Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues
Reexamination Certificate
1995-06-07
2001-08-07
Draper, Garnette D. (Department: 1646)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
C530S351000, C514S002600, C514S008100, C514S012200, C424S085100, C930S120000, C930S144000
Reexamination Certificate
active
06271346
ABSTRACT:
FIELD OF THE INVENTION
The invention is in the field of recombinant genetics. In particular, the invention relates to a TNF receptor and to a TNF binding protein produced by recombinant means.
BACKGROUND OF THE INVENTION
Tumour necrosis factor (TNF-&agr;) was first found in the serum of mice and rabbits which had been infected with Bacillus Calmette-Guerin and which had been injected with endotoxin, and was recognized on the basis of its cytotoxic and antitumor properties (Carswell, E. A., et al.,
Proc. Natl. Acad. Sci.
25: 3666-3670 (1975)). It is produced particularly by activated macrophages and monocytes.
Numerous types of cells which are targets of TNF have surface receptors with a high affinity for this polypeptide (Old, L. J.,
Nature
326:330-331 (1987)); it was assumed that lymphotoxin (TNF-&bgr;) binds to the same receptor (Aggarwal, B. B., et al.,
Nature
318:655-667 (1985); Gullberg, U., et al.,
Eur. J. Haematol.
39:241-251 (1987)). TNF-&agr; is identical to a factor referred to as cachectin (Beutler, B., et al.,
Nature
316:552-554 (1985)) which suppresses lipoprotein lipase and results in hypertriglyceridaemia in chronically inflammatory and malignant diseases (Torti, F. M. et al.,
Nature
229:867-869 (1985); Mahoney, J. R., et al.,
J. Immunol.
134:1673-1675 (1985)). TNF-&agr; would appear to be involved in growth regulation and in the differentiation and function of cells which are involved in inflammation, immune processes and hematopoieses.
TNF can have a positive effect on the host organism by stimulating neutrophils (Shalaby, M. R., et al.,
J. Immunol.
135:2069-2073 (1985); Klebanoff, S. J., et al.,
J. Immunol.
136:4220-4225 (1986)) and monocytes and by inhibiting the replication of viruses (Mestan, J., et al.,
Nature
323:816-819 (1986); Wong, G. H. W., et al.,
Nature
323:819-822 (1986)). Moreover, TNF-&agr; activates the immune defenses against parasites and acts directly and/or indirectly as a mediator in immune reactions, inflammatory processes and other processes in the body, although the mechanisms by which it works have not yet been clarified in a number of cases. However, the administration of TNF-&agr; (Cerami, A., et al.,
Immunol. Today
9:28-31 (1988)) can also be accompanied by harmful phenomena (Tracey, K. J., et al.,
Science
234:470-474 (1986)) such as shock and tissue damage, which can be remedied by means of antibodies against TNF-&agr; (Tracey, K. J., et al.,
Nature
330:662-666 (1987)).
A number of observations lead one to conclude that endogenously released TNF-&agr; is involved in various pathological conditions. Thus, TNF-&agr; appears to be a mediator of cachexia which can occur in chronically invasive, e.g. parasitic, diseases. TNF-&agr; also appears to play a major part in the pathogenesis of shock caused by gram negative bacteria (endotoxic shock); it would also appear to be implicated in some if not all the effects of lipopoly-saccharides (Beutler B., et al.,
Ann. Rev. Biochem.
57:505-18 (1988)). TNF has also been postulated to have a function in the tissue damage which occurs in inflammatory processes in the joints and other tissues, and in the lethality and morbidity of the graft-versus-host reaction (GVHR, Transplant Rejection (Piguet, P. F., et al.,
Immunobiol.
175:27 (1987)). A correlation has also been reported between the concentration of TNF in the serum and the fatal outcome of meningococcal diseases (Waage, A., et al.,
Lancet ii:
355-357 (1987)).
It has also been observed that the administration of TNF-&agr; over a lengthy period causes a state of anorexia and malnutrition which has symptoms similar to those of cachexia, which accompany neoplastic and chronic infectious diseases (Oliff A., et al.,
Cell
555-63 (1987)).
It has been reported that a protein derived from the urine of fever patients has a TNF inhibiting activity; the effect of this protein is presumed to be due to a competitive mechanism at the level of the receptors (similar to the effect of the interleukin-1 inhibitor (Seckinger, P., et al.,
J. Immunol.
139:1546-1549 (1987); Seckinger P., et al.,
J. Exp. Med.,
1511-16 (1988)).
EP-A2 308 378 describes a TNF inhibiting protein obtained from human urine. Its activity was demonstrated in the urine of healthy and ill subjects and determined on the basis of its ability to inhibit the binding of TNF-&agr; to its receptors on human HeLa cells and FS 11 fibroblasts and the cytotoxic effect of TNF-&agr; on murine A9 cells. The protein was purified until it became substantially homogeneous and characterized by its N-ending. This patent publication does indeed outline some theoretically possible methods of obtaining the DNA coding for the protein and the recombinant protein itself; however, there is no concrete information as to which of the theoretically possible solutions is successful.
SUMMARY OF THE INVENTION
The invention relates to DNA coding for a TNF receptor protein or a fragment thereof. In particular, the invention relates to DNA coding for the TNF receptor protein having the formula
ATG GGC CTC TCC ACC GTG CCT GAC CTG CTG CTG CCA
CTG GTG CTC CTG GAG CTG TTG GTG GGA ATA TAC CCC
TCA GGG GTT ATT GGA CTG GTC CCT CAC CTA GGG GAC
AGG GAG AAG AGA GAT AGT GTG TGT CCC CAA GGA AAA
TAT ATC CAC CCT CAA AAT AAT TCG ATT TGC TGT ACC
AAG TGC CAC AAA GGA ACC TAC TTG TAC AAT GAC TGT
CCA GGC CCG GGG CAG GAT ACG GAC TGC AGG GAG TGT
GAG AGC GGC TCC TTC ACC GCT TCA GAA AAC CAC CTC
AGA CAC TGC CTC AGC TGC TCC AAA TGC CGA AAG GAA
ATG GGT CAG GTG GAG ATC TCT TCT TGC ACA GTG GAC
CGG GAC ACC GTG TGT GGC TGC AGG AAG AAC CAG TAC
CGG CAT TAT TGG AGT GAA AAC CTT TTC CAG TGC TTC
AAT TGC AGC CTC TGC CTC AAT GGG ACC GTG CAC CTC
TCC TGC CAG GAG AAA CAG AAC ACC GTG TGC ACC TGC
CAT GCA GGT TTC TTT CTA AGA GAA AAC GAG TGT GTC
TCC TGT AGT AAC TGT AAG AAA AGC CTG GAG TGC ACG
AAG TTG TGC CTA CCC CAG ATT GAG AAT GTT AAG GGC
ACT GAG GAC TCA GGC ACC ACA GTG CTG TTG CCC CTG
GTC ATT TTC TTT GGT CTT TGC CTT TTA TCC CTC CTC
TTC ATT GGT TTA ATG TAT CGC TAC CAA CGG TGG AAG
TCC AAG CTC TAC TCC ATT GTT TGT GGG AAA TCG ACA
CCT GAA AAA GAG GGG GAG CTT GAA GGA ACT ACT ACT
AAG CCC CTG GCC CCA AAC CCA AGC TTC AGT CCC ACT
CCA GGC TTC ACC CCC ACC CTG GGC TTC AGT CCC GTG
CCC AGT TCC ACC TTC ACC TCC AGC TCC ACC TAT ACC
CCC GGT GAC TGT CCC AAC TTT GCG GCT CCC CGC AGA
GAG GTG GCA CCA CCC TAT CAG GGG GCT GAC CCC ATC
CTT GCG ACA GCC CTC GCC TCC GAC CCC ATC CCC AAC
CCC CTT CAG AAG TGG GAG GAC AGC GCC CAC AAG CCA
CAG AGC CTA GAC ACT GAT GAC CCC GCG ACG CTG TAC
GCC GTG GTG GAG AAC GTG CCC CCG TTG CGC TGG AAG
GAA TTC GTG CGG CGC CTA GGG CTG AGC GAC CAC GAG
ATC GAT CGG CTG GAG CTG CAG AAC GGG CGC TGC CTG
CGC GAG GCG CAA TAC AGC ATG CTG GCG ACC TGG AGG
CGG CGC ACG CCG CGG CGC GAG GCC ACG CTG GAG CTG
CTG GGA CGC GTG CTC CGC GAC ATG GAC CTG CTG GGC
TGC CTG GAG GAC ATC GAG GAG GCG CTT TGC GGC CCC
GCC GCC CTC CCG CCC GCG CCC AGT CTT CTC AGA TGA
or a fragment or a degenerate variant thereof.
The invention also relates to DNA coding for a secretable TNF-binding protein having the formula
R
2
GAT AGT GTG TGT CCC CAA GGA AAA TAT ATC CAC
CCT CAA AAT AAT TCG ATT TGC TGT ACC AAG TGC CAC
AAA GGA ACC TAC TTG TAC AAT GAC TGT CCA GGC CCG
GGG CAG GAT ACG GAC TGC AGG GAG TGT GAG AGC GGC
TCC TTC ACC GCT TCA GAA AAC CAC CTC AGA CAC TGC
CTC AGC TGC TCC AAA TGC CGA AAG GAA ATG GGT CAG
GTG GAG ATC TCT TCT TGC ACA GTG GAC CGG GAC ACC
GTG TGT GGC TGC AGG AAG AAC CAG TAC CGG CAT TAT
TGG AGT GAA AAC CTT TTC CAG TGC TTC AAT TGC AGC
CTC TGC CTC AAT GGG ACC GTG CAC CTC TCC TGC CAG
GAG AAA CAG AAC ACC GTG TGC ACC TGC CAT GCA GGT
TTC TTT CTA AGA GAA AAC GAG TGT GTC TCC TGT AGT
AAC TGT AAG AAA AGC CTG GAG TGC ACG AAG TTG TGC
CTA CCC CAG ATT GAG AAT
wherein R
2
is optionally absent or represents DNA coding for a polypeptide which can be cleaved in vivo; or a degenerate variant thereof.
The invention also relates to nucleic acid which hybridizes with the DNA of the invention under conditions of low stringency and which codes for a polypeptide having the ability to bind T
Hauptmann Rudolf
Himmler Adolf
Maurer-Fogy Ingrid
Stratowa Christian
Amgen Inc.
Draper Garnette D.
McDonnell & Boehnen Hulbert & Berghoff
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