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Combination therapy with an anti - CD19 antibody and a nitrogen mustard

An antibody and sequence technology, applied in the field of combined therapy using anti-CD-19 antibody and nitrogen mustard, can solve problems such as poor prognosis of cancer

Active Publication Date: 2014-04-16
MORFOZIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] Clearly, despite recent advances in the discovery and development of anticancer agents, many forms of cancer involving CD19-expressing tumors still have a poor prognosis

Method used

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  • Combination therapy with an anti - CD19 antibody and a nitrogen mustard
  • Combination therapy with an anti - CD19 antibody and a nitrogen mustard
  • Combination therapy with an anti - CD19 antibody and a nitrogen mustard

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0075] One aspect of the present disclosure includes a CD19-specific antibody in combination with a nitrogen mustard for the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and / or acute lymphoblastic leukemia. In an embodiment, the combination is synergistic.

[0076] Here, the exemplified combination of an anti-CD19 antibody and bendamustine acts synergistically in in vitro and in vivo models associated with NHL and CLL. Since both NHL and CLL are B cell related disorders and CD19 is highly expressed on B cells, the exemplified combination should have the same mechanism of action in the treatment of other B cell related disorders such as ALL and should also work synergistically effect. Thus, combinations of the exemplified CD19-specific antibodies with bendamustine will be effective in the treatment of human non-Hodgkin's lymphoma, chronic lymphocytic leukemia and / or acute lymphoblastic leukemia.

[0077] Since the mechanism of action of bendamustine and ...

Embodiment 1

[0092] Example 1 : MOR00208 and bendamustine alone and in combination inhibit the proliferation of MEC-1 cells

[0093] Material

[0094] MEC-1 cells: chronic B-cell leukemia cell line DSMZ#ACC497; cell culture medium: with GlutaMAX TM Iscove's Modified Dulbecco's Medium (IMDM), Invitrogen, Cat No.: 31980-048, 20% FCS; PBMC: RPMI1640 with stabilized glutamine, PAN Biotech GmbH, Cat No.: P04-13500 supplemented with 10 %FCS; Biocoll: Biochrome AG CAT No.:L6115LOT No.:1050T; Bendamustine: Mundipharma LOT No.:88018; FCS: PAN CAT No.:3302-P282403LOT No.:P282403; and RefmAb33 (anti- RSV), the Fc region is the same as MOR00208.

[0095] method

[0096] The cytotoxicity of MOR00208 and bendamustine alone and in combination was tested in MEC-1 cells. BEN is an alkylating agent and thus acts via direct cytotoxicity in MEC-1 cells. MOR00208 targets CD19 and additionally functions via ADCC in the killing of MEC-1 cells. MEC-1 cell killing was measured in the following groups: ...

Embodiment 2

[0125] MOR00208 and BEN alone and in combination were subcutaneously (SC)-implanted into a human Ramos Burkitt's B-cell lymphoma tumor growth model.

[0126] Material

[0127] RAMOS human Burkitt's lymphoma cells (ATCC number CRL-1596, lot #3953138); vehicle control: 150mM NaCl, 25mg / mL mannitol, pH5.5-6.0; (adjusted with 0.01M NaOH). Ref_mAb_33_IgG_Xen (10 mg / mL in PBS, called Ref_mAb_33). Six-week-old female C.B-17SCID mice (CB17 / lcr-Prkdcscid / lcrlcoCrl) were purchased from Charles River Laboratories (Wilmington, MA) and acclimatized in the laboratory for 9 days before experiments.

[0128] method

[0129] SCID mice were subcutaneously implanted with RAMOS cells (~5x10 6 cells / mouse). When the mouse has a size of about 150mm 3 , or ~14 days after inoculation, they were divided into groups, where each group had tumor volumes that were more similar in size. Treatment started on day 15. Treatment regimens are provided in Table 4. The study duration was 60 days.

[...

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Abstract

The present disclosure describes a pharmaceutical combination of an anti-CD19 antibody and a nitrogen mustard for the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia and / or acute lymphoblastic leukemia.

Description

[0001] cross reference [0002] This application claims U.S. Provisional Application No. 61 / 654,097, filed June 1, 2012, U.S. Provisional Application No. 61 / 647,539, filed May 16, 2012, and U.S. Provisional Application No. 61 / 523,861, which is hereby incorporated by reference in its entirety. field of invention [0003] The present disclosure relates to pharmaceutical combinations of anti-CD19 antibodies and nitrogen mustards for the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia and / or acute lymphoblastic leukemia. Background technique [0004] B cells are lymphocytes that play a major role in the humoral immune response. They are produced in the bone marrow of most mammals and represent 5-15% of the circulating lymphoid pool. The main function of B cells is to make antibodies against different antigens and is an essential part of the adaptive immune system. [0005] Due to their critical role in regulating the immune system, disregulation of B cells ...

Claims

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Application Information

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IPC IPC(8): A61K39/395C07K16/28
CPCA61K39/39558C07K16/30A61K39/3955A61K31/4184C07K16/2803A61K2039/505A61P35/00A61P35/02A61P43/00A61K2300/00C07K16/28
Inventor J·阿默斯道费尔S·施泰德尔M·温德尔里奇S·科龙L·罗伊杰尔
Owner MORFOZIS AG
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