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Methods for treating cancer using an immunotoxin

a technology of immunotoxin and cancer, which is applied in the direction of antibody medical ingredients, drug compositions, peptides, etc., can solve the problems of difficult and disfiguring palliative surgery, radiation therapy is rarely feasible or beneficial, and chemotherapy does not substantially improve the survival rate of hnscc patients

Inactive Publication Date: 2007-08-23
UNIV ZURICH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0015] Other features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples while indicating preferred embodiments of the invention are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

Problems solved by technology

However, palliative surgery is often difficult and disfiguring.
Furthermore, radiation therapy is rarely feasible or beneficial, and chemotherapy does not substantially improve survival rates in HNSCC patients.
Prognosis for these patients remains poor, such that the median survival after recurrence is only approximately six months.

Method used

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  • Methods for treating cancer using an immunotoxin
  • Methods for treating cancer using an immunotoxin
  • Methods for treating cancer using an immunotoxin

Examples

Experimental program
Comparison scheme
Effect test

example 1

VB4-845 Immunotoxin

[0177] VB4-845 is an immunotoxin comprised of a single-chain Fv recombinant human antibody fragment that is fused to a truncated form of Pseudomonas exotoxin A (ETA 252-608). The antibody fragment is derived from the humanized MOC31 single-chain antibody fragment, 4D5MOCB, which specifically binds to Ep-CAM.16-18

[0178] Exotoxin A is one of the toxic proteins released by pathogenic strains of Pseudomonas aeruginosa19. It is secreted as a proenzyme with a molecular weight of 66,000 daltons20. Exotoxin A is translocated into susceptible mammalian cells, where covalent alteration of the molecule renders it enzymatically active. Pseudomonas exotoxin A irreversibly blocks protein synthesis in cells by adenosine diphosphate-ribosylating a post-translationally modified histidine residue of elongation factor-2, called diphthamide, and induces apoptosis.4 The truncated version of ETA used in this construct, while still containing the domains for inducing cell death, lacks...

example 2

Dosage Forms and Compositions

[0184] VB4-845 has been studied as a nascent drug and has been found to be effective in binding to tumor cell lines and in some model systems, preventing tumor growth. VB4-845 is formulated at 1 mg / ml in 20 mM sodium phosphate, 500 mM NaCl, pH 7.2, and can be administered by an intratumoral route with a 22-gauge needle. It is packaged in 1 ml borosilicate glass vials, closed with a gray butyl stopper and an aluminum overseal. Two fill sizes are currently available: 0.1 and 0.2 mL (0.1 mg and 0.2 mg VB4-845, respectively). Drug is stored at −70° C. The final product is not preserved and is for single use only.

[0185] The sample product is labeled, stored, and shipped according to written and approved standard operating procedures. The product may be shipped under frozen conditions (e.g., on dry ice), and may be maintained, for example, at the study site in a limited access, controlled −70° C. freezer that is monitored regularly for temperature. The produ...

example 3

Stability of VB4-845

[0186] The shelf-life of the product when stored at −70° C. is at least six months. At physiological conditions (e.g., incubation of the drug product for four hours at 37° C. in PBS), the majority of the immunotoxin molecules (at least 91%) are still eluted as monomers of the appropriate molecular weight (approximately 70 kDa). The amount of VB4-845 slowly decreases with time with no less than approximately 47% of the initial protein being present in monomeric form after twenty hours at 37° C. Similar results were obtained upon incubation of 99mTc-labeled VB4-845 in human serum, further corroborating the suitability of the immunotoxin for in vivo application.

[0187] Short term stability studies have been conducted to evaluate the inherent stability of the investigational product under routine handling at the clinical site. VB4-845 was evaluated in its standard formulation at room temperature and at 2-8° C. In addition, VB4-845 was prepared in injection buffer of...

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Abstract

The present invention relates to methods for preventing or treating head and neck squamous cell cancer and bladder cancer using an immunotoxin comprising (a) a ligand that binds to a protein on the cancer cell attached to; (b) a toxin that is cytotoxic to the cancer cell. In a specific embodiment, the invention is directed to the prevention or treatment of head and neck squamous cell cancer or bladder cancer using VB4-845, which is a recombinant immunotoxin comprising a humanized, MOC31-derived, single-chain antibody fragment that is fused to a truncated form of Pseudomonas exotoxin A. Also encompassed by the invention are combination therapy methods, including the use of reduced dosages of chemotherapeutic agents, for the prevention or treatment of cancer. Also encompassed by the invention are formulations and methods for direct administration of the recombinant immunotoxin to the carcinoma, for the prevention or treatment of cancer.

Description

FIELD OF THE INVENTION [0001] The present invention is directed to methods for the prevention or treatment of cancer by administering to patients having cancer, or at risk of having cancer, an immunotoxin which binds to an antigen selectively expressed on the surface of cancer cells. BACKGROUND OF THE INVENTION [0002] Recently, immunotherapy has emerged as a potentially effective new approach to combat cancer. Murine and humanized / chimeric antibodies, and their respective antibody fragments, directed against tumor-associated antigens (“TAAs”) have been used for diagnosis and therapy of certain human cancers.5-13 Unconjugated, toxin-conjugated, and radiolabeled forms of these antibodies have been used in such therapies. [0003] One tumor associated antigen of interest for immunotherapy is Ep-CAM (for Epithelial Cell Adhesion Molecule, which also known as 17-1A, KSA, EGP-2 and GA733-2). Ep-CAM is a transmembrane protein that is highly expressed in many solid tumors, including carcinoma...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61K39/00A61K47/48C07K16/30
CPCA61K47/48484A61K47/48607A61K2039/505C07K14/21C07K14/34A61K45/06C07K2317/21C07K2317/24C07K2317/622C07K2319/30C07K16/30A61K47/6829A61K47/6861A61K47/6865A61P13/10A61P35/00C07K16/28C07K2317/565C07K2317/92
Inventor ZANGEMEISTER-WITTKE, UWEDI PAOLO, CLAUDIOTSCHUDI, DOMINIQUE CHRISTINEGLOVER, NICHOLAS RONALDFITSIALOS, DIMITRI PETER
Owner UNIV ZURICH
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