Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector
Reexamination Certificate
1997-03-28
2002-09-10
Minnifield, Nita (Department: 1645)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
C424S237100, C424S236100, C424S243100, C424S280100, C530S350000, C530S387100, C514S012200, C514S018700
Reexamination Certificate
active
06447777
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention in the fields of biochemistry and medicine is concerned with chemically crosslinked Staphylococcal protein A, Staphylococcal enterotoxins or functional derivatives thereof and their use alone or in combination with immunoglobulins or complement components in the treatment of autoimmune and neoplastic diseases.
2. Description of the Background Art
Protein A is a constituent of the cell wall of many strains of bacteria of the species
Staphylococcus aureus
. This protein (abbreviated “SpA” herein) has molecular weight of 42 kDa and binds selectively to immunoglobulins (Igs), particularly IgG, and immune complexes from many mammalian species. Ig binding sites for SpA are located in the Fc region of the Ig molecule. SpA-Ig complexes display diverse biological activities including complement binding and activation (Langone, J. J., Adv. Immunol. 32:157-252 (1982)).
An immunoadsorbent column consisting of SpA immobilized on collodion-coated charcoal was originally used for ex vivo immunoadsorption and provided successful extracorporeal treatment for patients with breast carcinoma (Terman, D. S., U.S.Pat. No. 5,091,091, Feb. 2, 1995). Subsequently, a SpA-silica immunoadsorbent column was developed by Bensinger, Kinet and others (Bensinger, U.S. Pat. No. 4,614,513., Sep. 30, 1986; Bensinger W. I. et al.,
New Eng. J Med
306:935 (1982); Kinet, J. P. et al.,
Eur. J Clin Invest.
16:50-55 (1986)) and later by Balint et al.(U.S. Pat. No. 4,681,870, Jul. 21, 1987). This column, known by its trade name of Prosorba®, produced by IMRE Corporation, has received FDA approval for treatment of idiopathic thrombocytopenic purpura (ITP) and hemolytic-uremic syndrome. Prosorba® columns have also been reported to show efficacy against advanced cancer and autoimmune diseases such as rheumatoid arthritis (RA) (Balint et al., supra; Snyder, H. W. et al.,
J Clin. Apheresis
7:110:118 (1992); Snyder, H. W. et al.,
Sem. Hematol
26:31 (1989); Mittelman, A. et al.,
Sem. Hematol.
26:15 (1989); Messerschmidt, G. L. et al.,
Sem. Hematol.
26:19 (1989); Snyder, H. W. et al,
J Clin. Apheresis
6:1 (1991); Snyder, H. W. et al.,
Blood
79:2237 (1992)). Clinically, these columns may be used in an “on-line” or “off-line” mode with identical therapeutic effects. In the off-line mode, 200 ml of plasma is collected by phlebotomy from a subject, passed over the column and then returned to the same donor. Publications sponsored by the manufacturer of the column (IMRE Corporation) indicate that the coupling of SpA to silica creates a “stable covalent bond” such that the bound SpA is not released into the perfused plasma (Snyder, H. W. et al.,
J Clin. Apheresis
7:110:118 (1992); Snyder, H. W. et al.,
Sem. HematoL
26:31 (1989); Mittelman, A. et al.,
Sem. Hematol.
26:15 (1989); Messerschmidt, G. L. et al,
Sem. Hematol.
26:19(1989); Snyder, H. W. et al.,
J Clin. Apheresis
6:1 (1991). Snyder, H. W. et al.,
Blood
79:2237 (1992); Balint, J. P.,
Blood
84:664 (1994)). The removal of immune complexes from plasma perfused over the column is said to be the basis of the column's therapeutic effect. However, despite the purported covalent bonding of the SpA to the column matrix, several investigators (including the manufacturer) have reported that SpA does indeed leach from the column surface into the perfused plasma in amounts that have been reported to vary from 200 &mgr;g to 1 mg of SpA per treatment dose of perfused plasma (Sato, H. et al.,
Transfusion Sci.
12:299 (1991); Kinet, J. P. et al.,
Eur. J Clin. Invest.
16:43 (1986);
IMRE Corporation FDA Safety and Efficacy Report on Prosorba® Column,
1987).
The clinical toxicity of the procedure (Smith, E. et al.,
J Clin. Apheresis
7:4 (1992); Ciavarella, D. et al.,
Int. J Clin. Lab. Res.
21:210 (1992); Dzic, W.,
New Eng. J Med
331:792 (1994)) and the known in vivo and in vitro biological effects of SpA (Langone, J. J.,
J Biol. Resp. Modif.
3:241 (1984)) might have hinted that leached SpA was of biotherapeutic significance. Nevertheless, according to the present state of the art, there is no pharmacologic significance ascribed to the leached material. Rather, the art teaches that the therapeutic effects of these columns are due entirely to the adsorption and removal by the column of immune complexes from plasma (supra). Accordingly, there has been no attempt, prior to the work leading up to the present invention, to examine carefully the composition of products leaching from these columns or to characterize their molecular structure and biologic activity.
IMRE Corporation scientists have demonstrated antitumor effects in human cancer patients (overall response rate of 30%) using the Prosorba® column. The best responses were seen in patients with breast cancer and Kaposi's sarcoma (Messerschmidt, G. L. et al.,
J Clin. Oncol.
6:203-212 (1988)). The authors ascribed the effect to adsorption of circulating immune complexes from tumor bearing plasma to the Prosorba® column. However, as viewed by the present inventor in light of the invention disclosed herein, it is more likely that the effects were due to complexes of (1) leached SpA and IgG, (2) leached SpA and Staphylococcal enterotoxin B (SEB) and/or (3) SpA, SEB and IgG. The variability of patient responses is likely due to the unpredictability and the broad range of the amount of leached polymeric or complexed SpA emerging from the column.
B. Anergy or Sensitization Induced by SpA-SEB-IgG Complexes
Enterotoxins are known to produce T cell anergy or sensitization depending on the dose (Sundstedt, A. et al.,
J Immunol.
154:6306-6313 (1995)). For example, very large or very small doses of enterotoxins produce anergy whereas intermediate doses produce sensitization. As noted above, the effectiveness of Prosorba® in the treatment of an autoimmune disease (ITP, RA) and cancer was thought to be due to the adsorption and removal of immune complexes by the column.
Based on the present invention, the contention that the therapeutic effects of Prosorba® (in ITP, for example) are due to “immune complex removal” from 200 ml of plasma by the column would seem far-fetched. According to such reasoning, the mere removal of this volume of plasma by phlebotomy (the first step of Prosorba® treatment) should show the same or greater therapeutic efficacy since withdrawing 200 ml of blood effectively, by definition, removes 100% of the immune complexes contained therein. However, neither phlebotomy alone nor plasmapheresis effects any change in the clinical course of ITP or other diseases in which Prosorba® has been effective. A comparative study of the therapeutic effects of the two treatments in ITP further corroborates this assertion (Kiprov, D. D. et al.,
J Clin. Apheresis
3:133 (1986)).
The present inventor is the first to have found that the basis for therapeutic activity of the Prosorba® column in ITP and RA is not what it is claimed to be. Rather, by analyzing what elutes from these columns under various conditions, including conditions of standard clinical use, the present inventor has discovered novel compositions which represent significant, totally unexpected improvements in the treatment of autoimmune diseases such as ITP and RA and of cancer. In making this invention, the present inventor has characterized this eluted material and has designed novel therapeutic compositions and methods for treating autoimmune and neoplastic diseases.
SUMMARY OF THE INVENTION
The present inventor has identified SpA in perfusates of SpA immunoadsorbent columns and has shown that it originates from material associated with the column which is not covalently bound to the column matrix. The fundamental discovery for the present invention, was that plasma emerging from the SpA column contained SpA that could be in a monomeric form or in a polymerized, crosslinked high molecular weight form. In fact, SpA which desorbs from the column using various forms of mild perfusion is predominantly in the form of SpA oligomers or polymers. These discoveries wer
Reiser Raoul F.
Terman David Stephen
Bortner Scott R
Minnifield Nita
Terman David S.
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