Anti-CD6 monoclonal antibodies and their uses

Details Anti-CD6 monoclonal antibodies and their uses Anti-CD6 monoclonal antibodies and their uses

1997-12-17

2003-06-03

Scheiner, Laurie (Department: 1648)

Drug, bio-affecting and body treating compositions

Immunoglobulin, antiserum, antibody, or antibody fragment,...

Structurally-modified antibody, immunoglobulin, or fragment...

C424S143100, C530S388220, C436S548000

Reexamination Certificate

active

06572857

ABSTRACT:

FIELD OF THE INVENTION
The present invention is related to the field of immunology and particularly with obtaining a pharmaceutical composition that contains a monoclonal antibody that recognizes the CD6 leukocyte differentiation antigen.
DESCRIPTION OF THE PRIOR ART
Monoclonal antibodies (mAbs) have permitted the characterization of molecules of physiological importance expressed on the cell surface. Defined in the cells of the Immune System the “Leukocyte Differentiation Clusters” or antigens (CD) (scholossman, S. F. et al. (1994) Immunol. Today 15 (3);98). The definition of the role of the CD′s in the differentiation and maturation of the lymphoid cells during their ontogenic development, in the mechanisms of cellular recognition and adhesion and in the mechanisms of activation and proliferation during the immune response have conducted to the use of their respective mAbs in diagnosis and immunotherapy, with promising results (Dantal, J. et al. (1991) Curr. Opin. Immunol. 3:740).
The murine mAbs directed against molecules expressed on the cell membrane of human T lymphocytes have contributed to improve the diagnosis of clinical entities in which there is dysfunction of these cells. Moreover they have been used to explore new therapeutic approachs with the purpose of modulating their functional activity as in the cases of Transplant Rejection, Graft Versus Host Disease (GvHD) and Autoimmune Diseases (Waldman, T. A. (1991) Science 252:1657; Waldman, T. A. (1992) Annu. Rev. Immunol. 10: 675).
The CD6 is a not well characterized molecule. It is known that it is a glycoprotein existing in two molecular forms maintained in dynamic equilibrium and differing only in the grade of phosphorylation. In the resting T lymphocytes it is a phosphorylated molecule of 105 kDa, while in activated cells it is a hyperphosphorylated form of 130 kDa (Cardenas, L. et al. (1990) J. Immunol. 145:1450; Swack, J. A. et al. (1991) J. Biol. Chem. 266: 7137), member of a family of membrane receptors and secretion proteins with a characteristic structure (Kodama, T. et al. (1990) Nature 343: 531; Aruffo, A. et al. (1991) J. Exp. Med. 174: 949). It is expressed on the surface of mature human thymocytes, in T lymphocytes of peripheral blood, constituting the majority of the CD3+ cell population, in a subtype of B lymphocytes and in the neurons of the brain cortex. In the T lymphocytes of peripheral blood it participates in the mechanisms of cellular activation (Reinhertz, E. L. et al. (1982) Cell 30: 735; Kamoun, M. et al (1981) J. Immunol. 127: 987; Mayer, B. et al. (1990) J. Neuroimmunol. 29: 193; Rasmussen, R. A. et al. (1994) J. Immunol. 152: 527).
The role of the CD6 molecule in the T cell ontogenesis as well as its possible role in the physiopathology of diseases of different etiology are unknown.
Recently a CD6 ligand was identified and characterized having an extensive cellular distribution in normal tissues such as thymus, spleen, lymph nodes, and skin (Dhavalkumar, D. P. et al. (1995) J. Exp. Med. 181:1563). This molecule, denominated ALCAM (Activated Leukocyte-Cell Adhesion Molecule due to its expression in activated T and B lymphocytes as well as monocytes, is a 100 kDa molecular weight type I membrane glycoprotein with five extracellular domains similar to those of the immunoglobulins. It can present different activation levels depending on divalent cations and can mediated heterophylic and homophylic interactions (Bowen, M. A. et al. (1995) J. Exp Med. 181: 2213).
Different anti CD6 mAbs have been used in clinical research for the prevention of the rejection crisis in organ transplantation (Kirkman, R. L. et al. (1983) Transplantation 36: 620) and to deplete bone marrow transplants from lymphocytes for preventing Graft versus Host Disease (GVHD) (Soiffer, R. J. et al. (1992) J. Clin. Oncol. 10:1191). The ior t1 mAb is in a Phase II Clinical Trial for the treatment of Cutaneous T-Cell Lymphomas (Garcia, C. A. et al. (1990) Biotecnologia Aplicada 7(2):176; Faxas, M. E. et al (1993) Biotecnologia Aplicada 10(1): 20).
The ior t1 monoclonal antibody of IgG2a isotype was classified as anti CD6 in the IV international Workshop of Leucocyte Differentiation Antigens, Vienna (1989). This mAb defines an epitope different from the ones recognized by other anti CD6 mAbs. The epitope has a stable conformation and is insensitive to reduction agents, being possibly located in the primary structure of the CD6 molecule (Osorio, L. M. et al. (1994) Cell Immunol. 154:123).
This monoclonal antibody has a lower recognition than other CD6 mAbs in peripheral mononuclear cells of healthy donors. The recognition pattern of ior t1 mAb in human cell culture lines of T lymphocytes origin is 47% in Jurkat cells, 23% in Molt-4 cells and no recognition of CCRF-CEM cells; of B lymphocytes origin is 9% in Raji, of erythroblastoid origin is 12% in K-562 and of myelomonocytic origin is 9% in U-937. It also recognizes peripheral mononuclear cells of Chronic B Lymphocytic Leukemia (89+/−4%) (Garcia C. A. et al. 1992) Biotecnologia Aplicada 9(1):70) and lymphocytes of cutaneous lesions in patients with Cutaneous T-Cell Lymphomas (Rodriguez, T. et al. (1985) Interferon y Biotec. 2(1): 41).
The ior t1 mAb does not inhibit the in vitro antigen specific cellular cytotoxicity (Faxas, M. E. et al. (1993) Biotecnologia Aplicada 10(1):47). It is capable of activating in vitro peripheral blood T lymphocytes of healthy donors. At suboptimum concentrations of OKT3 (anti CD3) the cross-linking with ior t1 induces higher responses than those achieved with other anti CD6 mAbs (Osorio, L. M. et al. (1994) Cell Immunol. 154:123).
Psoriasis is a disease whose physiopathology has not been defined (Hunziker, T. et al. (1993) Ther. Umsch. 50(2);110; Elder, J. T. et al. (1994) J. Invest. Dermatol. 102(6): 24S). It is characterized by presenting an inflammatory infiltrate in the target organ with predominance of activated T lymphocytes of CD4+ and CD8+ phenotypes (Chang, J. C. C. et al. (1994) Proc. Natl. Acad. Sci. USA 91:9282), as well as strong olygoclonality of the T-Cell receptors, the cells seem to present a marked tendency to migrate to the skin (homing) (Baker, J. N. W. N. et al (1992) Br. J. Dermatol. 127; 205; Menssen, A. et al. (1995) J. Immunol. 155:4078; Valdimarsson, H. et al. (1995) Immunol. Today 16(3):145).
The spontaneous remission of Psoriasis can be predicted if the number of T cells in the skin decrease. Thus, it is suggested they play an important role in the perpetuation of the disease by releasing soluble mediators of the immune response capable of inducing the proliferation of keratinocytes, responsible of clinical manifestations of the disease.
These considerations are supported by facts such as the cure of the disease following allogeneic bone marrow transplantation, the possible HLA association, the improvement, with steroids and specially with immunosupressocs like cyclosporine and the clinical improvement, although reversible, with anti T cells therapeutic monoclonal artibodies (Griffiths, C. E. M. et al. (1992) Springer Semin Immunopathol. 13:441; Nanney, L. B. et al. (1986) J. Invest. Dermatol. 86(3): 260; Ficassia, D. D. et al. (1987) J. Am. Acad. Dermatol 17)3: 408; Schopf, R. E. et al. (1986) Arch. Dermatol. Res. 279(2 ): 89; van de Kerkhof, P. C. et al. (1997) Dermatologica 174(5): 224).
The success o immunotherapy with monoclonal antibodies depends on the selection of the target molecule, which should participate in important cellular functions or in the selection of the mAb (Dantal, J. et al. (1991) urr. Opin. Immunol. 3:740). The mAbs evaluated in Psoriasis directed against CD3 (Weinshenker, B. G. at al. (1989) J. Am. Acad. Dermatol. 20:1132) and against CD4 (Poizot-Martin, I. et al. (1991) Lancet 337:1477; Prinz J. et al. (1991) Lancet 338: 320; Nicolas, J. F. et al. (1991) Lancet 338: 321) have produced clinical improvement in the patients after multiple high dose endovenous applications, with partial remissions of short duration and early relapse of the symptoms and signs of the

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