Use of antibodies against the MUC18 antigen

a technology of muc18 and antigen, which is applied in the field of antibodies binding muc18 antigen, can solve the problems of unclear contribution of 1/creb to the acquisition of metastasis and interfere with the inherent ability of muc18, and achieve the effect of increasing the survival of an animal and increasing the survival of the animal

Inactive Publication Date: 2006-11-02
BAR ELI MENASHE +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0013] In one aspect, the invention provides an anti-human MUC18 monoclonal antibody which binds to and neutralizes a biological activity of at least human MUC18 or stimulates the internalization and down-regulation of the protein. The antibody can significantly reduce or eliminate a biological activity of the human MUC18 in question.
[0016] Yet another embodiment of the invention is a method of increasing survival of an animal having a metastatic tumor. This method includes: selecting an animal in need of treatment for a metastatic tumor; providing a monoclonal antibody comprising a heavy chain amino acid, wherein the antibody has an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 5, 9, 13, 17, 21, 25, 29, 33 and 37, and wherein the monoclonal antibody binds MUC18; and contacting said animal with an effective amount of the antibody, wherein the contacting results in inhibited metastasis of the tumor resulting in increased survival of the animal.

Problems solved by technology

However, how overexpression of ATF-1 / CREB contributes to the acquisition of the metastasis is unclear.
Such antibodies would likely interfere with the inherent ability of MUC18 to mediate cell-cell and cell-matrix interactions.

Method used

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  • Use of antibodies against the MUC18 antigen
  • Use of antibodies against the MUC18 antigen
  • Use of antibodies against the MUC18 antigen

Examples

Experimental program
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example 1

Preparation of MUC18 Antigens

[0140] In the present study, recombinant MUC18 proteins were prepared. The extracellular domain (ECD) (aa#1-559) of human MUC18 was cloned from SK-MEL-28 cells (ATCC HTB-72) by Reverse Transcriptase-PCR (RT-PCR) with primers that incorporate an EcoRI site in the forward primer and an NheI site in the reverse primer based on the published NCBI sequence (Accession # NM—006500).

[0141] The primers used for the amplification of the ECD of MUC18 were as follows:

Forward primer:(SEQ ID NO: 83)5′-ATATTACGAATTCACTTGCGTCTCGCCCTCCGG-3′Reverse primer:(SEQ ID NO: 84)5′-CAGCTTAGAGCTAGCCGGCTCTCCGGCTCCGGCA-3′

[0142] MUC18 cDNA was amplified (Gene Amp XL PCR kit, Perkin Elmer) from RNA (RNAzol, Tel Test, INC) prepared from SK-MEL-28 cells (ATCC HTB-72). For construction of a V5-HIS or HuIgG2 fusion protein, the 1700 bp PCR product encoding amino acids 1-559 was digested with EcoRI and NheI and ligated into CD147HuIgG2DHFR vector (ABGX) digested with EcoRI and NheI or p...

example 2

Anti-MUC18 Antibodies

A. Antibody Generation

[0144] 1. Immunization and Selection of Animals for Harvesting by ELISA

[0145] Monoclonal antibody against MUC18 was developed by sequentially immunizing XenoMouse mice (XenoMouse G2, Abgenix, Inc. Fremont, Calif.). The initial immunization was with 5×106 SK-MEL-28 cells admixed 1:1 v / v with Complete Freund's Adjuvant (CFA). Subsequent boosts were made first with 5×106 SK-MEL-28 cells admixed 1:1 v / v with Incomplete Freund's Adjuvant (IFA), followed by four injections with 5 μg soluble MUC18-human IgG2 Fc fusion protein admixed 1:1 v / v with IFA, and then a final boost of 10 μg soluble MUC18-human IgG2 Fc fusion protein without adjuvant. In particular, each mouse was immunized either at the base of the tail by intraperitoneal injection or via hind footpad injection with MUC18 recombinant antigen followed by the generation of a large number of candidate mAbs, and the screening of antibodies for binding and activity.

[0146] The mice were in...

example 3

Antibody Conjugates

[0175] Antibodies specific to antigens such as anti-MUC18 are useful in targeting of tumor cells expressing such antigens for elimination.

A. Linkage of Anti-MUC18 Antibody to Ricin

[0176] Ricin, a cellular toxin, is finding unique applications, especially in the fight against tumors and cancer. Implications are being discovered as to the use of ricin in the treatment of tumors. Ricin has been suggested to have a greater affinity for cancerous cells than normal cells (Montfort et al. 1987) and has been often termed as a “magic bullet” for targeting malignant tumors. Toxins such as ricin remain active even if the B chain which is responsible for because of toxin nonspecific lectin activity leads to toxic side effects is removed. Accordingly, if the solitary A chain is coupled to a tumor-specific antibody, the toxin has a specific affinity for cancerous cells over normal cells (Taylorson 1996). For example, ricin immunotoxin has been developed to target the CD5 T-...

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Abstract

The present invention relates generally to the generation and characterization of anti-MUC18 monoclonal antibodies. The invention further relates to the use of such anti-MUC18 antibodies in the diagnosis and treatment of disorders associated with increased activity of MUC18, in particular, tumors, such as melanomas.

Description

RELATED APPLICATION [0001] The present application is a continuation of U.S. application Ser. No. 10 / 660,357, filed Sep. 10, 2003, and entitled “USE OF ANTIBODIES AGAINST THE MUC18 ANTIGEN,” which in turn is a continuation of U.S. application Ser. No. 10 / 330,580, filed Dec. 26, 2002, and entitled “USE OF ANTIBODIES AGAINST THE MUC18 ANTIGEN,” which claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application Ser. No. 60 / 346,460, filed Dec. 28, 2001, each of which are hereby expressly incorporated by reference in its entirety.BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] Embodiments of the present invention concern antibodies binding MUC18 antigen as well as methods and means for making and using such antibodies. [0004] 2. Description of the Related Art [0005] MUC18 is a cell-surface glycoprotein originally identified as a melanoma antigen, melanoma cell adhesion molecule (MCAM), whose expression is associated with tumor progression and the developme...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395C07H21/04C12P21/06C07K16/30C12N5/06A61K51/00A61K47/48A61K51/10A61P35/00A61P35/04A61P43/00C07K16/18C07K16/28
CPCA61K47/48623A61K51/1066A61K2039/505C07K16/3092C07K2319/30C07K2317/21C07K2317/56C07K2317/73C07K2317/92C07K2316/96C07K2317/76A61K47/6865C07K2317/33A61P35/00A61P35/04A61P43/00
Inventor BAR-ELI, MENASHEGREEN, LARRY L.
Owner BAR ELI MENASHE
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