Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Reexamination Certificate
1993-03-10
2003-03-25
Caputa, Anthony C. (Department: 1642)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
C530S388100, C530S387100, C530S387300, C530S388730, C530S388750, C530S388850, C435S007100, C435S007240, C435S007200
Reexamination Certificate
active
06538110
ABSTRACT:
When the immune system responds to an antigen various cells of the immune system are activated. These activated cells synthesize a series of lymphokines which then in turn regulate the activation, proliferation and differentiation of further cells of the immune system. The T lymphocytes play a central role in this process the growth of which is controlled by a specific factor, interleukin 2 (IL-2). IL-2 is a lymphokine of 133 amino acids and exerts its growth-promoting properties via binding to specific receptors on the cell surface.
The interleukin 2 receptor (IL-2R) is present in three forms which differ in their-composition and in their affinity to the ligand. The low-affinity IL-2R (K
d
=10
−8
M), which is also denoted &agr; chain, light (L) chain, p55 molecule and in humans is also designated CD25 or Tac antigen, is a glycoprotein of 55 kDa molecular weight. The genes for the &agr; chain of the murine, bovine and human IL-2R have been cloned and the amino acid sequences of their protein products have been determined (Miller et al., J. Immunol. 134 (1985) 4212-4217; Nikaido et al., Nature 311 (1984) 631; Weinberg et al., Immunology 63 (1988), 603).
The medium affinity IL-2R (K
d
=10
−9
M), which is also denoted &bgr; chain, heavy (H) chain or p75 molecule, is a glycoprotein with a molecular weight of 70 to 75 kDa in the mouse and humans (Tsudo et al., Proc. Natl. Acad. Sci. USA 83 (1986), 9694; Sharon et al., J. Exp. Med. 167 (1988), 1265).
The high affinity IL-2R (K
d
=10
−11
M) is a heterodimer which is composed of non-covalently bound &agr; and &bgr; chains (Wang and Smith, J. Exp. Med. 166 (1987), 1156; Waldman, J. Nat. Cancer Institute 81 (1989) 915).
Monoclonal antibodies against the &agr; chain as well as against the &bgr; chain of the human IL-2 receptor have been isolated and they have been demonstrated to have an immunosuppressive action in vitro as well as in vivo (Sakagami et al., Transplantation Proceedings Vol. XIX. (1) (1987), 586-590; Kupiec-Weglinski et al., Proc. Natl. Acad. Sci. USA 83 (1986), 2624-2627; Mouzaki et al., Eur. J. Immunol. 17 (1987), 335-341; Olive et al., Eur. J. Immunol. 16 (1986), 611-616; Friend et al., Transplantation Proceedings, Vol. XIX (1987), 4317-4418; Soulillou et al., Lancet, Jun. 13, (1987), 1339-1342; Kupiec-Weglinski et al., Eur. J. Immunol. 17 (1987), 313-319).
Monoclonal antibodies against IL-2R have a high potential for immunosuppressive therapy, in particular for treating graft rejections, adult T cell leukemia and autoimmune diseases such as e.g. rheumatoid arthritis.
It has, however, been shown that the in vivo administration of monoclonal antibodies of animal origin in humans is limited since they are recognized as being foreign and this leads to an immune reaction against the administered antibodies. This immune reaction can be reduced by using so-called chimeric or humanized antibodies. Chimeric antibodies are antibodies in which the constant domains of animal origin (e.g. the mouse) have been replaced by a human constant domain. Humanized antibodies are human antibodies of which only the antigen binding sites of the variable region (the CDR or hypervariable regions) are of animal origin (Verhoeyen and Riechmann, BioEssays 8 (1988), 74-78).
However, even when administering chimerized or humanized antibodies an undesired immune reaction of the patient can be observed in some cases at higher doses, which is caused by the production of anti-idiotypic antibodies.
The object of the present invention is therefore to provide antibodies which are effective in an immunosuppressive therapy and which can be used in substantially lower doses than previously known antibodies.
The present invention concerns an antibody composition which inhibits the binding of interleukin 2 to its high affinity receptor and contains
(1) monoclonal antibodies against the &agr; chain of the interleukin 2 receptor and
(2) monoclonal antibodies against the &bgr; chain of the interleukin 2 receptor.
Surprisingly the combined use of monoclonal antibodies against the &agr; chain as well as against the &bgr; chain of the IL-2 receptor in vitro leads to synergistic effects and thus the antibody composition according to the present invention results in a stronger inhibition of the IL-2 induced proliferation of human peripheral blood lymphocytes than when one of the two antibodies is used alone at the corresponding concentration.
An antibody composition according to the present invention preferably contains
(1) 1 to 99% in relation to the total antibody amount of monoclonal antibodies against the &agr; chain of the interleukin 2 receptor and
(2) 99 to 1% in relation to the total antibody amount of monoclonal antibodies against the &bgr; chain of the interleukin 2 receptor.
The composition preferably contains 4 to 96% in relation to the total antibody amount monoclonal antibodies against the &agr; chain of the interleukin 2 receptor and 96 to 4% in relation to the total antibody amount of monoclonal antibodies against the &bgr; chain of the interleukin 2 receptor. When the antibody ratio is 4:96 or 96:4, one already finds a five-fold reduction in the total amount of antibody compared to the use of only one monoclonal antibody against the &agr; or the &bgr; chain.
The composition according to the present invention is particularly preferred when it contains aproximately equal amounts (1) of monoclonal antibodies against the &agr; chain of the interleukin 2 receptor and (2) monoclonal antibodies against the &bgr; chain of the interleukin 2 receptor. At an equimolar ratio of antibodies it is found that the total concentration of monoclonal antibodies required for a 60 to 70% inhibition of the IL-2 action is reduced fifteen-fold.
The composition according to the present invention preferably contains an antibody against the &agr; chain which by itself already causes an inhibition of the interleukin 2 binding. It is also preferred that the composition according to the present invention contains an antibody against the &bgr; chain which by itself already causes an inhibition of the interleukin 2 binding. A composition according to the present invention is particularly preferred when it contains in each case an antibody against the &agr; chain and an antibody against the &bgr; chain each of which alone already causes an inhibition of the interleukin 2 binding.
The antibody 3G10/179 (ECACC 90071905) which was deposited at the European Collection of Animal Cell Cultures, PHLS Centre for Applied Microbiology & Research Portion Down, Salisbury, U.K. on Jul. 19, 1990, is preferably used as the antibody against the &agr; chain which is present in the composition according to the present invention. However, other antibodies against the &agr; chain of interleukin 2 are also suitable in particular when they by themselves already cause an inhibition of the interleukin 2 binding. The antibodies C68/41 (ECACC 90090704) which was deposited at the European Collection of Animal Cell Cultures, PHLS Centre for Applied Microbiology & Research Portion Down, Salisbury, U.K. on Sep. 7, 1990, and A23A41 (DSM ACC2015) &bgr; which was deposited at DSM-Deutsche Sammlung von Mikroorganismen Und Zellkulturen GmbH, Mascheroder Weg 1B, D-3300 Braunschweig on Jul. 30, 1991, are particularly suitable as the antibody against the &bgr; chain of the interleukin 2 receptor as are, antibodies known from the literature such as the Mik/&bgr;
1
antibody (Tsudo et al., Proc. Natl. Acad. Sci. USA 86 (1989), 1982-1986; Takeshita et al., J. Exp. Med. 169 (1989), 1323-1332).
The composition according to the present invention can also contain a covalent coupling product of a monoclonal antibody against the &agr; chain and a monoclonal antibody against the &bgr; chain of the interleukin 2 receptor.
The composition according to the present invention preferably contains one or several chimerized antibodies with human constant domains or humanized antibodies in which the non-hypervariable parts of the variable domain are also replaced by the corresponding human regions. I
Diamantstein Tiberiu
Hirth Klaus-Peter
Kaluza Brigitte
Russmann Eberhard
Weidle Ulrich
Caputa Anthony C.
Fulbright & Jaworski LLP
Holleran Anne L.
Roche Diagnostics
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