Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Binds hormone or other secreted growth regulatory factor,...
Reexamination Certificate
2000-03-21
2002-07-16
Wortman, Donna C. (Department: 1642)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Binds hormone or other secreted growth regulatory factor,...
C424S133100, C424S141100, C424S172100, C424S152100, C530S388100, C530S387300, C530S388730
Reexamination Certificate
active
06419928
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the field of immunology and particularly to monoclonal antibodies specific to transforming growth factor beta (TGF-B) and applications thereof.
BACKGROUND OF THE INVENTION
Transforming growth factor beta (TGF-B) is a family of related multifunctional regulators of cell growth which can affect cellular proliferation and differentiation. Two forms of TGF-B, TGF-B1 and TGF-B2, are, in general, multifunctional cytokines that have potent inhibitory effects on the proliferation and effector responses of mitogen-, lymphokine-, and alloantigen-activated lymphocytes (Kearl et al,
J Exp Med
(1986) 163:1037; Ellingsworth et al,
Cell Immunol
(1988) 113: in press; Kearl et al,
J Immunol
(1986) 137:3855; Ranges et al,
J Exp Med
(1987) 166:991). In addition, TGF-B1 and TGF-B2 affect the proliferation and differentiation of other cells of the immune system including macrophages (Wall et al,
Proc Natl Acad Sci USA
(1987) 84:5788), pre-B cells (Lee et al,
J Exp Med
(1987) 166:1290), hematopoietic stem cells (Ohta et al,
Nature
(1987) 329:539; Ishibashi et al,
Blood
(1987) 69:1737; Keller et al,
J Exp Med
(1988) in press, Sing et al,
Blood
(1988) in press), and NK cells (Rook et al,
J Immunol
(1986) 136:3916).
The generation of immunoprecipitating and neutralizing antibodies to native TGF-B has been extremely difficult due to the highly conserved nature of native TGF-B among different species. The human sequence of TGF-B1 is identical to the bovine and porcine sequences and differs from the murine sequence by one amino acid. TGF-B1 is a dimer composed of two identical disulfide-linked chains of 112 amino acid residues.
TGF-B2 is also a dimeric polypeptide and is disclosed in U.S. Pat. No. 4,774,322, filed Dec. 10, 1987, assigned to Collagen Corporation. Even though there are 14 amino acid differences in the first 36 amino acids residues of the two forms, their biological activities are similar (Cheifetz et al,
Cell
(1987) 48:409-415; Seyedin et al,
J Biol Chem
(1987) 262:1946-1949).
Western blots and immunohistochemical localization studies on TGF-B1 have been performed using a polyclonal rabbit antiserum obtained by immunization with a synthetic peptide corresponding to the NH
2
-terminal 30 amino acids of TGF-B1 (Ellingsworth et al,
J Biol Chem
(1986) 261:12362). Polyclonal antisera to human and porcine TGF-B (Keski-Oja et al,.
Cancer Res
(1987) 47:6451-6458) and to porcine TGF-B2 (Rosa et al,
Science
(1988) 239:783-785) have been shown to neutralize the biological activity of TGF-B1 and TGF-B2, respectively. Monoclonal antibodies specific to TGF-B have not been previously described. The availability of these specific antibodies is important for characterization of the role played by TGF-B in the immune system and other physiological processes.
Antibodies to TGF-B are needed to investigate the varied biological actions of TGF-B, to study TGF-B biosynthesis, and to determine differences in activity or effect, if any, between the forms of TGF-B. These antibodies would also have therapeutic applications for treating indications where there is an overproduction of TGF-B (e.g., acute liver injury, chronic hepatic fibrosis) and for diagnosing or treating malignancies (e.g., sarcomas and melanomas) and metastatic cancers.
SUMMARY OF THE INVENTION
The present invention provides a monoclonal antibody immunoreactive with TGF-B. A monoclonal antibody is described herein that is specific for TGF-B. This antibody, in preferred embodiments, binds to a neutralizing epitope on TGF-B or binds to an epitope on TGF-B which blocks the binding of TGF-B to its cellular receptors.
Another aspect of the invention is to provide a stable cell line which secretes a monoclonal antibody specific for TGF-B. In one embodiment of the invention, the cell line secretes a murine monoclonal antibody specific for TGF-B that has TGF-B neutralizing activity.
Another aspect of the invention is a method for treating acute and chronic disease states that result from an overproduction of TGF-B, by administering a therapeutically effective amount of a monoclonal antibody reactive with TGF-B, or an antigen-binding fragment of a monoclonal antibody reactive with TGF-B.
Another aspect of the invention is a method for treating tumor cells that produce TGF-B, by administering a therapeutically effective amount of a monoclonal antibody reactive with TGF-B to suppress the immunosuppressive effects of TGF-B.
Another aspect of the invention is a method for treating metastatic cancers by administering a therapeutically effective amount of a monoclonal antibody reactive with TGF-B to mark tumor cells for destruction by complement or by immune cells dedicated to tumor cell removal.
Another aspect of the invention is a capture-ELISA (CELISA) for diagnosing disease states such as cancer and connective tissue (fibrotic) disorders. comprising: coating a first monoclonal or polyclonal antibody reactive with TGF-B onto a surface, adding a sample containing an unknown amount of TGF-B or a standard concentration of purified TGF-B to the surface, adding polyclonal sera reactive with TGF-B or a monoclonal antibody of the invention to the surface, adding an enzyme-linked tertiary antibody (reactive to said monoclonal or polyclonal antibody), and determining the presence of TGF-B by quantifying the amount of enzymatic label present in a colorimetric reaction.
Another aspect of the invention is a chimeric monoclonal antibody, having an antigen-binding portion derived from the MAb of the invention, and the remainder derived from human antibodies. Such chimeric antibodies are described by S. L. Morrison,
Science
(1985) 229:1202.
Another aspect of the invention is an anti-idio-typic antibody reactive with the MAbs of the invention, which are useful as TGF-B mimics. These mimics are capable of binding to TGF-B receptors, and thus may act as TGF-B agonists or antagonists.
These and other objects and features of the invention will become more fully apparent from the following detailed description of the invention.
REFERENCES:
patent: 4774322 (1988-09-01), Seyedin et al.
patent: 5662904 (1997-09-01), Ferguson et al.
patent: 5693607 (1997-12-01), Segarini et al.
patent: 5821337 (1998-10-01), Carter et al.
patent: 0455482 (1991-11-01), None
patent: WO 91/19513 (1991-12-01), None
patent: WO 94/18991 (1994-09-01), None
Kawakami, T, et al, 1998, Increased expression of TGF-beta receptors by scleroderma fibroblasts: evidence for contribution of autocrine TGF-beta signaling to scleroderma phenotype, Journal of Investigative Dermatology, vol. 110, pp. 47-51.*
Adzik, NS, et al, 1994, Cells, matrix, growth factors, and the surgeon, Annals of Surgery, vol. 220, pp. 10-18.*
Van Vlasselaer, P, et al, 1994, Interleukin 10 inhibits transforming growth factor-beta (TGF-beta) synthesis required for osteogenic commitment of mouse bone marrow cells, Journal of Cell Biology, vol. 124, pp. 569-577.*
Berenson, et al., “Engraftment after infusion of CD34+marrow cells in patients with breast cancer or neuroblastoma”Blood(1991) 77:1717-1722.
Carlino, et al., “Transforming growth factor &bgr;1 systemically modulates granuloid, erythroid, lymphoid, and thrombocytic cells in mice”Exp. Hematol.(1992) 20:943-950.
Cashman, et al., “Mechanisms that regulate the cell cycle of very primitive hematopoietic cells in long-term human marrow cultures. I. Stimulatory role of a variety of mesenchymal cell activators and inhibitory role of TGF-&bgr;”Blood(1990) 75(1):96-101.
Cheifetz, et al., “The transforming growth factor-&bgr; system: A complex pattern of cross-reactive ligands and receptors”Cell(1987) 48:409-416.
Dasch, et al., “Monoclonal Antibodies Recognizing Transforming Growth Factor-&bgr;: Bioactivity Neutralization and Transforming Growth Factor-&bgr;2Affinity Purification”,J. Immunol.(1989) 142(5):1536-1547.
Durametal, “Proinflammatory Cytokines and Immunity”, inFundamental Immunology, 3rd Ed., Paul, W.E.; Ed. Raven Press, Ltd., New York (1993).
Eaves, et al., “Mechanisms that regulate the cell cycle
Dasch James R.
Pace, III Doran R.
Waegell Wendy O.
Genzyme Corporation
Kanter Madge R.
Rawlings Stephen L.
Wortman Donna C.
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