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Q3 sparc deletion mutant and uses thereof

An antibody and carrier technology, applied in the direction of antibodies, medical preparations containing active ingredients, peptide sources, etc., can solve problems such as the decline of renal SPARCmRNA levels

Inactive Publication Date: 2008-04-09
ABRAXIS BIOSCI LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Likewise, although renal enlargement due to hyperplasia, hypertrophy, and increased intercellular matrix is ​​a characteristic feature of human diabetes, renal SPARC mRNA levels were decreased in diabetic animals

Method used

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  • Q3 sparc deletion mutant and uses thereof
  • Q3 sparc deletion mutant and uses thereof
  • Q3 sparc deletion mutant and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0164] This example illustrates the co-localization of SPARC and albumin in MX-1 tumor xenografts.

[0165] Paclitaxel albumin nanoparticles (Abraxane, ABX or ABI-007) have been shown to have improved responses over taxol (TAX) in phase 3 metastatic breast cancer trials (33% vs. 19%, p<0.0001) ( See, eg, O'Shaughnessy, SABCS 2003). In the case of ABX versus TAX, albumin-mediated transendothelial transport of paclitaxel (P) and enhanced intratumoral accumulation of paclitaxel were recently demonstrated (see, eg, Desai, SABCS 2003). Albumin binds to SPARC (see, eg, Schnitzer, J. Biol. Chem. 269:6072-82 (1994)).

[0166] The MX-1 tumor cell line is derived from human breast cancer. Serial cryosections of human MX-1 tumor xenografts, human primary breast tumor tissue (n=141) and normal human breast tissue (n=115) were immunostained for albumin, SPARC (using anti-SPARC antibody) and kiln-1 staining were scored (0-4). Cultured MX-1 cells were also immunostained for SPARC. Pacli...

Embodiment 2

[0170] This example illustrates the endothelial receptor (gp60)-mediated transcytosis of paclitaxel albumin nanoparticles (ABI-007) into caveolae.

[0171] Paclitaxel (P) albumin nanoparticles (Abraxane, ABX, or ABI-007) demonstrated an improved response rate over Taxol in a phase III metastatic breast cancer trial (33% vs. 19%, p<0.0001) (SABCS, O 'Shaughnessy et al., 2003). Cremophor in Taxol (TAX) traps P in micelles in plasma, reducing paclitaxel available for cellular partitioning (see, eg, Sparreboom et al., Cancer. Res. 59, 1454 (1999)). Studies in athymic mice have shown that intratumoral paclitaxel concentrations are 30-40% higher with ABX compared to equivalent doses of TAX (SABCS, Desai et al., 2003). Albumin is transported across endothelial cells (EC) by specific receptor (gp60)-mediated caveolae transport (see, eg, John et al., Am. J. Physiol. 284, L187 (2001)). It was hypothesized that albumin-bound paclitaxel in ABX could be transported across tumor microvasc...

Embodiment 3

[0176] This example illustrates the expression of surface SPARC in MX-1 tumor cells.

[0177] MX-1 cells were grown on coverslips and stained with an antibody against human SPARC using methods known in the art. Observation of antibody staining indicated that MX-1 was expressing SPARC. These results suggest that the SPARC expression detected in MX-1 tumor cells is a consequence of SPARC secretion by MX-1 tumor cells. The staining was more intense for MX-1 tumor cells than for normal primary cells such as HUVEC (human umbilical vein endothelial cells), HLMVEC (human lung microvascular endothelial cells) and HMEC (human mammary epithelial cells). Although the majority of SPARC staining was internal SPARC, significant levels of surface SPARC were also detected, as indicated by confocal microscopy and staining of non-permeabilized cells.

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PUM

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Abstract

The invention provides for SPARC polypeptides with a mutation corresponding to a deletion of the third glutamine in the mature form of the human SPARC protein, nucleic acids encoding such polypeptides, antibodies against such polypeptides, and methods of the use of such polypeptides, nucleic acids, and antibodies.

Description

[0001] Cross References to Related Applications [0002] This patent application claims the benefit of US Provisional Patent Application No. 60 / 654,261, filed February 18, 2005, which is hereby incorporated by reference in its entirety. field of invention [0003] The present invention relates to methods of treating cancer, other diseases involving abnormal proliferation, hyperplasia, remodeling and inflammatory activity in tissues and organs using antibodies or other suitable ligands that recognize SPARC. The invention also relates to mutant SPARC polypeptides and nucleic acids and methods of use thereof, as well as targeting methods, imaging methods and methods of determining the response of mammalian tumors to anti-SPARC therapy. Background of the invention [0004] Acidic, cysteine-rich secreted protein (also known as osteonectin, BM40, or SPARC) (herein referred to as "SPARC"), a matrix that induces changes in cell shape, inhibits cell cycle progression, and affects the...

Claims

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Application Information

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IPC IPC(8): C07K14/47A61K39/395A61K38/39
CPCA61K38/191C07K14/51C07K16/18C07K14/82C07K14/4747C07K14/47G01N2800/52A61P35/00A61P35/02A61P43/00
Inventor V·特里鲁N·P·德塞P·索恩-希翁
Owner ABRAXIS BIOSCI LLC
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