Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,...
Reexamination Certificate
1999-11-24
2002-12-10
Ungar, Susan (Department: 1642)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
C424S131100, C424S138100, C424S141100, C424S152100, C424S155100, C424S156100, C424S172100, C424S174100, C424S278100
Reexamination Certificate
active
06491914
ABSTRACT:
TECHNICAL FIELD
The present invention relates generally to anti-idiotypic monoclonal antibodies and their use as immunomodulators. More particularly, the present invention involves a murine monoclonal antibody which was developed against a murine monoclonal antibody reactive with N-glycolyl containing gangliosides and with antigens expressed in cancer cells; and its inhibitory effect on tumor growth.
BACKGROUND
One of the strategies for the treatment of cancer has been the use of active immunotherapy, a treatment modality that has the objective of activating the natural potential of the immune system of the host against the tumor.
Since Niels Jerne proposed his idiotypic network theory in 1974 (Jerne, N. K. 1974.
Ann. Inimunol.
125C, 373-389), new possibilities have emerged in the study of effective therapies against cancer. Jerne's theory presented, for the first time, the immune system as a network of antibodies which can interact with each other and with a large number of natural epitopes, through their variable regions or idiotypes. (Id,) This complex set of idiotype-anti-idiotype interactions operate to regulate immune responses to antigens. Those antibodies made in response to the original antigen, which are typically referred to as Ab1, themselves become antigens and elicit the production of a second set of antibodies, which are typically referred to as anti-idiotype antibodies or Ab2, which may also be regulated by other antibodies that are typically referred as anti-anti-idiotype or Ab3.
The original theory of Jerne continues to be reviewed. It has been reported that the result of the interaction of Ab2 with lymphocytes bearing Ab1 does not necessarily suppress the immune response, but it may also stimulate the immune response. Moreover, Jerne limited his theory to B lymphocytes and antibodies, but it is now clear that T cells play an important role in the regulation of the immune response through the idiotypes of T cell receptors (Teitelbaum, D. et al, 1984
J. Immunol
132, 1282-1285, Zanetti, M, et al. (1986)
J. Immunol.
137, 3140-3196; Powell, J. et al. (1988) 140, 3266-3272; Baskin, J.G. et al. (1990)
J. Immunol.
145, 202-208; Furuyama, A. et al. (1992) Anticancer Res. 12, 27-32; Raychaudhuri, S. et al.
J. Immunol.
131, 271-278; Raychaudhuri et al. (1987)
J. Immunol.
139, 3902-3910, Durrant et al. (1994)
Cancer Res.
54, 4837-4840).
An idiotype is immunologically defined by reactivity with more than one anti-idiotype that recognizes an idiotypic determinant or idiotope within a given idiotype. Thus, as a particular Ab1 expresses multiple idiotopes, when this Ab1 was administered to syngeneic animals, a heterogeneous population of idiotypic antibodies is obtained.
Classification of the anti-idiotype antibodies focuses on their binding within the antigen-binding site or to some other region of the idiotype. If the binding of the Ab2 with the Ab1 is inhibited by the relevant antigen and if the Ab2 is also capable of inducing an antibody response of the same specificity as the Ab1, it mimics the natural antigen and is classified as Ab2&bgr;; this type of Ab2 is referred to as internal image anti-idiotype and can act as a surrogate antigen. Anti-idiotypes that are not inhibited by antigen are designated Ab2&agr;. Ab2&agr;. react with Ab1 idiotopes which are not structurally related with the antigen-binding site. In 1984 Bona and Köhler proposed a third type of anti-idiotype antibodies (Ab2&ggr;), which are inhibited by antigen because of steric interference, this type of anti-idiotype reacts with idiotopes structurally associated with the antigen-binding site, but they do not mimic the antigenic epitope recognized by the Ab1 (Bona and Köhler (1984) Anti-idiotypic antibodies and internal image, in Monoclonal and anti-idiotypic antibodies: Probes for receptor structure and function, Venter J.C., Frasser, C.M., Lindstrom, J. (Eds.) N.Y., Alan R. Liss, pp 141-149, 1984).
Based on Jerne's theory, two main approaches have been developed in the development of vaccines to a large number of antigens, including tumor-associated antigens. The first approach is based on the presentation of epitopes in a different molecular environment, using Ab2 &bgr;. Vaccines containing this type of anti-idiotype antibodies have been able to induce protective responses against viruses, bacteria, and parasites (Kennedy et al. (1986) 232, 220-223; 1047; McNamara et al. (1985)
Science
226, 1325-1326). Ab2&bgr; have also been used to induce immune responses to tumor-associated antigens and positive results have been obtained in animal models and in clinical trials (Raychauhuri et al. (1986)
J. Immunol.
137, 1743-1749; Raychauhuri et al. (1987)
J. Immunol.
139, 3902-3910; Bhattacharya-Chatterjee et al. (1987)
J. Immunol.
139, 1354-1360; Bhattacharya-Chatterjee et al. (1988)
J. Immunol.
141, 1398-1403; Herlyn, D. et al. (1989)
Intern. Rev. Immunol.
4, 347-357; Chen, Z-J et al.
Cell Imm. Immunother. Cancer
(1990) 351-359; Herlyn, D. et al. (1991)
In Vivo
5, 615-624; Furuya et al. (1992)
Anticancer Res.
12, 27-32; Mittelman, A. et al. (1992)
Proc. Natl. Acad. Sci., USA
89, 466-470; Durrant, L. G. et al. (1994)
Cancer Res.
54, 4837-4840; Mittelman, A. et al. (1994)
Cancer Res.
54, 415-421; Schmitt, H. et al. (1994) Hybridoma 13, 389-396; Chakrobarty, M. et al. (1995)
J. Immunother.
18, 95-103; Chakrobarty, M. et al. (1995)
Cancer Res.
55, 1525-1530; Foon, K. A. et al. (1995)
Clin. Cancer Res.
1, 1205-1294; Herlyn, D, et al. (1995)
Hybridoma
14, 159-166; Sclebusch, H. et al. (1995)
Hybridoma
14, 167-174; Herlyn, D. et al. (1996)
Cancer Immunol. Immunother.
43, 65-76). Nevertheless, it has been demonstrated that the &bgr; character of an Ab2 is not enough to predict the biological effect that could induce the Ab2 (Raychauhuri et al. (1986)
J. Immunol.
137, 1743-1749; Raychauhuri et al. (1987)
J. Immunol
139, 231-278; Maruyama et al. (1996)
Int. J. Cancer
65, 547-553).
The second approach is based on network manipulation through regulatory idiotopes that do not bind to antigens, but involucrate idiotopes shared with other antibodies or T cells. Evidence that these anti-idiotype antibodies are also able to produce immune responses and protective effects has been accumulated (Paul, W. E. and Bona, C. (1982)
Immunology Today
3, 230-234; McNamara M. K. et al. (1985)
Science
226, 1325-1326; Kohler y cols (1992) Proc. 8th Inter. Cong. Immunol. Budapest, pp. 619).
Gangliosides are glycosphingolipids that contain sialic acid and are expressed in the majority of mammalian cell membranes. Although these antigens are present in normal tissues, they can be found in larger quantities and expressed in a different organization and conformation on the surface of malignant cells (Hakomori, S. (1985),
Cancer Res.
45, 2405-2415; Miraldi, F. (1989)
Seminars in Nuclear Medicine
XIX, 282-294; Hamilton et al. (1993)
Int. J. Cancer
53, 1-81).
Although gangliosides are useful targets for immune responses, their immunogenicity is extremely poor, due to their carbohydrate nature and their self-antigen condition (Livingston, P. et al, (1995)
Seminars in Cancer Biology
6, 357-366).
The N-glycolyl variant of sialic acid is expressed in normal tissues of most mammals, but it is very difficult to detect it in normal human tissues (Watarai, S. et al. (1995)
J. Biochem.
117, 1062-1069. On the other hand, the presence of these antigens has been reported in colon cancer, melanoma, retinoblastoma and breast cancer, among others (Higachi, H. et al. (1984)
Jpn. J. Cancer Res.
(Gann) 75, 1025-1029; Higachi, H. et al. (1985) Cancer Res. 45, 3796-3802; Hirabayashi, I. et al. (1987) Jpn. J. Cancer Res. (Gann) 78, 1614-1620, Higachi, H. et al. (1980) Jpn. J. Cancer Res. (Gann) 79, 952-956, Miyake, M. et al. (1990)
Cancer
65, 499-505; Devine, P. L. et al. (1991)
Cancer Res.
51,5826-5306; Vázquez, A. M. et al. (1995)
Hybridoma
14,551-556; Marquina, G. et al. (1996)
Cancer Res.
56, 5165-5171).
Immunization with vaccines which contain gangliosides has resulted in the
Delgado Irene Beausoleil
Guerra Eladio Iglesis
Lopez Gumersinda Bombino
Perez Alexis
Pérez Rodríguez Rolando
Centro de Inmunologia Molecular
TraskBritt
Ungar Susan
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