TLR9 ligand trap

Patent metadata

Field	Value
Publication number	US-11976104-B2
Application number	US-202117181246-A
Country	US
Kind code	B2
Filing date	Feb 22, 2021
Priority date	Aug 23, 2018
Publication date	May 7, 2024
Grant date	May 7, 2024

Abstract

Myelodysplastic syndrome (MDS) hematopoietic stem and progenitor cells (HSPC) translocate endosomal Toll-Like receptor (TLR)-9 to the plasma membrane, thereby sensitizing these clonal propagating cells to respective ligands in the microenvironment. TLR9 is the cognate receptor for RNA:DNA hybrids (R-loops) and unmethylated CpG oligonucleotides in oxidized mitochondrial DNA, the latter of which is abundant in the bone marrow microenvironment as a result of massive medullary pyroptotic cytolytic cell death. Both ligands are important danger-associated molecular patterns (DAMPs) triggering innate immune activation and chronic inflammation that contributes to MDS pathogenesis. In an effort to neutralize these DAMPs and disrupt this feed-forward inflammatory cascade, a chimeric protein was designed fusing the external epitopes of TLR9 to the Fc domain of human IgG4 to serve as a decoy receptor or ligand trap recognizing extracellular RNA:DNA hybrids (R-loops) and oxidized mitochondrial DNA.

First claim

What is claimed is:

1. A fusion protein, comprising a TLR9 extracellular domain peptide, and an IgG4 Fc domain.

2. The fusion protein of claim 1 , defined by the formula:
TLR9-Fc,
wherein “TLR9” represents the TLR9 extracellular domain peptide,
wherein “Fc” represents an IgG4 Fc domain, and
wherein “—” represents a linker or hinge domain.

3. The fusion protein of claim 1 , wherein the TLR9 extracellular domain comprises the amino acid sequence SEQ ID NO:1, or a variant thereof having at least 90% sequence identity to SEQ ID NO:1.

4. The fusion protein of claim 1 , comprising the amino acid sequence SEQ ID NO:7, or a variant thereof having at least 90% sequence identity to SEQ ID NO:7.

5. A composition, comprising the fusion protein of claim 1 in a pharmaceutically acceptable excipient.

6. A method of treating myelodysplastic syndrome (MDS) in a subject, comprising administering to the subject a therapeutically effective amount of a composition of claim 5 .

7. The method of claim 6 , further comprising detecting in a biological sample from the subject a surrogate marker of pyroptosis to diagnose myelodysplastic syndrome (MDS) in the subject prior to treatment.

8. The method of claim 7 , wherein the surrogate marker of pyroptosis comprises oxidized mitochondrial DNA (ox-mtDNA).

9. The method of claim 7 , wherein the surrogate marker of pyroptosis comprises apoptosis associated speck-like protein containing a CARD (ASC).

10. The method of claim 7 , wherein the biological sample comprises peripheral blood.

Assignees

• H Lee Moffitt Cancer Ct & Res

Inventors

• Wei Sheng
• List Alan F

Classifications

• G01N33/57585

  involving compounds identifiable in body fluids · CPC title

• G01N33/57557

  of other specific parts of the body, e.g. brain · CPC title

• C07K14/705 Primary

  Receptors; Cell surface antigens; Cell surface determinants {(tumour specific antigens C07K14/4748)} · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• G01N33/57407

  Physics · mapped topic