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ErbB antagonists for pain therapy

Inactive Publication Date: 2006-02-16
AGUS DAVID
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0033] In another embodiment, the cancer is prostate cancer, and the patient's PSA shows no reduction during treatment, or becomes elevated during treatment.
[0034] In a further aspect, the invention concerns a method for treating non-cancer related pain in a patient co

Problems solved by technology

Pain is also a frequent symptom of advanced cancer.
Chemotherapy can also cause pain in several ways.
Some chemotherapy drugs, referred to as vesicants, can harm tissues if they leak out of the vein.
Radiation treatment can also cause pain because it can affect normal cells that surround the cancerous tumor being treated.
This treatment, however, is not optimal.
Common side effects include drowsiness and constipation.
In addition, patients often experience tolerance and develop a physical dependency on opiate analgesics, which reduces the effectiveness of the pain treatment and raises serious issues of drug dependency.
Severe, persisting pain is debilitating for patients and their caregivers, and is often under-treated due to fear of opioid addition by both patients and medical professionals.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Production and Characterization of Monoclonal Antibody 2C4

[0308] The murine monoclonal antibodies 2C4, 7F3 and 4D5 which specifically bind the extracellular domain of ErbB2 were produced as described in Fendly et al., Cancer Research 50:1550-1558 (1990). Briefly, NIH 3T3 / HER2-3400 cells (expressing approximately 1×105 ErbB2 molecules / cell) produced as described in Hudziak et al Proc. Natl. Acad. Sci. (USA) 84:7158-7163 (1987) were harvested with phosphate buffered saline (PBS) containing 25 mM EDTA and used to immunize BALB / c mice. The mice were given injections i.p. of 107 cells in 0.5 ml PBS on weeks 0, 2, 5 and 7. The mice with antisera that immunoprecipitated 32P-labeled ErbB2 were given i.p. injections of a wheat germ agglutinin-Sepharose (WGA) purified ErbB2 membrane extract on weeks 9 and 13. This was followed by an i.v. injection of 0.1 ml of the ErbB2 preparation and the splenocytes were fused with mouse myeloma line X63-Ag8.653.

[0309] Hybridoma supernatants were screened...

example 2

HRG Dependent Association of ErbB2 with ErbB3 is Blocked by Monoclonal Antibody 2C4

[0319] The ability of ErbB3 to associate with ErbB2 was tested in a co-immunoprecipitation experiment. 1.0×106 MCF7 or SK-BR-3 cells were seeded in six well tissue culture plates in 50:50 DMEM / Ham's F12 medium containing 10% fetal bovine serum (FBS) and 10 mM HEPES, pH 7.2 (growth medium), and allowed to attach overnight. The cells were starved for two hours in growth medium without serum prior to beginning the experiment.

[0320] The cells were washed briefly with phosphate buffered saline (PBS) and then incubated with either 100 nM of the indicated antibody diluted in 0.2% w / v bovine serum albumin (BSA), RPMI medium, with 10 mM HEPES, pH 7.2 (binding buffer), or with binding buffer alone (control). After one hour at room temperature, HRG was added to a final concentration of 5 nM to half the wells (+). A similar volume of binding buffer was added to the other wells (−). The incubation was continued ...

example 3

Humanized 2C4 Antibodies

[0325] The variable domains of murine monoclonal antibody 2C4 were first cloned into a vector which allows production of a mouse / human chimeric Fab fragment. Total RNA was isolated from the hybridoma cells using a Stratagene RNA extraction kit following manufacturer's protocols. The variable domains were amplified by RT-PCR, gel purified, and inserted into a derivative of a pUC119-based plasmid containing a human kappa constant domain and human CH1 domain as previously described (Carter et al. PNAS (USA) 89:4285 (1992); and U.S. Pat. No. 5,821,337). The resultant plasmid was transformed into E. coli strain 16C9 for expression of the Fab fragment. Growth of cultures, induction of protein expression, and purification of Fab fragment were as previously described (Werther et al. J. Immunol. 157:4986-4995 (1996); Presta et al. Cancer Research 57: 4593-4599 (1997)).

[0326] Purified chimeric 2C4 Fab fragment was compared to the murine parent antibody 2C4 with respe...

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Abstract

The present application describes the use of ErbB antagonist, especially ErbB2 antibodies such as rhuMAb 2C4, for treating pain.

Description

CROSS-REFERENCE TO RELATED APPLICATION(S) [0001] The is a non-provisional application filed under 37 CFR 1.53(b), claiming priority under USC Section 119(e) to Provisional Application Ser. No. 60 / 561,076, filed on Apr. 8, 2004.FIELD OF THE INVENTION [0002] The present invention concerns ErbB antagonists for treating pain. BACKGROUND OF THE INVENTION [0003] Anti-ErbB Antibodies and their Use in Cancer Treatment [0004] The ErbB family of receptor tyrosine kinases are important mediators of cell growth, differentiation and survival. The receptor family includes four distinct members including epidermal growth factor receptor (EGFR or ErbB1), HER2 (ErbB2 or p185neu), HER3 (ErbB3) and HER4 (ErbB4 or tyro2). [0005] EGFR, encoded by the erbB1 gene, has been causally implicated in human malignancy. In particular, increased expression of EGFR has been observed in breast, bladder, lung, head, neck and stomach cancer as well as glioblastomas. Increased EGFR receptor expression is often associa...

Claims

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Application Information

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IPC IPC(8): A61K39/395C07K16/28C07K16/30C07K16/32
CPCA61K2039/505C07K16/2863C07K16/30C07K16/32C07K2317/73C07K2317/24C07K2317/55C07K2317/565C07K2316/96C07K2317/76A61P25/04A61P29/00A61P35/00A61P43/00
Inventor AGUS, DAVID
Owner AGUS DAVID
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