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Humanized and chimeric anti-TROP-2 antibodies that mediate cancer cell cytotoxicity

A technology of humanized antibody and cytotoxicity, which is applied in the field of diagnosis and treatment of cancer diseases, and can solve problems such as unknown antibodies

Inactive Publication Date: 2010-03-24
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Second, the assumption that drug molecules that bind to a receptor with the greatest affinity usually have the greatest likelihood of initiating or inhibiting a signal may not always be the case
However, the study was limited to one patient and it is unknown whether any observed function was due to the unlabeled antibody

Method used

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  • Humanized and chimeric anti-TROP-2 antibodies that mediate cancer cell cytotoxicity
  • Humanized and chimeric anti-TROP-2 antibodies that mediate cancer cell cytotoxicity
  • Humanized and chimeric anti-TROP-2 antibodies that mediate cancer cell cytotoxicity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0171] In vivo tumor experiments using human MDA-MB-231 breast cancer cells

[0172] The efficacy of AR47A6.4.2 in the MCF-7 human breast cancer xenograft model was previously demonstrated (as disclosed in S.N. 11 / 709,676). To extend this finding, AR47A6.4.2 was tested in the MDA-MB-231 human breast cancer xenograft model, which is distinct from the MCF-7 model and is Her2 / neu negative, female Hormone and progesterone receptor negative. refer to figure 1 , 2 and 3, 8-10 week old female SCID mice were implanted with 5 million human breast cancer cells (MDA-MB-231 ) in 100 microliters of PBS solution by subcutaneous injection in the right loin of each mouse. The mice were randomly divided into two treatment groups, 10 in each group. 1 day after implantation, in a solution containing 2.7mM KCl, 1mM KH 2 PO 4 , 137mM NaCl and 20mM NaCl 2 HPO 4 After dilution of the diluent from the stock concentrate, each group was administered intraperitoneally with 20 mg / kg AR47A6.4.2 de...

Embodiment 2

[0176] In vivo tumor experiments using human PL45 pancreatic cancer cells

[0177] The efficacy of AR47A6.4.2 was previously demonstrated (as disclosed in S.N. 11 / 709,676) in a prophylactic PL45 human pancreatic cancer xenograft model. To determine effective dose levels, AR47A6.4.2 was tested at various doses in the established PL45 model. refer to Figure 4 , 5 and 6, 8-10 week old female SCID mice were implanted with 4 million human pancreatic cancer cells (PL45) in 100 microliters of PBS solution by subcutaneous injection at the nape of the neck of each mouse. When the average mouse tumor volume reaches about 100mm 3 , the mice were randomly divided into 5 treatment groups, 10 in each group. On the 32nd day after implantation, with 2.7mM KCl, 1mM KH 2 PO 4 , 137mM NaCl and 20mM NaCl 2 HPO 4 20, 10, 2, or 0.2 mg / kg AR47A6.4.2 detection antibody or buffer control was administered intraperitoneally to each group in a volume of 300 microliters after dilution from the st...

Embodiment 3

[0182] Human normal and multi-tumor tissue staining

[0183] Additional IHC studies (previous studies published in S.N. 11 / 709,676) were performed to further characterize the prevalence of the AR47A6.4.2 antigen in human cancers. Transfer slides from -80°C to -20°C. After 1 hour, slides were postfixed in cold (-20°C) acetone for 10 minutes and then allowed to reach room temperature. Slides were rinsed three times for 2 minutes each in cold phosphate buffered saline (PBS) at 4°C, followed by blocking endogenous peroxidase activity in 3% hydrogen peroxide for 10 minutes. Slides were then rinsed 3 times in PBS for 5 minutes, followed by incubation in universal blocking solution (Dako, Toronto, Ontario) for 5 minutes at room temperature. AR47A6.4.2, anti-human muscle actin (clone HHF35, Dako, Toronto, Ontario), anti-cytokeratin 7 clone OV-TL12 / 30 (Dako, Toronto, Ontario), anti-TROP-2 clone 77220.11 (R&D System Inc., MN, USA) or an isotype control antibody (against Aspergillus n...

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Abstract

Expression of TROP-2, an approximately 35 kDa transmembrane protein and a substrate of protein kinase C, has been linked to several cancers. TROP-2 is also known as GA733-1, epithelial glycoprotein 1(EGP-I) and tumor-associated calcium signal transducer-2. A monoclonal antibody against TROP-2 from the hybridoma AR47A6.4.2, deposited with the International Depository Authority of Canada (IDAC) asaccession number 141205-05, was previously shown to be a cancerous disease modifying antibody (CDMAB), preventing tumour growth and reducing tumour burden in several cancer models including prostate,pancreatic and breast cancer by cytotoxicity. The variable regions of this monoclonal antibody were also isolated, sequenced and complementarity determining regions (CDRs) determined. Now, a chimericantibody and humanized antibodies are generated that have similar TROP-2 binding activity as the parent 141205-05 monoclonal antibody. The monoclonal, chimeric and humanized antibodies can be conjugated to toxins, enzymes, radioactive compounds, cytokines, interferons, target or reporter moieties and hematogenous cells to treat cancer. These antibodies are also used in binding assays to determineTROP-2 expression on cells.

Description

field of invention [0001] The present invention relates to the diagnosis and treatment of cancerous disease, in particular, to mediating tumor cell cytotoxicity; and, more particularly, to antibodies (CDMAB) that ameliorate cancerous disease, optionally in combination with one or more CDMAB / chemotherapy agents Application as a tool for initiating a cytotoxic response. The invention also relates to binding assays utilizing the CDMABs of the invention. Background of the invention [0002] TROP-2 is a cell surface glycoprotein expressed on most cancers, as well as some normal human tissues. It was originally defined as the molecule recognized by two murine monoclonal antibodies raised against the human choriocarcinoma cell line BeWo, which recognizes an antigen on human trophoblast cells (Faulk 1978). Other investigators independently discovered the same molecule, leading to multiple names describing the same antigen. Therefore, TROP-2 is also known as GA733-1 and epithelial...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/30A61K39/395A61K47/48A61K51/10A61P35/00A61P37/04C07K16/28C07K16/46C12P21/08G01N33/574G01N33/577
CPCA61K2039/545C07K2317/92C07K2317/732A61K2039/505G01N33/574C07K2317/73C07K16/30C07K2317/56C07K2317/24C07K2317/34A61P35/00A61P37/04A61K39/395
Inventor 戴维·S·F·扬海伦·P·芬德利苏珊·E·哈恩路易斯·A·G·达克鲁兹艾莉森·L·费里
Owner F HOFFMANN LA ROCHE & CO AG
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