Elimination of heterogeneous or mixed cell population in tumors

a heterogeneous or mixed cell population technology, applied in the field of tumor elimination or killing methods, can solve the problems of general compromise of the efficacy of antibody-drug conjugates, and achieve the effect of enhancing their stability or activity

Inactive Publication Date: 2006-10-19
IMMUNOGEN INC
View PDF6 Cites 89 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0007] The objective of the present invention is to provide methods for eliminating heterogeneous or mixed cell populations AB, wherein A represents a cell population selectively expressing a specific ligand and B represents a cell population lacking the ligand expressed by A. The methods generally encompass; delivering a cell-binding agent drug conjugate, linked by a linker comprising a disulfide group, to the selected cell population A that expresses the ligand, allowing the binding of this agent to the ligand in the cell population A, with the option that the drug is internalized into cells comprising the cell population A. A drug attached to cell-binding agent in a conjugate is referred to as a pro-drug; the pro-drug, once cleaved from the conjugate is converted into a cytotoxic drug or “drug” and is capable of undergoing further modification, such as alkylation. A

Problems solved by technology

The efficacy of an antibody-drug conjugate is generally compromised by the heterogeneous expression of the target antigen in some tumors, because targeted deli

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
  • Elimination of heterogeneous or mixed cell population in tumors
  • Elimination of heterogeneous or mixed cell population in tumors
  • Elimination of heterogeneous or mixed cell population in tumors

Examples

Experimental program
Comparison scheme
Effect test

example 1

Bystander Effect of Antibody-Drug Conjugates

Materials and Methods

Immunoconjugates

[0193] Preparation of immunoconjugates: The maytansinoid DM1 (N2′-deacetyl-N2′-(3-mercapto-1-oxopropyl)-maytansine) was synthesized from the microbial fermentation product ansamitocin P-3 as described previously {Chari, R. V., et al., Cancer Res., 52, 127-31 (1992); U.S. Pat. No. 6,333,410}. The synthesis of the analogue of CC-1065, 5-[(3-mercapto-1-oxopropyl)amino]-bis-indolyl-(seco)-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one, DC1, has been reported elsewhere {Chari, R. V., et al., Cancer Res. 55, 4079-84 (1995)}. The humanization of the C242 antibody (huC242) was done by the resurfacing method that has been described previously {Roguska M. A., et al., Proc Natl Acad Sci USA, 91, 969-73 (1994)}. Antibody-drug conjugates were prepared using N-succinimidyl-4-(2-pyridyldithio)pentanoate for disulfide linkage or N-succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) for thioether ...

example 2

Intracellular Activation of Antibody-Maytansinoid Coniugates

Abbreviations

[0214] BafA1, Bafilomycin A1

[0215] BSA, bovine serum albumin

[0216] FACS, fluorescence-activated cell sorter

[0217] HPLC, high pressure liquid chromatography

[0218] MTT, 1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan

[0219] NEM, N-ethylmaleimide

[0220] SPDB, N-succinimidyl 4-(2-pyridyldithio)butyrate

[0221] SMCC, N-succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate

[0222] DM1, N2′-deacetyl-N2′-(3-mercapto-1-oxopropyl)-maytansine

[0223] DM4, N2′-deacetyl-N2′-(4-mercapto-4-methyl-1-oxopentyl)-maytansine

[0224] DM1-SMe, N2′-deacetyl-N2′-[(3-methyldithio)-1-oxopropyl]-maytansine

[0225] DTT, dithiothreitol

Materials and Methods

[0226] RPMI 1640 and glutamine were from Cambrex Bioscience. Ultima Flo™ M scintillation fluid was from PerkinElmer life and analytical sciences. Gentamicin sulfate was from Gibco BRL. N-ethylmaleimide (NEM) and all other chemicals were obtained from Sigma. All antibodies use...

example 3

Synthesis of some Thiomethyl Maytansinoids (FIG. 17)

[0244] N2′-deacetyl-N2′-(3-methylthio-1-oxopropyl)-maytansine (S-Methyl-DM1, DM1Me): To a solution of N2′-deacetyl-N-2′(3-mercapto-1-oxopropyl)-maytansine (DM1, 30 mg, 0.041 mmol) in dimethylacetamide (0.25 mL) was added a solution of iodomethane (5.8 mg, 0.041 mmol) in 0.2 mL of dimethylacetamide under an argon atmosphere, with magnetic stirring. Diisopropylethylamine (5.0 mg, 0.041 mmol) was then added and the reaction was stirred for 3 hours. Purification by high pressure liquid chromatography using a reverse phase C 18 column and a gradient of deionized water and acetonitrile gave 20 mg (65% yield) of the desired product DM1Me. Mass spectrum: found 774.5 (M+Na+), calculated 774.3 (M+Na+); 1H NMR (CDCl3) δ 0.84 (3H, s), 1.33 (3H, d, J=5 Hz), 1.35 (3H, d, J=5 Hz), 1.60 (3H, s), 1.68 (3H, s), 2.05 (3H, s) 2.22 (1H, dd, J=3 Hz, 14 Hz, 2.60-2.82 (2H, m), 2.88 (3H, s), 3.08-3.20 (2H, m), 3.25 (3H, s), 3.39 (3H, s), 3.55 (1H, d, J=9...

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

Methods of killing or inhibiting tumors comprising of heterogeneous or mixed cell populations is described. The killing or inhibition of tumors is achieved by selectively targeting a unique ligand suspected of being expressed on a particular cell population to also kill a cell population lacking the unique ligand. These conjugates have therapeutic use as they are delivered to a specific cell population to kill these cells and the cytotoxic drug is released to kill non-targeted cells, thereby eliminating the tumor.

Description

[0001] This application claims priority to U.S. provisional application No. 60 / 671,498, filed Apr. 15, 2005 and to U.S. provisional application No. 60 / 781,722, filed Mar. 14, 2006. The disclosures of both provisional applications are expressly incorporated herein by reference in their entireties.FIELD OF THE INVENTION [0002] The present invention relates to methods for elimination or killing of heterogeneous or mixed cell populations. In particular, the present invention relates to a method of killing a tumor comprised of heterogeneous or mixed cell populations by selectively targeting a unique ligand, such as an antigen, an epitope or a receptor, that is expressed on a particular cell population to also kill a cell population lacking the unique ligand. BACKGROUND OF INVENTION [0003] The therapeutic efficacy of cytotoxic anti-cancer drugs can be improved by increasing their selectivity towards cancer cells. One way to achieve this goal is to link a drug covalently to a monoclonal an...

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
IPC IPC(8): A61K39/395A61K31/5383C07K16/46A61K31/58A61K38/19C12N5/07C12N5/09
CPCA61K31/5383A61K31/58A61K47/48384C07K2317/24A61K2039/505C07D498/18C07K16/3046A61K47/48561A61K47/6803A61K47/6849A61P31/04A61P31/12A61P33/00A61P35/00A61P37/00A61K39/395A61K38/19
Inventor GOLDMAKHER, VIKTOR S.LUTZ, ROBERT J.CHARI, RAVI V.J.KOVTUN, YELENA V.LAMBERT, JOHN M.STEEVES, RITAERICKSON, HANS K.
Owner IMMUNOGEN INC
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

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

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap