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Compositions and methods for treating hemological disorders

A technology for blood disorders and red blood cells, applied in the field of compositions and methods for treating blood disorders, capable of solving problems such as not curing blood disorders

Pending Publication Date: 2022-07-12
ANNEXON
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Currently, there is no cure for blood disorders

Method used

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  • Compositions and methods for treating hemological disorders
  • Compositions and methods for treating hemological disorders
  • Compositions and methods for treating hemological disorders

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0409] Example 1: Anti-Clq antibody inhibits complement-mediated hemolysis in blood samples from CAD

[0410] Individual CAD serum samples were pooled together for hemolysis and FAC experiments with anti-Clq antibody titration. Hemolysis was performed by sensitizing RBCs with pooled CAD serum (1 hour at 4°C - 10 μL serum + 10 μL RBCs). Addition of 200 μL of 20x normal human serum at 37 °C triggers lysis for 35 min. After lysis, the supernatant was removed and hRBCs were stained with anti-C3 antibody (CT-C3), anti-C1q antibody and anti-C4 antibody for 30 min, washed once, and stained with fluorescent secondary anti-goat antibody for FACS analysis.

[0411] In CAD, RBCs are coated by the three major classical complement "opsonins" (C1q, C4b and C3b) that drive RBC clearance through "extravascular lysis". C1q, C4b and C3b are recognized by the reticuloendothelial system in the spleen and liver for RBC removal. Also in CAD, RBCs become coated with C5b, which triggers the form...

Embodiment 2

[0412] Example 2: Anti-Clq antibodies inhibit hemolysis and complement deposition in blood samples from CAD patients

[0413] CAD and control plasma samples

[0414] Human CAD plasma samples from 8 subjects were obtained according to IRB-approved protocols. Control serum and plasma samples were obtained from Innovative Research (Novi, MI).

[0415] In vitro sensitization of human RBCs

[0416] RBCs (Innovative Research, MI) were washed and suspended in GVB++ buffer (Comptech, TX) (80 μL of packaged RBCs in 2 mL GVB++ buffer). 25 μL of human RBCs were mixed with 25 μL of 5x diluted CAD or normal serum and incubated at 4°C for 30 minutes. This step allows the binding of cold agglutinin antibodies from CAD subjects to human RBC surface antigens.

[0417] Three subjects showed robust IgG deposition, while seven subjects showed robust IgM deposition. One subject showed low signal of cell surface IgG and IgM.

[0418] Hemolysis assay

[0419] Addition of normal human serum ...

Embodiment 3

[0426] Example 3 : Complement activation by PF4 / heparin via the classical pathway in plasma from patients with heparin-induced thrombocytopenia (HIT)

[0427]In HIT, RBCs are cleaved when the patient produces antibodies against heparin administered therapeutically in combination with the endogenous circulating protein PF4. To confirm that this cleavage is mediated by the classical pathway and not by the alternative pathway, differential sequestration studies using EDTA and EGTA were performed in vitro with plasma from HIT patients. The Mg2+-sensitive alternative pathway was inhibited by EDTA, but not by EGTA. like Figure 7A As shown in , addition of EDTA or EGTA to plasma prior to addition of PF4 / heparin abolished complement activation. Furthermore, Mg supplementation of EGTA-treated plasma did not rescue complement activation by PF4 / heparin. Plasma from healthy donors was incubated with or without C1 inhibitor (10 and 20 IU / mL) prior to incubation with PF4 / heparin, and ...

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Abstract

The present disclosure is generally directed to methods of preventing, reducing the risk of developing, or treating a blood disorder (e.g., hematologic disorders, etc. Condensate hemolytic anemia (condensate disease), cold antibody hemolytic anemia, ABO incompatible acute hemolytic reaction, thermal agglutinin hemolytic anemia, warm antibody hemolytic anemia, warm antibody autoimmune hemolytic anemia (WAIHA), autoimmune hemolytic anemia (AIHA), autoimmune thrombocytopenia, antiphospholipid syndrome, Evans syndrome, and the like. Red blood cell isoimmunity, Verpet syndrome, neonatal isoimmune thrombocytopenia, heparin-induced thrombocytopenia (HIT), heparin-induced thrombocytopenia and thrombus (HITT), thrombotic thrombocytopenic purpura (TTP), immune thrombocytopenic purpura (ITP), thrombocytopenia, thrombus, vasculitis, lupus nephritis, systemic lupus erythematosus (SEE), and the like. The present invention relates to methods for treating a subject (e.g., glomerulonephritis, anti-phospholipid antibody syndrome (APS), infection or drug-induced hematological disorder) comprising administering to the subject an inhibitor of the complement pathway.

Description

[0001] Related applications [0002] This patent application claims priority to US Provisional Patent Application No. 62 / 916,492, filed October 17, 2019, which is hereby incorporated by reference in its entirety. Background technique [0003] Blood disorders affect millions of people around the world each year, across boundaries of age, race, gender and socioeconomic status. Men, women, and children of all backgrounds suffer from complications associated with these conditions, many of which can be life-threatening. Blood disorders (often referred to as hematological disorders) are challenging to treat and are also a growing health concern in terms of mortality and cost of care for patients. It is estimated that more people die each year from complications of deep vein thrombosis (DVT) than breast cancer, motor vehicle accidents and HIV combined. [0004] Blood disorders can affect any of the three main components of blood: red blood cells, white blood cells, or platelets. B...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395A61P7/06
CPCA61P7/06C07K16/18C07K2317/76C07K2317/56C07K2317/55A61K2039/505C07K2317/92A61K2039/54A61K2039/55A61K2039/545C07K2317/94A61P7/00
Inventor T·耶德诺克S·桑卡拉纳拉亚南
Owner ANNEXON
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