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Antagonist Anti-cd40 antibody pharmaceutical compositions

an anti-cd40 and anti-cd40 technology, applied in the field of pharmaceutical formulations, can solve the problems of inconvenient reconstitution of polypeptides, loss of biological activity of polypeptides, and inability to manufacture antibodies,

Inactive Publication Date: 2015-04-23
XOMA TECH LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent is about stable liquid pharmaceutical compositions containing an antagonist anti-CD40 antibody as a therapeutic or prophylactic ingredient. The compositions have a pH between 5.0 and 7.0 and are near isotonic using arginine-HCl. They may also contain a citrate / citric acid buffer and other stabilizing agents like nonionic surfactants or L-methionine. The compositions are suitable for treating diseases involving proliferation, autoimmunity, and inflammation.

Problems solved by technology

Polypeptides, however, can lose biological activity as a result of physical instabilities, including denaturation and formation of soluble and insoluble aggregates, and a variety of chemical instabilities, such as hydrolysis, oxidation, and deamidation.
Also, the need for reconstitution is an inconvenience and introduces the possibility of incorrect dosing.
Thus, CD40 engagement by CD40L and subsequent activation of CD40 signaling are necessary steps for normal immune responses; however, dysregulation of CD40 signaling can lead to disease.
It has been shown that CD40 / CD40L binding acts synergistically with the Alzheimer amyloid-beta peptide to promote microglial activation, thus leading to neurotoxicity.

Method used

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  • Antagonist Anti-cd40 antibody pharmaceutical compositions
  • Antagonist Anti-cd40 antibody pharmaceutical compositions
  • Antagonist Anti-cd40 antibody pharmaceutical compositions

Examples

Experimental program
Comparison scheme
Effect test

example 1

Effect of Various Buffer Species and Methionine on Stabilization of CHIR-12.12

[0178]Solution conditions (e.g., pH, buffer species, and ionic strength) and excipients (e.g., surfactants and stabilizers) are critical factors for stability of a protein in liquid formulation. Physicochemical stability of CHIR-12.12 is optimal at pH 5.5. However, CHIR-12.12 protein can degrade via aggregation and fragmentation under unfavorable solution conditions; it can also oxidize, especially in the presence of peroxide impurities and / or trace amounts of metals introduced with raw excipient materials such as Tween. The following experiments were conducted to identify the best buffer species and appropriate excipients to stabilize CHIR-12.12 monoclonal antibody against aggregation, fragmentation, and oxidation when formulated at the optimum pH 5.5.

Materials

[0179]The CHIR-12.12 drug substance (DS) lots for the study were CHO-derived purified bulk lot #CD021105A and lot #PD010705A. The DS lots were prod...

example 2

Stabilizing Effect of Arginine-HCl on CHIR-12.12

[0189]The following study was aimed at selecting a tonicifying agent and stabilizer for long-term storage stability of CHIR-12.12 formulated as a liquid pharmaceutical composition intended for administration via intravenous infusion. Although NaCl is the most commonly used isotonizing agent for protein parenteral products, it may not have optimal stabilizing effects on antibody therapeutics. This study reports on the comparative stabilizing effects of sodium chloride and the acidic form of arginine (arginine-HCl) on CHIR-12.12 in an aqueous formuation.

[0190]The CHIR-12.12 bulk antibody drug substance was formulated with a citrate buffer at pH 5.5, employing either 150 mM NaCl or 150 mM L-arginine-HCl to achieve the target osmolality of 295 mOsm / kg for the CHIR-12.12 liquid formulation. Differential Scanning calorimetry (DSC), size-exclusion chromatograph (SEC-HPLC), SDS-PAGE, and Cation-Exchange HPLC (CIEX-HPLC) were used to evaluate b...

example 3

Effects of Tween 80 and Tween 20 in Minimizing Aggregation of CHIR-12.12 Bulk Drug Substance from Frozen Storage

[0211]Frozen storage of the CHIR-12.12 bulk drug substance is preferred over liquid storage for several reasons including increased product stability and shelf life, decreased microbial growth, as well as elimination of foaming during transport. However, freezing and subsequent thawing can induce stresses in protein solution by introducing ice-liquid interfaces and concentration gradient of solutes. The stresses may denature proteins and lead to aggregation and, in worse cases, formation of visible particulates or precipitates. As protein aggregates have been frequently associated with reduced drug potency and increased immunogenicity, minimizing aggregation by optimizing protein formulation components and freeze-thaw conditions is very critical.

[0212]Formulation excipients, such as sugars, polyhydric alcohols, amino acids, and surfactants can possibly stabilize proteins a...

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Abstract

Stable liquid pharmaceutical compositions comprising an antagonist anti-CD40 antibody as a therapeutically or prophylactically active component and methods useful in their preparation are provided. These compositions comprise the antagonist anti-CD40 antibody, a buffering agent to maintain the pH of the composition between about pH 5.0 and about pH 7.0, and an amount of arginine-HCl sufficient to render the liquid composition near isotonic. The stable liquid antagonist anti-CD40 antibody-containing pharmaceutical compositions of the invention find use in methods for treating proliferative diseases and diseases having an autoimmune and / or inflammatory component.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a divisional of U.S. application Ser. No. 12 / 297,382, which is a national stage of International Patent Application No. PCT / US2007 / 066757, filed Apr. 17, 2007, which claims the benefit of U.S. Provisional Application No. 60 / 794,011, filed Apr. 21, 2006; the contents of each of which are herein incorporated by reference in their entirety.FIELD OF THE INVENTION[0002]The present invention is directed to the field of pharmaceutical formulations, more particularly to stable liquid pharmaceutical compositions comprising antagonist anti-CD40 antibodies for use in treating proliferative diseases and diseases having an autoimmune or inflammatory component.BACKGROUND OF THE INVENTION[0003]Recent advances in the development of genetic engineering technology have provided a variety of biologically active polypeptides in sufficiently large quantities for use as drugs. Polypeptides, however, can lose biological activity as a result ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K16/28
CPCC07K16/2878C07K2317/24C07K2317/94C07K2317/34C07K2317/76C07K2317/73A61P1/04A61P1/16A61P11/00A61P11/06A61P17/00A61P17/04A61P17/06A61P19/02A61P19/06A61P21/04A61P25/00A61P25/28A61P29/00A61P35/00A61P35/02A61P37/00A61P37/02A61P37/04A61P37/06A61P37/08A61P43/00A61P5/14A61P7/00A61P7/02A61P7/06A61P9/00A61P9/10A61P3/10A61K39/395A61K47/12A61K47/18C07K16/28
Inventor LU, XIAOFENGCHEN, BAO-LUARAYA, KIDISTIOKHAMAFE, AUGUSTUS
Owner XOMA TECH LTD
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