Targeted innate immunity

a technology of innate immunity and immune system, applied in the field of cancer therapy agents and methods, can solve the problems of limited immunotherapy attempts, inadequate immune response,

Inactive Publication Date: 2006-06-22
UNIV OF SOUTHERN CALIFORNIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Most tumors express antigens that can be recognized to a variable extent by the host immune system, but in many cases, the immune response is inadequate.
Failure to elicit a strong activation of effector T-cells may result from the weak immunogenicity of tumor antigens or inappropriate or absent expression of co-stimulatory molecules by tumor cells.
However, attempts to use the innate immune system for cancer immunotherapy have been limited in comparison to the adaptive immune system.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Generation of CpG Immunostimulatory Oligonucleotide Linked chTNT-3 Immunoconjugates

[0124] Chimeric TNT-3 antibody was produced according to published results (Hornick et al., Cancer Biother. & Radiopharm. (1998)13:255-268). cTNT-3 was incubated with the cross-linker N-[ε-Maleimidocaproyloxy]sulfosuccinimide ester (Sulfo-EMCS; Pierce, Ill.) in a 100 mM EDTA-PBS buffer solution (pH 8.3) at a molar ratio of 1:20 for 1 h at room temperature.

[0125] Phosphothioate backbone CpG ODN modified with sulfhydral group at the terminal nucleotide (see FIG. 1), was custom synthesized by Norris Cancer Center Microchemical Core Facility (Los Angeles, Calif.). The phosphothioated sulfhydryl-modified ODN 1826 (SEQ ID NO:1) comprised a CpG motif with the sequence 5′-S-TCCATGACGTTCCTGACGTT-3′. Phosphothioated sulfhydryl-modified ODN 1745 (SEQ ID NO 6):, used as a negative control, 5′-S-TCCAATGAGCTTCCTGAGTCT-3′ for CpG activity along with Phosphothioated sulfhydryl-modified ODN 2006 (SEQ ID NO: 3), 5′-T...

example 2

In Vitro Conjugate Immunoreactivity

[0128] CpG / chTNT-3 preparations were radiolabeled with 125I using a modified chloramine-T method. Immunoreactivity was evaluated by a conventional fixed Raji cell radioimmunoassay. Briefly, Raji lymphoma cells (ATCC: Rockville, Md.) were resuspended in freshly prepared 2% paraformaldehyde in PBS to fix the cells and cause disruption of the cell membrane. Radioiodinated immunoconjugates (approximately 100,000 cpm / tube) were then incubated in triplicate with 106 fixed Raji cells for 1 h. Both the chTNT-3 parental antibody and chTNT-3 / CpG immunoconjugates showed immunoreactivities of 70% or greater.

[0129] The biological activity of the CpG motif in the immunoconjugates was assessed using the murine macrophage cell lines J7-74 and J77743A, available from the ATCC (Rockville, Md.) as described by Kandimalla et al. Bioconjug. Chem. (2002) 13:966-974. Briefly, cells were plated in 24 well dishes using 106 cells / ml. CpG alone (positive control) and the C...

example 3

In Vivo CpG Immunostimulatory Oligonucleotide Immunoconjugate Cancer Therapy Evaluation

[0131] In vivo cancer therapy studies were performed in tumor-bearing BALB / c mice. Groups of mice (n=5) were transplanted with the Colon 26 colon carcinoma in the left flank by the injection of 5×106 cells subcutaneously using a 0.2 ml inoculum. When the tumors reached 0.5 cm in diameter, treatment was initiated and consisted of 4 daily intravenous injections of chTNT-3 / CpG (1826) or control chTNT-3 for each group. In addition, one group was treated with 4 daily intratumoral injections of unconjugated CpG 1826. Tumor volumes were calculated every other day by caliper measurement.

[0132] As shown in FIG. 3, tumor reduction of about 50% was observed at day 21 post-treatment in the chTNT-3 / CpG 1826 group compared to control treated mice. The amount of tumor reduction by chTNT-3 / CpG 1826 at a 30 ug dose was comparable to that achieved with the 5 ug intratumoral administration of free CpG 1826 even th...

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Abstract

Provided is a cancer therapeutic agent comprising a cancer targeting molecule linked to a CpG oligodeoxynucleotide. Also provided are methods of reducing the size of a tumor or inhibiting the growth of cancer cells in an individual or inhibiting the development of metastatic cancer, comprising administering an effective amount of the cancer therapeutic agent. The methods may also include reducing immunoregulatory T cell activity in the individual.

Description

CROSS REFERENCE TO RELATED PATENT APPLICATIONS [0001] This application claims priority under 35 U.S.C. §119(e) to U.S. application Ser. No. 60 / 626,829, filed Nov. 9, 2004, incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTION [0002] The invention relates to cancer therapeutic agents and methods for cancer therapy. [0003] The following discussion of the background of the invention is merely provided to aid the reader in understanding the invention and is not admitted to describe or constitute prior art to the present invention. [0004] Surgery, radiation therapy, and chemotherapy have been the standard accepted approaches for treatment of cancers including leukemia, solid tumors, and metastases. Immunotherapy (sometimes called biological therapy, biotherapy, or biological response modifier therapy), which uses the body's immune system, either directly or indirectly, to shrink or eradicate cancer has been studied for many years as an adjunct to conventional cance...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K48/00C07H21/02A61K39/395C07K16/46
CPCA61K47/48092A61K47/48569C07K16/30C07K2317/80A61K47/549A61K47/6851A61P35/00
Inventor EPSTEIN, ALANKHAWLI, LESLIE
Owner UNIV OF SOUTHERN CALIFORNIA
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