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Tumor specific antibodies and uses therefor

An antibody and tumor technology, applied in the field of tumor-specific antibodies and their uses

Active Publication Date: 2014-01-01
JUNIVERSITI OF NORT KAROLINA EHT SHARLOTT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Several agents that modulate immune tolerance have been tested clinically, but with only moderate responses, possibly due to insufficient amounts of the agents reaching the tumor site and / or because the agents themselves are involved (eg, may result from their binding to normal cells) ) unwanted side effects

Method used

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  • Tumor specific antibodies and uses therefor
  • Tumor specific antibodies and uses therefor
  • Tumor specific antibodies and uses therefor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0235] Generation of pancreatic cancer mice expressing human MUC1

[0236] A strategy for generating 3 transgenic mouse lines expressing human MUC1 and developing pancreatic cancer is described in image 3 . Briefly, P48Cre / + mice expressing Cre recombinase throughout the developing and mature pancreas (Kawaguchi et al., 2002) were bred to LSL-KrasG12D / + mice, which contain the non-transcriptionally active K-rasG12D allele, It is activated in cells expressing Cre (Jackson et al., 2001; Kawaguchi et al., 2002). Their P48Cre / + and LSL-KrasG12D / + positive offspring (referred to as "PDA mice") were paired with a transgenic mouse line (MUC1.Tg) carrying the human MUC1 transgene and remaining heterozygous (see image 3 ). MUCl.Tg mice express human MUCl, exhibit tolerance to the B and T cell compartments, and are refractory to immunization with the protein encoded by the transgene (Rowse et al., 1998). Since the human MUCl transgene is driven by its own promoter in this mouse, i...

Embodiment 2

[0242] FACS sorting of tumor cells

[0243] The TAB-004 antibody was tested on different samples to confirm its ability to bind and sort tumor cells present in different environments and under different conditions using fluorescence activated cell sorting (FACS).

[0244] In the first experiment, TAB-004 antibody was used to stain cell populations purified from CD133+ and CD24+ / CD44+ / EpCAM+ cells. Parts from pancreatic cancer were mechanically homogenized and digested with collagenase IV and DNase for 30 min at 37 °C. Whole blood and single cell suspensions from tumors can be subject to lineage cell depletion using the lineage cell depletion kit (Miltenyi Biotec, Bergisch Gladbach, Germany, Cat. No. 130-092-211), thereby removing the expression of Cells for lineage antigens: CD2, CD3, CD11b, CD14, CD15, CD16, CD19, CD56, CD123 and CD235a. Lineage-negative (lin–) cells from whole blood samples or tumor samples from patients with pancreatic cancer were then screened for MUC1-e...

Embodiment 3

[0252] Generation of TAB-004 conjugates

[0253] The TAB-004 antibody of the subject matter disclosed herein is conjugated to 1-methyl-DL-tryptophan (1MT), an indoleamine 2,3-dioxygenase (IDO) inhibitor; EP2 / EP4 receptor antagonist and CpG oligodeoxynucleotides (CpG ODN), which function as dendritic cell activating agents (Rothenfusser et al., 2002). Functional data for the TAB-004 antibody conjugated to a CpG ODN is provided here as a non-limiting example of the function of the antibodies and conjugates of the subject matter disclosed herein.

[0254] The TAB-004 antibody alone or conjugated to a CpG ODN binds to a tumor cell line generated from 3 transgenic PDA.MUC1.Tg mice (referred to herein as the "KCM" cell line; see image 3 ). Although applicants do not wish to be bound by any particular theory of operation, it appears that antibodies that activate natural killer cells (NK cells) and conjugate to CpG ODN can further enhance the lytic activity of NK cells to their tar...

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Abstract

Provided are isolated antibodies, and fragments and derivatives thereof, which bind to tumor antigens. Also provided are compositions and delivery agents that include the disclosed antibodies and fragments and derivatives thereof; cells that produce the same; methods for producing the same; methods of using the same for detecting, targeting, and / or treating tumors and / or metastatic cells derived therefrom and / or tumor stem cells; and methods for predicting the recurrence of cancer in a subject.

Description

[0001] Cross References to Related Applications [0002] This application is a continuation-in-part of US Patent Application Serial No. 12 / 924,952, filed October 8, 2010, which itself claims the benefit of US Provisional Patent Application Serial No. 61 / 249,634, filed October 8, 2009. The disclosure of each of these applications is incorporated herein by reference in its entirety. [0003] Sequence listing involved [0004] The Sequence Listing associated with this disclosure is filed electronically with the United States Patent and Trademark Office as International Receiving Office as a 21 kilobyte ASCII text file created on May 25, 2011 and named "1276_5PCT_ST25.txt." The sequence listing submitted via EFS-Net is hereby incorporated by reference in its entirety. field of invention [0005] The subject matter disclosed herein relates to non-human isolated antibodies or fragments or derivatives thereof that bind to antigens present in tumors, and methods of use thereof. In ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28C12N15/13C12P21/08A61K47/48A61K49/00G01N33/574C12R1/91
CPCC07K2317/34G01N33/57438G01N33/6893C07K16/3092A61K31/415A61K45/06A61K47/48561A61K39/39558A61K47/486C07K2317/33A61K47/48569C07K16/2821A61K31/7068C07K16/30A61K49/0002A61K47/6803A61K47/6849A61K47/6851A61K47/6859A61K31/7088A61P35/00A61P35/04A61K39/00A61K39/39A61K39/395C07K16/18C07K16/22C07K16/24C07K16/28A61K2039/505C07K2317/10C07K2317/14C07K2317/565C07K2317/73
Inventor P·慕克吉
Owner JUNIVERSITI OF NORT KAROLINA EHT SHARLOTT
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