# US 12,594,323 B2 · Methods of reducing neuroinflammation > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 12,594,323 B2 - Document ID: US12594323B2 - Status: Granted - Kind: B2 - Application number: 18/300,354 - Filed: 2023-04-13 - Published: 2023-11-23 - Granted: 2026-04-07 - Earliest claimed: 2022-04-13 - Assignees: ImmunityBio, Inc. - Applicants: ImmunityBio, Inc. - Inventors: Hing C. Wong; Varghese George; Niraj Shrestha; Pallavi Chaturvedi - Web page: https://patentgrep.com/patent/US12594323B2 ## CPC - A61K 38/17: from animals; from humans {(enzyme inhibitors A61K38/005)} - A61K 38/1793: {for cytokines; for lymphokines; for interferons} - A61K 38/179: {for growth factors; for growth regulators} - A61K 38/20: Interleukins [IL] - A61K 38/2086: {IL-13 to IL-16} - A61P 25/16: Anti-Parkinson drugs - A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract Provided herein are multi-chain chimeric polypeptides and use thereof in reducing neuroinflammation in a subject. ## Claims ### Claim 1 A method of reducing the level of neuroinflammation in a tissue of a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a multi-chain chimeric polypeptide comprising: (a) a first chimeric polypeptide comprising: (i) a first target-binding domain comprising a sequence that is at least 90% identical to SEQ ID NO: 2; (ii) a soluble tissue factor domain comprising a sequence that is at least 90% identical to SEQ ID NO: 1; and (iii) a first domain of a pair of affinity domains comprising a sequence that is at least 90% identical to SEQ ID NO: 18; (b) a second chimeric polypeptide comprising: (i) a second domain of a pair of affinity domains comprising a sequence that is at least 90% identical to SEQ ID NO: 16; and (ii) a second target-binding domain comprising a sequence that is at least 90% identical to SEQ ID NO: 2, wherein: the first chimeric polypeptide and the second chimeric polypeptide associate through the binding of the first domain and the second domain of the pair of affinity domains; and the first target-binding domain and the second target-binding domain each bind specifically to a ligand of TGF-β receptor II (TGF-βRII). ### Claim 2 (depends on 1) The method of claim 1, wherein the first target-binding domain and the soluble tissue factor domain directly abut each other in the first chimeric polypeptide. ### Claim 3 (depends on 1) The method of claim 1, wherein the first chimeric polypeptide further comprises a linker sequence between the first target-binding domain and the soluble tissue factor domain in the first chimeric polypeptide. ### Claim 4 (depends on 1) The method of claim 1, wherein the soluble tissue factor domain and the first domain of the pair of affinity domains directly abut each other in the first chimeric polypeptide. ### Claim 5 (depends on 1) The method of claim 1, wherein the first chimeric polypeptide further comprises a linker sequence between the soluble tissue factor domain and the first domain of the pair of affinity domains in the first chimeric polypeptide. ### Claim 6 (depends on 1) The method of claim 1, wherein the second domain of the pair of affinity domains and the second target-binding domain directly abut each other in the second chimeric polypeptide. ### Claim 7 (depends on 1) The method of claim 1, wherein second chimeric polypeptide further comprises a linker sequence between the second domain of the pair of affinity domains and the second target-binding domain in the second chimeric polypeptide. ### Claim 8 (depends on 1) The method of claim 1, wherein the soluble tissue factor domain is a soluble human tissue factor domain. ### Claim 9 (depends on 8) The method of claim 8, wherein the soluble human tissue factor domain comprises the sequence of SEQ ID NO: 1. ### Claim 10 (depends on 1) The method of claim 1, wherein the first target-binding domain comprises a first sequence that is at least 90% identical to SEQ ID NO: 2 and a second sequence that is at least 90% identical to SEQ ID NO: 2, wherein the first and second sequence are separated by a linker. ### Claim 11 (depends on 10) The method of claim 10, wherein the linker comprises a sequence of SEQ ID NO: 3. ### Claim 12 (depends on 1) The method of claim 1, wherein the first target-binding domain comprises a sequence that is at least 90% identical to SEQ ID NO: 4. ### Claim 13 (depends on 1) The method of claim 1, wherein the first chimeric polypeptide comprises a sequence that is at least 90% identical to SEQ ID NO: 6. ### Claim 14 (depends on 13) The method of claim 13, wherein the first chimeric polypeptide comprises the sequence of SEQ ID NO: 6. ### Claim 15 (depends on 14) The method of claim 14, wherein the first chimeric polypeptide comprises the sequence of SEQ ID NO: 7. ### Claim 16 (depends on 1) The method of claim 1, wherein the second target-binding domain comprises a first sequence that is at least 90% identical to SEQ ID NO: 2 and a second sequence that is at least 90% identical to SEQ ID NO: 2, wherein the first and second sequence are separated by a linker. ### Claim 17 (depends on 16) The method of claim 16, wherein the linker comprises a sequence of SEQ ID NO: 3. ### Claim 18 (depends on 1) The method of claim 1, wherein the second target-binding domain comprises a sequence that is at least 90% identical to SEQ ID NO: 4. ### Claim 19 (depends on 1) The method of claim 1, wherein the second chimeric polypeptide comprises a sequence that is at least 90% identical to SEQ ID NO: 5. ### Claim 20 (depends on 19) The method of claim 19, wherein the second chimeric polypeptide comprises a sequence of SEQ ID NO: 8. ### Claim 21 (depends on 1) The method of claim 1, wherein the tissue is one or more of the brain, spinal cord, skeletal muscle, or optic nerve. ### Claim 22 (depends on 1) The method of claim 1, wherein the subject has been diagnosed or identified as having a neuroinflammatory disease. ### Claim 23 (depends on 22) The method of claim 22, wherein the neuroinflammatory disease is selected from the group consisting of: Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), schizophrenia, autism, depression, major depressive disorder (MDD), dysthymia, bipolar disorders, mood disorders, anxiety, fibromyalgia, Huntington's disease, amyotrophic lateral sclerosis (ALS), acute disseminated encephalomyelitis (ADEM), acute optic neuritis (AON), transverse myelitis, neuromyelitis optica (NMO), Lewy body dementia (LBD), and sarcopenia. ### Claim 24 (depends on 1) The method of claim 1, wherein the subject has been identified as having an increased risk of developing a neuroinflammatory disease. ### Claim 25 A method of treating a neuroinflammatory disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a multi-chain chimeric polypeptide comprising: (a) a first chimeric polypeptide comprising: (i) a first target-binding domain comprising a sequence that is at least 90% identical to SEQ ID NO: 2; (ii) a soluble tissue factor domain comprising a sequence that is at least 90% identical to SEQ ID NO: 1; and (iii) a first domain of a pair of affinity domains comprising a sequence that is at least 90% identical to SEQ ID NO: 18; (b) a second chimeric polypeptide comprising: (i) a second domain of a pair of affinity domains comprising a sequence that is at least 90% identical to SEQ ID NO: 16; and (ii) a second target-binding domain comprising a sequence that is at least 90% identical to SEQ ID NO: 2, wherein: the first chimeric polypeptide and the second chimeric polypeptide associate through the binding of the first domain and the second domain of the pair of affinity domains; and the first target-binding domain and the second target-binding domain each bind specifically to a ligand of TGF-β receptor II (TGF-βRII). ### Claim 26 A method of maintaining and/or improving learning and memory in a subject, the method comprising administering to the subject a therapeutically effective amount of a multi-chain chimeric polypeptide comprising: (a) a first chimeric polypeptide comprising: (i) a first target-binding domain comprising a sequence that is at least 90% identical to SEQ ID NO: 2; (ii) a soluble tissue factor domain comprising a sequence that is at least 90% identical to SEQ ID NO: 1; and (iii) a first domain of a pair of affinity domains comprising a sequence that is at least 90% identical to SEQ ID NO: 18; (b) a second chimeric polypeptide comprising: (i) a second domain of a pair of affinity domains comprising a sequence that is at least 90% identical to SEQ ID NO: 16; and (ii) a second target-binding domain comprising a sequence that is at least 90% identical to SEQ ID NO: 2, wherein: the first chimeric polypeptide and the second chimeric polypeptide associate through the binding of the first domain and the second domain of the pair of affinity domains; and the first target-binding domain and the second target-binding domain each bind specifically to a ligand of TGF-β receptor II (TGF-βRII).