Compositions comprising a combination of an Anti-pd-1 antibody and another antibody

a technology of anti-pd-1 antibody and antibody, which is applied in the field of compositions containing a combination of anti-pd-1 antibody and another antibody, can solve the problems of multiple intravenous injections at different times, and the difficulty of single formulation identification

Inactive Publication Date: 2016-10-20
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
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Benefits of technology

[0032]The pharmaceutical composition of the invention can exhibit a minimal change of an acidic peak upon stress, e.g., after being stored at a particular temperature for a long period of time. In one embodiment, the composition exhibits a change of an acidic peak less than about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, or about 1% after being stored for about 6 months or about 3 months at about 5° C. In certain embodiments, the composition exhibits a change of an acidic peak that is less than about 15%, about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2% or about 1% after being stored for about 3 months at about 25° C. In other embodiments, the composition exhibits a change of an acidic peak that is less than about 15%, about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2% or about 1% after being stored for about 3 months at about 40° C.
[0033]The composition of the invention can also exhibit a minimal change of high molecular weight peak after being stored for a long period of time, several weeks, months, or years. In one embodiment, the composition exhibits a change of a high molecular weight peak less than about 5%, about 4%, about 3%, about 2%, about 1.5%, about 1.4%, about 1.3%, about 1.2%, about 1.1%, about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1% after being stored for about 3 months at about 4° C. In another embodiment, the composition exhibits a change of a high molecular weight peak that is less than about 5%, about 4%, about 3%, about 2%, about 1.5%, about 1.4%, about 1.3%, about 1.2%, about 1.1%, about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1% after being stored for about 2 months or about 3 months at about 25° C. In other embodiments, the composition exhibits a change of a high molecular weight peak that is less than about 5%, about 4%, about 3%, about 2%, about 1.5%, about 1.4%, about 1.3%, about 1.2%, about 1.1%, about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1% after being stored for about 2 months or about 3 months at about 40° C.
[0034]Furthermore, in certain embodiments, the composition can exhibit a minimal

Problems solved by technology

Nonetheless, administering two antibodies can be burdensome due to different dosing and dosing interval between two antibodies, thereby causing multiple intravenous injections at different t

Method used

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  • Compositions comprising a combination of an Anti-pd-1 antibody and another antibody
  • Compositions comprising a combination of an Anti-pd-1 antibody and another antibody
  • Compositions comprising a combination of an Anti-pd-1 antibody and another antibody

Examples

Experimental program
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example 1

[0203]A feasibility study was performed to evaluate the stability of ipilimumab and nivolumab in a single fixed dose ratio combination (FDRC) formulation created by mixing the individual formulations of ipilimumab and nivolumab (FIG. 1) to a final ratio of ipilimumab to nivolumab of 1:1.

[0204]Ipilimumab (BMS-734016) DP contains 5 mg / mL ipilimumab in 20 mM Tris-HCl, 100 mM NaCl, 1.0% (w / v) Mannitol, 100 μM pentetic acid (DTPA), and 0.01% polysorbate 80 (PS80), at pH 7.0, and it is available as 40 mL in a 50 mL bottle and 10 ml in a 10 ml vial (FIG. 1). Nivolumab (BMS-936558) DP contains 10 mg / mL nivolumab in 20 mM citrate buffer (sodium citrate dihydrate), 50 mM NaCl, 3.0% (w / v) Mannitol, 20 μM DTPA, and 0.02% PS80, at pH 6.0, and it is available as 10 mL in a 10 ml vial (FIG. 1).

[0205]To achieve a 1:1 ratio of ipilimumab to nivolumab, 80 mL of ipilimumab DP (2 bottles) was mixed with 40 mL of nivolumab DP (4 vials), yielding a combined product having 3.3 mg / mL ipilimumab and 3.3 mg / ...

example 2

[0213]A feasibility study was performed to evaluate the stability of an ipilimumab / nivolumab FDRC created by mixing the individual formulations of ipilimumab and nivolumab to final ratios of 3:1, 1:1, and 1:3 (Table 3). The FDRC formulations were generated by mixing the ipilimumab DS at 5 mg / mL and nivolumab DS at 20 mg / mL to achieve 3:1, 1:1, and 1:3 protein ratios (Table 3). Each combined solution was further mixed with a stir bar at room temperature for 30 min, transferred to vials, and stored for stability over time. The vials were stored at 5° C., 25° C., and 40° C. for up to 12 months.

TABLE 3EC FDRC (3:1; 1:1; 1:3)—Combinations of Formulations of Ipilimumab DP andNivolumab DPFinal Conc'n in Vial:(mg / mL)MannitolNaClDTPAPS 80PrototypeRatioIpiNivopH% w / vmMμM% w / vEC: pH 6.63:14.621.546.61.1596.1593.850.012EC: pH 6.01:32.868.576.01.8678.5765.710.023EC: pH 6.21:14.004.006.21.6783.3373.330.013Prototype EC: pH 6.6, having a 3:1 ratio of ipilimumab to nivolumab, contained 4.62 mg / mL ip...

example 3

[0219]A design of experiments (DoE) study was performed to identify new candidate ipilimumab / nivolumab formulations. Prototype ipilimumab / nivolumab FDRC (3:1) formulations were made in selected histidine or citrate formulations, as shown in Table 4. All DoE FDRC prototypes were prepared to a final concentration of ipilimumab / nivolumab of 10 mg / mL at a ratio of 3:1 (Table 4). FDRC prototype “Combo 4” contained 20 mM citrate, 50 mM NaCl, 50 μM DTPA, 6% w / v sucrose, and 0.05% w / v PS80, at a theoretical pH of 6. FDRC prototype “Combo 5” contained 20 mM histidine, 50 mM NaCl, 50 μM DTPA, 6% w / v sucrose, and 0.05% w / v PS80, at a theoretical pH of 6.0. FDRC prototype “Combo 6” contained 20 mM histidine, 50 mM NaCl, 50 μM DTPA, 6% w / v sucrose, and 0.05% w / v PS80, at a theoretical pH of 7. FDRC prototype “Combo New” contained 20 mM histidine, 50 μM DTPA, 8.5% w / v sucrose, and 0.05% w / v PS80, at a theoretical pH of 6. FDRC prototype “Combo 8,” which was similar to the current nivolumab DP for...

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Abstract

This provides pharmaceutical compositions that comprise a combination of an anti-cancer agent which is an first antibody and a second antibody. In some embodiments, the first antibody is an anti-Programmed Death-1 (PD-1) antibody. In certain embodiments, the composition is a fixed dose formulation. In certain embodiments, the composition is administered as a flat-dose. The disclosure also provides a kit for treating a subject afflicted with a disease, the kit comprising a dosage of any composition disclosed herein and instructions for using the composition in any of the disclosed methods for treating a disease.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The present application claims benefit to U.S. Provisional Application No. 62 / 303,855, filed Mar. 4, 2016; 62 / 269,000, filed Dec. 17, 2015; 62 / 265,268, filed Dec. 9, 2015; and 62 / 149,325, filed Apr. 17, 2015, which are incorporated herein by reference in their entireties.REFERENCE TO A SEQUENCE LISTING SUBMITTED ELECTRONICALLY VIA EFS-WEB[0002]The content of the electronically submitted sequence listing (Name: 3338_0260004_SL.txt; Size: 16,819 bytes; and Date of Creation: Apr. 15, 2016) is herein incorporated by reference in its entirety.[0003]Throughout this application, various publications are referenced in parentheses by author name and date, or by patent number or patent Publication number. The disclosures of these publications are hereby incorporated in their entireties by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described a...

Claims

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Application Information

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IPC IPC(8): C07K16/28C07K16/30
CPCC07K16/2803C07K2317/94C07K16/2878C07K16/28C07K16/30C07K16/3015C07K16/3023C07K16/303C07K16/3038C07K16/3046C07K16/3053C07K16/3069C07K2317/76C07K2317/21C07K16/2818A61K39/39591A61K47/02A61K47/12A61K47/18A61K47/183A61K47/26A61P35/00A61P35/02A61K2039/507A61K9/0019A61P1/04A61P1/18A61P11/00A61P13/00A61P13/08A61P13/10A61P13/12A61P15/00A61P17/00A61P19/00A61P25/00A61P27/02A61P31/00A61P5/00A61K2039/545
Inventor SADINENI, VIKRAMQUAN, YONGKASERER, WALLACE
Owner BRISTOL MYERS SQUIBB CO
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