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Human monoclonal antibodies to prostate specific membrane antigen (PSMA)

A human monoclonal antibody, human antibody technology, applied in the direction of antibody, anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, anti-animal/human immunoglobulin, etc., can solve the problem of indistinguishable benign prostatic hyperplasia Prostate cancer and other issues

Inactive Publication Date: 2005-08-10
MEDAREX LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, PSA in the range of 4-10 ng / ml cannot distinguish benign prostatic hyperplasia (BPH) from prostatitis or prostate cancer, therefore, cytological and / or histological evaluation is required to confirm an appropriate diagnosis (Barren, R.J. et al. (1998) Prostate 36:181-188)

Method used

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  • Human monoclonal antibodies to prostate specific membrane antigen (PSMA)
  • Human monoclonal antibodies to prostate specific membrane antigen (PSMA)
  • Human monoclonal antibodies to prostate specific membrane antigen (PSMA)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0284] Example 1 Generation of Cmu-targeted mice for the production of anti-PSMA human antibodies

[0285] Construction of CMD targeting vector:

[0286] Plasmid pICEmu contains an EcoRI / XhoI fragment spanning the murine Ig heavy chain locus of the mu gene obtained from the Balb / C genomic lambda phage library (Marcu et al. Cell 22:187, 1980). This genomic fragment was subcloned into the XhoI / EcoRI site of plasmid pICEMI9H (Marsh et al.; Gene 32, 481-485, 1984). The heavy chain sequence included in PICEmu is amplified from an EcoRI site located 3′ downstream of the mu intronic enhancer to an XhoI site approximately 1 kb downstream of the last transmembrane exon of the mu gene; Passaging in Bacillus deleted most of the mu-switched repeat regions.

[0287] The targeting vector was constructed as follows. A 1.3 kb HindIII / SmaI fragment was excised from pICEmu and subcloned into HindIII / SmaI digested pBluescript (Stratagene, LaJolla, CA). This pICEmu fragment was amplified fr...

Embodiment 2

[0297] Example 2 Generation of HCO12 Transgenic Mice for Anti-PSMA Human Antibody Production

[0298] HCO12 Human Heavy Chain Transgene:

[0299] The HCO12 transgene was generated by co-injecting the 80 kb insert of pHC2 (Taylor et al., 1994, Int. Immunol., 6:579-591 ) and the 25 kb insert of pVx6. Plasmid pVx6 was constructed as described below.

[0300] The 8.5kb HindIII / SalI DNA fragment, including germline human V H The 1-18 (DP-14) gene and approximately 2.5 kb of 5' flanking, and 5 kb of 3' flanking genomic sequence, were subcloned into plasmid vector pSP72 (Promega, Madison, WI), resulting in plasmid p343.7.16.7 kb BamHI / HindlII DNA fragments, including germline human V H The 5-51 (DP-73) gene and approximately 5 kb of 5' flanking, and 1 kb of 3' flanking genomic sequence, were subcloned into a pBR322-based plasmid cloning vector (Taylor et al. 1992, Nucleic Acids Res. 20:6287-6295 ), the plasmid p251f was generated. A new cloning vector derived from pGP1f, pGP1k...

Embodiment 3

[0302] Example 3 Generation of Anti-PSMA Human Monoclonal Antibodies and Bispecificity

[0303] antigen : antigen (Northwest Biotherapeutics, Inc): (1) cell membrane and (2) purified protein (PSMA) isolated from LNCaP cells (Cat # CRL-1740; American Type Culture Collection, Rockville, MD) provided in two forms: ). Purified antigen (1.05 mg / ml) was used for one immunization and a final tail vein boost. Monoclonal antibody 7E11. C5 was obtained from Cytogen, Inc, Princeton, NJ.

[0304] Solubilized PSMA and membranes from LNCaP cells were mixed with complete or incomplete Freund's adjuvant (CFA and IFA). Mice were injected intraperitoneally with 0.2 cc of the prepared antigen. A final tail vein immunization was performed with soluble PSMA in sterile PBS.

[0305] transgenic mice : Mice were housed in mesh cages and assessed for good physiological status on the day of immunization, bleeding and fusion. (CMD)++; (HCo12)15087+; (JKD)++; (KCo5)9272+ genotype Male mouse ID#...

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Abstract

The present invention discloses isolated human monoclonal antibodies that bind to PSMA and relates to related antibody-based compositions and molecules. Such human antibodies can be produced by V-D-J recombination and isotype switching in non-human transgenic animals, such as transgenic mice, capable of producing multiple isotypes of human monoclonal antibodies. Also disclosed are pharmaceutical compositions containing the human antibodies, non-human transgenic animals, and hybridomas producing the human antibodies, as well as therapeutic and diagnostic methods using the human antibodies.

Description

[0001] related application [0002] This application claims priority to U.S. Application Registration No. 10 / 059,989, filed January 28, 2002, which is a continuation-in-part of PCT International Application PCT / US00 / 20247, filed July 26, 2000, which U.S. Provisional Application Serial No. 60 / 146,285 filed July 29, 1999, U.S. Provisional Application Serial No. 60 / 158,759 filed October 12, 1999, and U.S. Provisional Application Serial No. 60 / 158,759 filed March 9, 2000 Priority to application Registration No. 60 / 188,087. The entire contents of these patent applications are hereby incorporated by reference. Background of the invention [0003] Prostate cancer is the leading cause of morbidity and mortality in men. Treatment for prostate cancer includes surgery, hormones, radiation therapy, and chemotherapy. There are few effective treatments for metastatic prostate disease. Therefore, the identification of genes and / or gene products representing diagnostic and prognostic mark...

Claims

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Application Information

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IPC IPC(8): A01K67/027A61K39/395A61K45/00A61K47/42A61K47/48A61K51/00A61P13/08A61P13/10A61P35/00A61P43/00C07K16/28C07K16/30C07K16/40C12N5/10C12N15/02C12N15/09C12P21/08
CPCC07K2317/31C07K2317/565C07K2317/77C07K2317/21C07K2317/54C07K16/28C07K2317/732A61K2039/505C07K16/3069C07K16/283C07K2317/56A61P13/08A61P13/10A61P35/00A61P43/00C07K16/30
Inventor Y·M·德奥R·格拉奇尔诺D·哈森E·H·霍尔梅斯W·T·蒂诺A·布拉克
Owner MEDAREX LLC
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