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Antibody formulation

a technology of antibody and formulation, which is applied in the direction of antibody medical ingredients, immunoglobulins, peptides, etc., can solve the problems of chemical instability, physical instability, special problems in the formulation of such proteins

Inactive Publication Date: 2005-07-21
GENENTECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0007] Accordingly, the invention provides a stable aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody not subjected to prior lyophilization, a buffer maintaining the pH in the range from about 4.5 to about 6.0, a surfactant and a polyol. Preferably the formulation is stable at a temperature of about 2-8° C. for at least one year, and / or is stable at a temperature of about 30° C. for at least one month and / or is stable following freezing and thawing of the formulation.

Problems solved by technology

Because proteins are larger and more complex than traditional organic and inorganic drugs (i.e. possessing multiple functional groups in addition to complex three-dimensional structures), the formulation of such proteins poses special problems.
Chemical instability can result from deamidation, racemization, hydrolysis, oxidation, beta elimination or disulfide exchange.
Physical instability can result from denaturation, aggregation, precipitation or adsorption, for example.
Reperfusion following resuscitation exacerbates the edema and necrosis, and leads to multi-organ failure and death.

Method used

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Examples

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example 1

[0146] This example describes an aqueous formulation comprising the antibody, recombinant humanized anti-CD18 antibody (rhuMAb CD18). RhuMAb CD18 having the amino acid sequence shown in FIG. 1A (heavy chain; SEQ ID NO:1) and FIG. 1B (light chain; SEQ ID NO:2) was created by humanization of the murine monoclonal antibody muMAb H52 (Hildreth et al. J. Immunology 134:3272-3280 (1985)).

[0147] The rhuMAb CD18 was produced recombinantly as described below. Plasmid pS1130 was constructed to direct production of a rhuMAb CD18 precursor molecule with a leucine zipper domain in E. coli. The precursor is cleaved during the purification process by the protease pepsin to yield rhuMAb CD18. rhuMAb CD18 is an F(ab′)2 molecule composed of two different peptides (light and heavy chains) linked by disulfide bonds. Fusion of a yeast GCN4 leucine zipper dimerization domain to the C-terminus of an Fab′ substitutes for the Fc region and allows for efficient F(ab′)2 production in E. coli. The GCN4 leucin...

example 2

[0204] This example describes the production of a stable aqueous multidose formulation comprising a recombinant humanized anti-CD20 antibody, rhuMAb CD20. Acetate (pH 5) formulations stored at 40° C. for one month demonstrated greater stability than those samples formulated in histidine (pH 5 or 6). The histidine formulations after accelerated temperature storage became very opalescent and yellow in color. A buffering capacity of 10-30 mM acetate was sufficient to maintain the pH at 5.0. The effective amount of tonicity modifier needed to stabilize the antibody against freeze or thermal induced aggregation was compared using sodium chloride (NaCl) ortrehalose. Trehalose was found to protect the formulation from freeze induced aggregation, particularly at levels ≧134 mM (500:1 molar ratio). The trehalose formulations (67-270 mM) were much more effective than NaCl in stabilizing formulations placed at 40° C. as evidenced by the clarity of the solution. These results led to the develop...

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Abstract

A method of treating hemorrhagic shock with a stable aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody not subjected to prior lyophilization, a buffer maintaining the pH in the range from about 4.8 to about 5.5, a surfactant and a polyol.

Description

RELATED APPLICATION [0001] This is a divisional of co-pending application Ser. No. 09 / 724,868, filed on Nov. 28, 2000, which is a continuation of application Ser. No. 09 / 097,171 filed on 12 Jun. 1998 (now U.S. Pat. No. 6,171,586), which claims the benefit under §119(e)(1) to Provisional Patent Application No. 60 / 053,087, filed on 13 Jun. 1997, which applications are incorporated herein by reference.FIELD OF THE INVENTION [0002] This invention is directed to a stable aqueous pharmaceutical formulation comprising an antibody. BACKGROUND OF THE INVENTION [0003] In the past ten years, advances in biotechnology have made it possible to produce a variety of proteins for pharmaceutical applications using recombinant DNA techniques. Because proteins are larger and more complex than traditional organic and inorganic drugs (i.e. possessing multiple functional groups in addition to complex three-dimensional structures), the formulation of such proteins poses special problems. For a protein to ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395C07K16/28
CPCA61K39/39591C07K2317/54C07K16/2896C07K16/2845
Inventor LAM, XANTHEOESWEIN, JAMESONGPIPATTANAKUL, BOONSRISHAHROKH, ZAHRAWANG, SHARONWEISSBURG, ROBERTWONG, RITA
Owner GENENTECH INC
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