# US 2020/0399351 A1 · Polypeptides that bind complement component c5 or serum albumin and fusion proteins thereof

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- Number: US 2020/0399351 A1
- Document ID: US20200399351A1
- Status: Published application
- Kind: A1
- Application number: 16/629,687
- Filed: 2018-07-11
- Published: 2020-12-24
- Earliest claimed: 2017-07-11
- Assignees: Alexion Pharmaceuticals, Inc.
- Applicants: Alexion Pharmaceuticals, Inc.
- Inventors: Bridget PUFFER; Julian CHANDLER; Nimish GERA; Douglas L. SHERIDAN; Siddharth JINDAL; Paul P. TAMBURINI
- Web page: https://patentgrep.com/patent/US20200399351A1

## CPC

- C07K 16/18: against material from animals or humans
- A61K 38/47: acting on glycosyl compounds (3.2), e.g. cellulases, lactases
- A61K 39/395: Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- C07K 16/46: Hybrid immunoglobulins (hybrids of an immunoglobulin with a peptide not being an immunoglobulin C07K19/00)
- C12Y 302/01035: Hyaluronoglucosaminidase (3.2.1.35), i.e. hyaluronidase
- A61K 2039/505: {comprising antibodies}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/31: multispecific
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/569: Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C07K 2317/94: Stability, e.g. half-life, pH, temperature or enzyme-resistance
- 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)
- C12Y: ENZYMES

## Abstract

The disclosure provides engineered polypeptides that specifically bind to human complement component C5 and/or serum albumin. The disclosure also provides fusion proteins comprising such engineered polypeptides, wherein such fusion proteins may be multivalent and multi-specific fusion proteins. The disclosure further provides nucleic acid molecules that encode such engineered polypeptides or fusion proteins, and methods of making such engineered polypeptides or fusion proteins. The disclosure further provides pharmaceutical compositions that comprise such engineered polypeptides or fusion proteins, and methods of treatment using such engineered polypeptides or fusion proteins.

## Claims

### Claim 1

A fusion protein comprising an engineered polypeptide comprising a VHH domain that specifically binds to human complement component C5 and an engineered polypeptide comprising a VHH domain that specifically binds to human serum albumin, wherein the engineered polypeptide comprising the VHH domain that specifically binds to human complement component C5 is fused to the engineered polypeptide comprising the VHH domain that specifically binds to human serum albumin either directly or via a peptide linker; wherein the VHH domain that specifically binds to human complement component C5 comprises three complementarity determining regions, CDR1, CDR2 and, CDR3, wherein CDR1 comprises any one of the amino acid sequences of SEQ ID NOS:13-17, CDR2 comprises an amino acid sequences of SEQ ID NO:18 or 19, and CDR3 comprises an amino acid sequences of SEQ ID NO:20 or 21; and wherein the VHH domain that specifically binds to human serum albumin comprises three complementarity determining regions, CDR1, CDR2, and CDR3, wherein CDR1 comprises any one of the amino acid sequences of SEQ ID NOS:35-43, CDR2 comprises any one of the amino acid sequences of SEQ ID NOS:44-51, and CDR3 comprises any one of the amino acid sequences of SEQ ID NOS:52-63.

### Claim 2 (depends on 1)

The fusion protein of claim 1, wherein the C-terminal residue of the polypeptide that specifically binds to human serum albumin is fused either directly or via a linker to the N-terminal residue of the polypeptide that specifically binds to human complement component C5.

### Claim 3 (depends on 1)

The fusion protein of claim 1, wherein the C-terminal residue of the polypeptide that specifically binds to human complement component C5 is fused either directly or via a linker to the N-terminal residue of the polypeptide that specifically binds to human serum albumin.

### Claim 4 (depends on 1)

The fusion protein of claim 1, wherein the polypeptide that specifically binds to human complement component C5 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:1-12 and fragments thereof; and the polypeptide that specifically binds to human serum albumin comprises an amino acid selected from the group consisting of SEQ ID NOs:22-34 and fragments thereof.

### Claim 5 (depends on 4)

The fusion protein of claim 4, wherein the polypeptide that specifically binds to human complement component C5 comprises the amino acid sequence of SEQ ID NO:11 and the polypeptide that specifically binds to human serum albumin comprises the amino acid sequence of SEQ ID NO:26.

### Claim 6 (depends on 5)

The fusion protein of claim 5, further comprising a peptide linker having an amino acid sequence of SEQ ID NO:102 or 103.

### Claim 7 (depends on 6)

The fusion protein of claim 6, wherein the peptide linker comprises the amino acid sequence of SEQ ID NO:102.

### Claim 8 (depends on 1)

The fusion protein of claim 1, wherein the fusion protein comprises a sequence that is at least 95% identical to a sequence selected from the group consisting of SEQ ID NOS:96-101.

### Claim 9 (depends on 8)

The fusion protein of claim 8, wherein the fusion protein consists of a sequence selected from the group consisting of SEQ ID NOS:96-101.

### Claim 10 (depends on 9)

The fusion protein of claim 9, wherein the fusion protein consists of a polypeptide sequence of SEQ ID NO:96.

### Claim 11

(canceled)

### Claim 12

(canceled)

### Claim 13 (depends on 1)

The fusion protein of claim 1, wherein either or both of the polypeptides that bind to human complement component C5 or albumin bind in a pH-dependent manner.

### Claim 14 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a fusion protein of claim 1 and a pharmaceutically acceptable carrier.

### Claim 15 (depends on 14)

The pharmaceutical composition of claim 14, further comprising hyaluronidase.

### Claim 16 (depends on 1)

An isolated nucleic acid molecule comprising a nucleotide sequence encoding a fusion protein claim 1.

### Claim 17 (depends on 16)

An expression vector comprising the nucleic acid molecule of claim 16.

### Claim 18 (depends on 16)

An isolated host cell comprising the nucleic acid molecule of claim 16.

### Claim 19 (depends on 17)

An isolated host cell comprising the expression vector of claim 17.

### Claim 20 (depends on 19)

The isolated host cell of claim 19, wherein the host cell is a mammalian cell or a yeast cell.

### Claim 21

An engineered polypeptide comprising a VHH domain that binds to human complement component C5, wherein the engineered polypeptide comprises an amino acid sequence that is at least 90% identical to a sequence selected from the group consisting of SEQ ID NOS:1-12; wherein the VHH domain that specifically binds to human complement component C5 comprises three complementarity determining regions, CDR1, CDR2 and, CDR3, wherein CDR1 comprises any one of the amino acid sequences of SEQ ID NOS:13-17, CDR2 comprises an amino acid sequences of SEQ ID NO:18 or 19, and CDR3 comprises an amino acid sequences of SEQ ID NO:20 or 21.

### Claim 22 (depends on 21)

The engineered polypeptide of claim 21, wherein the engineered polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:1-12 and fragments thereof.

### Claim 23

An engineered polypeptide comprising a VHH domain that specifically binds to human serum albumin, wherein the polypeptide comprises an amino acid sequence that is at least 90% identical to any one of the amino acid sequences of SEQ ID NOS:22-34; wherein the VHH domain that specifically binds to human serum albumin comprises three complementarity determining regions, CDR1, CDR2, and CDR3, wherein CDR1 comprises any one of the amino acid sequences of SEQ ID NOS:35-43, CDR2 comprises any one of the amino acid sequences of SEQ ID NOS:44-51, and CDR3 comprises any one of the amino acid sequences of SEQ ID NOS:52-63.

### Claim 24 (depends on 23)

The engineered polypeptide of claim 23, wherein the engineered polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:22-34 and fragments thereof.

### Claim 25

(canceled)

### Claim 26 (depends on 22)

The engineered polypeptide of claim 22, wherein the polypeptide specifically binds to the same epitope on human serum albumin as Alb1.

### Claim 27 (depends on 1)

A method for making a fusion protein of claim 1, comprising expressing in a host cell at least one nucleic acid molecule comprising a nucleotide sequence encoding the fusion protein.

### Claim 28 (depends on 1)

A therapeutic kit comprising:
(a) a container comprising a label; and
(b) a composition comprising the fusion protein of claim 1;
wherein the label indicates that the composition is to be administered to a patient having, or that is suspected of having, a complement-mediated disorder.

### Claim 29 (depends on 28)

The kit of claim 28, further comprising hyaluronidase.

### Claim 30 (depends on 1)

A method for treating a patient having a complement-mediated disorder, the method comprising administering to the patient a therapeutically effective amount of a fusion protein of claim 1.

### Claim 31 (depends on 30)

The method of claim 30, wherein the complement-mediated disorder is selected from the group consisting of: rheumatoid arthritis; lupus nephritis; asthma; ischemia-reperfusion injury; atypical hemolytic uremic syndrome; dense deposit disease; paroxysmal nocturnal hemoglobinuria; macular degeneration; hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome; Guillain-Barré Syndrome; CHAPLE syndrome; myasthenia gravis; neuromyelitis optica; post-hematopoietic stem cell transplant thrombotic microangiopathy (post-HSCT-TMA); post-bone marrow transplant TMA (post-BMT TMA); Degos disease; Gaucher's disease; glomerulonephritis; thrombotic thrombocytopenic purpura (TTP); spontaneous fetal loss; Pauci-immune vasculitis; epidermolysis bullosa; recurrent fetal loss; multiple sclerosis (MS); traumatic brain injury; and injury resulting from myocardial infarction, cardiopulmonary bypass and hemodialysis.