Mucosal vascular addressins and uses thereof

Inactive Publication Date: 2006-03-16
BRISKIN MICHAEL +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0013] The invention further relates to methods of therapy, including a method of treating an individual suffering from a disease associated with leukocyte (such as lymphocyte or monocyte) recruitment to the gastrointestinal tract or other tissues as a result of binding of leukocytes to gut-associated endothelium expressing the molecule MAdCAM, comprising administering to the individual (e.g., a mammal, such as a primate) an effective amount of an agent or compound, such as an antibody, which inhibits the binding of leukocytes to endothelial MAdCAM. The antibody is preferably a monoclonal, chimeric and/or humanized a

Problems solved by technology

However, these therapeutic targets are likely to be involved in inflammatory processes in multiple organs, and a functional blockade could cause systemic immune dysfunction.

Method used

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  • Mucosal vascular addressins and uses thereof
  • Mucosal vascular addressins and uses thereof
  • Mucosal vascular addressins and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Cloning of Macaque and Human MAdCAM-1 cDNAs RNA Isolation and Selection of Message

[0125] Total RNA was isolated from (a) primate (macaque) mesenteric lymph nodes (MLN); (b) histologically normal human mesenteric lymph nodes; (c) human mesenteric lymph nodes (inflamed ileal nodes) from a patient with Crohn's disease; and (d) tissue culture cells by use of the CsTFA™ (cesium trifluoroacetate) reagent (Pharmacia; Cat. #17-087-02). Total RNA from mesenteric lymph node was obtained from two species of macaque (Macaca fascicularis, and Macaca mulatta), and was combined prior to isolation of poly-A RNA. Tissue was first snap frozen in liquid nitrogen and subjected to dounce homogenization in a solution consisting of 5.5 M guanidinium isothiocyanate, 25 mM sodium citrate, 0.5% sodium laurel sarcosine and 0.2 M 2-mercaptoethanol, while tissue culture cells (1-5×108) were washed once in phosphate buffered saline (PBS) and homogenized by pipetting. A clarified lysate was then layered on a cus...

example 2

Characterization of MAdCAM-1 Clones

[0169] Functional Adhesion Assays

[0170] Plasmids:

[0171] The following plasmids were used in the functional adhesion assays: (1) pSV-SPORT-1 (Gibco / BRL) or pcDNA-3 (Invitrogen) were used as controls; (2) murine MAdCAM-1 in pCDM8 (pCDMAD-7; Briskin, M. J., et al., Nature, 363:461 (1993)); (3) seven domain human VCAM-1 (Polte, T., et al., Nucleic Acids Res., 18:5901 (1990)) in pcDNA3 (pCD3VCAM); and (4) human MAdCAM-1 in pcDNA-3 (pCDhuMAd4) (see above).

[0172] Monoclonal Antibodies:

[0173] The following monoclonal antibodies (MAb) were used in the functional adhesion assays: (1) anti-murine MAdCAM-1 MAb MECA-367 (American Type Culture Collection (Rockville, Md.), Accession No. HB9478; Streeter, P. R., et al., Nature, 331:41 (1988); and U.S. Pat. No. 5,403,919 to Butcher); (2) anti-human VCAM-1 MAb 2G7 (American Type Culture Collection (Rockville, Md.); Graber, N. T., et al., J. Immunol., 145:819-830 (1990)); (3) anti-murine α4β7 MAb DATK 32 (Andrew...

example 3

Design and Functional Analysis of a Human MAdCAM-1-IgG Chimera Construction of MAdCAM-IgG Chimera

[0198] Human MAdCAM-1 clone 4 cDNA in pCDNA3 (Invitrogen, San Diego, Calif.), called pcD3huMAd4 (Example 1) was used as a template for PCR amplification of extracellular regions of human MAdCAM-1 to be fused with the constant region of human IgG1. Primer HUMADIG4 / 2 (SEQ ID NO:11), which contains the 5′ end of human MAdCAM-1 coding sequence (ATG codon, bold), was synthesized:

     HindIII5′-GGAAGCTTCCACCATGGATTTCGGACTGGCCC-3′

[0199] This 5′ primer was used in conjunction with a 3′ primer designated HUMADIG2 (SEQ ID NO:12) to amplify regions encoding the two amino-terminal immunoglobulin-like (Ig) domains of human MAdCAM-1. Primer HUMADIG2 (SEQ ID NO:12), which contains a portion complementary to coding strand nucleotides 667-683 of SEQ ID NO:1, has the following sequence:

      SpeI5′-CCGACTAGTGTCGGGCTGTGCAGGAC-3′

[0200] Alternatively, the 5′ primer was used in conjunction with 3′ primer...

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Abstract

The present invention relates to pharmaceutical compositions which comprise an antibody and / or antigen-binding fragments which have the epitopic specificity of ACT-1 monoclonal antibody.

Description

RELATED APPLICATIONS [0001] This application is (1) a continuation of U.S. patent application Ser. No. 08 / 875,849, filed Sep. 8, 1997, which is the U.S. National stage of International Application No. PCT / US96 / 02153, filed Feb. 12, 1996, published in English, which is a continuation-in-part of U.S. patent application Ser. No. 08 / 523,004, filed Sep. 1, 1995, and (2) a continuation-in-part of U.S. patent application Ser. No. 10 / 118,600, filed Apr. 8, 2002, which is a continuation of U.S. patent application Ser. No. 08 / 386,857, filed Feb. 10, 1995 (now U.S. Pat. No. 6,551,593 B1). The entire teachings of the above applications are incorporated herein by reference.BACKGROUND OF THE INVENTION [0002] Lymphocyte homing from the circulation to the lymphoid tissues and migration to sites of inflammation is regulated by interaction with receptors expressed in postcapillary venules, including high endothelial venules (HEV) found in secondary lymphoid tissues (e.g., mesenteric lymph nodes, Peye...

Claims

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Application Information

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IPC IPC(8): C07H21/04C12P21/06A61K39/395C07K14/74C07K16/28A61K39/00C07K14/705
CPCA61K39/00A61K2039/505C07K14/70503C07K2319/30C07K16/2839C07K2316/96C07K2319/00C07K16/2803C07K2317/76Y10S530/866A61P1/00A61P29/00
Inventor BRISKIN, MICHAELRINGLER, DOUGLASPICARELLA, DOMINICNEWMAN, WALTER
Owner BRISKIN MICHAEL
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