# US 2011/0256180 A1 · Factor H Binding Proteins (FHBP) with Altered Properties and Methods of Use Thereof

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- Number: US 2011/0256180 A1
- Document ID: US20110256180A1
- Status: Published application
- Kind: A1
- Application number: 13/074,957
- Filed: 2011-03-29
- Published: 2011-10-20
- Earliest claimed: 2010-03-30
- Assignees: Children's Hospital & Research Center Oakland
- Inventors: PETER T. BEERNINK; DAN M. GRANOFF; ROLANDO PAJON FEYT
- Web page: https://patentgrep.com/patent/US20110256180A1

## CPC

- A61K 39/095: Neisseria
- A61P 31/04: Antibacterial agents
- A61P 37/04: Immunostimulants
- C07K 14/22: from Neisseriaceae (F)
- A61K 2039/55505: {Inorganic adjuvants}
- A61K 2039/55566: {Emulsions, e.g. Freund's adjuvant, MF59}
- 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
- 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)

## Abstract

Factor H binding proteins that can elicit antibodies that are bactericidal for at least one strain of N. meningitidis, and methods of use of such proteins, are provided.

## Claims

### Claim 1

A non-naturally occurring factor H binding protein (fHbp) that has lower affinity for human factor H (1H) than fHbp ID 1, wherein said non-naturally occurring fHbp presents a conformational epitope bound by antibodies that have bactericidal activity toward at least one Neisseria meningitidis strain.

### Claim 2 (depends on 1)

The non-naturally occurring fHbp of claim 1, wherein said fHbp comprises at least one amino acid substitution compared to a naturally-occurring reference fHbp.

### Claim 3 (depends on 1)

The non-naturally occurring fHbp of claim 1, wherein said fHbp binds human fH with affinity that is 50% or less of the affinity of fHbp ID 1 for human fH.

### Claim 4 (depends on 1)

The non-naturally occurring fHbp of claim 1, wherein said fHbp binds human fH with affinity that is 40%, 30%, 20%, 10%, 5%, 2%, 1%, 0.1%, or less than 0.1%, of the affinity of fHbp ID 1 for human fH.

### Claim 5 (depends on 1)

The non-naturally occurring fHbp of claim 1, wherein said fHbp elicits a level of serum bactericidal antibodies that is at least as high as that elicited by fHbp ID 1.

### Claim 6

(canceled)

### Claim 7 (depends on 1)

The non-naturally occurring fHbp of claim 1, wherein said fHbp is derived from a variant 1 fHbp, a variant 2 hHbp, or from a variant 3 fHbp.

### Claim at position 8

-9. (canceled)

### Claim 10 (depends on 1)

The non-naturally occurring fHbp of claim 1, wherein said fHbp comprises variable segments VA, VC, and VE that are all derived from lineage 1.

### Claim 11 (depends on 7)

The non-naturally occurring fHbp of claim 7, wherein said fHbp is derived from a modular group I fHbp, a modular group IV fHbp, a modular Group III fHbp, a modular Group VI fHbp, a modular Group II fHbp, a modular Group V fHbp, a modular Group VII fHbp, a modular Group VIII fHbp, or a modular Group X fHbp.

### Claim at position 11

-14. (canceled)

### Claim 15 (depends on 1)

The non-naturally occurring fHbp of claim 1, wherein said fHbp is a man-made chimera.

### Claim 16 (depends on 15)

The non-naturally occurring fHbp of claim 15, wherein said fHbp is derived from the amino acid sequence of chimera I.

### Claim 17 (depends on 1)

The non-naturally occurring fHbp of claim 1, wherein said fHbp comprises an amino acid substitution at a position corresponding to amino acid residue 41, 60, 80, 113, 114, 117, 119, 121, 128, 130, 147, 148, 149, 178, 195, 199, 211, 220, 222, 236, 241, 247, or 248, based on the numbering of the mature fHbp ID 1.

### Claim 18 (depends on 1)

The non-naturally occurring fHbp of claim 1, wherein said fHbp comprises an amino acid substitution at a position corresponding to amino acid residue 87, 109, 115, 118, 126, 138, 197, 201, 202, 203, 209, 217, 225, 235, or 245, based on the numbering of the mature fHbp ID 1.

### Claim 19 (depends on 17)

The non-naturally occurring fHbp of claim 17, wherein the fHbp is derived from fHbp ID 1, wherein said fHbp comprises an amino acid substitution at a position corresponding to amino acid residue position 41, and wherein said fHbp comprising R41S or R41A as said amino acid substitution.

### Claim at position 17

-21. (canceled)

### Claim 22 (depends on 17)

The non-naturally occurring fHbp of claim 17, wherein the fHbp is derived from fHbp ID 1, and wherein said fHbp comprises R130A, H119A, E218A, or E239A as said amino acid substitution.

### Claim at position 19

-25. (canceled)

### Claim 26 (depends on 17)

The non-naturally occurring fHbp of claim 17, wherein said fHbp comprises:
a) fHbp ID 14 comprising R41S as said amino acid substitution;
b) fHbp ID 4 comprising R41S as said amino acid substitution;
c) fHbp ID 9 comprising R41S as said amino acid substitution;
d) fHbp ID 74 comprising R41S as said amino acid substitution; or
e) fHbp ID 15 comprising S41P as said amino acid substitution.

### Claim at position 21

-30. (canceled)

### Claim 31 (depends on 17)

The non-naturally occurring fHbp of claim 17, wherein the fHbp is derived from fHbp ID 22, and wherein said fHbp comprises R80A, D211A, E218A, E248A, G236I, T220A, or H222A as said amino acid substitution.

### Claim at position 23

-38. (canceled)

### Claim 39 (depends on 17)

The non-naturally occurring fHbp of claim 17, wherein the fHbp is derived from fHbp ID 77, and wherein said fHbp comprises amino acid substitutions at one or more of positions 41, 113, 119, and 121.

### Claim 40 (depends on 17)

The non-naturally occurring fHbp of claim 17, wherein the fHbp is derived from fHbp ID 77, and wherein said fHbp comprises R41S and K113A, R41S and K119A, R41S and D121A, or R41S, K113A, and D121A as said amino acid substitutions.

### Claim at position 26

-44. (canceled)

### Claim 45 (depends on 17)

The non-naturally occurring fHbp of claim 17, wherein said fHbp is derived from the amino acid sequence of chimera I and comprises R41S as said amino acid substitution.

### Claim 46 (depends on 17)

The non-naturally occurring fHbp of claim 17, wherein said fHbp is fHbp ID 28 comprising E218A and/or K199A as said amino acid substitution.

### Claim 47 (depends on 1)

An immunogenic composition comprising:
a) a fHbp according to claim 1; and
b) a pharmaceutically acceptable excipient.

### Claim 48

An immunogenic composition comprising:
a) an isolated factor H binding protein (fHbp) comprising at least 85% amino acid sequence identity to fHbp ID 4, fHbp ID 14, fHbp ID 15, wherein said fHbp has lower affinity for human factor H (1H) than fHbp ID 1; and
b) a pharmaceutically acceptable excipient.

### Claim 49 (depends on 47)

The immunogenic composition of claim 47, wherein said fHbp is in a vesicle preparation prepared from a Neisseria meningitidis strain.

### Claim 50 (depends on 47)

The immunogenic composition of claim 47, wherein said pharmaceutically acceptable excipient comprises an adjuvant.

### Claim 51 (depends on 47)

The immunogenic composition of claim 47, further comprising NspA.

### Claim 52 (depends on 47)

A method of eliciting an antibody response in a mammal, the method comprising administering to a mammal the immunogenic composition of claim 47.

### Claim 53 (depends on 52)

The method of claim 52, wherein said mammal is a human.

### Claim 54 (depends on 52)

The method of claim 52, wherein said administering provides for production of bactericidal antibodies to N. meningitidis.

### Claim 55 (depends on 1)

A nucleic acid encoding the fHbp according to claim 1.

### Claim 56 (depends on 55)

A recombinant expression vector comprising the nucleic acid of claim 55.

### Claim 57 (depends on 55, 56)

A genetically modified host cell comprising the nucleic acid of claim 55 or the recombinant expression vector of claim 56.

### Claim 58 (depends on 1)

An immunogenic composition comprising
a) a vesicle obtained from a genetically modified Neisseria host cell that is genetically modified with a nucleic acid encoding the fHbp according to claim 1, such that the encoded non-naturally occurring fHbp is produced by the genetically modified host cell, wherein the vesicle comprises the encoded non-naturally occurring fHbp; and
b) a pharmaceutically acceptable excipient.

### Claim 59 (depends on 58)

The immunogenic composition of claim 58, wherein the vesicle is a native outer membrane vesicle.

### Claim 60 (depends on 58)

The immunogenic composition of claim 58, wherein the fHbp binds human fH with affinity that is 40%, 30%, 20%, 10%, 5%, 2%, or 1% of the affinity of fHbp ID 1 for human fH.

### Claim 61 (depends on 58)

The immunogenic composition of claim 58, wherein the host cell is genetically modified to provide for decreased or no activity of a polypeptide product of the lpxL1 gene and/or the lpxL2 gene.

### Claim 62 (depends on 58)

The immunogenic composition of claim 58, wherein the host cell is genetically modified to provide for increased expression of NspA.

### Claim 63 (depends on 58)

A method of eliciting an antibody response in a mammal, the method comprising administering to a mammal the immunogenic composition of claim 58.

### Claim 64

A method of determining the likelihood that a factor H binding protein (fHbp) will elicit a bactericidal response in an individual to at least one Neisseria meningitidis strain, the method comprising:
determining the ability of antibody, present in serum obtained from an individual who has been immunized with a fHbp, to inhibit binding of human factor H (1H) to fHbp, wherein inhibition of binding of fH to fHbp by the antibody at a level that is at least about 25% higher than the level of inhibition of fH to fHbp by a control antibody that inhibits fH binding to fHbp but that does not generate a bactericidal response indicates that the fHbp is likely to elicit a bactericidal response to at least one Neisseria meningitidis strain.

### Claim 65 (depends on 64)

The method of claim 64, wherein the fHbp is a non-naturally occurring fHbp that has lower affinity for fH than fHbp ID 1.

### Claim 66

A method of determining the likelihood that a non-naturally occurring factor H binding protein (fHbp) that has lower affinity for human factor H (fH) than fHbp ID 1 will elicit bactericidal antibodies in an individual to at least one Neisseria meningitidis strain, the method comprising:
determining the ability of an antibody elicited in a test non-human animal to the non-naturally occurring fHbp to inhibit binding of fH to fHbp,
wherein inhibition of binding of fH to fHbp by the antibody elicited to the non-naturally occurring fHbp at a level that is at least about 25% higher than the level of inhibition of fH to fHbp by an antibody elicited in the test non-human animal to fHbp ID 1 indicates that the non-naturally occurring fHbp is likely to elicit a bactericidal response to at least one Neisseria meningitidis strain.