
and that is when the linker is cleaved due to the proteases and the mild acidic
environment inside the lysosome. The cytotoxic agent is then free from the ADC
complex and can freely cross the lysosome membrane to enter the cytoplasm
and/or other organelles like the nucleus or the mitochondria where they bind to
their target molecules, and cause cell death. This highly specific MOA is what
puts ADCs in the forefront of biotechnological and chemical therapies to treat
specific cancers. If ADCs are so effective, why don’t we have more FDA approved
ADC drugs in the market?

The reason is their development
stages can be longer than traditional drugs which are usually just chemical in
nature. The selection of a candidate antigen to which the antibody should be targeted
is a long process, following which the antibody selection process begins. Once
a monoclonal antibody is selected, then the cytokine and the linker are
sequentially selected. The stages can take long R&D stages. After a ADCs or
a few candidate ADCs are selected then the process of testing their
availability begins. All of these processes can take upto years, even before
any therapeutic MOA can be confirmed.

Although development of ADCs is
fraught with challenges, they continue to be a worthwhile endeavor for
researchers and companies investigating therapeutic cancer drugs because of
their specificity, effectiveness, and bio-compatibility.

 

 

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