Human CTLA-4 antibodies and their uses

a human ctla4 and human sequence technology, applied in the field of molecular immunology and the treatment of human diseases, can solve problems such as acute toxicity, and achieve the effects of enhancing or suppressing or prolonging an immune response, reducing the risk of infection, and improving the immune respons

Inactive Publication Date: 2005-09-15
MEDAREX INC
View PDF4 Cites 239 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0053] For in vivo methods, the antibody, or antigen-binding portion thereof (or a bispecific or multispecific molecule of the invention), can be administered to a human subject suffering from a T-cell-related disease, or a disease that can be ameliorated or prevented by augmenting or suppressing or prolonging an immune response.
[0054] Human sequence monoclonal antibody and human sequence antibody compositions of the invention also can be administered in combination with other known therapies, e.g., an anti-cancer therapy. Accordingly, the invention provides a method for treating cancer in a subject comprising administering a therapeutically effective amount of a pharmaceutical composition of a human sequence antibody together with a pharmaceutical carrier to the subject. Some such methods include a vaccine. Some such vaccines include a tumor cell vaccine, a GM-CSF-modified tumor cell vaccine, or an antigen-loaded dendritic cell vaccine. In some such methods, the cancer is prostate cancer, melanoma, or epithelial cancer.

Problems solved by technology

However, one of the major impediments facing the development of in vivo therapeutic and diagnostic applications for antibodies in humans is the intrinsic immunogenicity of non-human immunoglobulins.
For example, when immunocompetent human patients are administered therapeutic doses of rodent monoclonal antibodies, the patients produce antibodies against the rodent immunoglobulin sequences; these human anti-mouse antibodies (HAMA) neutralize the therapeutic antibodies and can cause acute toxicity.

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
  • Human CTLA-4 antibodies and their uses
  • Human CTLA-4 antibodies and their uses
  • Human CTLA-4 antibodies and their uses

Examples

Experimental program
Comparison scheme
Effect test

example 1

Generation of Cmu Targeted Mice

[0274] Construction of a CMD Targeting Vector.

[0275] The plasmid pICEmu contains an EcoRI / XhoI fragment of the murine Ig heavy chain locus, spanning the mu gene, that was obtained from a Balb / C genomic lambda phage library (Marcu et al. Cell 22: 187, 1980). This genomic fragment was subcloned into the XhoI / EcoRI sites of the plasmid pICEMI9H (Marsh et al; Gene 32, 481-485, 1984). The heavy chain sequences included in pICEmu extend downstream of the EcoRI site located just 3′ of the mu intronic enhancer, to the XhoI site located approximately 1 kb downstream of the last transmembrane exon of the mu gene; however, much of the mu switch repeat region has been deleted by passage in E. coli.

[0276] The targeting vector was constructed as follows (see FIG. 1). A 1.3 kb HindIII / SmaI fragment was excised from pICEmu and subcloned into HindIII / SmaI digested pBluescript (Stratagene, La Jolla, Calif.). This pICEmu fragment extends from the HindIII site located ...

example 2

Generation of HCol2 Transgenic Mice

[0284] The HCol2 Human Heavy Chain Transgene.

[0285] The HCo12 transgene was generated by coinjection of the 80 kb insert of pHC2 (Taylor et al., 1994, Int. Immunol., 6: 579-591) and the 25 kb insert of pVx6. The plasmid pVx6 was constructed as described below.

[0286] An 8.5 kb HindIII / SalI DNA fragment, comprising the germline human VH1-18 (DP-14) gene together with approximately 2.5 kb of 5′ flanking, and 5 kb of 3′ flanking genomic sequence was subcloned into the plasmid vector pSP72 (Promega, Madison, Wis.) to generate the plasmid p343.7.16. A 7 kb BamHI / HindIII DNA fragment, comprising the germline human VH5-51 (DP-73) gene together with approximately 5 kb of 5′ flanking and 1 kb of 3′ flanking genomic sequence, was cloned into the pBR322 based plasmid cloning vector pGP1f (Taylor et al. 1992, Nucleic Acids Res. 20: 6287-6295), to generate the plasmid p251f. A new cloning vector derived from pGP1f, pGP1k (Seq. ID #1), was digested with EcoRV / ...

example 3

Generation of Human IgG Kappa Anti-Human CTLA-4 Monoclonal Antibodies

[0287] Cell Based Antigen

[0288] A DNA segment encoding a fusion protein comprising sequences from the human CTLA-4 and the murine CD3zeta genes was constructed by PCR amplification of cDNA clones together with bridging synthetic oligonucleotides. The encoded fusion protein contains the following sequences: i. human CTLA-4 encoding amino acids 1-190 (containing the signal peptide, the extracellular domain of human CTLA-4 and the entirety of the presumed transmembrane sequence of human CTLA-4) and ii. murine CD3zeta from amino acid 52 to the carboxy terminus (Weissman et al. (1988) Science 239: 1018-1021). The amplified PCR product was cloned into a plasmid vector and the DNA sequence was determined. The cloned insert was then subcloned into the vector pBABE (which contains a gene encoding for puromycin resistance (Morganstern, J P and Land, H Nucl. Acids Res. 18: 3587-96 (1990)) to create pBABE-huCTLA-4 / CD3z. pBAB...

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

PropertyMeasurementUnit
Tmaaaaaaaaaa
temperatureaaaaaaaaaa
temperatureaaaaaaaaaa
Login to view more

Abstract

The present invention provides novel human sequence antibodies against human CTLA-4 and methods of treating human diseases, infections and other conditions using these antibodies.

Description

REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation of copending U.S. patent application Ser. No. 09 / 948,939, filed on Sep. 7, 2001, which is a continuation-in-part of U.S. patent application Ser. No. 09 / 644,668, filed Aug. 24, 2000, Which claims the priority to U.S. provisional application Ser. No. 60 / 150,452, filed Aug. 24, 1999.FIELD OF THE INVENTION [0002] The present invention relates generally to molecular immunology and the treatment of human diseases. In particular, it relates to novel human sequence antibodies against human CTLA-4 and methods of treating human diseases and infections using these antibodies. BACKGROUND OF THE INVENTION [0003] The vertebrate immune system requires multiple signals to achieve optimal immune activation; see, e.g., Janeway, Cold Spring Harbor Symp. Quant. Biol. 54:1-14 (1989); Paul William E., ed. Raven Press, N.Y., Fundamental Immunology, 4th edition (1998), particularly chapters 12 and 13, pages 411 to 478. Interactions...

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): A01K67/027C07K16/28C12N15/85
CPCA01K67/0275C07K2317/92A01K67/0278A01K2207/15A01K2217/00A01K2217/05A01K2217/072A01K2217/075A01K2227/105A01K2267/01A01K2267/025A01K2267/03A01K2267/0325A01K2267/0381A61K2039/505C07K16/2818C07K2317/21C07K2317/732C07K2319/00C12N15/8509A61K39/3955C07K2316/96A01K67/0276A61P35/04Y02A50/30C07K2317/33C07K2317/56C07K2317/565C07K2317/76
Inventor KORMAN, ALANHALK, EDWARDLONBERG, NILS
Owner MEDAREX 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