Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Structurally-modified antibody – immunoglobulin – or fragment...
Reexamination Certificate
2001-08-03
2003-11-25
Chan, Christina (Department: 1644)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Structurally-modified antibody, immunoglobulin, or fragment...
C424S154100, C424S173100, C514S012200, C530S387300, C530S388700, C530S388230
Reexamination Certificate
active
06652854
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to methods for treating autoimmune and inflammatory disorders that involve administering agents that block the interaction between CD30 and CD30L or IL-1 and IL-1R1, and also provides an animal model for testing the ability of a compound to treat inflammatory conditions that respond poorly to treatment with TNF&agr; inhibitors.
BACKGROUND OF THE INVENTION
CD30 and its ligand, CD30L, are membrane proteins of the TNFR and TNF ligand superfamilies, respectively, and are expressed on various lymphoid and myeloid cells. CD30 was first described as an antigen on Hodgkin's disease cells, and presently is widely used as a clinical marker for a number of hematologic malignancies (for review, see Horie and Watanabe,
Immunol
10:457-470 (1998)). A naturally-occurring soluble form of the CD30 protein is found in human serum, and levels of this protein are elevated in a variety of pathological conditions including viral infection, allergic and autoimmune conditions and neoplastic diseases.
CD30 and CD30L are expressed on T cells, and appear to be involved in regulation of the immune system. Their expression on T cells is activation-dependent. CD30 has been reported to be a specific marker of T
H
2 type T cells (Romagnani,
J Leukocyte Biol
57:726 (1995); Romagnani,
J Clin Immunol
15:121-129 (1995)). The T
H
1 and T
H
2 subsets of CD4
+
T cells can be distinguished based on which cytokines they predominantly express. Though individual T cells may actually secrete mixtures of these two groups of cytokines, chronic immune reactions are often dominated by one type or the other of CD4
+
T cells. T cells that produce T
H
2 cytokines, which include IL-4, generally are considered to be mediators of allergic reactions. It has been suggested that the detection of circulating CD30
+
T cells could serve as a marker for T
H
2-dominated allergic conditions such as atopic dermatitis (Yamamoto et al.,
Allergy
55:1011-18 (2000)); however, the correlation between CD30 expression and T
H
2 phenotype has not held up over time (see, for example, Bengtsson et al,
J Leukocyte Biol
58:683 (1996); Hamann et al.,
J Immunol
156:1387-91 (1996)). Based on experiments using a mouse model of diabetes, it has been proposed also that CD30-mediated signaling may protect against autoimmune disease (Kurts et al.,
Nature
398:341-344 (1999)). Others have reported that IL-4 upregulates, whereas IFN&ggr; downregulates, the expression of CD30 on activated T cells (Nakamura et al.,
J Immunol
158:2090-98 (1997); Gilfillan et al.,
J Immunol
160:2180-87 (1998)).
The naturally-occurring ligand for CD30, CD30L, is a type II membrane glycoprotein that binds specifically with CD30, thus triggering CD30 to transmit a signal via its cytoplasmic domain. The isolation of mouse and human cDNAs encoding CD30L is described in U.S. Pat. No. 5,480,981. In addition to being expresed on activated T cells, CD30L is expressed on monocytes/macrophages, granulocytes and a subset of B cells (see, for example, U.S. Pat. No. 5,480,981). CD30L has been reported to induce murine B cell differentiation and the proliferation of activated T cells in the presence of an anti-CD3 co-stimulus (see, for example, Smith et al.,
Cell
73:1349-1360 (1993)). Moreover, it has been reported that CD30L exhibits “reverse signaling,” that is, the cell surface CD30L that is expressed on neutrophils and peripheral blood T cells can be activated by cross-linking to stimulate metabolic activities in those cells (Wiley et al.,
J Immunol
157: 3235-39 (1996)).
There is a need to better understand the biological activities of CD30 and CD30L, and to exploit this knowledge in the treatment of human disease.
SUMMARY OF THE INVENTION
In accord with this invention, an agent capable of inhibiting the binding of CD30 to CD30L is used for treating an autoimmune or chronic inflammatory condition, the method comprising administering the agent to the patient according to a regimen of dose and frequency of administration that is adequate to induce a sustained improvement in at least one indicator that reflects the severity of the patient's condition. The improvement is considered to be sustained if the patient exhibits the improvement on at least two occasions separated by at least one day. The agent may be formulated into a physiologically acceptable pharmaceutical preparation, which may be packaged with a written matter describing the foregoing use. Moreover, an inhibitor of the CD30/CD30L interaction according to this invention may be administered concurrently with other treatments being used to treat the same disorder. In a preferred embodiment, the patient is a human.
In one of the embodiments of the invention, preferred agents for use in treating an autoimmune or inflammatory condition include an antibody that is specific for CD30L, a non-agonistic antibody that is specific for CD30, and a soluble CD30 polypeptide that comprises all or part of the extracellular region of human CD30. The nucleotide and amino acid sequences of human CD30 are shown in SEQ ID NO:6. Suitable CD30 polypeptides for use as therapeutic agents include proteins that comprise amino acids 19-390 of SEQ ID NO:6, or a fragment thereof that retains the ability to bind CD30L, including polypeptides having an at least 80%, at least 85%, at least 90%, at least 95%, at least 97.5%, or at least 99%, and most preferably at least 99.5% sequence identity with amino acids 19-390 of SEQ ID NO:6. Such polypeptides if administered in vivo are expected to bind with endogenous CD30L thereby interfering with the interaction between endogenous CD30 and endogenous CD30L. Such polypeptides may if desired be conjugated with another moiety, usually another protein, that promotes oligomerization. A moiety suitable for this purpose is the Fc region from an immunoglobulin molecule. Agents that antagonize the CD30/CD30L interaction may be used to prepare a pharmaceutical preparation to be administered in accord with the methods of the invention, either alone or concurrently with other treatments. Such pharmaceutical preparations may be packaged with a written matter describing the aforedescribed uses.
The hereindescribed therapeutic agents that inhibit the CD30/CD30L interaction may be used to treat a variety of diseases, including various arthritic conditions. For example, rheumatoid arthritis may be treated with the CD30/CD30L antagonists that are described above.
In one aspect of the invention, an agent capable of inhibiting the interaction of CD30 and CD30L is used concurrently with a second agent that is capable of antagonizing TNF&agr;, IL-1&agr;, IL-1&bgr; or IL-4. Medical disorders expected to be especially responsive to these combination treatments include multiple sclerosis, systemic sclerosis, acute inflammatory demyelinating polyneuropathy, acute motor axonal neuropathy, acute motor sensory axonal neuropathy, Fisher syndrome and systemic lupus erythematosus. As an example, the foregoing medical disorders may be treated with an antibody specific for CD30L used together with an antagonist of IL-4. The anti-CD30L antibody and the IL-4 antagonist are used for formulating pharmaceutical preparations for this purpose, and may be packaged separately or together in one package with a written matter describing this use. Suitable IL-4 antagonists for use in this method of treatment include but are not limited to an antibody specific for IL-4, an antibody specific for IL-4R and a soluble IL-4 receptor comprising amino acids 1-207 or 2-207 of SEQ ID NO:16. In one of the preferred embodiments of the invention, a patient who is suffering from systemic lupus erythematosus, scleroderma or pemphigus vulgaris is treated concurrently with an inhibitor of the CD30/CD30L interaction and an antibody specific for IL-4, an antibody specific for IL-4R or a soluble IL-4 receptor, wherein the receptor comprises amino acids 1-207 or amino acids 2-207 of SEQ ID NO:16.
In other aspects of the invention, provided are compounds, pharmaceutical preparations and m
Barone Dauphine S.
Kennedy Mary K.
Mohler Kendall M.
Chan Christina
Haddad Maher
Immunex Corporation
Krischner Michael K.
Perkins Patricia Anne
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