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Antibodies for the treatment of cancers

An antibody and monoclonal antibody technology, applied in the field of anti-EGFR immunoconjugates, can solve problems such as cancer chemotherapy obstacles, malignant cell destruction, and inability to recognize tumor cells

Inactive Publication Date: 2008-10-01
WELSON PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Current cancer drugs fail to recognize tumor cells from normal cells
The amount of anticancer drug required to achieve clinically effective levels of cell killing often causes severe damage to actively proliferating non-malignant cells, such as cells of the gastrointestinal tract and bone marrow, resulting in a number of undesired side effects
This property requires a careful balance of treatment regimens between killing tumor cells and being unduly toxic to the patient, which poses a major hurdle in cancer chemotherapy
Such considerations often result in efficacy limitations on the dose administered (Aboud-Pirak, E. et al., Proc. Natl. Acad. Sci. USA, 86:3778-3781, 1989)

Method used

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  • Antibodies for the treatment of cancers
  • Antibodies for the treatment of cancers
  • Antibodies for the treatment of cancers

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] A431 cells (human epidermoid carcinoma cell line (ATCC No. CRL-1551)) were seeded in a 96-well plate containing DMEM-10% FBS at an amount of 2000 cells / well. After 4 hours, the control medium, mAb LA22 (40nM), LA22-PYM immunoconjugate (LA22-P, 40nM), LA22-MMC immunoconjugate (LA22-M, 40nM), mAb LA1 (40nM) , LA1-PYM immunoconjugate (LA1-P, 40nM), LA1-MMC immunoconjugate (LA1-M, 40nM), PYM-SPDP (P-linker, 40nM), or MMC-SPDP (M- Linker, 40 nM) was added to the cell culture. After 4 days, the number of cells in each well was determined by MTT assay (Mosmann, J. Immunol. Methods, 65:55-63 (1983)). The numbers are expressed as percent cell death (Figure 1).

[0058] As shown in Figure 1, no significant cell death was observed with 40 nM anti-EGFR mAb LA22 applied alone, while LA22-PYM and LA22-MMC caused 42% and 84% cell death, respectively. At the same dose (4OnM), anti-EGFR mAb LA1 alone caused 35% cell death. Increased cell killing activity was observed for LA1-PYM and...

Embodiment 2

[0060] In order to evaluate the concentration dependence of the above-mentioned in vitro cytotoxicity of LA22 antibiotic immunoconjugates, 4 hours after the cells were inoculated in a 96-well plate of DMEM-10% FBS at an amount of 2000 cells / well, different amounts of LA22, LA22-PYM and LA22-MMC were added to A431 cell cultures. After 4 days, the number of cells per well was determined by MTT assay. The numbers are expressed as percent cell death (Figure 2). Figure 2 illustrates that anti-EGFR mAb LA22-PYM or LA22-MMC caused A431 human cancer cell death in a dose-dependent manner.

[0061] Another LA22-MMC cytotoxicity assay was performed along with additional controls. A431 cells and human lung adenocarcinoma A549 cells (ATCC No.CCL-185) were inoculated (2×10 3 cells / well, 100 μL / well) in a 96-well cell culture plate (Corning, Corning, NY) in the presence of DMEM medium and 10% FBS, at 37°C and 5% CO 2 conditions for 4 hours. Add MMC, naked mAb LA22, or LA22-MMC immunocon...

Embodiment 3

[0064] Likewise, in vitro cytotoxicity assays using LA1 antibiotic immunoconjugates were evaluated in a similar manner. A431 cells were seeded in a 96-well plate in DMEM-10% FBS at an amount of 2000 cells / well. After 4 hours, different amounts of LA1, LA1-PYM or LA1-MMC were added to the cell culture. After 4 days, the number of cells per well was determined by MTT assay. The numbers are expressed as percent cell death (Figure 4). As shown in Figure 3, mAb LA1 and its immunoconjugates induced A431 human cancer cell death in a dose-dependent manner. Conjugation with pingyangmycin or mitomycin C significantly increased the cell killing potency of mAb LA1.

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Abstract

The present invention features monoclonal antibodies LA1 or LA22 conjugated with mitomycin C, pingyangmycin or other anti-cellular agents. The present invention also features other anti-EGFR antibodies conjugated with mitomycin C or pingyangmycin. The antibodies of the present invention can be used to treat cancers, including but not limited to, those of epithelial origin, such as glioblastoma or cancer of the lung, breast, head and neck, and bladder.

Description

[0001] Cross-References to Associated Applications [0002] This application claims priority to US Provisional Patent Application No. 60 / 675,094, filed April 27, 2005, the entire contents of which are incorporated herein by reference. technical field [0003] The present invention relates to anti-EGFR immunoconjugates and methods of using them to treat cancer. Background technique [0004] Epidermal growth factor receptor (EGFR) is a transmembrane protein involved in signaling pathways essential for cell proliferation. Overexpression of this receptor often accompanies the development and growth of malignant tumors. There is increasing evidence that high expression of EGFR is associated with aggressive tumor growth and with poorer clinical outcomes in common human cancers, including breast, cervical, lung and head and neck cancers (Baselga, J. et al. al., J. Clin. Oncol., 18:904-914, 2000; Nicholson, R.I. et al., Eur. J. Cancer, 37:S9-S15, 2001). The pivotal role of EGFR i...

Claims

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Application Information

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IPC IPC(8): A61K39/00C07K16/00A61K39/395C12P21/08
CPCA61K47/48561A61K47/48384A61K47/48584A61K2039/505C07K16/2863A61K47/6803A61K47/6849A61K47/6855
Inventor 孙乐
Owner WELSON PHARMA
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