# US 12,180,254 B1 · Factor H variants for treatment of disease

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- Number: US 12,180,254 B1
- Document ID: US12180254B1
- Status: Granted
- Kind: B1
- Application number: 18/494,883
- Filed: 2023-10-26
- Granted: 2024-12-31
- Earliest claimed: 2015-09-24
- Assignees: The Trustees of the University of Pennsylvania
- Applicants: The Trustees of the University of Pennsylvania
- Inventors: Wenchao Song; Damodar Gullipalli; Takashi Miwa
- Web page: https://patentgrep.com/patent/US12180254B1

## CPC

- C07K 14/472: {Complement proteins, e.g. anaphylatoxin, C3a, C5a}
- A61K 47/6911: {the form being a liposome}
- A61K 48/00: Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K 48/005: {characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered}
- A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
- A61P 13/12: of the kidneys
- C07K 14/4702: {Regulators; Modulating activity}
- C12N 15/85: for animal cells
- C12N 15/86: Viral vectors
- C12N 2750/14143: viral genome or elements thereof as genetic vector
- C12N 2750/14145: Special targeting system for viral vectors
- C12N 2750/14171: Demonstrated in vivo effect
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- 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
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

Disclosed herein are factor H variants, vectors comprising said factor H variants, and pharmaceutical compositions comprising the same for treatment of disorders.

## Claims

### Claim 1

A recombinant vector having packaged therein an expression cassette comprising an engineered human complement factor H (hfH) gene operably linked to expression control sequences which direct expression thereof, wherein the hfH gene encodes a soluble hfH protein variant that retains complement regulatory function, wherein the hfH protein variant comprises:
amino acids 1 to 62 of SEQ ID NO: 3 (SCR1)—L1—amino acids 1 to 57 of SEQ ID NO: 5 (SCR2)—L2—amino acids 1 to 60 of SEQ ID NO: 7 (SCR3)—L3—amino acids 1 to 53 of SEQ ID NO: 9 (SCR4)—L4—amino acids 1 to 61 of SEQ ID NO: 13 (SCR6)—L4′—amino acids 1 to 54 of SEQ ID NO: 14 (SCR7)—L5—amino acids 1 to 58 of SEQ ID NO: 16 (SCR8)—L5″—amino acids 1 to 56 of SEQ ID NO: 33 (SCR17)—L5″′—amino acids 1 to 55 of SEQ ID NO: 35 (SCR18)—L5″″—amino acids 1 to 55 of SEQ ID NO: 37 (SCR19)—L6—amino acids 1 to 65 of SEQ ID NO: 38 (SCR20), wherein “L” refers to a linker, and each of L1, L2, L3, L4, L4′, L5, L5″, L5″′, L5″″, and L6 is independently selected from an amino acid sequence of 1 to 18 amino acids, and wherein SCR5, SCR9, SCR10, SCR11, SCR12, SCR13, SCR14, SCR15, and SCR16 are absent.

### Claim 2 (depends on 1)

The recombinant vector according to claim 1, wherein the hfH protein variant comprises an amino acid sequence at least 95% identical to amino acids 1 to 701 of SEQ ID NO: 48.

### Claim 3 (depends on 1)

The recombinant vector according to claim 1, wherein the vector is an adeno-associated virus (AAV) vector, an adenovirus vector, an RNA virus vector, a lentivirus vector, or a vaccinia virus vector.

### Claim 4 (depends on 1)

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the recombinant vector according to claim 1.

### Claim 5 (depends on 1)

The recombinant vector according to claim 1, wherein each of L1, L2, L3, L4, L4′, L5, L5″, L5″′, L5″″, and L6 is independently selected from an amino acid sequence of 1 to 12 amino acids.

### Claim 6 (depends on 5)

The recombinant vector according to claim 5, wherein the hfH protein variant comprises an amino acid sequence at least 95% identical to amino acids 1 to 701 of SEQ ID NO: 48.

### Claim 7

A recombinant AAV vector comprising an AAV capsid having packaged therein an expression cassette comprising an engineered human complement regulator factor H (hfH) gene operably linked to expression control sequences which direct expression thereof, wherein the hfH gene encodes a soluble hfH protein variant that retains complement regulatory function, wherein the hfH protein variant comprises:
amino acids 1 to 62 of SEQ ID NO: 3 (SCR1)—L1—amino acids 1 to 57 of SEQ ID NO: 5 (SCR2)—L2—amino acids 1 to 60 of SEQ ID NO: 7 (SCR3)—L3—amino acids 1 to 53 of SEQ ID NO: 9 (SCR4)—L4—amino acids 1 to 61 of SEQ ID NO: 13 (SCR6)—L4′—amino acids 1 to 54 of SEQ ID NO: 14 (SCR7)—L5—amino acids 1 to 58 of SEQ ID NO: 16 (SCR8)—L5″—amino acids 1 to 56 of SEQ ID NO: 33 (SCR17)—L5″′—amino acids 1 to 55 of SEQ ID NO: 35 (SCR18)—L5″″—amino acids 1 to 55 of SEQ ID NO: 37 (SCR19)—L6—amino acids 1 to 65 of SEQ ID NO: 38 (SCR20), wherein “L” refers to a linker, and each of L1, L2, L3, L4, L4′, L5, L5″, L5″′, L5″″, and L6 is independently selected from an amino acid sequence of 1 to 18 amino acids, and wherein SCR5, SCR9, SCR10, SCR11, SCR12, SCR13, SCR14, SCR15, and SCR16 are absent.

### Claim 8 (depends on 7)

The recombinant AAV vector according to claim 7, wherein the hfH protein variant comprises an amino acid sequence at least 95% identical to amino acids 1 to 701 of SEQ ID NO: 48.

### Claim 9 (depends on 7)

The recombinant AAV vector according to claim 7, wherein the AAV capsid is an AAV1, an AAV2, an AAV5, an AAV8, an rh64R1, an AAV9, or an rh10 capsid.

### Claim 10 (depends on 7)

The recombinant AAV vector according to claim 7, wherein the expression control sequences comprise a liver-specific promoter sequence.

### Claim 11 (depends on 7)

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the recombinant AAV vector according to claim 7.

### Claim 12 (depends on 9)

The recombinant AAV vector according to claim 9, wherein the AAV capsid is an AAV2 capsid.

### Claim 13 (depends on 7)

The recombinant AAV vector according to claim 7, wherein the expression control sequences comprise a constitutive promoter sequence.

### Claim 14 (depends on 7)

The recombinant AAV vector according to claim 7, wherein the expression control sequences comprise a chicken beta-actin promoter sequence.

### Claim 15 (depends on 7)

The recombinant AAV vector according to claim 7, wherein the hfH gene is codon optimized.

### Claim 16 (depends on 7)

The recombinant AAV vector according to claim 7, wherein each of L1, L2, L3, L4, L4′, L5, L5″, L5″′, L5″″, and L6 is independently selected from an amino acid sequence of 1 to 12 amino acids.

### Claim 17 (depends on 16)

The recombinant AAV according to claim 16, wherein the hfH protein variant comprises an amino acid sequence at least 95% identical to amino acids 1 to 701 of SEQ ID NO: 48.

### Claim 18

A plasmid comprising a nucleotide sequence that encodes an engineered human complement regulator factor H (hfH) gene operably linked to expression control sequences which direct expression thereof, wherein the hfH gene encodes a soluble hfH protein variant that retains complement regulatory function, wherein the hfH protein variant comprises:
amino acids 1 to 62 of SEQ ID NO: 3 (SCR1)—L1—amino acids 1 to 57 of SEQ ID NO: 5 (SCR2)—L2—amino acids 1 to 60 of SEQ ID NO: 7 (SCR3)—L3—amino acids 1 to 53 of SEQ ID NO: 9 (SCR4)—L4—amino acids 1 to 61 of SEQ ID NO: 13 (SCR6)—L4′—amino acids 1 to 54 of SEQ ID NO: 14 (SCR7)—L5—amino acids 1 to 58 of SEQ ID NO: 16 (SCR8)—L5″—amino acids 1 to 56 of SEQ ID NO: 33 (SCR17)—L5″′—amino acids 1 to 55 of SEQ ID NO: 35 (SCR18)—L5″″—amino acids 1 to 55 of SEQ ID NO: 37 (SCR19)—L6—amino acids 1 to 65 of SEQ ID NO: 38 (SCR20), wherein “L” refers to a linker, and each of L1, L2, L3, L4, L4′, L5, L5″, L5″′, L5″″, and L6 is independently selected from an amino acid sequence of 1 to 18 amino acids, and wherein SCR5, SCR9, SCR10, SCR11, SCR12, SCR13, SCR14, SCR15, and SCR16 are absent.

### Claim 19 (depends on 18)

The plasmid according to claim 18, wherein the hfH protein variant comprises an amino acid sequence at least 95% identical to amino acids 1 to 701 of SEQ ID NO: 48.

### Claim 20 (depends on 18)

The plasmid according to claim 18, wherein the expression control sequences comprise a constitutive promoter sequence.

### Claim 21 (depends on 18)

The plasmid according to claim 18, wherein the expression control sequences comprise a chicken beta-actin promoter sequence and/or a Kozak sequence.

### Claim 22 (depends on 18)

A packaging host cell comprising the plasmid according to claim 18.

### Claim 23 (depends on 18)

The plasmid according to claim 18, wherein each of L1, L2, L3, L4, L4′, L5, L5″, L5″′, L5″″, and L6 is independently selected from an amino acid sequence of 1 to 12 amino acids.

### Claim 24 (depends on 23)

The plasmid according to claim 23, wherein the hfH protein variant comprises an amino acid sequence at least 95% identical to amino acids 1 to 701 of SEQ ID NO: 48.