Compsns. comprising comjugates of stable, active, human ob protein with antibody FC chain and methods

A protein, immunoglobulin technology, applied in drug combinations, animal/human proteins, antibody mimics/scaffolds, etc., can solve the problems of impairing patient compliance, inconvenience, and expensive storage.

Inactive Publication Date: 2000-11-22
AMGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Furthermore, the lyophilized form must be diluted and mixed, which is inconvenient and may compromise patient compliance
From a manufacturer's point of view, cryogens are expensive to manufacture, store and ship, and require more regulatory work than sales of off-the-shelf formulations
Additionally, manufacturing or otherwise making available suitable diluents for lyophilized formulations is more costly and less efficient than methods that do not require such diluents

Method used

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  • Compsns. comprising comjugates of stable, active, human ob protein with antibody FC chain and methods
  • Compsns. comprising comjugates of stable, active, human ob protein with antibody FC chain and methods
  • Compsns. comprising comjugates of stable, active, human ob protein with antibody FC chain and methods

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Embodiment 1: the preparation of amorphous OB protein suspension

[0063] This example illustrates the preparation of a suspension of human OB protein of the present invention. Suspensions of amorphous human OB protein were prepared by precipitation with zinc salts. A liquid with a final pH of 6.0 to pH 8.0 and a concentration of 100 mg protein / ml was obtained. A control composition of a pH 4.0 human OB protein solution is also given.

[0064] combination

[0065] Protein component: Recombinant methionyl human OB protein ("rmetHu-leptin") described in SEQ ID NO: 4 of PCT publication WO 96 / 05309, amino acid number starting at position 22 (Val) and amino acid number 167 end with a methionyl residue at the N-terminus.

[0066] Precipitating agent: zinc chloride

[0067] Buffers: Tris, MES, and Pipes

[0068] Final pH: 6.0-8.0

[0069] Preparation method: Recombinant methionyl human OB protein (“rmetHu-leptin”) solution was concentrated by injection in water to about...

Embodiment 2

[0071] Example 2: Preparation of crystallized OB protein suspension

[0072] This example illustrates the preparation of a crystalline OB protein suspension of the invention.

[0073] Protein component: Recombinant methionyl human OB protein was used as in Example 1 above.

[0074] Method: rmetHu-leptin at a concentration of 15 mg / ml in 1 mM HCl was incubated with 4M NaCl, 100 mM Tris, pH 8.5, 2% v / v ethanol in a 1:1 ratio at 4°C. Crystals formed spontaneously by slowly adjusting the temperature between 14°C and 25°C for several hours, maintaining this temperature for at least 2 hours depending on the duration of incubation to the final temperature. The crystals are harvested by centrifugation, suspended in a suitable crystallization stabilizing solvent, and the "mother liquor" (ie, the liquid in which the crystals grow) is replaced by a more stable solvent by injection. A suitable substituting solvent is 20-25% polyethylene glycol (having a molecular weight of about 4000 Da...

Embodiment 3

[0075] Example 3: Improved dose response of OB protein suspension compared to OB protein solution

[0076] This example illustrates that the OB protein suspension of the present invention is more effective than the OB protein in solution. Normal lean mice were injected with 1, 10 and 50 mg protein suspension of the present invention or OB protein solution of the same dose for 5 consecutive days. Mice given the suspension lost more weight than mice given an equivalent dose of the solution formulation, calculated per unit weight of the amount of OB protein given. The results are illustrated in Figures 1A and 1B. Figure 1A shows the percentage change in body weight when the suspension of Example 1 was administered. Figure 1B shows the percentage change in body weight when the control solution of Example 1 was administered.

[0077] The results demonstrate that the suspension of the present invention is more effective than the protein given in solution at the same dose. While ...

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Abstract

The present invention relates to OB protein compositions and related methods. Provided herein are OB protein suspensions which are stable and active at physiologic pH. Such OB protein suspensions are useful for the treatment or modulation of weight adiposity level, diabetes, and other conditions.

Description

field of invention [0001] The present invention relates to a stable and active human OB protein composition under high concentration and physiological pH or close to physiological pH conditions. Related compositions, methods of making and methods of using the above compositions are also provided. Background technique [0002] Although the molecular basis of obesity is largely unknown, the identification of the "OB gene" and the encoded protein ("OB protein") sheds some light on the mechanisms that apply to regulate fat deposition in the body. Zhang et al., Nature 372:425-432 (1994); see also revised article, Nature 374:479 (1995). PCT Publication No. WO 96 / 05309, published February 22, 1996, entitled "Bodyweight Regulating Agents, Corresponding Nucleic Acids and Proteins, and Diagnostic and Therapeutic Uses Thereof," fully discloses the OB protein and related compositions and methods, It is incorporated here for reference only. The amino acid sequence of the human OB prot...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/09A61K9/10A61K38/00A61K38/22A61P3/04A61P3/06A61P3/10C07K14/47C07K14/575C07K19/00
CPCC07K2319/00C07K14/5759A61K38/00A61P3/04A61P3/06A61P3/10
Inventor D·N·布雷姆斯D·L·弗伦奇M·A·斯皮德
Owner AMGEN INC
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