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Composition and method for the diagnosis and treatment of diseases associated with neurite degeneration

a technology of neurite degeneration and composition, applied in the direction of drug composition, peptide, metabolic disorder, etc., can solve the problems of no cure, no cure, no cure, and no improvement in sensation, movement, cognition, etc., and achieve the effect of increasing the level of rgma

Inactive Publication Date: 2013-12-12
ABBVIE INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about an isolated antibody that binds to a protein called Repulsive Guidance Molecule a (RGMa). The antibody has specific amino acid sequences in its variable heavy and light domains. The invention provides a method for making the antibody and a use for it in treating disorders associated with RGMa. The technical effect of the invention is to provide a tool for research and development of new treatments for disorders related to RGMa.

Problems solved by technology

Neurite degeneration often leads to neuronal cell death and can impair the conduction of signals in the affected nerves, causing impairment in sensation, movement, cognition, or other functions depending on which nerves are involved.
MS is an autoimmune, neurodegenerative disease that affects about 350,000 people in the United States and is a major cause of nervous system disability or death in young adults.
Currently, there is no cure for diseases associated with neurite degeneration, so treatment typically involves management of symptoms and treatment of the frequency and severity of relapses.

Method used

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  • Composition and method for the diagnosis and treatment of diseases associated with neurite degeneration
  • Composition and method for the diagnosis and treatment of diseases associated with neurite degeneration
  • Composition and method for the diagnosis and treatment of diseases associated with neurite degeneration

Examples

Experimental program
Comparison scheme
Effect test

example 1

Anti-RGMa Human Monoclonal Antibody Production and Isolation

[0352]Using PROfusion mRNA display technology, pooled human spleen, tonsil, PBMC and lymph node antibody libraries were selected through eight rounds against RGMa antigens: 100 nM biotin-labeled human or rat RGMa. PROfusion technology is described in U.S. Patent Application Publication Nos: 20100099103 and 20100105569, the contents each of which are herein incorporated by reference. Selected sc-Fv fragments were reformatted into fully human IgGs. Following screening of IgGs in RGMa-based ELISAs, AE12-1 through AE12-8 were identified as positive binders to human and rat RGMa.

[0353]Antibodies AE12-13, AE12-15, AE12-20, AE12-21, AE12-23, and AE12-24 are fully human anti-RGMa antibodies identified from large naïve human scFv yeast libraries selected against human RGMa using standard yeast display technologies. 2 rounds of Magnetic-activated cell sorting (MACS) and 4 rounds of Fluorescence-activated cell sorting (FACS) were perf...

example 2

Antibody Characterization

[0354]The 8 PROfusion mAbs (AE12-1, AE12-2, AE12-3, AE12-4, AE12-5, AE12-6, AE12-7, and AE12-8), were tested by direct binding ELISAs to examine binding to human RGMa (hRGMa) and rat RGMa and cross-reactivity to hRGMc. hRGMa competition ELISA was employed to test if any of these mAbs would compete h5F9.23 for binding to hRGMa. h5F9.23 is a humanized anti-RGMa lead mAb derived from rat hybridoma and known to bind the N-terminal domain of RGMa. H5F9.23 has the following sequences:

VH h5F9.23151EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGMNWIRQAPGKGLEWIGMIYYDSSEKHYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGTTPDYWGQGTMVTVSSVL h5F9.23152DVVLTQSPLSLPVTLGQPASISCRSSQSLEYSDGYTFLEWFQQRPGQSPRLLIYEVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQATHDPLTFGQGTKLEIKRVH h5F9.23 CDR-H1153NYGMNVH h5F9.23 CDR-H2154MIYYDSSEKHYADSVKGVH h5F9.23 CDR-H3155GTTPDYVL h5F9.23 CDR-L1156RSSQSLEYSDGYTFLEVL h5F9.23 CDR-L2157EVSNRFSVL h5F9.23 CDR-L3158FQATHDPLT

Neogenin or BMP-2 / BMP-4 competition ELISA was employed ...

example 3

Antibody Variants and Binding Data

[0367]Table 4 shows that by substituting for the Cys residue in AE12-1 VL CDR3 (SEQ ID NO:8), one can generate variants having improved affinity to hRGMa. See SEQ ID NOs:67-73. For example, see Table 4, wherein antibody clone AE12-1-Y showed at least a 10-fold increased affinity to hRGMa and AE12-1-F showed a 5-fold increased affinity to hRGMa. Others showed comparable affinity as the parental AE12-1. All variants blocked hRGMa binding to SH-SY5Y cells in MSD-based cell binding assay, neutralized RGMa but not RGMc activity in BMP reporter assays, and exhibited high thermal stability and good solubility in preformulation studies.

TABLE 4AbAE12-1AE12-1-FAE12-1-HAE12-1-LAE12-1-VAE12-1-IAE12-1-KAE12-1-YhRGMa binding (ELISA)+++++++++++++++++++Cyno RGMa binding (ELISA)+++++++++++++++++++++++hRGMa-Hiska (M-1s-1)3.1 × 104 2.7 × 104 3.2 × 104 3.8 × 104 2.5 × 104   3 × 1043.4 × 104 2.2 × 104kd (s-1)2.3 × 10−43.9 × 10−51.2 × 10−42.5 × 10−41.5 × 10−4 1.3 × 10−43...

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Abstract

Provided herein are antibodies and methods of using the antibodies to treat and diagnose neurite degenerative diseases and disorders.

Description

RELATED APPLICATION INFORMATION[0001]This application claims the benefit of U.S. Ser. No. 61 / 591,324, filed on Jan. 27, 2012, the contents of which are herein incorporated by reference in their entirety.SEQUENCE LISTING[0002]The instant application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Jan. 25, 2013, is named 11423USO.txt and is 100,936 bytes in size.FIELD OF THE INVENTION[0003]The present invention relates to antibodies and methods of using the antibodies to treat and diagnose diseases associated with neurite degeneration, such as multiple sclerosis.BACKGROUND[0004]The early stages of many neurodegenerative diseases are characterized by neurite damage and compromised synaptic function. Neurite degeneration often leads to neuronal cell death and can impair the conduction of signals in the affected nerves, causing impairment in sensation, movement, cognition...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K16/18
CPCC07K16/18C07K16/22A61K2039/505C07K2317/92C07K2317/76C07K2317/33C07K2317/34C07K16/28C07K2317/21C07K2317/24A61P25/00A61P25/28A61P27/02A61P27/06A61P3/02A61P9/10A61K39/3955A61K49/0002A61K49/0058A61K51/1018A61K51/1021C07B59/008C07B2200/05C07K2317/31C07K2317/54C07K2317/55C07K2317/56C07K2317/565C07K2317/622C07K2317/624G01N33/6896G01N2333/705G01N2800/28G01N2800/285
Inventor MUELLER, BERNHARDHUANG, LILIBARDWELL, PHILIP D.KUTSKOVA, YULIYAMEMMOTT, JOHN
Owner ABBVIE INC
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