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VEGF-conjugate combined methods for tumor vasculature targeting and tumor treatment

a combined method and tumor vasculature technology, applied in the direction of immunoglobulins, peptides, drugs against animals/humans, etc., can solve the problems of cell death and tumor necrosis

Inactive Publication Date: 2006-09-21
BOARD OF RGT THE UNIV OF TEXAS SYST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0047] The assay may be any one of a range of immunological assays based upon antibody binding and the TEC-4 or TEC-11 antibodies would be detected by means of detecting their label, e.g., using streptavidin in the case of biotinylated antibodies or by using a chromogenic substrate in connection with an enzymatic label or by simply detecting the radiolabel. An antibody that binds to the same epitope as TEC-4 or TEC-11 will be able to effectively compete for binding and thus will significantly reduce TEC-4 or TEC-11 binding, as evidenced by a reduction in labelled antibody binding. In the present case, after mixing the labelled TEC-4 or TEC-11 antibodies with the test antibodies, suitable assays to determine the remaining reactivity include, e.g., ELISAs, RIAs or western blots using human endoglin; immunoprecipitation of endoglin; ELISAs, RIAs or immunofluorescent staining of recombinant cells expressing human endoglin; indirect immunofluorescent staining of tumor vasculature endothelial cells; reactivity with HUVEC or TCM-activated HUVEC cell surface determinants indirect immunofluorescence and FACS analysis. This latter method is most preferred and was employed to show that the epitopes recognized by TEC-4 and TEC-11 are distinct from that of 44G4 (Gougos and Letarte, 1988).

Problems solved by technology

This attack is intended to lead to a tumor-localized vascular collapse, depriving the tumor cells, particularly those tumor cells distal of the vasculature, of oxygen and nutrients, ultimately leading to cell death and tumor necrosis.

Method used

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  • VEGF-conjugate combined methods for tumor vasculature targeting and tumor treatment
  • VEGF-conjugate combined methods for tumor vasculature targeting and tumor treatment
  • VEGF-conjugate combined methods for tumor vasculature targeting and tumor treatment

Examples

Experimental program
Comparison scheme
Effect test

example i

A Murine Model for Antibody-Directed Targeting of Vascular Endothelial Cells in Solid Tumors

[0185] This example describes the development of a model system in which to investigate the antibody-directed targeting of vascular endothelial cells in solid tumors in mice. A neuroblastoma transfected with the mouse interferon-γ (IFN-γ) gene, C1300(Muγ), was grown in SCID and antibiotic-treated BALB / c nude mice. The INF-γ secreted by the tumor induces the expression of MHC Class II antigens on the tumor vascular endothelium. Class II antigens are absent from the vasculature of normal tissues, although they are present on B-lymphocytes, cells of monocyte / macrophage lineage and some epithelial cells. Intravenously-administered anti-Class II antibody strongly stains the tumor vasculature whereas an anti-tumor antibody, directed against a MHC Class I antigen of the tumor allograft, produces classical perivascular tumor cell staining.

A. Materials and Methods

[0186] 1. Animals

[0187] BALB / c nu...

example ii

Solid Tumor Therapy Using A Vascular Targeted Immunotoxin

[0236] This example describes the successful therapy of the solid tumor model described in Example I, using the anti-tumor endothelial cell immunotoxin, MS / 114dgA, and the anti-tumor cell immunotoxin, 11-4.1dgA, alone as well as in combination therapy.

A. Materials and Methods

[0237] 1. Animals

[0238] BALB / c nu / nu mice were purchased from Simonsen (Gilroy, Calif.). SCID mice were from the National Cancer Institute (Bethesda, Md.). Germ-free SCID mice were from the University of Wisconsin (Madison, Wis.). All animals were maintained in microisolation units on sterilized food and water.

[0239] 2. Cells and Culture Conditions

[0240] All cell lines used in this study were cultured in modified Eagle's medium (MEM) supplemented with 10% (v / v) fetal calf serum, 2.4 mM L-glutamine, 200 units / ml penicillin and 100 μg / ml streptomycin. Cultures were maintained at 37° C. in a humidified atmosphere of 90% air / 10% CO2. The C1300 neuroblas...

example iii

Targeting the Vasculature of Breast Tumors

[0270] This example describes an approach for targeting the vasculature of breast cancer and other solid tumors in humans. This approach is exemplified through the use of bispecific antibodies to selectively induce the activation antigens, Class II and ELAM-1, on the vascular endothelial cells of syngeneic breast tumors in mice and then targeting these antigens with immunotoxins.

[0271] Murine models may first be employed. The results from such studies will be understood to parallel the situation in humans, as mouse models are well accepted and routinely employed for such purposes. Following successful vascular targeting in the mouse, success in man is likely as highly specific anti-breast cancer antibodies are available (Denekamp, 1984; Girling et al., 1989; Griffin et al., 1989; Lan et al., 1987; Boyer et al., 1989).

[0272] In the case of clinical (as opposed to diagnostic applications), the central issue is to confine the expression of t...

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Abstract

The present invention relates generally to methods and compositions for targeting the vasculature of solid tumors using immunological- and growth factor-based reagents. In particular aspects, antibodies carrying diagnostic or therapeutic agents are targeted to the vasculature of solid tumor masses through recognition of tumor vasculature-associated antigens, such as, for example, through endoglin binding, or through the specific induction of endothelial cell surface antigens on vascular endothelial cells in solid tumors.

Description

[0001] The present application is a continuation of co-pending U.S. patent application Ser. No. 10 / 376,194, filed Feb. 27, 2003; which is a divisional of co-pending U.S. patent application Ser. No. 09 / 738,970, filed Dec. 14, 2000; which is a continuation of U.S. patent application Ser. No. 09 / 207,277, filed Dec. 8, 1998, now issued as U.S. Pat. No. 6,261,535; which is a continuation of U.S. patent application Ser. No. 08 / 350,212, filed Dec. 5, 1994, now issued as U.S. Pat. No. 5,965,132; which is a continuation-in-part of U.S. patent application Ser. No. 08 / 205,330, filed Mar. 2, 1994, now issued as U.S. Pat. No. 5,855,866; which is a continuation-in-part of U.S. patent application Ser. No. 07 / 846,349, filed Mar. 05, 1992. The entire text and figures of which disclosures are specifically incorporated by reference herein without disclaimer.[0002] The U.S. government owns rights in the present invention pursuant to NIH Grant CA-28149 and NIH Grant CA54168.BACKGROUND OF THE INVENTION [...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K51/00A61K49/00C07K16/46C07K16/30A61K38/00A61K47/48A61K49/08A61K51/10A61P35/00C07K16/22C07K16/28C12P21/08
CPCA61K38/00A61K47/48438A61K47/48476A61K47/48561A61K47/48569A61K47/48584A61K49/085A61K49/16A61K51/1045A61K2039/505A61K2123/00C07K16/22C07K16/28C07K16/2818C07K16/2833C07K16/2896C07K16/30C07K16/3015C07K16/46C07K2317/31C07K2317/55C07K2317/73C07K2317/77C07K2319/33C07K2319/55Y10S530/807Y10S530/828C07K2317/34A61K47/6817A61K47/6827A61K47/6849A61K47/6851A61K47/6855A61P35/00
Inventor THORPE, PHILIPBURROWS, FRANCIS
Owner BOARD OF RGT THE UNIV OF TEXAS SYST
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