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Methods and compositions for treating tumor diseases

a tumor and composition technology, applied in the field of tumor diseases, can solve the problems of acute toxicity, secondary malignancies, serious limitations for a young patient population, etc., and achieve the effects of reducing metabolic activity, improving symptom associated, and eliminating metabolic activity

Inactive Publication Date: 2010-07-01
AMGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0030]In another aspect, the present invention provides a method of increasing the longevity of a subject comprising administering to said subject said pharmaceutical composition.

Problems solved by technology

The side effects of such treatment often include acute toxicity, and can include secondary malignancies, a serious limitation for a young patient population.
Moreover, metastatic Ewing's sarcoma is particularly resistant to conventional treatment.
In spite of intense research efforts, no targeted therapeutic has been found that is effective against tumors containing activating RAS mutations.

Method used

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  • Methods and compositions for treating tumor diseases
  • Methods and compositions for treating tumor diseases
  • Methods and compositions for treating tumor diseases

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of Antibodies

[0204]This example demonstrates a method of preparing antibodies recognizing the IGF-1 receptor.

[0205]IGF-1 receptor polypeptides may be employed as immunogens in generating monoclonal antibodies by conventional techniques. It is recognized that polypeptides in various forms may be employed as immunogens, e.g., full length proteins, fragments thereof, fusion proteins thereof such as Fc fusions, cells expressing the recombinant protein on the cell surface, etc.

[0206]To summarize an example of such a procedure, an IGF-1R immunogen emulsified in complete Freund's adjuvant is injected subcutaneously into Lewis rats, in amounts ranging from 10-100 μl. Three weeks later, the immunized animals are boosted with additional immunogen emulsified in incomplete Freund's adjuvant and boosted every three weeks thereafter. Serum samples are periodically taken by retro-orbital bleeding or tail-tip excision for testing by dot-blot assay, ELISA (enzyme-linked immunosorbent ass...

example 2

Isolation of Human IGF-1R(ECD)-C3-muIgG1

[0209]This example provides a method of making a soluble fragment of IGF-1R useful for raising antibodies.

Cloning of pDSRα:huIGF-1R(ECD)-C3-muIgG1Fc

Primers 2830-36:SEQ ID NO: 256)5′ AGCAAGCTTCCACCATGAAGTCTGGCTCCGGAGGAGG 3′and 2830-38:SEQ ID NO: 257)5′ ATTTGTCGACTTCGTCCAGATGGATGAAGTTTTCAT 3′,

were used to amplify the human IGF-1R extracellular domain (1-906) cDNA sequence. The primers included a Kozak translation initiation sequence (underlined above) preceding the start codon, restriction sites for subsequent subcloning, and a caspace-3 site, which is inserted next to the extracellular domain C-terminus. PCR was performed on a PerkinElmer 2400 (PerkinElmer, Torrance, Calif.) under the following conditions: 1 cycle at 95° C. for 2 min, 23 cycles at 95° C. for 30 sec, 58.5° C. for 30 sec, and 72° C. for 3 min, and 1 cycle at 72° C. for 10 min. Final reaction conditions were 1×pfu TURBO® buffer (Stratagene, La Jolla, Calif.), 200 μM dNTPs, 2 μM ea...

example 3

Initial Screen for Anti-IGF-1R Phage Fab

[0216]This example provides a method of identifying Anti-IGF-1R antibodies.

[0217]A Target Quest Q Fab library (“the TQ library”; Target Quest, Maastricht, the Netherlands), which was constructed using peripheral blood lymphocytes from four healthy donors and splenic lymphocytes from one patient with gastric carcinoma, was obtained. The library diversity was 3.7×1010 clones, containing 3×109 heavy chains. The source, screening methods, and characterization of the library have been published (de Haard et al, 1999, J Biol Chem 274:18218-30). Dynabeads (200 μl) M-450 Uncoated (catalog #140.02, Dynal, Lake Success, N.Y.) were washed 3 times with PBS, resuspended in 200 μl of IGF1R(ECD)-C3-mFc to a concentration of 0.5 μM in PBS, and incubated at 4° C. on a rotator overnight. The IGF-1R(ECD)-C3-mFc coated beads were washed 3× with 1 ml of 2% non-fat dry milk (M) in PBS (2% MPBS), and then blocked with 1 ml of 2% MPBS at room temperature for 1 hour. ...

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Abstract

The present invention provides, in part, methods for treating a tumor in a human subject comprising inhibiting IGF-1 receptor signaling, methods of determining whether a tumor is more or less likely to respond to such treatment, and compositions for practicing such methods. In particular embodiments, the invention provides fully human, humanized, or chimeric anti-IGF-1R antibodies that bind human IGF-1R, IGF-1R-binding fragments and derivatives of such antibodies, and IGF-1R-binding polypeptides comprising such fragments. Other embodiments provide nucleic acids encoding such antibodies, antibody fragments and derivatives and polypeptides, cells comprising such polynucleotides, methods of making such antibodies, antibody fragments and derivatives and polypeptides, and methods of using such antibodies, antibody fragments and derivatives and polypeptides, including methods of treating or diagnosing subjects having IGF-1R-related disorders or conditions.

Description

FIELD OF THE INVENTION[0001]This application provides methods and compositions relating to the treatment of tumor diseases such as Ewing's sarcoma, other sarcomas, tumors comprising EWS-FLI genetic translocations, tumors comprising activating RAS mutations, carcinoid tumors, and other cancers and proliferative diseases.BACKGROUND OF THE INVENTION[0002]Ewing's sarcoma is the most common solid tumor in children and adolescents. The current standard of care comprises aggressive chemotherapy. The side effects of such treatment often include acute toxicity, and can include secondary malignancies, a serious limitation for a young patient population. Moreover, metastatic Ewing's sarcoma is particularly resistant to conventional treatment. Twenty-five percent of Ewing's sarcoma patients have metastases when they are diagnosed; their five year survival rate can be as low as 20%.[0003]Activating RAS mutations are associated with many different types of cancers and are found in well over 50% o...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395A61K38/00A61K31/7088A61P35/04A61K39/00C12Q1/68C12Q1/02
CPCA61K2039/505C07K16/2863C07K2317/76C07K2317/55C07K2319/30C07K2317/21A61P35/00A61P35/04
Inventor BELTRAN, PEDRO J.CALZONE, FRANK J.FRIBERG, GREGORYHAQQ, CHRISTOPHERTOLCHER, ANTHONY W.
Owner AMGEN INC
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