Drug – bio-affecting and body treating compositions – Lymphokine – Interleukin
Patent
1993-03-04
1995-01-17
Wityshyn, Michael G.
Drug, bio-affecting and body treating compositions
Lymphokine
Interleukin
424 851, A61K 3702, C07K 1300
Patent
active
053824270
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to methods of using interleukin-4 ("IL-4"), the use of IL-4 for making medicaments, and pharmaceutical compositions containing IL-4, for treating solid tumors in mammals afflicted with solid tumors by systemically administering to said mammals an effective amount of IL-4.
INTRODUCTION
Interleukin-4 [hereinafter "IL-4" but also known as B Cell Stimulatory Factor 1, (BSF-1)]was originally described by M. Howard et al. in J. Exp. Med. (1982), Vol. 155, pp. 914-23 as a T cell-derived growth factor, distinct from IL-2, which permitted long-term tissue culture of normal mouse B lymphocytes and which interacted with activated B lymphocytes to maintain the proliferation thereof for as long as 4 months. Although mixed B lymphocyte explants have been used to initiate cultures, it appears that B lymphocytes with immature phenotype are specifically enhanced by IL-4 in tissue culture. See for example C. Perchel et al., J. Immunol. (1989), Vol. 142, 1558-1568. In addition, G. Trenn et al. J. Immunol, (1988) Vol. 140, 1101-1106 discloses that IL-4 stimulates the development of cytotoxic T cells from the Lyt-2+ subpopulation of resting murine T lymphocytes.
The mouse IL-4 gene was cloned and expressed in COS-7 cells [See T. Otsuka et al., Nuc. Acids Res. (1987), Vol. 15, 333-334]. The cloned factor had all the activities in tissue culture seen for the factor purified from T cell culture supernatants. Cloning and expression of the human IL-4 gene have been described by N. Arai et al., J. Immunol. (1989), Vol. 142, 274-282 and T. Yokota et al., Proc. Nat. Acad. Sci. (1986), Vol. 83, 5844-5848 with the factor produced in COS-7 cells having similar activities to the native molecule as studied in tissue culture. As IL-4 was studied both in human and murine cell systems, additional in-vitro activities were attributed to the molecule: i) IL-4 plays an important role in the induction and regulation of IgE synthesis, a process occuring as B lymphocyte subpopulations are induced into proliferation [See S. Romagnani et el., Clin. Immunol. Immunopathol (1989,) Vol. 50, 513-523]; ii) IL-4 induces low affinity Fc.epsilon. receptors (CD23) on normal human B lymphocytes in tissue culture [See T. DeFrance et el., J. Exp. Med. (1987), Vol. 165, 1459-1457]; iii) IL-4 interacts in an extremely precise way with other lymphokines, notably interferon-.gamma.,[See R. L. Coffman et al., Immunol, Res. (1988), Vol. 102, 5-27 and S. Romagnani et al., supra]and T cells [See R. L. Coffman et el. supra, S. Romagnani et el. supra, and M. D. Widmer et el., Nature, (1987), Vol. 326, 795-98]to bring about B cell proliferation and alteration; and (iv) IL-4 increases class 11 1 a antigent expression on resting B cells (R Noelle et el., PNAS 81.6149-6153,1984). T. R. Mosmann et el. in J. Immuno., Vol. 138, 1813-1816 disclose that human and murine I-4 which are 50% homologous at amino acid sequence 1-90 and 129-149 are species specific.
Studies in humans showed that IL-4 has an affect on monoclonal B cell tumors. S. Karray et el. in J. Exp. Med. (1988) Vol. 168, 85-94, disclose that human IL-4 suppresses the IL-2-dependent proliferation of B-type chronic lymphocytic leukemia (B-CLL) in vitro. C. M. Higuchi et el. in Can. Res. (1989) Vol. 49:6487-6492, disclose that in human peripheral blood lymphocytes preactivated by IL-2, IL-4 induces lymphokine-activated killer activity (LAK). J. J. Mule et al. in J. Exp. Med., (1987) Vol. 166; 792-797, disclose that in the murine system, resting splenocytes treated with murine IL-4 alone or in combination with IL-2 generate LAK activity against fresh syngenic tumor cells in vitro. G. Forni et al. in Int. J. Can. Sup., (1989) Vol. 4, 62-65, disclose that antitumor activity can be induced by injecting murine IL-4 around the tumor draining lymph node and that when IL-4 is used in combination with a nonapeptide from human IL-1.beta., very active lymphokine-activated tumor inhibition (LATI)is observed. J. J. Mule et al. in J. Immuno., (1984) Vol. 142, 726-733 disclose that
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Catino Joseph J.
Plunkett Marian L.
Hoffman Thomas D.
Sayala C.
Schering-Plough Corporation
Wityshyn Michael G.
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