Human antibodies to the glucagon receptor

A glucagon and antibody technology, applied in the direction of antibodies, antibody medical components, anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, etc., can solve the problem of not recognizing mice

Active Publication Date: 2013-09-18
REGENERON PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The antibody described by Buggy et al. competes with glucagon for the receptor's hormone

Method used

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  • Human antibodies to the glucagon receptor
  • Human antibodies to the glucagon receptor
  • Human antibodies to the glucagon receptor

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0129] Production of Human Antibodies

[0130] Methods for producing human antibodies in transgenic mice are known in the art. Any such known methods can be used in the context of the present invention to prepare human antibodies that specifically bind to human GCGR.

[0131] Use VELOCIMMUNE TM technology (see, for example US6,596,541, Regeneron Pharmaceuticals, ) or any other known method for producing monoclonal antibodies, initially isolating a high affinity chimeric antibody to GCGR having human variable regions and mouse constant regions. Techniques include the generation of transgenic mice having a genome comprising human heavy and light chain variable regions operably linked to endogenous mouse constant region loci such that the mice respond to antigenic stimulation to produce human variable regions and Antibodies against mouse constant regions. DNA encoding the variable regions of the heavy and light chains of the antibody is isolated and operably linked to DNA e...

Embodiment 1

[0205] Example 1 Production of Human Antibodies to Human GCGR

[0206] Antibodies to hGCGR can be raised using immunogens including any of the following. For example, in certain embodiments, cells expressing hGCGR are used as immunogens to generate antibodies to hGCGR. Furthermore, in certain embodiments, DNA encoding hGCGR is used as an immunogen to prepare antibodies of the invention. Furthermore, in certain embodiments, a peptide comprising the amino acid sequence of the N-terminal domain of hGCGR is used as an immunogen to generate antibodies to human GCGR. Furthermore, in certain embodiments, a peptide comprising the amino acid sequence of any of the extracellular loop regions ECl, EC2, or EC3 of hGCGR can be used as an immunogen to generate antibodies to human GCGR. Cells, DNA or peptides used as immunogens as described above are administered directly to the A mouse comprising DNA encoding human immunoglobulin heavy chain and kappa light chain variable regions. Anti...

Embodiment 2

[0209] Example 2 Amino Acid Sequences of Heavy Chain and Light Chain Variable Regions

[0210] Table 1 presents the heavy chain and light chain variable region amino acid sequence pairs of selected anti-GCGR antibodies and their corresponding antibody identifiers. Antibody names with the same numerical value but different letter suffixes N, B, or P refer to antibodies that have heavy and light chains that contain the same CDR sequences but sequence changes in regions outside the CDR sequences (i.e., within the framework regions). chain of antibodies. Thus, N, B and P variants of a particular antibody have identical CDR sequences within their heavy and light chain variable regions, but differ from each other within their framework regions.

[0211] Table 1

[0212]

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PUM

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Abstract

The present invention provides antibodies that bind to the human glucagon receptor, designated GCGR and methods of using same. According to certain embodiments of the invention, the antibodies are fully human antibodies that bind to human GCGR. The antibodies of the invention are useful for lowering blood glucose levels and blood ketone levels and are also useful for the treatment of diseases and disorders associated with one or more GCGR biological activities, including the treatment of diabetes, diabetic ketoacidosis and long-term complications associated with diabetes, or other metabolic disorders characterized in part by elevated blood glucose levels.

Description

technical field [0001] The present invention relates to human antibodies and antigen-binding fragments of human antibodies that specifically bind to the glucagon receptor and methods of treatment using these antibodies. Background technique [0002] Glucagon is a 29 amino acid hormone produced by the alpha cells of the pancreatic islets. Glucagon keeps glucose at normal levels in animals, including humans, by balancing the action of insulin. An imbalance of glucagon and insulin can play an important role in several diseases such as diabetes and diabetic ketoacidosis. In particular, studies have shown that higher basal glucagon levels and lack of inhibition of postprandial glucagon secretion contribute to the diabetic condition in humans (Muller et al., N Eng J Med 283: 109-115 (1970)). [0003] The effect of glucagon to raise blood glucose levels is thought to be mediated in part through the activation of certain cellular pathways following binding of glucagon (GCG) to its...

Claims

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Application Information

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IPC IPC(8): C07K16/28
CPCA61K39/39541A61K2039/505A61K2039/507C07K2317/21C07K2317/33C07K2317/34C07K2317/76C07K2317/92C12N15/64C07K16/2869A61P13/12A61P17/02A61P25/00A61P27/02A61P27/12A61P3/00A61P3/02A61P3/04A61P3/08A61P43/00A61P9/00A61P9/10A61P3/10A61K2300/00A61K39/3955A61K45/06C07K16/40C07K16/468C12N15/1137C12N15/85C07K2317/56C07K2317/565C07K2317/94C07K2317/31C07K2317/30C12N2320/31C12N2310/14C12N2310/11C12N15/70
Inventor 冈本悠马克·斯利曼乔伊斯·哈普
Owner REGENERON PHARM INC
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