Compositions and methods for enhancing the killing of target cells by nk cells

一种NK细胞、B细胞的技术，应用在化学仪器和方法、抗受体/细胞表面抗原/细胞表面决定因子免疫球蛋白、药物组合等方向，能够解决患者不适合免疫疗法等问题

Pending Publication Date: 2021-02-19
COMPASS THERAPEUTICS LLC
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, patients with low levels of antigen expression are not candidates for some of the available immunotherapies

Method used

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  • Compositions and methods for enhancing the killing of target cells by nk cells
  • Compositions and methods for enhancing the killing of target cells by nk cells
  • Compositions and methods for enhancing the killing of target cells by nk cells

Examples

Experimental program
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Effect test

example 1

[0490] Multispecific antigen-binding constructs targeting BCMA and NKp30 enhance NK effector function

[0491] To analyze the effect of multispecific antigen-binding constructs targeting BCMA and NKp30 on NK cells, primary human NK cells were primed with 10 ng / mL IL-15 and treated with BCMA-expressing target cells from the multiple myeloma cell line H929 and 10 nM of a multispecific antigen-binding construct described herein in a format comprising an intact antibody (IgG1 ) in which each arm is specific for an overnight incubation (in the presence of 10 IU / mL IL-2). A scFv that specifically binds BCMA and specifically binds human NKp30 at the C-terminus of each heavy chain. The first antigen binding domain comprises the heavy chain (SEQ ID NO: 2) and light chain variable region (SEQ ID NO: 1 ) of the exemplary CA8 antibody described in US Patent No. 9,273,141. The scFv comprises an antibody produced by hybridoma I-2576 (described in detail in U.S. Patent No. 7,517,966 relatin...

example 2

[0501] Multispecific antigen-binding constructs targeting BCMA and NKp30 enhance NK effector function in the absence of CD16 expression by NK cells

[0502] To analyze the effect of multispecific antigen-binding constructs targeting BCMA and NKp30 on NK cells in the absence of CD16 expression, antibodies that cannot bind CD16 ( Figure 2A and Figure 2B ). Glycosylated multispecific antigen-binding constructs targeting BCMA and NKp30 retained the ability to bind CD16, whereas aglycosylated antibodies lacked the ability to bind CD16.

[0503] Peripheral blood mononuclear cells (PBMC) were isolated from the buffy coat of human peripheral blood using density gradient centrifugation. NK cells (CD3-CD56+) are isolated from PBMCs using magnetic beads for negative selection, and the purity of isolated NK cells is typically greater than 90%. Isolated NK cells were cultured overnight in media supplemented with IL-2 and IL-15 and then used for cytotoxicity or IFNγ release assays. Th...

example 3

[0508] Multispecific antigen-binding constructs targeting BCMA and NKp30 exhibit superior activity

[0509] To analyze the effect of multispecific antigen-binding constructs targeting BCMA and NKp30 targeting both NKp30 and CD16, various constructs ( Figure 5A , Figure 5B and Figure 5C ). Multispecific antigen-binding constructs targeting BCMA and NKp30 targeting both NKp30 and CD16 were demonstrated to exhibit superior activity as measured by the amount of IFNγ produced or the percentage of specific lysis.

[0510] Figure 5A shows the results when using H929 tumor cells, and Figure 5B and Figure 5C Results are shown when using MM.1S tumor cells, which express BCMA at low levels. Multispecific antigen-binding constructs targeting BCMA and NKp30 exhibited resistance to NKp30-BCMA Fc-null constructs ( Figure 4A), BCMA monoclonal antibody ( Figure 5A , Figure 5B and Figure 5C ), Her2IgG1 isotype control ( Figure 4A Middle), CD16-BCMA bispecific construct ( ...

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Abstract

The present disclosure provides immunotherapeutic compositions and methods for enhancing an immune response and for treating cancer or inflammatory conditions mediated by autoreactive B cells in a subject. In some aspects, multispecific antigen-binding constructs are provided that recognize at least one tumor antigen or B-lineage cell antigen and NKp30 and / or another activating NK receptor. In some aspects, multispecific antigen-binding constructs are provided that recognize at least two tumor antigens or two antigens expressed by B-lineage cells, NKp30, and another activating NK receptor. Themultispecific antigen-binding constructs and methods disclosed herein can be used for the treatment of cancer, even a cancer characterized by a CD16 deficient microenvironment and / or characterized bytarget cells (e.g., cancer cells) having a low level of expression of the tumor antigen.

Description

[0001] Cross References to Related Applications [0002] This application claims U.S. Provisional Patent Application No. 62 / 674,289 filed May 21, 2018; U.S. Provisional Patent Application No. 62 / 674,279 filed May 21, 2018; U.S. Provisional Patent Application No. 62 / 674,286; U.S. Provisional Patent Application No. 62 / 728,542 filed September 7, 2018; U.S. Provisional Patent Application No. 62 / 731,030 filed September 13, 2018; U.S. Provisional Patent Application No. 62 / 731,045 filed on the 13th; U.S. Provisional Patent Application No. 62 / 731,047 filed on September 13, 2018; U.S. Provisional Patent Application No. 62 / 756,012 filed on November 5, 2018; U.S. Provisional Patent Application No. 62 / 760,473, filed November 13, 2018; U.S. Provisional Patent Application No. 62 / 760,670, filed November 13, 2018; U.S. Provisional Patent Application No. 62, filed November 13, 2018 / 760,644; U.S. Provisional Patent Application No. 62 / 767,786, filed November 15, 2018; U.S. Provisional Patent App...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28C07K16/30C07K16/32A61P37/06A61P35/00A61P35/02
CPCA61K2039/505A61K2039/585A61P35/00A61P35/02A61P37/06C07K16/2803C07K16/2878C07K16/30C07K16/32C07K2317/31C07K2317/34C07K2317/35C07K2317/41C07K2317/565C07K2317/64C07K2317/732C07K2317/74C07K2317/90C07K2317/92A61K47/6849A61K47/6851C07K2317/32C07K2317/40C07K2317/52C07K2317/622C07K2317/72C07K2317/76
Inventor J·沃特金斯M·M·施密特M·德拉吉A·F·乌潘特S·M·哈尔莫斯T·J·舒茨J·M·拉乔伊A·内尔松
Owner COMPASS THERAPEUTICS LLC
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