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Sirp-alpha immunoglobulin fusion proteins

A technology of immunoglobulin and fusion protein, applied in the direction of immunoglobulin, anti-animal/human immunoglobulin, anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, etc., which can solve the reverse immune control mechanism And other issues

Pending Publication Date: 2017-08-29
MERCK PATENT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, as cancer cells strive to enhance their survival, they reverse normal immune control mechanisms to evade immune surveillance by overexpressing CD47, making them resistant to macrophages

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0185] Example 1: Effect of anti-CD47 B6H12 on cynomolgus monkey erythrocytes

[0186] The in vivo effect of an anti-CD47 B6H12 monoclonal antibody (chimeric B6H12-human IgG4 (Lindberg et al., JBC 269: 1567, 1994)) on red blood cells (RBC) was evaluated in cynomolgus monkeys. A group of 3 monkeys received a single intravenous dose of 12 mg / kg of B6H12 on day 0. Blood samples were taken for RBC counts and hematocrit (HCT) determinations at -10 (10 days prior to injection to obtain baseline levels), 0, 1, 3, 5 and 7 days after the single intravenous administration. Figure 2A -B shows that on day 5 ( Figure 2A ), red blood cells from 5.8×10 9 Drastically reduced to 3.7×10 9 RBC / mL, a 40% decrease, and a corresponding decrease in hematocrit levels ( Figure 2B ). Therefore, treatment with anti-CD47 antibodies can lead to severe anemia.

Embodiment 2

[0187] Example 2: Anti-CD20-huIgG1-SIRPα immunoglobulin fusion protein

[0188] 2 (A) Construction and expression of anti-CD20-huIgG1-SIRPα

[0189] An exemplary anti-CD20-huIgG1-SIRPα generation was based on an anti-CD202B8 (rituximab) monoclonal antibody (Reff et al., Blood 83:435, 1994) and the SIRPα protein (Jiang et al., JBC 274:559, 1999). The DNA and protein sequences of the Fab light chain of 2B8 are provided in SEQ ID NO: 1 and SEQ ID NO: 2, respectively. The DNA and protein sequences of the Fab heavy chain of 2B8 are provided in SEQ ID NO: 3 and SEQ ID NO: 4, respectively. The DNA and protein sequences of SIRPα allele V1 are provided in SEQ ID NO: 5 and SEQ ID NO: 6, respectively. The DNA and protein sequences of the IgV domain of SIRPα allele V2 are provided in SEQ ID NO: 7 and SEQ ID NO: 8, respectively. By via (G4S) 4 A linker joined the C-terminus of the anti-CD20 heavy chain polypeptide to the IgV domain of SIRPαV2 to generate anti-CD20-huIgG1-SIRPαV2.

[...

Embodiment 3

[0201] Example 3: Anti-CD20 / anti-CD47 bispecific antibody

[0202]3(A) Description of anti-CD20 / anti-CD47

[0203] Generation of an exemplary tetravalent bispecific antibody (TetBiAb) against CD20 and CD47 was based on the anti-CD202B8 (rituximab) monoclonal antibody (Reff et al., Blood 83:435, 1994) and the anti-CD47 B6H12 monoclonal antibody ( Lindberg et al., JBC 269:1567, 1994). In anti-CD20 / anti-CD47 TetBiAbs against CD20 and CD47, the C-terminus of the anti-CD20 heavy chain polypeptide was linked to the N-terminus of the anti-CD47 Fab light chain via a G4S linker ( Figure 1D +E). International Patent Application Publication No. WO2014 / 144357 describes the construction, expression, and binding properties of anti-CD20 / anti-CD47.

[0204] 3(B) In vivo biological activity of anti-CD20 / anti-CD47

[0205] The following in vivo experiments used anti-CD20 / anti-CD47 as a surrogate for anti-CD20-huIgG1-SIRPα. In a diffuse lymphoma model, SCID mice were injected intravenously...

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PUM

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Abstract

The invention discloses immunoglobulin fusion proteins designed to bind both CD47 and a tumor cell antigen. The immunoglobulin fusion proteins include a SIRP afla moiety that binds CD47 and an antigen binding site for a tumor cell antigen.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Patent Application 62 / 038,196, filed August 15, 2014, which is hereby incorporated by reference in its entirety. technical field [0003] The present invention generally relates to fusion proteins capable of binding CD47 and surface antigens on disease-promoting cells, such as tumor cells. Background technique [0004] Macrophages are the main phagocytic cells that clear diseased cells, such as cancer cells, by phagocytosis. Whether macrophages phagocytize target cells depends on the relative strength of pro-phagocytic and anti-phagocytic signals. [0005] Normal, healthy cells are protected from phagocytosis because CD47, which is ubiquitously expressed on normal cells, interacts with Signal Regulatory Protein Alpha (SIRPα) on macrophages, automatically triggering the "don't eat me" signal. [0006] However, as cancer cells strive to enhance their survival, they ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K19/00C12N15/62A61K39/395A61K47/64A61P35/00A61P35/02
CPCC07K14/4702C07K16/2863A61K2039/505C07K2319/33C07K14/70596C07K2317/31A61K38/00C12N9/16C07K16/2887C07K16/30C07K16/32C07K16/2827C07K16/2803C12Y301/03048C07K2317/622C07K2319/74A61P35/00A61P35/02A61K47/6811
Inventor 劳健明N·泽兹斯佩格A·斯尔卡
Owner MERCK PATENT GMBH
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