Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1999-02-12
2001-03-06
Huff, Sheela (Department: 1642)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C436S063000
Reexamination Certificate
active
06197528
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to compositions and methods for the treatment or prevention of cancer, autoimmune diseases, viral, microbial, parasitic and fungal diseases in mammals. More specifically, this invention relates to the potentiation of immunoconjugates by retinoids.
BACKGROUND
Classic modalities for treatment of diseases such as human cancers, autoimmune diseases, viral, microbial, parasitic and fungal diseases include surgery, radiation, chemotherapy, antibiotics or combination therapies. However, extended therapy with these agents may cause greater morbidity than the underlying disease. Alternate therapies for preventing or treating human diseases are greatly needed. In the past decade immunotherapy has emerged as a new and promising method for treating cancers.
Immunotoxins are being used in the treatment of diseases such as cancers, autoimmune diseases, viral, microbial, parasitic and fungal diseases. In one approach, antibodies targeting tumor associated antigens or tumor specific antigens are administered as a form of treatment. To augment the therapeutic efficacy of the antibodies, the antibodies are often conjugated to cytotoxic drugs, toxins or radioisotopes. Monoclonal antibodies coupled to protein toxins, called immunotoxins, are being examined in numerous clinical trials for treatment of cancer and autoimmune diseases (Rybak, S. M., et al. (1991)
Immunology and Allergy Clinics of North America
11:359-380). Subsequent to cell surface binding by the monoclonal antibody, the toxic protein subunit crosses the membrane surrounding the cytosol to reach the intracellular substrate. Ricin, for example, enzymatically inactivates ribosomes, inhibiting protein synthesis and causing cell death (Endo, Y., et al (1987)
J. Biol. Chem
. 262:5908-5912; Olsnes, S., et al. (1973)
Biochemistry
. 12:3121-3126; Olsnes, S., et al. (1976)
J. Biol. Chem
. 257:3985-3992). How the hydrophilic enzyme crosses into the cytosol is unknown, although endocytosis and intracellular routing to the proper compartment are required (Johnson, V. G., et al. (1991)“Intracellular Routing And Membrane Translation Of Diphtheria Toxin And Ricin”
In Intracellular Trafficking of Proteins
. 183-225 C. J. Steer and J. A. Hanover (eds) Karger (Basel)). The Golgi apparatus appears to be one compartment through which ricin must pass en route to the cytosol. Native ricin efficiently routes through the Golgi apparatus to the cytosol due to galactose binding sites on the ricin B chain (Gonatas, N., et al. (1975)
Exp. Cell Res
. 94:426-431; Hudson, T. H., et al. (1991)
J. Biol. Chem
. 266:18586-18592; Sandvig, K., et al. (1991)
J. Cell Biol
. 115:971-981; Youle, R. J., et al. (1987)
J. Biol. Chem
. 262:4676-4682). When the ricin B chain is removed and enzymatically active A chain is linked to monoclonal antibodies reactive with cell surface molecules such as the transferrin receptor, much less efficient entry into the cytosol ensues (Youle, R. J., et al. (1982)
J. Biol. Chem
. 257:1598-1601). Although the immunotoxin is rapidly endocytosed via the transferrin receptor, it does not traffic such that the enzymatically active A chain rapidly reaches the cytosol. In addition to ricin B chain, some drugs that cause alterations in the Golgi apparatus such the ionophore, monensin, and lysosomotropic amines cause a large increase in cell sensitivity to the immunotoxins (Casellas, P., et al. (1984)
J. Biol. Chem
. 259:9359-9364). Chloroquine (Laurent, G., et al. (1986)
Blood
. 67:1680-1687), a lysosomotropic agent, and the ricin B chain (Grossbard, M. L., et al. (1992)
Blood
79:576-585) have been tested in man for their ability to improve the anti-cancer activity of immunotoxins.
Retinoids are a large family of molecules encompassing over three thousand members. Retinoic acid, a member of the retinoid family, is a morphogen that defines certain cell fates during development and has the potential to treat cancer by inducing tumor cell differentiation (Petkovich, M. (1992)
Ann. Rev. Nutr
. 12:443-471; Thaller, C., et al. (1991)
In Retinoids
: 10
Years On
89-108 J. H. Saurat (ed) Karger/Basel). Retinoid acid binds the retinoic acid receptor (RAR) causing it to form heterodimers with the retinoid X receptor (RXR) and induce gene transcription (Chambon, P., et al. (1991)“The family of retinoid acid nuclear receptors” In
Retinoids
: 10
Years On
. 10-27 J. H. Saurat (ed), Karger/Basel; Kliewer, S. A., et al. (1992)
Nature
. 355:446-449; Zhang, X. K., et al. (1992)
Nature
. 355:441-446). In addition to the well accepted role of retinoids in transcription activation, some retinoids may have direct effects on cell second messengers (Evain-Brion, D., et al. (1991) “Retinoid Acid & Cellular Signal Transduction” In
Retinoids
: 10
Years On
. 46-55; J. H. Saurat(ed) Karger/Basel).
Additional therapies that potentiate the toxicity of the immunotoxins to a high degree of specificity for the affected target cell would greatly facilitate treatment of human diseases with these immunotherapeutic agents.
SUMMARY OF THE INVENTION
This intention relates, in general, to compositions and methods of treating mammalian diseases. This invention provides a method of potentiating the efficacy of immunotoxins used in treating mammalian diseases by administration of retinoids with the immunotoxins.
It is an object of this invention to provide a in vitro method for assessing the ability of a retinoid to potentiate the activity of immunotoxins.
One aspect of the invention provides a method for inhibiting the growth of target cells using a composition of an immunotoxin and a retinoid.
It is yet another object of this invention to provide an in vivo method for assessing the ability of a retinoid to potentiate the activity of an immunotoxin.
It is a further object of the present invention to provide compositions comprising retinoids and immunotoxins for preventing or treating mammalian diseases.
It is another object of this invention to provide compositions comprising retinoids and immunotoxins for preventing or treating mammalian cancers.
It is yet another object of this invention to provide a method of potentiating the activity of immunoconjugates in the prophylactic or therapeutic treatment of mammalian diseases.
It is a further object of this invention to provide a kit comprising the compositions for use in the methods described herein.
REFERENCES:
patent: 4894227 (1990-01-01), Stevens et al.
patent: 5112607 (1992-05-01), Hudson et al.
Funatsu et al, “Conserved amino acid residues in ribosome-inactivating proteins for plants”,Biochimie(1991) 73, pp. 1157-1161.
Montecucchi et al, “N-terminal sequence of some ribosome-inactivating proteins”,Peptide Protein Res.33, 1989, pp. 263-267.
Fong et al, “Minireview: Enzymatic Properties of Ribosome-Inactivating Proteins (RIPs) And Related Toxins”,Life Sciences,(1991) vol. 49, pp. 1859-1869.
Gerald B. Dermer, “Another Anniversary for the War on Cancer”,Bio/Technology,vol. 12, Mar. 1994, p. 320.
Rybak et al, “Monoclonal Antibodies Conjugated to Protein Toxins”,Clinical Use of Immunotoxins,vol. 11, No. 2, May 1991.
Thorpe et al, Improved Antitumor Effects of Immunotoxins Prepared with Deglycosylated Ricin A-Chain and Hindered Disulfide Linkages,Cancer Research,48, No. 22, pp. 6257-6623, Nov. 15, 1988.
Vitetta et al, “Redesigning Nature's Poisons to Create Anti-Tumor Reagents”,Science,vol. 238, pp. 1015-1202, Nov. 1987.
Pastan et al, “Immunotoxins”,Cell,vol. 47, pp. 641-648, Dec. 8, 1986.
Blakely et al, “Comparison of the Pharmacokinetics and Hepatotoxic Effects of Saporin and Ricin A-Chain Immunotoxins on Murine Liver Parenchymal Cells”,Cancer Research,vol. 48, No. 24, pp. 6977-7338 (Dec. 15, 1988).
Laurent et al, “Effects of Therapy With T101 Ricin A-Chain Immunotoxin in Two Leukemia Patients”,Blood,vol. 67, No. 6, pp. 1680-1687, Jun. 1986.
Grossbard et al, “Serotherapy of B-Cell Neoplasma With Anti-B4-Blocked Ricin: A Phase I Trial of Daily Bolus Infusion”,Blood,vol. 79, No. 3 (Feb. 1992) pp. 576-585.
Wu et al, (Abstract) “Retinoic acid alters intra
Wu YouNeng
Youle Richard J.
Huff Sheela
Morgan & Finnegan L.L.P.
The United States of America as represented by the Department of
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