# US 2019/0375831 A1 · Neutralizing antibodies to plasmodium falciparum circumsporozoite protein and their use

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- Number: US 2019/0375831 A1
- Document ID: US20190375831A1
- Status: Published application
- Kind: A1
- Application number: 16/485,354
- Filed: 2018-02-12
- Published: 2019-12-12
- Earliest claimed: 2017-02-10
- Assignees: The United States of America, as represented by the Secretary, Department of Health and; Human Services; Sanaria Inc.
- Applicants: The United States of America, AS Represented By the Secretary, Department of Health and Human Servic; Sanaria Inc
- Inventors: Robert Seder; Neville Kisalu; Azza Idris; Barbara Flynn; Stephen Hoffman
- Web page: https://patentgrep.com/patent/US20190375831A1

## CPC

- C07K 16/205: {Plasmodium}
- A61P 33/06: Antimalarials
- C07K 2317/21: from primates, e.g. man
- C07K 2317/34: Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Antibodies and antigen binding fragments that specifically bind to P. falciparum circumsporozoite protein and neutralize P. falciparum are disclosed. Nucleic acids encoding these antibodies, vectors and host cells are also provided. The disclosed antibodies, antigen binding fragments, nucleic acids and vectors can be used, for example, to inhibit a P. falciparum infection.

## Claims

### Claim 1

An isolated monoclonal antibody, comprising:
a heavy chain variable region and a light chain variable region comprising a heavy chain complementarity determining region (HCDR)1, a HCDR2, and a HCDR3, and a light chain complementarity determining region (LCDR)1, a LCDR2, and a LCDR3 of the VH and VL set forth as one of:
(a) SEQ ID NOs: 11 and 12, respectively (CIS43);
(b) SEQ ID NOs: 7 and 8, respectively (CIS34);
(c) SEQ ID NOs: 5 and 6, respectively (CIS23);
(d) SEQ ID NOs: 1 and 2, respectively (CIS04);
(e) SEQ ID NOs: 9 and 10, respectively (CIS42);
(f) SEQ ID NOs: 3 and 4, respectively (CIS06); or
(g) SEQ ID NOs: 81 and 82, respectively (mAb10); and
wherein the monoclonal antibody specifically binds to P. falciparum circumsporozoite protein (CSP) and neutralizes P. falciparum.

### Claim 2 (depends on 1)

The antibody of claim 1, wherein the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2, and the LCDR3 comprise the amino acids sequences set forth as:
(a) SEQ ID NOs: 15, 45, 17, 18, 46, and 20, respectively (CIS43);
(b) SEQ ID NOs: 33, 34, 35, 36, 37, and 38, respectively (CIS34);
(c) SEQ ID NOs: 27, 28, 29, 30, 31, and 32, respectively (CIS23);
(d) SEQ ID NOs: 15, 16, 17, 18, 19, and 20, respectively (CIS04);
(e) SEQ ID NOs: 39, 40, 41, 42, 43, and 44, respectively (CIS42);
(f) SEQ ID NOs: 21, 22, 23, 24, 25, and 26, respectively (CIS06); or
(g) SEQ ID NOs: 88, 89, 90, 91, 92, and 93, respectively (mAb10).

### Claim 3 (depends on 1)

The antibody of claim 1, wherein the VH and the VL comprise the amino acid sequences at least 90% identical to the amino acid sequences set forth as:
(a) SEQ ID NOs: 11 and 12, respectively (CIS43);
(b) SEQ ID NOs: 7 and 8, respectively (CIS34);
(c) SEQ ID NOs: 5 and 6, respectively (CIS23);
(d) SEQ ID NOs: 1 and 2, respectively (CIS04);
(e) SEQ ID NOs: 9 and 10, respectively (CIS42);
(f) SEQ ID NOs: 3 and 4, respectively (CIS06); or
(g) SEQ ID NOs: 81 and 82, respectively (mAb10).

### Claim 4 (depends on 1)

The antibody of claim 1, comprising human framework regions.

### Claim 5 (depends on 1)

The antibody of claim 1, wherein the VH and the VL comprise the amino acid sequences set forth as:
(a) SEQ ID NOs: 11 and 12, respectively (CIS43);
(b) SEQ ID NOs: 7 and 8, respectively (CIS34);
(c) SEQ ID NOs: 5 and 6, respectively (CIS23);
(d) SEQ ID NOs: 1 and 2, respectively (CIS04);
(e) SEQ ID NOs: 9 and 10, respectively (CIS42);
(f) SEQ ID NOs: 3 and 4, respectively (CIS06); or
(g) SEQ ID NOs: 81 and 82, respectively (mAb10).

### Claim 6 (depends on 1)

The antibody of claim 1, wherein the antibody comprises a human constant domain.

### Claim 7 (depends on 1)

The antibody of claim 1, wherein the antibody is a human antibody.

### Claim 8 (depends on 1)

The antibody of claim 1, wherein the antibody is an IgG.

### Claim 9 (depends on 8)

The antibody of claim 8, comprising heavy and light chains comprising the amino acid sequences set forth as SEQ ID NOs: 13 and 14, respectively (CIS43 IgG1).

### Claim 10 (depends on 1)

The antibody of claim 1, comprising a recombinant constant domain comprising a modification that increases the half-life of the antibody.

### Claim 11 (depends on 10)

The antibody of claim 10, wherein the modification increases binding to the neonatal Fc receptor.

### Claim 12 (depends on 11)

The isolated monoclonal antibody of claim 11, wherein the recombinant constant domain is an IgG1 constant domain comprising M428L and N434S mutations.

### Claim 13 (depends on 1)

An isolated antigen binding fragment of the antibody of claim 1, wherein the antigen binding fragment comprises the VH and the VL of the antibody, specifically binds to P. falciparum CSP, and neutralizes P. falciparum.

### Claim 14 (depends on 13)

The antigen binding fragment of claim 13, wherein the antigen binding fragment is a Fv, Fab, F(ab′)2, scFV or a scFV2 fragment.

### Claim 15 (depends on 1)

The antibody or antigen binding fragment of claim 1, conjugated to an effector molecule or a detectable marker.

### Claim 16 (depends on 1)

An isolated nucleic acid molecule encoding the antibody or antigen binding fragment of claim 1.

### Claim 17 (depends on 16)

The nucleic acid molecule of claim 16, comprising the VH and the VL nucleotide sequences set forth as one of:
(a) SEQ ID NOs: 57 and 58, respectively (CIS43);
(b) SEQ ID NOs: 53 and 54, respectively (CIS34);
(c) SEQ ID NOs: 51 and 52, respectively (CIS23);
(d) SEQ ID NOs: 47 and 48, respectively (CIS04);
(e) SEQ ID NOs: 55 and 56, respectively (CIS42);
(f) SEQ ID NOs: 49 and 50, respectively (CIS06); or
(g) SEQ ID NOs: 83 and 84, respectively (mAb10).

### Claim 18 (depends on 16)

The nucleic acid molecule of claim 16, wherein the nucleic acid molecule is a recombinant nucleic acid molecule.

### Claim 19 (depends on 16)

The nucleic acid molecule of claim 16, wherein the nucleic acid molecule comprises a cDNA encoding the antibody or antigen binding fragment.

### Claim 20 (depends on 16)

The nucleic acid molecule of claim 16, wherein the nucleic acid molecule is an RNA molecule encoding the antibody or antigen binding fragment.

### Claim 21 (depends on 16)

The nucleic acid molecule of claim 16, operably linked to a promoter.

### Claim 22 (depends on 16)

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

### Claim 23 (depends on 1)

A pharmaceutical composition for use in inhibiting P. falciparum infection, comprising an effective amount of the antibody of claim 1, an antigen binding fragment thereof, a nucleic acid molecule encoding the antibody or antigen binding fragment, or a vector comprising the nucleic acid molecule; and
a pharmaceutically acceptable carrier.

### Claim 24 (depends on 1)

A method of producing an antibody or antigen binding fragment that specifically binds to P. falciparum CSP, comprising:
expressing one or more nucleic acid molecules encoding the antibody of claim 1 or an antigen binding fragment thereof in a host cell; and
purifying the antibody or antigen binding fragment.

### Claim 25 (depends on 1)

A method of detecting the presence of P. falciparum in a biological sample from a human subject, comprising:
contacting the biological sample with an effective amount of the antibody of claim 1 or an antigen binding fragment thereof under conditions sufficient to form an immune complex; and
detecting the presence of the immune complex in the biological sample, wherein the presence of the immune complex in the biological sample indicates the presence of the P. falciparum in the sample.

### Claim 26 (depends on 25)

The method of claim 25, wherein detecting the detecting the presence of the immune complex in the biological sample indicates that the subject has a P. falciparum infection.

### Claim 27 (depends on 1)

A method of inhibiting a P. falciparum infection in a subject, comprising administering an effective amount of the antibody of claim 1, an antigen binding fragment thereof, a nucleic acid molecule encoding the antibody or antigen binding fragment, a vector comprising the nucleic acid molecule, or a pharmaceutical composition comprising the antibody, antigen binding fragment, nucleic acid molecule, or the vector to the subject, wherein the subject has or is at risk of a P. falciparum infection.

### Claim 28

(canceled)