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Methods for characterizing and treating acute myeloid leukemia

A Myeloid Leukemia, Acute Technology Applied in the Improved Field of Treatment for AML Relapse

Inactive Publication Date: 2017-02-22
IMMUNOGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Despite high initial response rates to chemotherapy, many patients with acute myeloid leukemia (AML) fail to achieve complete remission

Method used

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  • Methods for characterizing and treating acute myeloid leukemia
  • Methods for characterizing and treating acute myeloid leukemia
  • Methods for characterizing and treating acute myeloid leukemia

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0318] Example 1: IMGN779 exhibits CD33-specific in vitro cytotoxicity against primary patient AML cells

[0319] CD33 levels and P-glycoprotein (Pgp) activity were measured by flow cytometry. Staining with WST-8 viability, the cytotoxic potency of DGN462 and IMGN779 in AML cell lines was assessed using serial exposure up to 7 days. The potency of IMGN779 was assessed against primary AML samples and normal bone marrow (NBM) using a colony formation assay after 24 hours of exposure and after long-term liquid culture to assess potency in leukemic progenitor and leukemic stem cells, respectively. The antitumor activity of IMGN779 was evaluated in SCID mice bearing subcutaneous HL60 / QC and EOL-1 xenografts.

[0320] Pharmacokinetic parameters in CD-1 mice were determined from plasma concentrations of IMGN779 conjugate and its total Z4681A antibody fraction at various time points measured by ELISA. The biological activity of a subset of these plasma samples was confirmed by assay...

Embodiment 2

[0323] Example 2: CD33 Expression on Primary Patient AML Cells

[0324] CD33 expression on primary patient AML cells was measured using a calibrated flow cytometry method ( figure 1). Staining of AML samples with fluorescently-labeled anti-CD33 antibodies and comparison of the fluorescence signal with the calibration curve obtained using fluorescently-labeled beads at different marker-to-bead ratios allows the determination of the total number of CD33 antibodies bound per AML cell (ABC value ). CD33 is expressed at relatively low levels in patient AML cells, with a maximum expression of approximately 17,000 antigens per cell (ABC).

Embodiment 3

[0325] Example 3: IMGN779 demonstrates highly potent and CD33-specific in vitro cytotoxicity against primary patient AML cells.

[0326] The cytotoxic activity of IMGN779 was assessed against a panel of primary patient AML cells in a colony formation assay after 24 hours of conjugate exposure ( figure 2 ).

[0327] The activity of CD33-targeting maytansinoid ADCs (using the same antibody in IMGN779) was assessed on a subset of these samples. IMGN779 is highly active against patient AML cells, IC 50 Values ​​range from 11 pM to 1.6 nM, dependent on CD33 expression level. CD33 levels range from approximately 200 to 16,000 antigens per cell. In comparison, CD33-targeting maytansinoid ADCs were 60 to 9,000-fold less active than IMGN779, independent of CD33 expression levels. figure 2 In vitro potency of IMGN779 compared to CD33-targeted maytansinoid ADC against patient AML cells is shown.

[0328] Use 0.3nM IC 50 Cut-off defines a high level of sensitivity (compared to the...

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PUM

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Abstract

The invention features methods for characterizing and treating acute myeloid leukemia (AML) (e.g., newly diagnosed, relapsed, and refractory AML) in a subject using immunoconjugates of the invention. In one aspect, the invention generally features a method of treating acute myeloid leukemia in a subject (e.g., a human), the method involving administering an effective amount of an immunoconjugate to a pre-selected subject, where the immunoconjugate contains a humanized or chimeric antibody or fragment conjugated to a cytotoxic benzodiazepine dimer compound via a cleavable disulfide linker.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to, respectively, U.S. Provisional Patent Application Serial Nos. 62 / 001,015, filed May 20, 2014; 62 / 011,456, filed June 12, 2014; and 62 / 075,715, filed November 5, 2014 and rights and interests. The entire contents of each of these applications are hereby incorporated by reference herein. [0003] Background of the invention [0004] Acute myeloid leukemia (AML) is associated with the accumulation of abnormal blast cells in the bone marrow. Acute myeloid leukemia (AML) is one of the most common types of leukemia in adults. In the United States alone, more than 18,000 new cases of AML are identified each year, and more than 10,000 deaths are related to AML. Despite high initial response rates to chemotherapy, many patients with acute myeloid leukemia (AML) fail to achieve complete remission. In fact, most AML patients relapse within 3-5 years from diagnosis. AML relapse is thought to ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395
CPCA61K47/6889A61K47/6803A61K47/6867C07K16/2803A61K2039/505C07K2317/73C07K2317/94A61P35/02A61K31/5517C12Q1/6886C12Q2600/158G01N33/57426G01N2333/70596G01N2333/82
Inventor K·R·怀特曼P·努尔德修斯Y·科夫通R·J·卢茨G·J·舒尔修斯R·M·沃克
Owner IMMUNOGEN INC
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