Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1996-06-10
2001-02-13
O'Sullivan, Peter (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S463000, C514S510000, C549S432000, C554S063000, C560S174000, C564S223000
Reexamination Certificate
active
06187819
ABSTRACT:
BACKGROUND OF THE INVENTION
Throughout this application, various publications are referenced by Arabic number within brackets. Full citations for these publications may be found at the end of the specification immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed therein.
The expression of both histocompatibility antigens and tumor associated antigens (TAAs) of tumor cells can be augmented by treatment with bioresponse modulators, such as interferon and tumor necrosis factor-&agr;, and phorbol ester tumor promoters, such as TPA [1,13,14,16,18,22,23,27,28]. Upregulation of additional cellular antigens can be induced to a similar extent in both normal and tumor cells by bioresponse modulators indicating that this effect is a general property of these compounds and not restricted to TAAs or cells of a specific histotype (for review see [1,23]). For example, various interferons have been shown to enhance the expression of histocompatibility antigens, cellular antigens and TAAs in breast carcinoma, central nervous system tumors, colon carcinoma and melanoma cells [21-23,27,28,31,38]. In addition, when administered to animals containing human tumor xenografts, recombinant human interferon augments the ability of excised tumors to bind monoclonal antibodies specific for TAAs [13,21,36,42]. The use of bioresponse modifiers for increasing the expression of TAAs by tumor cells may prove useful in reducing the antigenic heterogeneity in tumors in vivo and augmenting the ability of monoclonal antibodies to bind to tumors (for review see [1,23,25,26]).
TPA and recombinant human leukocyte (IFN-&agr;), fibroblast (IFN-&bgr;) and immune (IFN-&ggr;) interferons increase both the expression and shedding of the tumor associated antigen BCA 225 by T47D cells and MCF-7 human breast carcinoma cells [36]. These compounds also increase the expression of the TAA carcinoembryonic antigen (CEA) and HLA Class II-DR antigen in both T47D and MCF-7 cells [20,36]. The mechanism by which TPA induces its diversity of effects in target cells is believed to be mediated initially by its binding to the Ca
2+
-activated and phospholipid-dependent enzyme PKC which is the high affinity receptor for TPA (for review see [10, 43,44]). As a consequence of activation of PKC many important biochemical processes are initiated in target cells, including both positive and negative feedback controls in signal transduction pathways (for review see [43,44]). Recent studies have implicated PKC activation in mediating both antiviral activity and specific gene regulatory changes induced by IFN-&agr;, IFN-&bgr;, and IFN-&ggr; [6,8,37,46,47,50] and for review see [9]. The purpose of the present study was to explore the possible relationship between PKC activation and antigen upregulation induced by phorbol esters and interferon. With this aim in mind applicants have determined the effect of the synthetic PKC-activator ADMB, the natural PKC activators TPA and MEZ and the combination of PKC-activators and the PKC-inhibitor H-7 on the antigenic phenotype of T47D cells. To determine if similar biochemical pathways are involved in the ability of IFN-&bgr; and IFN-&ggr; to alter the antigenic phenotype of T47D cells, applicants have also evaluated the effect of H-7 on interferon upregulation of the same antigens in T47D cells.
The effect of a synthetic protein kinase C (PKC) activator 3-(N-acetylamino)-5-(N-decyl-N-methylamino)-benzyl alcohol (ADMB) and the natural PKC-activating tumor promoting agents 12-0-tetradecanoyl-phorbol-13-acetate (TPA) and mezerein (MEZ) on the antigenic phenotype of carcinoma cells was studied. All three agents increased the surface expression of the tumor associated antigen such as BCA 225 and also of various cellular antigens, including HLA Class II antigens, intercellular adhesion molecule-1 (ICAM-1) and c-cerbB-2. Expression of the same antigens was also upregulated to various extent in T47D cells by recombinant fibroblast (IFN-&bgr;) and immune (IFN-&ggr;) interferon. Shedding of BCA 225 from T47D cells was induced by TPA, MEZ, IFN-&bgr; and IFN-&ggr;, whereas ADMB did not display this activity. The ability of ADMB, TPA and MEZ to modulate the antigenic phenotype of T47D cells appears to involve a PKC-mediated pathway, since the PKC inhibitor, H-7, eliminates antigenic modulation. In contrast, the ability of IFN-&bgr; and IFN-&ggr; to enhance HLA Class II antigens, c-erbB-2 and ICAM-1 expression, was either unchanged or modestly reduced by simultaneous exposure to H-7. Analysis of steady-state mRNA levels for HLA Class I antigens, HLA Class II-DR&bgr; antigen, ICAM-1, and c-erbB-2 indicated that the ability of H-7 to inhibit expression of these antigens in TPA-, MEZ-, and ADMB-treated cells was not a consequence of a reduction in the steady-state levels of mRNAs for these antigens. The results of the present investigation indicate that the biochemical pathways mediating enhanced antigenic expression in T47D cells induced by TPA, MEZ and the synthetic PKC activator ADMB are different than those induced by recombinant interferons. Furthermore, upregulation of antigenic expression in T47D cells can occur by both a PKC-dependent or a PKC-independent pathway.
SUMMARY OF THE INVENTION
This invention provided a composition for the upregulation of expression of all antigens without inducing shedding which comprises a protein kinase C activation for the upregulation of expression of a cell antigen without inducing shedding of said antigen from the cell.
Further provided by this invention is a method for decreasing tumor cell heterogeneity by upregulating the expression of an antigen without inducing shedding of said antigen which comprises administering an amount of a protein kinase C activator to cells to induce upregulation of expression of an antigen without inducing shedding of said antigen.
Additionally, this invention provides a method of detecting tumor cells comprising contacting tumor cells with an effective amount of a protein kinase C activator for the upregulation of expression of antigens of tumor cells, without inducing shedding, and detecting the presence of said antigen.
A method for treating tumor cells is also provided. This method comprises contacting tumor cells with an effective amount of a protein kinase C activator for the upregulation of expression of antigens of tumor cells without inducing antigen shedding and then contacting said tumor cells with an effective amount of an antibody directed to said antigen.
This invention also provides a pharmaceutical composition for upregulating the expression of antigens without inducing antigen shedding which comprises a pharmaceutically acceptable carrier and an effective amount of a protein kinase C activator.
REFERENCES:
Barton, K., et al (1989) “The effects of the Antitumor agent mazerein on the cytotoxic capacity and oxidative metabolism of human blood cells.”Chemical Abstracts111: abstract No. 146415w,Invest. New Drugs(1989) 7: 79-188 (Exhibit B).
Celada, A. and Maki, R.A. (1991) “IFN-&ggr; induces the expression of the genes for MHC Class II I-A&bgr;and tumor necrosis factor through a protein kinase C-independent pathway.”J. Immunol. 146:114-120.
Downey, G.P., et al. (1992) “Phorbol ester-induced actin assembly in neutrophils: role of protein kinase C.”J. Cell Biol. 116:695-706.
Fisher, P.B. and Rowley, P.T. (1991) “Regulation of growth, differentiation and antigen expression in human tumor cells by recombinant cytokines: potential applications for the differentiation therapy of human cancer.”In: Waxam, S., Rossi, B.B., and Takaku, F. (eds.)Status of differentiation therapy of cancer, vol. II Raven Press, New York, pp. 201-213.
Fuith, L.C., et al. (1991) “Enhancement of CA 125 expression by interf
Fisher Paul B.
Leon Jorge A.
Cooper & Dunham
O'Sullivan Peter
The Trustees of Columbia University in the City of New York
White John P.
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