Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2001-01-08
2004-12-28
Canella, Karen A. (Department: 1642)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S023100, C536S023500
Reexamination Certificate
active
06835823
ABSTRACT:
BACKGROUND AND FIELD OF THE INVENTION
The present invention in the field of immunology and medicine relates to anti-tumor necrosis factor (TNF) antibodies, anti-TNF peptides and nucleic acids encoding therefor, and to pharmaceutical and diagnostic compositions and production, diagnostic and therapeutic methods thereof, and to methods for treating human TNF-mediated pathologies.
DESCRIPTION OF THE BACKGROUND ART
Tumor Necrosis Factor
Monocytes and macrophages secrete cytokines known as tumor necrosis factor-&agr; (TNF&agr;) and tumor necrosis factor-&bgr; (TNF&bgr;) in response to endotoxin or other stimuli. TNF&agr; is a soluble homotrimer of 17 kD protein subunits (Smith, et al.,
J. Biol. Chem
. 262:6951-6954 (1987)). A membrane-bound 26 kD precursor form of TNF also exists (Kriegler, et al.,
Cell
53:45-53 (1988)). For reviews of TNF, see Beutler, et al.,
Nature
320:584 (1986), Old,
Science
230:630 (1986), and Le, et al.,
Lab. Invest
. 56:234.
Cells other than monocytes or macrophages also make TNF&agr;. For example, human non-monocytic tumor cell lines produce TNF (Rubin, et al.,
J. Exp. Med
. 164:1350 (1986); Spriggs, et al.,
Proc. Natl. Acad. Sci. USA
84:6563 (1987)). CD4
+
and CD8
+
peripheral blood T lymphocytes and some cultured T and B cell lines (Cuturi, et al.,
J. Exp. Med
. 165:1581 (1987); Sung, et al.,
J. Exp. Med
. 168:1539 (1988)) also produce TNF&agr;.
TNF causes pro-inflammatory actions which result in tissue injury, such as inducing procoagulant activity on vascular endothelial cells (Pober, et al.,
J. Immunol
. 136:1680 (1986)), increasing the adherence of neutrophils and lymphocytes (Pober, et al.,
J. Immunol
. 138:3319 (1987)), and stimulating the release of platelet activating factor from macrophages, neutrophils and vascular endothelial cells (Camussi, et al.,
J. Exp. Med
. 166:1390 (1987)).
Recent evidence associates TNF with infections (Cerami, et al.,
Immunol. Today
9:28 (1988)), immune disorders, neoplastic pathologies (Oliff, et al.,
Cell
50:555 (1987)), autoimmune pathologies and graft-versus host pathologies (Piguet, et al.,
J. Exp. Med
. 166:1280 (1987)). The association of TNF with cancer and infectious pathologies is often related to the host's catabolic state. Cancer patients suffer from weight loss, usually associated with anorexia.
The extensive wasting which is associated with cancer, and other diseases, is known as “cachexia” (Kern, et al., (
J. Parent. Enter. Nutr
. 12:286-298 (1988)). Cachexia includes progressive weight loss, anorexia, and persistent erosion of body mass in response to a malignant growth. The fundamental physiological derangement can relate to a decline in food intake relative to energy expenditure. The cachectic state causes most cancer morbidity and mortality. TNF can mediate cachexia in cancer, infectious pathology, and other catabolic states.
TNF also plays a central role in gram-negative sepsis and endotoxic shock (Michie, et al.,
Br. J. Surg
. 76:670-671 (1989); Debets, et al.,
Second Vienna Shock Forum
, p.463-466 (1989); Simpson, et al.,
Crit. Care Clin
. 5:27-47 (1989)), including fever, malaise, anorexia, and cachexia. Endotoxin strongly activates monocyte/macrophage production and secretion of TNF and other cytokines (Kornbluth, et al.,
J. Immunol
. 137:2585-2591 (1986)). TNF and other monocyte-derived cytokines mediate the metabolic and neurohormonal responses to endotoxin (Michie, et al.,
New. Engl. J. Med
. 318:1481-1486 (1988)). Endotoxin administration to human volunteers produces acute illness with flu-like symptoms including fever, tachycardia, increased metabolic rate and stress hormone release (Revhaug, et al.,
Arch. Surg
. 123:162-170 (1988)). Circulating TNF increases in patients suffering from Gram-negative sepsis (Waage, et al., Lancet 1:355-357 (1987); Hammerle, et al.,
Second Vienna Shock Forum
p. 715-718 (1989); Debets, et al.,
Crit. Care Med
. 17:489-497 (1989); Calandra, et al.,
J. Infect. Dis
. 161:982-987 (1990)).
TNF Antibodies
Polyclonal murine antibodies to TNF are disclosed by Cerami et al. (EPO Patent Publication 0212489, Mar. 4, 1987). Such antibodies were said to be useful in diagnostic immunoassays and in therapy of shock in bacterial infections.
Rubin et al. (EPO Patent Publication 0218868, Apr. 22, 1987) discloses murine monoclonal antibodies to human TNF, the hybridomas secreting such antibodies, methods of producing such murine antibodies, and the use of such murine antibodies in immunoassay of TNF.
Yone et al. (EPO Patent Publication 0288088, Oct. 26, 1988) discloses anti-TNF murine antibodies, including mAbs, and their utility in immunoassay diagnosis of pathologies, in particular Kawasaki's pathology and bacterial infection. The body fluids of patients with Kawasaki's pathology (infantile acute febrile mucocutaneous lymph node syndrome; Kawasaki,
Allergy
16:178 (1967); Kawasaki,
Shonica
(
Pediatrics
) 26:935 (1985)) were said to contain elevated TNF levels which were related to progress of the pathology (Yone et al., infra).
Other investigators have described rodent or murine mAbs specific for recombinant human TNF which had neutralizing activity in vitro (Liang, et al., (
Biochem. Biophys. Res. Comm
. 137:847-854 (1986); Meager, et al.,
Hybridoma
6:305-311 (1987); Fendly et al.,
Hybridoma
6:359-369 (1987); Bringman, et al.,
Hybridoma
6:489-507 (1987); Hirai, et al.,
J. Immunol. Meth
. 96:57-62 (1987); Moller, et al., (
Cytokine
2:162-169 (1990)). Some of these mAbs were used to map epitopes of human TNF and develop enzyme immunoassays (Fendly et al., infra; Hirai et al., infra; Moller et al., infra) and to assist in the purification of recombinant TNF (Bringman et al., infra). However, these studies do not provide a basis for producing TNF neutralizing antibodies that can be used for in vivo diagnostic or therapeutic uses in humans, due to immunogenicity, lack of specificity and/or pharmaceutical suitability.
Neutralizing antisera or mAbs to TNF have been shown in mammals other than man to abrogate adverse physiological changes and prevent death after lethal challenge in experimental endotoxemia and bacteremia. This effect has been demonstrated, e.g., in rodent lethality assays and in primate pathology model systems (Mathison, et al.,
J. Clin. Invest
. 81:1925-1937 (1988); Beutler, et al.,
Science
229:869-871 (1985); Tracey, et al.,
Nature
330:662-664 (1987); Shimamoto, et al.,
Immunol. Lett
. 17:311-318 (1988); Silva, et al.,
J. Infect. Dis
. 162:421-427 (1990); Opal,et al.,
J. Infect. Dis
. 161:1148-1152 (1990); Hinshaw, et al.,
Circ. Shock
30:279-292 (1990)).
Putative receptor binding loci of hTNF has been disclosed by Eck and Sprang (
J. Biol. Chem
. 264(29), 17595-17605 (1989)), who identified the receptor binding loci of TNF-&agr; as consisting of amino acids 11-13, 37-42, 49-57 and 155-157.
PCT publication W091/02078 (1991) discloses TNF ligands which can bind to monoclonal antibodies having the following epitopes: at least one of 1-20, 56-77, and 108-127; at least two of 1-20, 56-77, 108-127 and 138-149; all of 1-18, 58-65, 115-125 and 138-149; all of 1-18, and 108-128; all of 56-79, 110-127 and 135- or 136-155; all of 1-30, 117-128 and 141-153; all of 1-26, 117-128 and 141-153; all of 22-40, 49-96 or 49-97, 110-127 and 136-153; all of 12-22, 36-45, 96-105 and 132-157; both of 1°and 76-90; all of 22-40, 69-97, 105-128 and 135-155; all of 22-31 and 146-157; all of 22-40 and 49-98; at least one of 22-40, 49-98 and 69-97, both of 22-40 and 70-87.
To date, experience with anti-TNF murine mAb therapy in humans has been limited. In a phase I study, fourteen patients with severe septic shock were administered a murine anti-TNF mAb in a single dose from 0.4-10 mg/kg (Exley, A. R. et al.,
Lancet
335:1275-1277 (1990)). However, seven of the fourteen patients developed a human anti-murine antibody response to the treatment, which treatment suffers from the known problems due to immunogenicity from the use of murine heavy and light chain portions of the antibody. Such immunogenicity causes decrea
Daddona Peter
Ghrayeb John
Knight David
Le Jumming
Siegel Scott
Canella Karen A.
Hamilton Brook Smith & Reynolds P.C.
New York University
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