Principles and Practice of Pharmaceutical Medicine

(TNF) antibodies in human rheumatoid arthritis.
There would also have been a lot of data available
concerning cellular infiltrates in joint effusions,
with monocytes and T-lymphocytes being the
most prevalent. High concentrations of other med-
iators of inflammation, such as interleukin-1b, leu-
kotrienes and phospholipases had also been
reported in rheumatoid joints. The scientist might
then conclude that inhibitors of TNF receptor acti-
vations, rather than antibodies to the ligand (TNF)
itself, could also benefit inflammatory arthropathy.
A range of ways how this might be accomplished
would then present itself: irreversible antagonism
of the TNF receptor, interruption of that receptor’s
transduction mechanism or prevention of the
expression of either TNF itself, or its TNF receptor,
in the nucleus or ribosome.
The investigator might then seek the counsel of
marketing experts and physicians regarding the use
of the antibodies, and again review the clinical trial
data available through the literature on the anti-
TNF antibodies. Such antibodies will be compet-
ing products for a long time in the future, given that
it is difficult to obtain regulatory approval for

‘generic’ biotechnology products, regardless of

the patent situation. But the antibodies are also

unattractive drugs. They are not orally available,

and they elicit of immune responses after several

doses (anti-anti-TNF antibody humoral response).

Thus, these criteria would then be applied when

sorting through the alternative modes of attack on

the TNF receptor. An orally bioavailable, non-

peptide drug might become the goal.

The next question to be answered is whethera

priorithe receptor itself, or one of the associated

regulatory enzymes, is likely to be specifically

targetable using an oral, non-peptide drug. Little

literature on this subject was available in 1997,

and no competitor seems to have taken this

approach. The company’s laboratories are then

set to work.

Each individual laboratory (‘lab’) working on

TNF as a therapeutic target approaches the pro-

blem from a different direction. For example, one

lab may seek to inhibit transcription factor activa-

tion by phosphorylation or proteolysis, and to

examine the sorts of compound that may be cap-

able of this. Another group might seek to interfere

TARGET IDENTIFICATION

Medical market +Clinical need Therapeutic target

Physiological target, system or organ

Cellular target

Drug target = Protein (enzyme, receptor, etc.)

Molecular design

Antibodies, proteins or small chemicals

Figure 4.2 Target identification

46 CH4 DRUG DISCOVERY: DESIGN AND SERENDIPITY