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Antibodies to natural killer stimulatory factor

a natural killer and stimulatory factor technology, applied in the field of antibodies to natural killer stimulatory factor, can solve the problems of hampered biochemical and biological identification and characterization of certain cytokines, and achieve the effect of enhancing natural killer cell functions and showing synergistic effects

Inactive Publication Date: 2007-05-10
WYETH & THE WISTAR INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a novel human natural killer stimulating factor (NKSF) that is free from other mammalian proteins. The NKSF is a heterodimer formed by the association of two polypeptides, a larger subunit and a smaller subunit. The larger subunit has an apparent molecular weight of about 70-80 kD and the smaller subunit has an apparent molecular weight of about 30-35 kD. The NKSF is biologically active in inducing the production of gamma interferon in vitro in human peripheral blood lymphocytes and has been shown to have various biological activities such as inducing the production of granulocyte-macrophage colony stimulating factor, activating Natural Killer cells, inducing tumor necrosis factor, and synergizing with IL-2 in inducing gamma interferon production. The invention also provides DNA sequences encoding the expression of the NKSF and recombinant NKSF protein. The therapeutic effects of the invention include the treatment of cancer, viral infections, and other disease states that benefit from enhanced immune function.

Problems solved by technology

The biochemical and biological identification and characterization of certain cytokines was hampered by the small quantities of the naturally occurring factors available from natural sources, e.g., blood and urine.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

PREPARATION OF SERUM-FREE RPMI 8866 CELL-CONDITIONED MEDIUM

[0076] The human B-lymphoblastoid cell line RPMI 8866 was maintained in RPMI 1640 medium containing 5% heat-inactivated fetal calf serum (FCS). For preparation of serum free conditioned medium, cells were washed and suspended (106 cells / ml) in serum free RPMI 1640 medium containing 10−7 M phorbol-12-13-dibutvrate (PdBU) and cultured for 48 hours at 37° C., 5% CO2. The cell free supematants were harvested by filtration through a 0.2 μm filter [Durapore® hydrophilic cartridge filter, Millipore, Bedford, Mass. and Tween-20 and phenylmethylsulfonyl-fluoride (PMSF) were added to 0.02% and 0.1 mM, respectively. The cell conditioned medium was then concentrated 50 fold under pressure using an ultra-filtration cartridge [Spiral-Wound, S1, Amicon, Danvers, Mass.].

example 2

PURIFICATION OF NKSF FROM CONDITIONED MEDIUM

[0077] The following procedures are presently employed to obtain homogeneous NKSF protein from RPMI 8866 conditioned medium, as described in Example 1 above.

a. Anion Exchange Cartridge Chromatography

[0078] Two liters of the crude concentrated conditioned medium was diluted with distilled water to a conductivity of 6m Os / cm and adjusted to pH 8 with 1 M Tris-HCl buffer (pH 8). The concentrate was then applied to five QAE Zetaprep 250 cartridges [Pharmacia] connected in parallel and previously equilibrated with 0.1 M Tris-HCl buffer (pH 8) at a flow rate of 150 ml / min. Unless otherwise cited, all the buffers used for purification contained 0.02% Tween-20 and 0.1 mM PMSF. The cartridges were washed with 3 liters of 0.1 M Tris-HCI buffer (pH 6.8) followed by washing with 1.5 liters of 0.5 M NaCl in 0.1 M Tris-HCl buffer (pH 6.8) and 300 ml fractions were collected. The NKSF activity was eluted with the 0.5 M NaCl-containing wash.

b. Lentil-...

example 3

SODIUM DODECYL SULFATE-POLYACRYLAMIDE GEL ELECTROPHORESIS

[0085] SDS-PAGE was performed according to the method of Laemmli [Laemmli, U. K., Nature, 227:680-685 (1970)] on 10% acrylamide slab gels (0.75 mm thickness). After electrophoresis the gels were either stained by the silver-nitrate method using a silver staining reagents [BioRad] or cut into 2 mm slices and eluted in 0.5 m! RPMI medium for 4 hours at 24° C. and assayed for NKSF activity. Apparent molecular weight was determined with protein standards, phospholipase b (94 kD), bovine serum albumin (67 kD), ovalbumin (43 kD), carbonic anhydrase (30 kD), soybean trypsin inhibitor (20 kD) and lactalbumin (14.4 kD).

[0086] SDS-PAGE analysis (non-reducing conditions) of the Mono Q column fractions (Example 2, step (e)) beginning with several fractions which eluted before the NKSF activity, continuing right through the active fractions and ending with fractions which eluted after the peak of NKSF activity, revealed that the presence...

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Abstract

This application relates to antibodies reactive with a novel homogenous human cytokine, Natural Killer Stimulator Factor (NKSF), having the ability to induce the production of gamia interferon in vitro in human peripheral blood lymphocytes, and a pharmaceutical preparation containing such antibodies.

Description

[0001] This is a division of application Ser. No. 09 / 325,958, filed Jun. 4, 1999; which was a division of application Ser. No. 08 / 858,000, filed May 16,1997, now abandoned; which was a continuation of application Ser. No. 08 / 403,013, filed Mar. 13, 1995 and issued as U.S. Patent No. 5,648,467; which was a division of application Serial No. 07 / 584,941 filed Sep. 18, 1990 and issued as U.S. Pat. No. 5,457,038, which was a continuation-in-part of Ser. No. 07 / 307,817, filed Feb. 7, 1989, now abandoned; which was a continuation-in-part of Ser. No. 07 / 269,945, filed Nov. 10, 1988, now abandoned, all of which are incorporated herein by reference. [0002] The present invention relates to a novel cytokine that stimulates the function of natural killer cells and other cells of the immune system, and to processes for obtaining the factor in homogeneous form and producing it by recombinant genetic engineering techniques.BACKGROUND OF THE INVENTION [0003] Natural killer (NK) cells are a subset of...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/19A61K38/20A61K38/18C07K14/52C07H21/04C12P21/02A61K38/00C07K14/54
CPCA61K38/00C07K14/52C07K14/5434
Inventor TRINCHIERI, GIORGIOPERUSSIA, BICEWOLF, STANLEY F.CLARK, STEVEN C.WONG, GORDON G.HEWICK, RODNEYKOBAYASHI, MICHIKO
Owner WYETH & THE WISTAR INST