Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Anti-Integrin Immunoconjugates, Methods and Uses

an immunoconjugation and anti-integrin technology, applied in the field of tumor specific antibody conjugates, can solve the problems of inability to meet the needs of patients, and inability to meet the needs of patients, and achieve the effect of therapeutically effective rate of releas

Inactive Publication Date: 2014-04-03
IMMUNOGEN INC +1
View PDF0 Cites 1 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention provides novel antibodies that can kill cancer cells by delivering a toxic substance called maytansinoid. These antibodies are directed to specific antigens on the surface of cancer cells. The antibodies are attached to a disulfide bond, which is designed to release the toxic substance quickly after administration. The invention targets specific integrin proteins on cancer cells and can potentially treat various types of cancer.

Problems solved by technology

These attempts have encountered unforeseen limitations, such as the requirement for relatively high intracellular concentrations of the toxin compared to the number of external binding sites per cell.
Secondly, the drug must either be released upon binding to the target and penetrate the cell or the entire construct must be transported into the cell and toxin cleaved or otherwise activated there.
Maytansinoids, however, have unacceptable toxicity, causing both central and peripheral neuropathies, and side effects: particularly nausea, vomiting, diarrhea, elevations of hepatic function tests and, less commonly, weakness and lethargy.
However, the application of these conjugates is restricted due to the limited expression of the respective target antigens.
While the problems of targeted delivery are now clearly recognized, finding a suitable combination of antibody specificity and affinity, conjugation chemistry, and toxin is unpredictable.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Anti-Integrin Immunoconjugates, Methods and Uses
  • Anti-Integrin Immunoconjugates, Methods and Uses
  • Anti-Integrin Immunoconjugates, Methods and Uses

Examples

Experimental program
Comparison scheme
Effect test

example 1

Production and Characterization of Monoclonal Antibody CNTO95

[0156]Preparation of the anti-alpha V integrin antibody CNTO95 is described in detail in PCT publication no. WO 02 / 12501 and in U.S. Publication No. 2003 / 040044, both incorporated by reference herein. Specifically, the human Mab CNTO 95 was generated by immunizing (CBA / J×C57 / BL6 / J, GenPharm International) F2 hybrid mice with αvβ3 integrin purified from human placenta. The antibody is composed of human variable and IgG1 kappa constant regions. The method of making and the desirable characteristics of CNTO95 have been previously described in WO0212501 and Trikha, et al. 2004, Int. J. Cancer 110 (3): 326-335.

[0157]Transgenic mice from GenPharm International express human immunoglobulins but not mouse IgM or Igκ were used. These mice contain human sequence transgenes that undergo V(D)J joining, heavy-chain class switching and somatic mutation to generate a repertoire of human sequence immunoglobulins (Taylor et al., Internatio...

example 2

Preparation of CNTO 95-Maytansine Conjugates

[0171]Antibody conjugates of thiolated maytansines were prepared for further biological testing starting using bifunctional linkers as described.

[0172]CNTO 95 antibody was supplied by Centocor for conjugation. CNTO 95 was supplied at approximately 20 mg / ml (260 mg) total. The antibody was dialysed into Buffer A (50 mM KPi, 50 mM NaCl, 2 mM EDTA pH6.5), then brought to 8 mg / ml in 95% Buffer A, 5% ETOH. The antibody was modified with 6.5 fold molar excess of SPP to introduce the linker for drug conjugation, forming CNTO 95-SS-Py where S-Py is 2-mercaptopyridine. Residual SPP was removed by G25 gel filtration chromatography. The linker to Ab ratio was measured as 4.7. The Ab-SS-Py conjugate was modified with 1.7 fold molar excess of DM1 (MW=737.5 g / mole) to linker, using an antibody concentration of 3.2 / mlin 97% Buffer A, 3% dimethylacetamide. Following conjugation, the conjugate was rechromatographed on G25 using PBS, pH 6.5 as the buffer. T...

example 3

CNTO 95-Maytansine Conjugate Binding to Tumor Cells

[0204]The ability and affinity of CNTO95-Maytansinoid conjugate binding to living cells was tested.

[0205]Materials and Methods. CNTO 95, Centocor lot #95-VF30A03-1, 20 mg / ml in PBS; CNTO 364 (CNTO 95-SPP-DM1), ImmunoGen lot #1806-164, 37.6 mg / ml of DM1, 2.74 mg / ml of conjugated antibody, Endotoxin level <0.1 EU / mg; CNTO 365 (CNTO 95-SPDB-DM4), ImmunoGen lot #2020-78, 41.2 mg / ml of DM4, 2.36 mg / ml of conjugated antibody, Endotoxin level <0.1 EU / mg; CNTO 366 (CNTO95-SPP-DM4), ImmunoGen lot #2020-48, 3.1.5 mg / ml of DM4, 2.19 mg / ml of conjugated antibody, Endotoxin level <0.1 EU / mg.

[0206]Cells: HT29 human colon carcinoma and A549 human lung carcinoma cells were from ATCC and maintained in alphaMEM supplemented with 10% fetal bovine serum (FBS). A2780 human ovarian carcinoma cells were obtained from National Cancer Institute. A2780 cells were cultured in RPMI 1640 medium containing 10% FBS. Cells were harvested, rinsed, suspended in seru...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention relates to conjugates of anti-integrin specific antibodies with cytotoxic compounds, the synthesis, selection, and use of such conjugates for use in cancer therapy or other diseases mediated by cell proliferation, cell migration, or inflammation and which pathology involves angiogenesis or neovascularization of new tissue. In addition the invention relates to combination therapy of such diseases wherein the treatment comprises use of said conjugates in combination with one or more other treatment modalities including but not limited to: chemotherapy, surgery or radiation therapy. The preferred conjugates contain maytansinoid compounds linked to the antibody by a disulfide linkage, and preferred chemotherapeutic agents are doxorubicin, a taxane, a camptothecin, a podophyllotoxin, a nucleoside analog, or a pyrimidine analog.

Description

RELATED APPLICATIONS[0001]This application is a continuation of U.S. application Ser. No. 11 / 290,249, filed Nov. 30, 2005, which claims the benefit of U.S. Provisional Application No. 60 / 634,445, filed on Dec. 9, 2004.[0002]The entire teachings of the above applications are incorporated herein by reference.BACKGROUND OF THE INVENTION[0003]1. Field of the Invention[0004]The invention relates to conjugates of tumor specific antibodies with cytotoxic compounds. The preferred conjugates contain maytansinoid compounds linked to an anti-integrin antibody by a disulfide linkage.[0005]2. Background of the Invention[0006]There have been numerous attempts to improve the efficacy of antineoplastic drugs by conjugating such drugs to monoclonal antibodies (Mabs) against tumor-associated antigens in order to elevate local concentration of the drug by targeted delivery to the tumor. Conversely, the potential for antibodies to actually destroy tumor cells is limited to those antibodies directed to ...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(United States)
IPC IPC(8): A61K47/48
CPCA61K47/48569A61K2039/505C07K16/2839C07K2317/21C07K2317/73A61K47/6803A61K47/6849A61P17/00A61P17/06A61P17/08A61P17/10A61P19/02A61P27/02A61P27/06A61P29/00A61P35/00A61P35/02A61P43/00A61P9/00A61P9/10A61K47/50A61K39/395C07K16/46
Inventor CHEN, QIMINGTRIKHA, MOHITLUTZ, ROBERT J.STEEVES, RITA M.AMPHLETT, GODFREY
Owner IMMUNOGEN INC
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com