Human Oncostatin M Antibodies and Methods of Use

Inactive Publication Date: 2012-04-19
ALMAGRO JUAN CARLOS +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0006]The present invention provides OSM binding, monoclonal antibodies capable of blocking activities associated with one or more bioactivities associated with OSM and OSM binding receptor interaction on cells, tissues, or organs in a host subject. Amino acid sequences of exemplary OSM binding monoclonal antibodies are provided which can be encoded by nucleic acids for expressi

Problems solved by technology

However, OSM is also involved in early events in inflammatory and hypertrop

Method used

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  • Human Oncostatin M Antibodies and Methods of Use
  • Human Oncostatin M Antibodies and Methods of Use
  • Human Oncostatin M Antibodies and Methods of Use

Examples

Experimental program
Comparison scheme
Effect test

example 1

Reagents and Assays

[0105]In order to select and characterize OSM-binding antibodies, constructs of human and Cyno OSM were generated for mammalian cell expression. Human OSM (NP—065391 encoded by NM—020530) is a 252 amino acid precursor processed into a full-length secreted protein of 227 amino acids (SEQ ID NO: 11), which is a proprotein further processed into the more fully active mature form, amino acids, 1-184. Human OSM cDNA was ordered from OriGene (Cat. No. SC121421) and the ORF of human OSM from the OriGene clone was amplified by PCR and a signal peptide (murine IgG1) was introduced along with a hexa-His tag for protein purification and an AviTag (SEQ ID NO: 56) for site-directed protein biotinylation. The latter was chosen to avoid random chemical biotinylation of lysine residues present in the vicinity of OSM intereaction with receptors.

[0106]Cynomolgous monkey OSM was cloned from cyno PBMC's RNA using Superscript III first strand synthesis system (InVitrogen) to obtain th...

example 2

Selection Of OSM Binding Fabs

[0128]The de novo Fab-pIX libraries have been described Shi et al. J Mol Biol 397:385-396, 2010; WO09085462A1; U.S. Ser. No. 12 / 546,850; and herein above are designated 169, 323 and 551 which references the heavy-chain human germline framework being used: IGHV1-69 (SEQ ID NO: 1), IGHV3-23 (SEQ ID NO: 2), or IGHVS-51(SEQ ID NO: 3) in IMGT nomenclature. The three heavy-chain library frameworks are combined with four light-chain library VLkappa frameworks: A27 (IGKV3-20*01 (SEQ ID NO: 5)), B3 (IGKV4-1*01 (SEQ ID NO: 6)), L6 (IGKV3-11*01 (SEQ ID NO: 7)), and 012 (IGKV1-39*01 (SEQ ID NO: 8)). In the libraries, the Fabs V-regions are completed by the addition of a J-region (FR4) comprising SEQ ID NO: 4 in the heavy chains and SEQ ID NO: 10 in the light chains. The heavy chain CDR3 is of variable length from 7-14 residues. Examples of the complete V-regions for each library are shown in FIG. 1 and numbered and CDR regions shown according to Kabat.

[0129]The init...

example 3

Characterization of OSM Binding Mabs

[0132]The four-helix bundle architecture OSM is characterized by four α helical segments designated A, B, C and D linked by relatively unstructured loops. OSM interacts with gp130 via an surface located in helices A and C (Site II) which was determined to include contact by amino acid residues Q16, Q20, G120, N123, N124 of SEQ ID NO: 1 (Deller et al. Structure 8(8): 863-874, 2000; Liu et al. Int. J. Mol. Med. 23: 161-172, 2009). The surface responsible for OSM interaction with OSMRβ and LIFRα (Site III) is believed to be largely defined by residues located in helix D (Deller et al. ibid).

[0133]It was the objective to select high affinity binders to OSM capable of preventing OSM driven gp130 signaling either through the prevention of OSM binding to gp130 (Site II or B-blocker) or prevention of OSM bound gp130 recruitment of the LIFRα or OSMRb (Site III or R-blocker).

[0134]Of the 30 initially selected OSM-binding Fabs, 29 were cloned into vectors fo...

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Abstract

Antibodies and compositions capable of neutralizing oncostatin M biological functions are useful in treating diseases and disorders associated with oncostatin M, such as osteoarthritis and idiopathic pulmonary fibrosis.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Application Ser. No. 61 / 392,683, filed 13 Oct. 2010, the entire contents of which are incorporated herein by reference in their entirety.FIELD OF THE INVENTION[0002]The present invention relates to a human antibody capable of neutralizing the biological activity produced by oncostatin M binding to membrane receptors on human cells, and uses.BACKGROUND OF THE INVENTION[0003]Oncostatin M (OSM) is a 28 kDa multifunctional member of the IL-6 family of cytokines secreted by monocytes, macrophages, neutrophils and activated T-lymphocytes (Tanaka & Miyajima, Rev Physiol Biochem Pharmacol 149: 39-53, 2003). Proteolytic cleavage near the carboxy-terminus of the secreted OSM yields the fully active form of OSM, 209 amino acids length having two N-linked glycosylation sites. OSM belongs to the IL-6 family of cytokines that includes (IL-6, IL-11, leukemia inhibitory factor (LIF), cardiotrophin-1...

Claims

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Application Information

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IPC IPC(8): C07K16/24C12N15/13C12N5/10C12P21/02A61P19/02A61P17/06A61P11/00A61P11/06A61P25/00A61P29/00A61P19/08A61P9/10A61P13/12A61P35/00A61K39/395
CPCC07K2317/526A61K2039/54C07K2317/565C07K2317/76C07K2317/92C07K2317/55C07K16/248C07K2317/94C07K2317/33C07H21/00A61P1/00A61P1/16A61P11/00A61P11/06A61P13/12A61P15/00A61P17/00A61P17/06A61P19/02A61P19/08A61P21/00A61P25/00A61P29/00A61P31/04A61P35/00A61P37/00A61P37/02A61P43/00A61P9/00A61P9/10A61P3/10C07K16/18C12P21/00A61K39/395C07K2317/00C12N15/09C07K2317/14C07K2317/21A61K2039/505C07K2317/56C07K2317/72
Inventor ALMAGRO, JUAN CARLOSDUBELL, WILLIAMFRANSSON, JOHANPARDINAS, JOSE
Owner ALMAGRO JUAN CARLOS
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