Antibodies are highly valuable
tools in most steps of drug development and as drugs themselves. The basic
antibody technology for generating antibodies from immunized animals is widely
used and is decades old. Consequently, the low hanging fruit is long gone and
new technology is required to extend the technology to largely inaccessible but
valuable drug targets.
GPCRs represent a large and
important group of proteins rich in drug targets. Unfortunately, they are
multispan membrane proteins that are extremely difficult to create antibodies
against using traditional approaches, especially for critical applications in
the drug discovery process.. The difficulties are many-fold: a) The
epitopes are largely dependent on the membrane for structure and purification,
and thus removal of the membrane, typically results in denaturation of the
protein and destruction of the epitopes. Alternatively, immunizing with whole
cells and thus maintaining the structure means immunizing with a very impure
mix of protein and the immune response is greatly diminished if not
non-existent. b) The epitopes are made up of small discontinuous segments
making them inaccessible to standard peptide or recombinant protein technology
since these small segments in isolation cannot fold or assemble together. c) These
proteins in general are expressed at very low levels and it is difficult to
generate sufficient material for immunization and can take many months to years
to produce sufficient amounts.
Utilization of Genomic Antibody
Technology, a method where the antigen is produced in vivo and directly drives an immune response, solves a number of
the problems faced when making antibodies against proteins such as GPCRs.
Because the antigen is expressed in vivo
and is never purified, there is little risk of the protein being denatured.
Moreover, maintaining the antigen in the natural milieu of the cell with
its endogenous chaperones and other machinery ensures the correct folding,
assembly, post-translational modifications, and transport of the antigen to its
natural location. Finally, one of the most challenging issues with this class
of antigens is generating appropriate levels of expression. GPCRs are
inherently difficult to overexpress and require engineering to overcome the
natural biological controls. Using Genomic Antibody Technology, the antigen is
amenable to the rapid and powerful techniques of molecular biology to solve
these problems.
While simple in theory, Genomic
Antibody Technology is, in practice, very complex and difficult to master.
Successful execution of the technology requires the optimization of multiple
steps, including: antigen design, appropriate expression of the antigen,
targeting the appropriate immune cells, and use of the right adjuvants. SDIX
has carefully optimized and continues to improve each of these steps to ensure
success. While some targets can be somewhat forgiving, for difficult targets
such as GPCRs, careful optimization is absolutely critical for success.