Therapeutic use of anti-tweak receptor antibodies

An antibody, monoclonal antibody technology, applied in the field of therapy

Inactive Publication Date: 2011-04-06
菲赛特生物技术公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, none of these reports found monoclonal antibodies that bind to TweakR and exhibit anti-tumor effects

Method used

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  • Therapeutic use of anti-tweak receptor antibodies
  • Therapeutic use of anti-tweak receptor antibodies
  • Therapeutic use of anti-tweak receptor antibodies

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0169] Example 1: TweakR Expression in Primary Tumors

[0170] Gene expression profiling was used to detect TweakR mRNA expression in various primary solid tumors, including lung, pancreatic, renal, breast, and head and neck cancers. mRNA was isolated from various cancers and 347 normal adult tissues and hybridized to Eos Hu03, a custom Affymetrix gene chip containing approximately 59,000 probe sets representing 46,000 genes, EST clusters, and predicted exons .

[0171] Significant TweakR expression was detected in: 31 / 44 lung adenocarcinomas, 27 / 56 lung squamous cell carcinomas, 37 / 47 pancreatic tumors, 14 / 23 tumors of head and neck origin, 48 / 66 ovarian cancers , 190 / 253 primary and metastatic colorectal cancers, 11 / 11 esophageal cancers, 16 / 35 melanomas, 15 / 20 kidney cancers, 29 / 39 gastric cancers, 25 / 43 uterine cancers, 7 / 14 cervical cancers, 8 / 26 sarcomas, 23 / 93 bladder cancers, and 16 / 27 glioblastomas (data not shown). In breast cancer, 24 / 47 primary tumor samples fr...

Embodiment 2

[0175] Example 2: Generation and Characterization of Anti-TweakR Antibodies

[0176] Generation of anti-TweakR antibody

[0177] Monoclonal antibodies

[0178] Monoclonal antibodies were produced by immunizing Balb / c mice intraperitoneally with mouse 3T12 cells overexpressing human TweakR. Spleens were harvested and splenocytes were fused with the multiple myeloma cell line NSO. Hybridomas were selected with aminopterin. Hybridomas expressing the anti-TweakR antibody of interest were subcloned several times to isolate individual clones.

[0179] Humanization of 19.2.1 to generate PDL192

[0180] Humanization of 19.2.1 was performed essentially according to the procedure of Queen, C. et al. (Proc. Natl. Acad. Sci. USA 86:10029-10033 (1989)). First, human VH and VL segments with high homology to the 19.2.1 VH and VL amino acid sequences, respectively, were identified. Second, the CDR sequences are grafted into selected human framework sequences along with framework amino a...

Embodiment 3

[0205] Example 3: In vivo tumor activity of anti-TweakR antibodies

[0206] In vivo treatment with anti-TweakR antibodies was performed in xenograft models derived from a number of cancer cell lines. As shown in Table 2, anti-TweakR antibodies are effective in reducing and / or inhibiting the growth of many different cancers.

[0207] Table 2. Summary of antitumor activity in xenograft models

[0208]

[0209] 1 Percent inhibition was calculated by comparing the mean tumor volume of control animals to treated animals, using measurements made on the day the control group of animals was sacrificed (when the majority of tumors were within permissible limits).

[0210] 2 nt: not detected.

[0211] 3 NS: No significant difference between anti-TweakR antibody and isotype control treated groups.

[0212] Severe combined immunodeficiency (SCID) mice were inoculated subcutaneously with SN12C renal carcinoma cells. When the tumor reaches about 100mm 3 1, or isotype control anti...

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Abstract

Compositions and methods for treating solid tumors are provided herein.

Description

[0001] 1. Cross-references to related applications [0002] This application claims under U.S.C. § 119(e) 35 application serial numbers 60 / 953,745, filed August 3, 2007 and 60 / 61 / 123,623, filed April 9, 2008 (the contents of which are incorporated by reference incorporated herein). [0003] 2. Statement Regarding Federally Funded Research [0004] Not applicable. 3. Background of the invention [0005] The TWEAK receptor (TweakR), also known as Fn14 or TNFRSF12A, is a member of the tumor necrosis factor receptor superfamily. It is expressed on the surface of cancer cells derived from various solid tumors. TweakR expression can be detected on some normal tissues, including kidney (Bowman's capsule), liver (hepatocytes), and on proliferating endothelial cells and fibroblasts (Meighan-Mantha, et al., 1999, J. Biol. Chem. 1999; 274:33166-33176; and Jakubowski, et al., 2002, J. Cell Sci. 2002; 115:267-274). In vitro and in vivo, TweakR expression is upregulated by growth facto...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395A61P35/00C07K16/28
CPCC07K2317/92A61K2039/505C07K2316/52C07K16/2878C07K2317/24C07K2316/96C07K2317/73C07K2317/75C07K2317/52C07K2317/732C07K2317/76A61P31/00A61P35/00A61K39/00C07K16/00C07K16/30C07K2319/55
Inventor P·库尔普
Owner 菲赛特生物技术公司
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