Appeal No. 1999-0197
Application 08/054,970
intracellular signals for cell response to TNF (Englemann et al., 1990a). Two
molecular species of the TNF-Rs, the p55 and the p75 TNF-R, expressed
differentially in different types of cells, have been identified (Engelmann et
al., 1990b; Brockhaus et al., 1990).
Appellants also explain on page 2 of the specification that:
The main mediator for the cytotoxic effect of the TNF on fibroblastoid and
epithelial cells is the p55 TNF-R, which also is the prevalent TNF-R type on
these cell lines. Blocking this receptor species abolishes the cytocidal effect
of TNF, while inducing aggregation of the receptor molecules can mimic the
cytocidal effect of the TNF.
The soluble form of this receptor, as well as the soluble form of the other
(p75) TNF-R, have been shown to have inhibitory effects on TNF function.
Evidence was presented that these soluble forms are derived proteolitically
from the cell surface forms, (Nophar et al., 1990; Porteu and Nathan, 1990;
Porteu et al., 1991).
The claimed invention is summarized at page 3 of the specification as follows:
The present invention provides a method of modulating signal transduction
and/or cleavage in tumor necrosis factor receptors (TNF-Rs) comprising
interfering with one or more amino acids in the sequence of a TNF-R or with
an effector protein interacting with the TNF-R.
This interference influences the normal functioning of the TNF-Rs or
influences an effector protein interacting therewith, and thereby modulates
signal transduction by causing partial or total inhibition thereof, or influences
shedding, i.e. abolishes cleavage of the soluble form of the receptor.
The present invention further provides peptides or other molecules which
interact either with the receptor itself, i.e. interact with one or more amino
acids in the receptor sequence, or interact with the effector proteins, and
thus modulate the normal functioning of the TNF-Rs. The above molecules
also include antibodies or fragments thereof.
Appellants have found the role certain amino acids of human p55 TNF-R have in
determining how the receptor functions. For example, appellants have found that
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