Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-08-03
2004-12-28
Carlson, Karen Cochrane (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C424S236100, C424S241100, C424S094100
Reexamination Certificate
active
06835710
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to verotoxin pharmaceutical compositions and to methods of treating mammalian neoplasia, particularly, ovarian and skin cancers, therewith.
BACKGROUND OF THE INVENTION
Bacteriocins are bacterial proteins produced to prevent the growth of competing microorganisms in a particular biological niche. A preparation of bacteriocin from a particular strain of
E. coli
(HSC
10
) has long been shown to have anti-neoplastic activity against a variety of human tumour cell lines in vitro (1,2). This preparation, previously referred to as PPB (partially purified bacteriocin (2)) or ACP (anti-cancer proteins (2)) was also effective in a murine tumour model, of preventing metastases to the lung (2).
Verotoxins, also known as SHIGA-like toxins, comprise a family known as Verotoxin 1, Verotoxin 2, Verotoxin 2c and Verotoxin 2e of subunit toxins elaborated by some strains of
E. coli
(3). These toxins are involved in the etiology of the hemolytic uremic syndrome (3,4) and haemorrhagic colitis (5). Cell cytotoxicity is mediated via the binding of the B subunit of the holotoxin to the receptor glycolipid, globotriaosylceramide, in sensitive cells (6).
The verotoxin family of
E coli
elaborated toxins bind to the globo series glycolipid globotriaosylceramide and require terminal gal &agr;-1-4 gal residue for binding. In addition, VT2e, the pig edema disease toxin, recognizes globotetraosylceramide (Gb
4
) containing an additional &bgr; 1-3 linked galNac residue. These glycolipids are the functional receptors for these toxins since incorporation of the glycolipid into receptor negative cells renders the recipient cells sensitive to cytotoxicity. The toxins inhibit protein synthesis via the A subunit—an N-glycanase which removes a specific adenine base in the 28S RNA of the 60S RNA ribosomal subunit. However, the specific cytotoxicity and specific activity is a function of the B subunit. In an in vitro translation system, the verotoxin A subunit is the most potent inhibitor of protein synthesis yet described, being effective at a concentration of about 8 pM. In the rabbit model of verocytotoxemia, pathology and toxin targeting is restricted to tissues which contain the glycolipid receptor and these comprise endothelial cells of a subset of the blood vasculature. Verotoxins have been strongly implicated as the etiological agents for hemolytic uremic syndrome and haemorrhagic colitis, microangiopathies of the glomerular or gastrointestinal capillaries respectively. Human umbilical vein endothelial cells (HUVEC) are sensitive to verotoxin but this sensitivity is variable according to cell line. Human adult renal endothelial cells are exquisitely sensitive to verotoxin in vitro and express a correspondingly high level of Gb
3
. However, HUS is primarily a disease of children under three and the elderly, following gastrointestinal VTEC infection. It has been shown that receptors for verotoxin are present in the glomeruli of infants under this age but are not expressed in the glomeruli of normal adults. HUVEC can be sensitized to the effect of verotoxin by pretreatment by tumour necrosis factor which results in a specific elevation of Gb
3
synthesis (7,8). Human renal endothelial cells on the other hand, although they express high levels of Gb
3
in culture, cannot be stimulated to increase Gb
3
synthesis (8). It has been suggested that the transition from renal tissue to primary endothelial cell culture in vitro results in the maximum stimulation of Gb
3
synthesis from a zero background (9). We therefore suspect that HUS in the elderly is the result of verotoxemia and a concomitant stimulation of renal endothelial cell Gb
3
synthesis by some other factor, e.g. LPS stimulation of serum &agr; TNF. Thus under these conditions, the majority of individuals (excepting the very young) would not be liable to VT induced renal pathology following systemic verotoxemia.
It has also shown that the verotoxin targets a sub-population of human B cells in vitro (10). These Gb
3
containing B cells are found within the germinal centres of lymph nodes (11). It has been proposed that Gb
3
may be involved in a germinal centre homing by CD19 positive B cells (12) and that Gb
3
may be involved in the mechanisms of antigen presentation (13).
Elevated levels of Gb
3
have been associated with several other human tumours (14-16), but ovarian tumours have not been previously investigated. Gb
3
is the p
k
blood group antigen (17). Tissue surveys using anti-p
k
antisera have shown that human ovaries do not express this glycolipid (18, 19).
Sensitivity to VT1 cytotoxicity in vitro has been shown to be a function of cell growth, the stationary phase cells being refractile to cytotoxicity (20). The sequence homology between the receptor binding B subunit and the human &agr;2-interferon receptor and the B cell marker CD19 suggests that expression of Gb
3
is involved in the mechanism of &agr;2-interferon and CD19 signal transduction (12). On surface ligation, Gb
3
has been shown to undergo a retrograde intracellular transport via the rough endoplasmic reticulum to the nuclear membrane (21).
Reference List
The present specification refers to the following publications, each of which is incorporated herein by reference:
1. Farkas-Himsley, H. and R. Cheung. Bacterial Proteinaceous Products (bacteriocins as cytotoxic agents of neoplasia).
Cancer Res
. 36:3561-3567, (1976).
2. Hill, R. P. and H. Farkas-Himsley. Further studies of the action of a partially purified bacteriocin against a murine fibrosarcoma.
Cancer Res
. 51:1359-1365 (1991).
3. Karmali, M. A. Infection by Verocytotoxin-producing
Escherichia coli. Clin. Microbiol. Rev
. 2:15-38 (1989).
4. Karmali, M. A., M. Petric, C. Lim, P. C. Fleming, G. S. Arbus and H. Lior, 1985. The association between hemolytic uremic syndrome and infection by Verotoxin-producing
Escherichia coli
, J. Infect. Dis. 151:775.
5. Riley, L. W., R. S. Remis, S. D. Helgerson, H. B. McGee, J. G. Wells, B. R. Davis, R. J. Hebert, E. S. Olcott, L. M. Johnson, N. T. Hargrett, P. A. Blake and M. C. Cohen. Haemorrhagic colitis associated with a rare
Escherichia coli
serotype.
N. Engl. J. Med
. 308:681 (1983).
6. Lingwood, C. A., Advances in Lipid Research. R. Bell, Y. A. Hannun and A. M. Jr.
Academic Press
. 25:189-211 (1993).
7. van de Kar, N. C. A. J., L. A. H. Monnens, M. Karmali and V. W. M. van Hinsbergh. Tumour necrosis factor and interleukin-1 induce expression of the verotoxin receptor globotriaosyl ceramide on human endothelial cells. Implications for the pathogenesis of the Hemolytic Uremic Syndrome.
Blood
. 80:2755, (1992).
8. Obrig T., C. Louise, C. Lingwood, B. Boyd, L. Barley-Maloney and T. Daniel. Endothelial heterogeneity in Shiga toxin receptors and responses.
J. Biol. Chem
. 268:15484-15488 (1993).
9. Lingwood, C. A. Verotoxin-binding in human renal sections.
Nephron
. 66:21-28 (1994).
10. Cohen, A., V. Madrid-Marina, Z. Estrov, M. Freedman, C. A. Lingwood and H. M. Dosch. Expression of glycolipid receptors to Shiga-like toxin on human B lymphocytes: a mechanism for the failure of long-lived antibody response to dysenteric disease.
Int. Immunol
. 2:1-8 (1990).
11. Gregory, C. D., T. Turz, C. F. Edwards, C. Tetaud, M. Talbot, B. Caillou, A. B. Rickenson and M. Lipinski. 1987. Identification of a subset of normal B cells with a Burkitt's lymphoma (BL)-like phenotype.
J. Immunol
. 139:313-318 (1987).
12. Maloney, M. D. and C. A. Lingwood, CD19 has a potential CD77 (globotriaosyl ceramide) binding site with sequence similarity to verotoxin B-subunits: Implications of molecular mimicry for B cell adhesion and enterohemorrhagic
E. coli
pathogenesis.
J. Exp. Med
. 180: 191-201, (1994).
13. Maloney, M. and C. Lingwood. Interaction of verotoxins with glycosphingolipids.
TIGG
. 5:23-31 (1993).
14. Li, S. C., S. K. Kundu, R. Degasperi and Y. T. Li. Accumulation of globotriaosylceramide in a case of leiomyosarcoma.
Biochem. J
. 240:925-927 (1986).
15. Mannori G., O. Cecconi, G. Mugnai and S. Ruggieri. Role of glycolipids in the me
Farkas-Himsley Hannah
Geva Ruth
Hill Richard
Kroyanker Leorah
Lingwood Clifford A.
Carlson Karen Cochrane
DeConti, Jr. Giulio A.
Geva Ruth
HSC Research & Development Limited Partnership
Kroyanker Leorah
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