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Antibody formulations

Inactive Publication Date: 2006-04-27
GENENTECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0053] Moreover, the invention provides a method of making a pharmaceutical formulation comprising: (a) preparing the monoclonal antibody f

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.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

[0409] Pertuzumab Fab and F(ab′)2 antibody fragments were formulated at protein concentration of 1.0 mg / mL in the following buffer conditions: [0410] 10 mM citrate, 140 mM NaCl, pH 4.0; [0411] 10 mM succinate, 140 mM NaCl, pH 5.0; [0412] 10 mM succinate, 140 mM NaCl, pH 6.0; [0413] 10 mM histidine, 140 mM NaCl, pH 7.0; and [0414] 10 mM glycylglycine, 140 mM NaCl, pH 8.0.

[0415] Each formulation was filtered then aliquoted into 3 cc WHEATON™ USP Type I glass vials sealed with TEFLON™ coated gray butyl stoppers. Samples were stored at 40±2° C. The stability analyses of drug product showed that the Fab and F(ab′)2 were most stable between pH 5.0 and 6.0.

TABLE 2Effect of pH on degradation of Fab or F(ab′)2 stored at 40° C.FabF(ab′)2CZESEC% MainSECCZE% MainFormulation pHPeak% Main Peak% Main PeakPeak4.074.196.743.689.45.083.296.465.494.06.082.996.269.092.37.083.996.462.391.38.072.796.449.289.8

example 2

[0416] Pertuzumab was formulated into 20 mM histidine-acetate buffer with 120 mM sucrose and 0.02% polysorbate 20. The pHs of formulations were adjusted with acetic acid to final pH between 5.0 and 7.0. The protein concentration was 30 mg / mL. Each formulation was filled into 3 cc USP Type I glass vials and stored at 40° C. for stability analysis. The results showed that Pertuzumab was most stable around pH 6.0.

TABLE 3Effect of pH on degradation of Pertuzumab stored at 40° C.FormulationTemperatureStorageSECIEXpH(° C.)Time (wks)% Monomer% Main Peak5.040299.457.45.540299.459.26.040299.460.66.540299.360.57.040299.154.05.040497.348.15.540499.150.56.040499.153.36.540499.052.37.040498.642.3

example 3

[0417] Pertuzumab formulations at protein concentration of 100 mg / mL were prepared in the following excipients: [0418] (1) 10 mM histidine-HCl, 240 mM sucrose, 0.02% polysorbate 20, pH 6.0; [0419] (2) 10 mM histidine-acetate, 240 mM sucrose, 0.02% polysorbate 20, pH 6.0; [0420] (3) 10 mM histidine-phosphate, 240 mM sucrose, 0.02% polysorbate 20, pH 6.0; [0421] (4) 10 mM histidine-sulfate, 240 mM sucrose, 0.02% polysorbate 20 at pH 6.0.

[0422] Each formulation was filled into 3 cc FORMA VITRUM™ USP Type I glass vial sealed with FLUROTEC™ faced butyl rubber stoppers. Samples were stored at 30° C. and 40° C. and stability was evaluated for quality (CAC) and purity (SEC, IEC). The stability results showed that Pertuzumab in histidine-phosphate buffer degraded much faster than in other histidine buffers upon storage at 40° C. (FIG. 8 and FIG. 9).

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Abstract

The present application describes antibody formulations, including monoclonal antibodies formulated in histidine-acetate buffer, as well as a formulation comprising an antibody that binds to domain II of HER2 (for example, Pertuzumab), and a formulation comprising an antibody that binds to DR5 (for example, Apomab).

Description

[0001] This is a non-provisional application filed under 37 CFR 1.53(b) claiming priority to provisional application 60 / 620,413 filed Oct. 20, 2004, the contents of which are incorporated herein by referenceFIELD OF THE INVENTION [0002] The present invention concerns antibody formulations, including monoclonal antibodies formulated in histidine-acetate buffer, as well as a formulation comprising an antibody that binds to domain II of HER2 (for example, Pertuzumab), and a formulation comprising an antibody that binds to DR5 (for example, Apomab). 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 probl...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61K31/7012
CPCA61K39/39591C07K16/2878A61K39/39541C07K2317/24C07K16/32A61P35/00A61K39/395A61K31/7012A61K47/18A61K39/39558A61K47/22A61K47/26C07K16/40A61K2039/505C07K2317/94
Inventor ANDYA, JAMESGWEE, SHIANGLIU, JUNSHEN, YE
Owner GENENTECH INC
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