Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Animal or plant cell
Reexamination Certificate
1999-04-08
2003-04-08
Witz, Jean C. (Department: 1651)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Animal or plant cell
Reexamination Certificate
active
06544514
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to compositions comprising, as the main ingredient, allogenic activated-CD4+ cells which are derived from a different person, and a method for producing and dispensing the same. More particularly, this invention relates to compositions effective in preventing recidivation of a tumor and remedying various infections such as viral infections, and autoimmune diseases such as phagocytosis.
2. Description of the Related Art
Lymphocytes take part in the immune system concerned in biophylaxis. In particular, T-lymphocytes are one kind of important cells playing a major role in cellular immunity. The lymphocytes are sorted in accordance with the reactivity of the monoclonal antibody. For example, the T-lymphocytes having the reactivity to anti-CD3 antibodies are regarded as CD3+ cells. There have been many studies in the relation between antigens manifested in the lymphocytes and its function. The T-lymphocyte manifests not only the CD3 antigen, but also other antigens of various kinds at the same time. The lymphocytes manifesting CD4 antigens (hereinafter referred to as “CD4+ cells”) have been considered to have a function of activating lymphocytes manifesting CD8 antigens (hereinafter referred to as “CD8+ cells”). The CD8+ cell has intense cytotoxic activity. However, the T-lymphocytes have various functions, and thus, they have been generally considered to be difficult to sort only in accordance with the manifesting superficial antigen. It has been reported that the CD4+ cells have the cytotoxic activity in, for example, “Cytotoxic Activity of CD4+ T-cells against Autologous Tumor Cells” by Y. Konishi, T. Sekine, T. Takayama, M. Fujii, and T. Tanaka, Jpn J. Cancer, Res., Vol.86, pp.854-860 (1995).
T. Sekine, one of the inventors of the present invention, disclosed that the lymphocytes can be proliferated by solid-phase anti-CD3 antibody and interleukin-2, and autologous lymphocytes thus proliferated have an antitumor effect (Japanese Patent Application Public Disclosure No. HEI 3-80076(A)). There have been many other reports that the lymphocytes derived from peripheral blood and so on can be proliferated by the anti-CD3 antibody and interleukin-2, and the autologous lymphocytes have antitumor activity.
Ito et al., ones of the inventors of the present invention, reported that the autologous lymphocytes proliferated from the anti-CD3 antibody and interleukin-2 are effective in the treatment of viral infections of a sufferer from congenital immunodeficiency (“Course of Medicine” by Kiminari Ito and Teruaki Sekine, Vol.181, No.6, pp.426-427 (1997)).
A bone-marrow transplant is performed when leukocyte blood types (hereinafter called “HLA” for short) of both donor and recipient agree therewith. However, because various types of HLA are in existence, it is exceedingly rare for the HLA types of the donor and recipient to agree with each other. Accordingly, when the major components of HLA of the donor are in agreement with those of the recipient, the bone-marrow transplant is generally carried out. Failure of complete agreement of the HLA types sometimes causes the graft-versus-host disease (hereinafter called “GVHD” for short) which bring about severe symptoms. For the purpose of remedying the disease, an immunosuppressant has been used. A patient developing the disease may possibly recuperate from GVHD with administration of the immunosuppressant, as a result of which the patient will infrequently manifest viral infections attributable to cytomegalovirus or Epstein-Barr virus and eventually be brought death in most cases.
Elizabeth et al. reported that CD8+ cells specific to cytomegalovirus are derived from lymphocytes of a bone-marrow donor for the purpose of preventing and treating the viral infections caused in the immunosuppressive conditions, so that the viral infections attributable to cytomegalovirus which the recipient is infected with can be treated. (Elizabeth A. Walter, M.D. et al., N. Engl. J. of Med., Vol.333, pp.1038-1044 (1995))
In the actual clinical cases, allogenic lymphocytes prepared by a pheresis operation have been used for the purpose of treating diseases such as leukemia. This treatment is called “donor leukocyte transfusion” (hereinafter called “DLT” for short). DLT shows a beneficial effect, but it has been found that 50% to 80% of acute GVHD or 20% of fatal GVHD emerged in the recipient (H. J. Kolb et al., “Blood”, vol.86, pp.2041-2050 (1995); S. Slavin et al., “Exp. Hematol”, Vol. 23, pp.1553-1562 (1995)). To make matters worse, it takes several hours to perform the pheresis operation, and the operation imposes a severe burden on the donor.
Giralt et al. reported about DLT using leukocytes excluding CD8+ cells (Giralt et al., “Blood”, vol.86, pp.4337-4343 (1995). Ritz et al. reported about DLT using CD4+ cells prepared by a pheresis operation (Claret E. J. et al., “J. Clin. Invest”, vol.100, No.4, pp.588-866 (1997)). In either case, it was reported that the effect of GVL (graft-versus-leukemia, a slight case of which favorably reacts on a patient) was derived without causing GVHD, but it is feeble.
The allogenic lymphocytes specific to the antigen are efficacious against the viral infections without causing GVHD. However, the effective spectrum thereof is confined only to the specified viruses. Consequently, the necessity of deriving various types of antigen-specific lymphocytes to cope with various kinds of viral infections arises. In particular, when infections caused by unexpected pathogens such as viruses are developed, the antigen-specific allogenic lymphocytes cannot be used because it takes much time to derive the antigen-specific lymphocytes.
Furthermore, it is difficult to derive the antigen-specific lymphocytes effective for infections in which their pathogenic germs cannot be identified. Thus, there has been a need for allogenic lymphocytes which have wider effective spectrum or are not restricted to the specific effective spectrum.
Administration of the allogenic lymphocytes such as DLT can be expected to produce the intended beneficial curative effect, e.g. antitumor effect, but it consequently increases a possibility of causing serious GVHD with greater frequency. DLT using simply sorted CD4+ cells does not produce GVHD, but has little curative effect. Moreover, DLT necessitates gathering of leukocytes from a donor by the pheresis operation which imposes a severe physical burden on the donor and requires special facilities for fulfilling the operation. Particularly, when the donor is an infant, it is difficult to extract the leukocytes in large quantities therefrom. It has been desired to devise medicaments or preparations which have wide applicability and high efficiency, and besides, can be prepared lessening a burden on the donor without using special facilities and applied clinically without causing GVHD.
An object of the present invention is to provide compositions of lymphocytes applicable for remedying various diseases without causing serious GVHD, which have an excellent curative effect of restraining recidivation of a tumor, and remedying viral infections and autommune diseases and can be widely applied to immunological diseases and bring about marked curative effects in performing a specific treatment.
Another object of the invention is to provide a medical kit for preparing, with high efficiency, the compositions of lymphocytes applicable for remedying various diseases without causing serious GVHD, which have an excellent curative effect of restraining recidivation of a tumor, and remedying viral infections and autommune diseases and can be widely applied to immunological diseases.
Still another object of the invention is to provide a method for preparing, with high efficiency, the compositions of lymphocytes applicable for remedying various diseases without causing serious GVHD, which have an excellent curative effect of restraining recidivation of a tumor, and remedying viral infections and autommune d
Bamba Kenzo
Ito Kiminari
Kuroiwa Yasuyuki
Sekine Teruaki
Sekine Teruaki
Witz Jean C.
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