Formulation for Anti-alpha4beta7 antibody

Inactive Publication Date: 2012-11-08
MILLENNIUM PHARMA INC
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009]The invention relates to the identification of a non-reducing sugar and at least one amino acid, as useful excipients for formulating anti-α4β7 antibody formulations whose instability mak

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.
Proteins may suffer from a lack of stability, and monoclonal and polyclonal antibodies in particular may be relatively unstable (See e.g., Wang et al., J.
A large number of formulation options are available, and not one approach or system is suitable for all proteins.
In fact, even in the case of purified antibodies, the antibody structures may be heterogeneous, which further complicates the formulation of such systems.
Physical instability can result from denaturation,

Method used

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  • Formulation for Anti-alpha4beta7 antibody
  • Formulation for Anti-alpha4beta7 antibody
  • Formulation for Anti-alpha4beta7 antibody

Examples

Experimental program
Comparison scheme
Effect test

Example

Example 1

Comparative Data for Varying % Sugar and Amino Acids in Lyophilized Formulations

[0204]A design of experiments approach was performed to look at the effect of varying the molar ratio of sugar (sucrose and mannitol) to protein, the molar ratio of arginine to protein, and the molar amount of histidine buffer. Histidine and arginine are known not to crystallize during the lyophilization process, making them potential cryo or lyo protectants. 1.5 mL of formulation was filled into 5 mL vials lyophilized with Primary Drying at −30° C., 150 mT and Secondary Drying at 20° C., 150 mT. The stability of the lyophilized formulations reconstituted to 1.5 ml after different storage conditions is shown in Tables 1-3 (compiling 60 mg / ml results from two experiments). FIG. 6A shows the predictive models for changes in Percent Monomer, Percent Aggregates, and Percent Major Isoform when stored at 40° C. when pH and the molar ratio of sugar and arginine was varied. The stability of the formulat...

Example

Example 2

Stability Data

[0207]Three primary stability batches of the formulation (Batch A, B, and C) were tested for stability after storage at the prescribed storage condition (5 and 25° C. / 60% RH for up to 24 months). All three batches contain the same liquid formulation that was lyophilized: 60 mg / mL anti-α4β7 antibody, 50 mM histidine, 125 mM arginine, 10% sucrose, 0.06% polysorbate 80, pH 6.3. For Batch A, 3.5 mL of solution was filled into 20 mL vials and lyophilized, for Batches B and C, 5.52 mL of solution was filled into 20 mL vials and lyophilized.

[0208]In a separate study, a single drug formulation of 60 mg / ml anti-α4β7 antibody, 50 mM histidine, 125 mM arginine, 10% sucrose, 0.06% polysorbate 80, pH 6.3 was lyophilized in two volumes, 3.5 ml and 9.5 ml, respectively, to yield Batches R and S for stability samples, which were analyzed over 38 months. Blanks are NT (not tested).

[0209]The data (Tables 4-19) showed that the antibody formulations remained stable when stored fo...

Example

Example 3

Modeling the Scale-Up of the Lyophilization Process

[0226]Quality by design was used while manipulating the load in the freeze dryer and the solids content of the formulation. The load was varied from 33 to 100%. The formulation solids content was varied from 9 to 27% by including in the loads a formulation which was either 0.5×, 1.0× and 1.5× of the target formulation. These formulations had similar Tg′. With higher % solids, the primary drying time increased. In addition, at higher solids content, the product temperature increased due to larger Rp. The load also has an effect on both stages of drying (FIG. 8).

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Abstract

Antibody formulations are described comprising a mixture of a non-reducing sugar, an anti-α4β7 antibody and at least one amino acid. The disclosed formulations have improved stability, reduced aggregate formation, and may retard degradation of the anti-α4β7 antibody therein or exhibit any combinations thereof. The present invention further provides a safe dosing regimen of these antibody formulations that is easy to follow, and which results in a therapeutically effective amount of the anti-α4β7 antibody in vivo.

Description

RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Application 61 / 585,859 filed on Jan. 12, 2012, U.S. Provisional Application 61 / 550,545 filed on Oct. 24, 2011, and U.S. Provisional Application 61 / 481,533 filed on May 2, 2011. The entire contents of the foregoing applications are hereby incorporated by reference.SEQUENCE LISTING[0002]The instant application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Apr. 30, 2012, is named 92596614.txt and is 17,047 bytes in size.BACKGROUND OF THE INVENTION[0003]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 fo...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61P29/00A61P1/04A61P1/00
CPCC07K16/2839A61K2039/505C07K2317/565A61K2039/545C07K2317/24A61K2039/54A61K9/0019A61K9/19A61K39/39591A61K47/183A61K47/26C07K2317/94C07K2317/92C07K2317/14A61P1/00A61P1/04A61P29/00A61P37/00A61P37/02A61K9/08A61K47/22
Inventor FOX, IRVING H.SCHOLZ, CATHERINE
Owner MILLENNIUM PHARMA INC
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