Method of treatment with IL-9 conjugate

Details Method of treatment with IL-9 conjugate Method of treatment with IL-9 conjugate

2000-01-25

2003-11-11

Mertz, Prema (Department: 1646)

Drug, bio-affecting and body treating compositions

Lymphokine

Interleukin

C514S826000

Reexamination Certificate

active

06645486

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to methods for making cytokine specific antibodies. This invention also relates to methods for inducing in an animal a high titre antibody response specific for the cytokine. This invention further relates to the treatment of pathological conditions, e.g., eosinophilia, associated with the production of the cytokines. In addition, this invention relates to cytokine conjugates per se and compositions comprising the cytokine conjugates.
BACKGROUND
Cytokines are involved in many biological functions and are major mediators of the immune response. They are associated with the initiation and progression of various autoimmune diseases. For example, tumor necrosis factor &agr; (TNF&agr;), interferon &ggr; (IFN&ggr;) and interleukin-1 (IL-1) have been associated with diabetes and the destruction of islet cells, the elevated production of Th2 cytokines have been associated with asthma, and interleukin-12 (IL-12) has been associated with rhuematoid arthritis.
Interleukin-9 (“IL-9” hereafter), is a glycoprotein which has been isolated from both murine and human cells. See, e.g., U.S. Pat. No. 5,208,218, incorporated by reference. This reference also teaches isolated nucleic acid molecules encoding the protein portion of the molecule, and how to express it.
Since its discovery as a T- and mast cell-growth factor produced by Th2 cells, the physiological processes in which for IL-9 is known to have a role have been gradually expanded (Uyttenhove, et al.,
Proc. Natl. Acad. Sci. USA
85:6934-6938 (1988); Hültner, et al.,
Eur. J. Immunol
. 20:1413-1416 (1990); and Gessner, et al.,
Immunobiol
. 189:419-435 (1993)) (Renauld, J.-C., & Van Snick, J. (1998), The
Cytokine Handbook
313-331). Prominent features, disclosed by analysis of transgenic mice overexpressing IL-9, include increased susceptibility to lymphoma-genesis (Renauld, et al.,
Oncogene
9:1327-1332 (1994)), intestinal mastocytosis (Godfraind, et al.,
J. Immunol
. 160:3989-3996 (1998)), expansion of the B-1 lymphocyte population (Godfraind, et al.,
J. Immunol
. 160:3989-3996 (1998)), bronchial hyper-responsiveness (Temann, et al.,
J. Exp. Med
. 188:1307-1320 (1998), and McLane, et al.,
Am J. Resp. Cell. Mol
. 19:713-720 (1998)) and airway eosinophilia (Dong, et al.,
Eur. J. Immunol
. 29:2130-2139 (1999)). In line with these observations, genetic analyses revealed a linkage between both IL-9 and IL-9 receptor (IL-9R) genes to human asthma (Holroyd, et al.,
Genomics
52:233-235 (1998) and Marsh, et al.
Science
264:1152-1156 (1994)), a finding that was confirmed with respect to IL-9 in murine models (Nicolaides, et al.,
Proc. Natl. Acad. Sci. USA
, 94: 13175-13180 (1997)).
Various uses of IL-9 are disclose in, e.g., U.S. Pat. No.5,164,317 (proliferation of mast cells); U.S. Pat. Nos. 5,246,701 and 5,132,109 (enhancing production of IgG and inhibiting production of IgE), in addition to its first recognized utility, which is as a T cell growth factor. Exemplary of the vast scientific literature on IL-9 are Van Snick, et al,
J. Exp. Med
. 169(1): 363-368 (1989) (cDNA for the murine molecule, then referred to as P40). Houssiau, et al,
J. Immunol
148, (10): 3147-3151 (1992) (IL-2 dependence of IL-9 expression in T lymphocytes). Renauld, et al,
Oncogene
9(5):1327-1332 (1994) (effect on thymic lymphomas); Renauld, et al,
Blood
85(5):1300-1305 (1995) (anti-apoptotic factor for thymic lymphoma); U.S. Pat. No. 5,830,454 (treatments of cell mediated autoimmune disorders); and U.S. Pat. No.5,935,929 (treating or preventing interstitial lung disease). Review articles may be found at, e.g., Renauld, et al,
Cancer Invest
, 11(5): 635-640 (1993); Renauld, et al,
Adv. Immunol
54:79-97 (1993).
While detrimental in asthma, elevated production of Th2 cytokines has been reported to correlate with resistance to certain parasite infections (Finkelman, et al.,
Annu. Rev. Immunol
., 15:505-533 (1997)). IL-9, for example, was found to enhance mouse resistance to infection with the caecal dwelling nematode
T.muris
(Faulkner, et al.,
Infect. Immun
., 66:3832-3840 (1998)). This resistance was associated with high IgE and IgG1 levels, as well as with pronounced intestinal mastocytosis.
The absence of T cell help has previously been suggested to be crucial for B cell tolerance toward self-proteins (Dalum, et al.,
J. Immunol
., 157 ; 4786-4804 (1996)). Using bovine luteinizing hormone (LH) as a self protein coupled to ovalbumin (OVA), Johnson, et al. (
J. Anim. Sci
. 66, 719-726 (1988)) were able to induce high titers of autoantibodies against LH, causing cows to become anestrous. Similarly, a vaccine that prevents pregnancy in women was developed by coupling human chorionic gonadotropin and ovine luteinizing hormone to tetanus and diphtheria toxoids (Talwar, et al.,
Proc. Natl. Acad. Sci. USA
, 91:8532-8536 (1994)). More recently, immunization with a fusion protein of an OVA epitope and mouse TNF&agr; was found to prevent experimental cachexia and collagen-induced arthritis in mice (Dalum, et al.,
Nature Biotechnology
, 17:666-669 (1999)).
Earlier attempts to generate autoantibodies capable of regulating biological processes, were successfully carried out mainly with hormones (Johnson, et al.,
J. Anim. Sci
., 66:719-726 (1988) and Talwar, et al.,
Proc. Natl. Acad. Sci. USA
, 91:8532-8536 (1994)), hormone receptors (Chackerian, et al.
Proc. Natl. Acad. Sci. USA
, 96:2773-2778 (1999)) or cellular components (Dong, et al.,
J. Exp. Med
., 179:1243-1252 (1994) and Dalum, et al.,
Mol. Immunol
., 34:1113-1120 (1997)). These observations were recently extended to cytokines with reports of anti-IFN&agr; induction in AIDS patients (Zagury, et al.,
Biomed. Pharmacother
, 53:90-92 (1999)) and of anti-TNF&agr; vaccination in mice, the latter preventing cachexia and rheumatoid arthritis (Dalum, et al.,
Nature Biotechnology
, 17:666-669 (1999)).
SUMMARY OF THE INVENTION
This invention is directed to methods for making cytokine specific antibodies, particularly antibodies specific for interleukins. This invention is also directed to a method for preventing or treating a pathological condition associated with the production of a cytokine by immunizing an animal with a conjugate of the cytokine and a carrier. Preferably, the cytokine is an interleukin, more preferably, IL-4, IL-5, IL-9, or IL-13 and most preferably the interleukin is IL-9. The IL-9 may be a mammalian IL-9, in particular a murine or human IL-9, preferably a recombinant form or a portion of the IL-9 molecule sufficient to provoke a response.
The invention is also directed to a method for producing prolonged high titre antibodies specific for the cytokine by immunizing a subject with conjugates of the cytokine and a carrier. Preferably, the high titre persists for at least 6 months after the subject is immunized with the conjugate, more preferably, the high titre persists for at least 9 months after the immunization and most preferably, at least 12 months after the immunization.
This invention is further directed to conjugates of a carrier and the cytokine, or portions thereof, and to compositions comprising the conjugates. Preferably, the cytokine is an interleukin and the carrier is ovalbumin (OVA), a substituted OVA, a keyhole limpet hemocyanin (KLH), an acetylated BSA or a pertussis toxin. More preferably the conjugate comprises an interleukin selected from the group consisting of IL-4, IL-5, IL-9 or IL-13, and most preferably comprises IL-9. Especially preferred is a conjugate of IL-9 and ovalbumin. The interleukin may be a recombinant interleukin or an interleukin modified to permit or enhance its conjugation to a carrier.
Those of skill in the art appreciate that many methods are suitable for conjugating a carrier and a conjugation partner. The partners in a conjugate may be treated with a cross-linking agent, e.g., glutaraldehyde, carbodilmide or bis-diazobenzidine. The conjugation partners be also be modified to permit or enhance the formation of conjugates. For example, the carrier may be substituted with maleimide, e.g., a malei

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