Genmab has recently developed UniBody®, a new
proprietary antibody technology that creates a stable, smaller antibody
format with an anticipated longer therapeutic window than current small
antibody formats. Genmab believes its UniBody technology has the potential to
expand the market for targeted therapeutics, in particular for some cancer
and autoimmune diseases.
The Creation of a New Antibody Format
Most currently used antibody therapeutics are of the IgG1 type. IgG1
antibodies interact well with the body’s immune system, which is necessary
for treatment of most types of cancer. Some diseases, however, may be
best treated with an antibody that does not cause immune system interaction
that can result in the destruction of the target cell. One such type of
antibody is called IgG4. IgG4 antibodies are considered inert and thus
do not interact with the immune system. It is difficult to use these
antibodies in therapeutic settings, though as they are also unstable and
normally fall apart. In order to use IgG4 antibodies in a treatment
setting the molecule must be stabilized, which may not be effective.
Like the IgG1 antibodies, the IgG4 molecules also bind bivalently to disease
targets. In other words, these antibodies bind to targets in two places
and may actually signal cancer cells to grow, a clear disadvantage for
certain disease targets.
In attempting to address the unstable nature and bivalent binding of IgG4
antibodies, Genmab modified fully human IgG4 antibodies by eliminating the
hinge region of the antibody. The hinge region is the part of the
antibody that holds together the two halves of antibodies giving them their
“Y” shape. After deletion of the hinge region of the IgG4 antibody,
half of an antibody molecule was left. Unlike the full size IgG4
antibody, the half molecule fragment is very stable. This half molecule
is what we call a UniBody.
Halving the IgG4 molecule left only one area on the UniBody that can bind to
disease targets. The UniBody therefore binds univalently to only one
site on target cells. This univalent binding does not stimulate cancer
cells to grow like bivalent antibodies might and opens the door for treatment
of some types of cancer which ordinary antibodies cannot treat.
The UniBody is also about half the size of a regular IgG4 antibody.
This small size can be a great benefit when treating some forms of cancer,
allowing for better distribution of the molecule over larger solid tumors and
potentially increasing efficacy.
Longer Therapeutic Window
Other biotechnology and pharmaceutical companies have also created antibody
fragments (Fabs). The UniBody, however, holds a distinct
advantage over other Fabs in several ways. Fabs typically do not have a
very long half-life. This means that the fragments do not last very
long in the body and therefore cannot continue to treat the disease as long
as full size antibodies. In order to increase the half-life of Fabs,
the molecules need to be modified which can be an expensive process and may
decrease the effectiveness of the antibody. UniBody molecules,
however, were cleared at a similar rate to whole IgG4 antibodies
and were able to bind as well as whole antibodies and antibody fragments
in pre-clinical studies. UniBody molecules differ from both of
these however, when it comes to how they affect target cells. Other
antibodies primarily work by killing the targeted cells whereas UniBody
molecules only inhibit or silence the cells. This could be an
advantage therapeutically when treating, for example, allergies or asthma,
when killing the cells is not the objective.
New Business Opportunities
We believe UniBody molecules can be manufactured in the same way as
traditional antibodies and offer key advantages over current antibody
therapies. Genmab believes these advantages will create the opportunity
for therapies in indications such as asthma, inflammation and some types of
cancer. We intend to use the UniBody technology to develop our own
antibody products, work with partners who have access to targets for which
this technology may be beneficial and may out-license the technology to other
companies.