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Therapeutic combinations comprising Anti-cd123 immunoconjugates

An immunoconjugate, BCL-2 technology, applied in the field of treatment of hematological malignancies, can solve the problems of inability to treat hematological malignancies and poor long-term survival of patients

Pending Publication Date: 2021-12-28
IMMUNOGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the long-term survival of these patients remains poor
[0007] Given the inability of currently available therapeutic agents to treat many hematological malignancies, more effective interventions are needed

Method used

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  • Therapeutic combinations comprising Anti-cd123 immunoconjugates
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  • Therapeutic combinations comprising Anti-cd123 immunoconjugates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0320] In vitro study of the combination of IMGN632 and venetoclax in AML cell lines

[0321] IMGN632 alone, venetoclax alone and IMGN632 with venetide were studied in in vitro cytotoxicity assays in four different acute myeloid leukemia (AML) cell lines EOL-1, KG-1, Molm-13 and MV4-11 Tork's combined activity.

[0322] EOL-1 , KG-1 , Molm-13 and MV4-11 cell lines were obtained at low passage (less than 10 passages), and cell cultures were maintained as recommended by their suppliers. Cells were harvested from the cell culture in logarithmic growth phase, counted by an automated hemocytometer, and distributed evenly into wells in a 96-well plate such that each well would contain five thousand viable cells / well. Each well contains an Fc receptor blocking, non-mammalian targeting chKTI monoclonal antibody such that the final well volume (200 μL) will contain 100 nM of chKTI. Dosage ranges of IMGN632 alone, venetoclax alone and IMGN632+venetoclax (in the case of venetoclax, t...

Embodiment 2

[0328] Materials and methods for subcutaneous and disseminated xenograft models

[0329] For all subcutaneous xenograft models, mice were weighed twice weekly and clinical signs were monitored throughout the study. Animals were euthanized upon hind leg paralysis, body weight loss greater than 20% of pre-treatment body weight, tumor ulceration, or when any signs of distress were visible.

[0330] Three-dimensionally measure tumor volume in the subcutaneous xenograft model using calipers once to twice a week. The tumor volume uses the formula V=length×width×height×1 / 2 in mm 3 indicated (Tomayko and Reynolds, Cancer Chemother. Pharmacol. 24:148-54 (1989)). Activity was assessed as described in Bissery et al., Cancer Res. 51:4845-52 (1991).

[0331]Tumor growth inhibition (T / C value) was assessed in a subcutaneous xenograft model using the formula: T / C (%) = (median tumor volume treated / median tumor volume control) x 100%. When the tumor volume of the vehicle control reached...

Embodiment 3

[0335] In vivo efficacy of the combination of IMGN632 (single dose) and venetoclax (QDx28) in the EOL-1 subcutaneous model

[0336] To test the efficacy of IMGN632, venetoclax, or the combination of these two agents in their ability to reduce tumor burden in vivo, a subcutaneous tumor model was used as described in the protocol below.

[0337] Female athymic nude mice were each subcutaneously inoculated on the right flank with 1×10 in 100 μl of 50% Matrigel:50% serum-free medium (v / v). 7 EOL-1 cells (human AML cell line). On day 9 (i.e., 24 hours prior to administration of the conjugate for groups receiving conjugate treatment (alone or in combination with venetoclax)), all mice in these treatment groups were injected intraperitoneally with 150 mg / kg of Antibody targeting chKTI to block Fc receptors on EOL-1 AML cells, thereby preventing non-specific uptake of the conjugate. On day 9 after EOL-1 inoculation, mice were randomized into study groups based on tumor volume.

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Abstract

Therapeutic combinations of immunoconjugates that bind to CD123 (e.g., IMGN632) with BCL-2 inhibitors (e.g., venetoclax), and / or a hypomethylating agent (e.g., azacitidine or decitabine) are provided. Methods of administering the combinations to treat hematological malignancies with clinical efficacy and / or decreased toxicity are also provided. Methods of treating hematological malignances present as minimal residual disease using immunoconjugates that bind to CD123 (e.g., IMGN632) are also provided.

Description

technical field [0001] The field of the invention relates generally to combinations of anti-CD123 immunoconjugates with hypomethylating agents (HMA) and / or B-cell leukemia / lymphoma-2 (BCL-2) antagonists for the treatment of blood Malignant tumor. Background technique [0002] Cancer is one of the leading causes of death in the developed world, where more than one million people are diagnosed with cancer and 500,000 die each year in the United States alone. Altogether, it is estimated that more than 1 in 3 people will develop some form of cancer in their lifetime. [0003] CD123 is the α-subunit of the interleukin-3 receptor (IL-3Rα). CD123 expression is low on normal hematopoietic stem cells (Testa et al., Biomark Res., 10; 2(1):4. (2014); Jordan et al., Leukemia, 14(10):1777-84 (2000)). However, CD123 is overexpressed in a variety of hematological malignancies of myeloid and lymphoid origin, including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), B-cell a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395
CPCA61K39/395C07K16/2866C07K2317/77A61K31/635A61P35/02A61K38/00A61K31/706A61K47/6849A61K45/06A61K47/68035A61K2300/00A61K47/6803A61P35/00A61K31/551
Inventor 沙琳·亚当斯卡勒姆·M·斯洛斯帕特里克·茨威德勒-麦凯
Owner IMMUNOGEN INC
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