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Methods of use of soluble cd24 for treating immune related adverse events in cancer therapies

A CD24, immune-related technology, applied in the direction of immunoglobulin, chemical instruments and methods, pharmaceutical formulations, etc.

Pending Publication Date: 2020-02-14
ONCOIMMUNE INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, traditional immunosuppressants can be problematic with respect to adverse events in cancer therapy, as all forms of cancer therapy are thought to require direct or indirect anticancer immune responses

Method used

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  • Methods of use of soluble cd24 for treating immune related adverse events in cancer therapies
  • Methods of use of soluble cd24 for treating immune related adverse events in cancer therapies
  • Methods of use of soluble cd24 for treating immune related adverse events in cancer therapies

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0077] CD24 pharmacokinetics in mice

[0078] Inject 1 mg of CD24Fc (CD24Fc) into pure C57BL / 6 mice and at different time points (5 min, 1 h, 4 h, 24 h, 48 h, 7 days, 14 days, and 21 days) in 3 mice Blood samples were collected at each time point. Serum was diluted 1:100 and the level of CD24Fc was detected using a sandwich ELISA with purified anti-human CD24 (3.3 μg / ml) as capture antibody and peroxidase-conjugated goat anti-human IgG Fc (5 μg / ml) as detection Antibody. Such as image 3 As shown in A. The decay curve for CD24Fc shows the typical biphasic decay of the protein. The half-life of the first biodistribution phase was 12.4 hours. The second stage follows a model of first-order elimination from the central compartment. The half-life of the second phase was 9.54 days, similar to that of antibodies in vivo. These data indicate that the fusion protein is very stable in the bloodstream. In another study where the fusion protein was injected subcutaneously, an alm...

Embodiment 2

[0080] CD24-Siglec 10 interaction in the host response to tissue injury

[0081] About two decades ago, Matzinger proposed what is commonly referred to as hazard theory. Essentially, she thinks the immune system turns on when it senses danger to its host. Although the nature of the danger was not well defined at the time, it was established that necrosis was associated with the release of intracellular components such as HMGB1 and heat shock proteins, known as DAMPs, for danger-associated molecular patterns. DAMPs were found to promote the production of inflammatory cytokines and autoimmune diseases. In animal models, inhibitors of HMGB1 and HSP90 were found to improve RA. The involvement of DAMPs raises the prospect that negative regulation of host responses to DAMPs by RA therapy could be explored.

[0082] Using acetaminophen-induced hepatic necrosis and ensuring inflammation, it has been observed that through the interaction of Siglec G, CD24 provides a powerful negativ...

Embodiment 3

[0085] CD24 and the prevention of GvHD

[0086] CD24Fc interacts with HMGB1, Siglec 10 and induces association between Siglec G and SHP-1.

[0087] To measure the interaction between CD24Fc and Siglec 10, we immobilized CD24Fc on CHIP and used Biacore to measure the binding of different concentrations of Siglec-10Fc. Such as Figure 5A As shown, CD24Fc with 1.6x10 -7 Kd of M bound to Siglec 10. This is a 100-fold higher affinity than the control Fc. The interaction between CD24Fc and HMGB1 was confirmed by pull-down experiments using CD24Fc-bound protein G beads followed by western blotting with anti-IgG or anti-HMGB1. These data demonstrate that CD24Fc, but not Fc, binds to HMGB1 and that the binding is cation-dependent ( Figure 5B ). To determine whether CD24Fc is an agonist of Siglec G, the mouse counterpart of human Siglec 10, we stimulated CD24- / - splenocytes for 30 min with CD24Fc, control Fc, or vehicle (PBS) control. Siglec G was then immunoprecipitated and ...

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Abstract

The present invention relates to a CD24 protein for treating immune-related adverse events (irAEs) associated with cancer immunotherapy. Provided herein is a method of treating, mitigating, minimizing, or preventing immunerelated adverse events (irAEs) associated with a cancer immunotherapy by administering a CD24 protein to a subject in need thereof. The irAE may be diarrhea or another gastrointestinal disorder, pure red cell aplasia, microcytic anemia, lupus, autoimmune nephritism, autoimmune hepatitis, pneumonitis, myocarditis, pericarditis, endocrinopathy, Addison's disease, hypogonadism,Sjogren's syndrome, or type I diabetes. The CD24 protein may comprise a mature human CD24 or a variant thereof.

Description

[0001] field of invention [0002] The present invention relates to the use of CD24 protein in the treatment of immune-related adverse events (irAE) associated with cancer immunotherapy. [0003] Background of the invention [0004] The immune system has the ability to recognize and eliminate cancer in experimental model systems as well as in patients. As a result, cancer immunotherapy is emerging as one of the most promising areas of cancer treatment. Active cancer immunotherapy involves agents that amplify the natural immune response (including antibodies against PD-1, PD-L1, or CTLA-4); small molecules that modulate the tumor microenvironment; or the use of ex vivo stimulated tumor-infiltrating lymphocytes (TIL ), activated natural killer (NK) cells, or genetically engineered T cells (chimeric antigen receptor [CAR] and T cell receptor [TCR] modified T cells) for adoptive cell transplantation (ACT). In addition, other cancer immunotherapies that directly target the tumor c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/17C07K14/705
CPCC07K14/70596C07K2319/30A61K38/00A61P37/02A61P1/12A61P7/06A61P1/16A61P31/12A61P11/00A61P3/10A61P9/00C07K16/2818A61K2039/505A61P37/06A61K38/177C07K2317/21C07K2317/41C07K2317/524C07K2317/526C07K2317/528C07K2317/53C07K2317/94
Inventor Y.刘P.郑M.德文波特
Owner ONCOIMMUNE INC
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