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Combination of lenalidomide or pomalidomide and CD38 antibody-attenuated interferon-alpha constructs, and the use thereof

A technology of lenalidomide and interferon α, applied in the direction of interferon, cytokines/lymphokines/interferons, antibodies, etc., can solve the problem of undesired activity of IFN on healthy cells and other problems

Active Publication Date: 2017-03-22
TEVA PHARMA AUSTRALIA PTY LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this approach can lead to increased IFN activity against cancer cells, it does not fully address the problem of the undesirable activity of IFN on healthy cells

Method used

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  • Combination of lenalidomide or pomalidomide and CD38 antibody-attenuated interferon-alpha constructs, and the use thereof
  • Combination of lenalidomide or pomalidomide and CD38 antibody-attenuated interferon-alpha constructs, and the use thereof
  • Combination of lenalidomide or pomalidomide and CD38 antibody-attenuated interferon-alpha constructs, and the use thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0111] Cell line model of IFNα-2b construct + lenalidomide combination therapy inactivated by anti-CD38 antibody

[0112] In these experiments, 0.2 ml of 50% The matrix was implanted subcutaneously in the flank of 8-12 week old female CB.17 severe combined immunodeficiency (SCID) mice. When the tumor reaches 200-300mm 3When the average size of , mice were pair-matched into different groups and then treated with vehicle (PBS), 0.5 mg / kg of free non-sterilized interferon-α (IFN-α), a suboptimal dose of Anti-CD38 antibody-IFNα-2b-145D construct (2.5mg / kg molar equivalent equivalent to 0.5mg / kg IFN; intraperitoneally, biweekly as determined by the aforementioned in vivo efficacy study), isotype-matched antibody-IFNα - 2b-145D construct (isotype matched to anti-CD38 antibody, not anti-CD38 specific), lenalidomide alone (2.5mg / kg), free non-sterilized interferon alpha and lenalidomide combination of lenalidomide and suboptimal doses of anti-CD38 antibody-IFNα-2b-145D construct o...

example 2

[0116] Cell line model of glycosylated IFNα-2b construct + lenalidomide combination therapy inactivated by anti-CD38 antibody

[0117] In this experiment, will contain 1×10 7 50% of H929 multiple myeloma cells 8-12 week old female CB.17 severe combined immunodeficiency (SCID) mice were implanted subcutaneously in the flank. Tumor volumes were measured biweekly by calipers. When the tumor reaches 170-350mm 3 At an average size of , mice were randomly assigned and treatment was initiated. If the tumor grows to more than 2000mm before completing the study by day 60 3 volume, then sacrifice the animal.

[0118] In this example, the dose levels and dosing intervals of the administration of a fusion of an anti-CD38 antibody and killed glycosylated interferon-α2b (A10.21(T106A)) in combination with lenalidomide were studied. A10.21(T106A) is an anti-CD38 IgG4 antibody x10.21 fused to glycosylated inactivated IFNα2b with substitutions A145D and T106A. Treatment regimens and re...

example 3

[0124] Pollidomide Research

[0125] These experiments were performed to determine the non-curative dose therapy of anti-CD38 antibody fused to sterilized interferon-α2b compared with the non-curative effect of polilidomide in the H929 human multiple myeloma xenograft model in female CB17SCID mice. Efficacy of combinations of curative dose therapies. Pollidomide, like lenalidomide, is a derivative and analog of thalidomide with increased efficacy and reduced toxicity against multiple myeloma.

[0126] Simply put, the 1×10 7 Sixty female CB.17 SCID mice were injected subcutaneously into the right flank of each H929 tumor cell. When the tumor reaches 150mm 3 Treatment with polilidomide and anti-CD38 antibody fused to sterilized interferon to α2b was initiated at the mean volume of . Study in tumor volume up to 2000mm 3 when terminated. The cohorts were divided as follows, as outlined in Table 6: Group 1, vehicle (PBS); Group 2, polilidomide alone (2.5 mg / kg); Group 3, IFNα...

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Abstract

Methods for cancer treatment include administering to a cancer patient an anti- CD38 antibody-attenuated human IFN alpha-2b construct and lenalidomide or pomalidomide. Tumors that may be treated according to these methods include tumors which comprise CD-38 expressing tumor cells, including B-cell lymphoma, multiple myeloma, non-Hodgkin's lymphoma, chronic myelogenous leukemia, chronic lymphocytic leukemia, and acute lymphocytic leukemia.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Application Serial No. 61 / 986,913, filed May 1, 2014, which is hereby incorporated by reference in its entirety and for all purposes. [0003] References to Sequence Listings [0004] This application includes an electronically filed Sequence Listing created on May 1, 2015 in the text file SEQ_LST_Lenalidomide_ST25.TXT, which is 284,000 bytes in size. The Sequence Listing is incorporated herein by reference. technical field [0005] The present invention relates generally to the field of cancer treatment. More specifically, the present invention relates to cancer therapy that synergistically combines lenalidomide or polilidomide with an anti-CD38 antibody inactivated interferon alpha-2b construct. The combination therapy substantially enhances tumor growth inhibition or delay compared to tumor growth inhibition or delay exhibited by administration of lenalidomide, ...

Claims

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Application Information

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IPC IPC(8): C07K16/46C07K16/30C07K14/56A61K39/395A61K38/21A61K31/454A61P35/00
CPCC07K14/56C07K2319/035A61K45/06A61K47/6813A61K47/6867A61K38/212C07K16/2896C07K2319/33A61K31/454A61K39/39558A61P35/00A61P35/02A61K2300/00A61K2039/505C07K16/28C07K16/3061C07K2317/515C07K2317/56
Inventor 莎拉·L·波格大卫·S·威尔逊安东尼·杰拉德·道尔科莱特·简·贝伦斯
Owner TEVA PHARMA AUSTRALIA PTY LTD
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