# US 2014/0193417 A1 · Membrane Transporter NaPi2b (SCL34A2) Epitope for Antibody Therapy, Antibodies Directed Thereto, and Target for Cancer Therapy

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- Number: US 2014/0193417 A1
- Document ID: US20140193417A1
- Status: Published application
- Kind: A1
- Application number: 14/037,504
- Filed: 2013-09-26
- Published: 2014-07-10
- Earliest claimed: 2008-01-29
- Assignees: Ludwig Institute for Cancer Research; Sloan-Kettering; Institute for Molecular Biology
- Inventors: Gerd Ritter; Beatrice Yin; Anne Murray; George Mark; Lloyd J. Old; Kenneth Lloyd; Serhiy Souchelnytskiy; Ivan Gout; Valeriy Filonenko; Ramziya Kiyamova
- Web page: https://patentgrep.com/patent/US20140193417A1

## CPC

- C07K 16/3069: {Reproductive system, e.g. ovaria, uterus, testes, prostate}
- A61K 39/001102: {Receptors, cell surface antigens or cell surface determinants}
- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- C07K 7/08: having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68)
- C07K 14/4748: {Tumour specific antigens; Tumour rejection antigen precursors [TRAP], e.g. MAGE}
- C07K 14/705: Receptors; Cell surface antigens; Cell surface determinants {(tumour specific antigens C07K14/4748)}
- C07K 16/18: against material from animals or humans
- C07K 16/28: against receptors, cell surface antigens or cell surface determinants
- C07K 16/30: from tumour cells
- G01N 33/57545: of the ovaries
- A61K 39/00: Medicinal preparations containing antigens or antibodies (materials for immunoassay G01N33/53)
- A61K 2039/505: {comprising antibodies}
- A61K 2039/53: {DNA (RNA) vaccination}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- 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 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/622: Single chain antibody (scFv)
- G01N 2333/705: Assays involving receptors, cell surface antigens or cell surface determinants
- G01N 2500/04: Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
- 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
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

The present disclosure relates generally to the membrane transporter NaPi2b (SLC34A2) as a target for therapy, including immunotherapy, and particularly cancer therapy. The SLC34A2 epitope peptide encompassing amino acids 312-340 of SLC34A2 has been identified as an ovarian cancer epitope using the monoclonal antibody MX35. The invention also relates to the use of SLC34A2 and particularly SLC34A2 peptides in generating antibodies which have anti-tumor or anti-cancer activity or in stimulating an immunological response. The invention further relates to antibodies specifically directed against NaPi2b (SLC34A2) and the SLC34A2 peptide(s), including veneered, chimeric, single chain and humanized antibodies. Methods for generating an immune response and for treatment of tumors and cancer are also provided. Assays for screening and identifying compounds directed against SLC34A2, including the SLC34A2 epitope peptide, and additional antibodies are provided.

## Claims

### Claim 1

An isolated antibody which specifically binds the extracellular region of SLC34A2.

### Claim 2 (depends on 1)

The antibody of claim 1 which recognizes amino acids 312-340 of SLC34A2.

### Claim 3 (depends on 1)

The antibody of claim 1 wherein said antibody was raised to or selected by binding to any of SEQ ID NOS: 1-8.

### Claim 4 (depends on 1)

The antibody of claim 1 wherein said antibody comprises the variable region sequence substantially as set out in FIG. 5 (SEQ ID NO: 25) and FIG. 6 (SEQ ID NO: 30).

### Claim 5 (depends on 1)

The antibody of claim 1 having a heavy chain and a light chain wherein the heavy chain variable region comprises the CDRs as set out in SEQ ID NOs: 26-28 and the light chain variable region comprises the CDRs as set out in SEQ ID NO: 31-33.

### Claim 6 (depends on 1)

The antibody of claim 1 having a heavy chain and a light chain wherein the heavy chain variable region comprises CDRs highly homologous to SEQ ID NOs: 26-28 and the light chain variable region comprises CDRs highly homologous to SEQ ID NO: 31-33.

### Claim 7 (depends on 1)

The antibody of claim 1 having a heavy chain and a light chain wherein the heavy chain variable region is selected from SEQ ID NO: 25, 37, 38 and 40 and the light chain variable region is selected from SEQ ID NO: 30, 35, 39 and 41.

### Claim 8 (depends on 1)

The antibody of claim 1 having a heavy chain and a light chain wherein the heavy chain variable region is highly homologous to a sequence selected from SEQ ID NO: 37, 38 and 40 and the light chain variable region is highly homolohous to a sequence selected from SEQ ID NO: 35, 39 and 41.

### Claim 9 (depends on 1, 2, 3, 4, 5, 6, 7, 8)

The An isolated antibody of claim 1 or 5 according to any one or more of claims 1-8 which is fully human, humanized or chimerized.

### Claim 10

(canceled)

### Claim 11

(canceled)

### Claim 12 (depends on 1)

The antibody of claim 1 wherein said antibody is a humanized antibody comprising a heavy chain and a light chain, wherein the heavy chain variable region has the sequence set out in SEQ ID NO: 37 or a sequence highly homologous thereto and the light chain variable region has the sequence set out in SEQ ID NO: 35 or a sequence highly homologous thereto.

### Claim 13 (depends on 1)

The antibody according to claim 1 in the form of an antibody F(ab′)2, scFv fragment, diabody, triabody or tetrabody.

### Claim 14 (depends on 1)

The antibody according to claim 1 which carries a detectable or functional label.

### Claim 15 (depends on 13)

The single chain Fv (scFv) antibody of claim 13 which recognizes SLC34A2 and comprises an amino acid sequence highly homologous to SEQ ID NO: 42 or 44.

### Claim 16 (depends on 1)

A method of treatment of cancer in a human patient which comprises administering to said patient an effective amount of an antibody of claim 1.

### Claim 17 (depends on 1)

A method for inhibiting phosphate transport in cells of a mammal comprising administering to said patient an effective amount of an antibody of claim 1.

### Claim 18 (depends on 1)

A pharmaceutical composition comprising an antibody of claim 1 and a pharmaceutically acceptable vehicle, carrier or diluent.

### Claim 19 (depends on 1)

A method for treating or preventing ovarian cancer in a mammal comprising administering an effective amount of an antibody of claim 1.

### Claim 20 (depends on 19)

The method of claim 19 wherein the antibody is an antibody having a heavy chain and a light chain wherein the heavy chain variable region comprises the CDRs as set out in SEQ ID NOs: 26-28 and the light chain variable region comprises the CDRs as set out in SEQ ID NO: 31-33.

### Claim 21 (depends on 19)

The method of claim 19 wherein the antibody is an antibody having a heavy chain and a light chain wherein the heavy chain variable region is selected from SEQ ID NO: 25, 37, 38 and 40 and the light chain variable region is selected from SEQ ID NO: 30, 35, 39 and 41.

### Claim 22 (depends on 1, 5)

An isolated nucleic acid which comprises a sequence encoding an antibody as defined in any of claim 1 or 5.

### Claim 23

(canceled)

### Claim 24 (depends on 1, 22)

A method of preparing an antibody as defined in claim 1 which comprises expressing the nucleic acid of claim 22 under conditions to bring about expression of said antibody, and recovering the antibody.

### Claim 25 (depends on 1)

A unicellular host transformed with a recombinant DNA molecule comprising a DNA sequence or degenerate variant thereof, which encodes the antibody of claim 1, or a fragment thereof, selected from the group consisting of:
(a) the DNA sequence of FIG. 5 (SEQ ID NO: 24), the DNA sequence of FIG. 11 (SEQ ID NO: 36), the DNA sequence of FIG. 16 (SEQ ID NO: 43), or the DNA sequence of FIG. 17 (SEQ ID NO: 45);
(b) the DNA sequence of FIG. 6 (SEQ ID NO: 29), the DNA sequence of FIG. 11 (SEQ ID NO: 34);
(c) the DNA sequence of FIG. 5 (SEQ ID NO: 24) and the DNA sequence of FIG. 6 (SEQ ID NO: 29) or the DNA sequence of SED ID NO: 36 and SEQ ID NO: 34;
(d) DNA sequences that hybridize to any of the foregoing DNA sequences under standard hybridization conditions; and
(e) DNA sequences that code on expression for an amino acid sequence encoded by any of the foregoing DNA sequences;
wherein said DNA sequence is operatively linked to an expression control sequence.

### Claim 26 (depends on 25)

The unicellular host of claim 25, wherein the unicellular host is selected from the group consisting of E. coli, Pseudomonas, Bacillus, Streptomyces, yeasts, CHO, YB/20, NSO, SP2/0, R1.1, B-W, L-M, COS 1, COS 7, BSC1, BSC40, and BMT10 cells, plant cells, insect cells, and human cells in tissue culture.

### Claim 27

An isolated immunogenic SLC34A2 polypeptide which comprises the amino acid sequence set out in any of SEQ ID NOS: 1-8 and immunogenic fragments thereof

### Claim 28 (depends on 27)

A method for immunizing a mammal comprising administering the polypeptide of claim 27 or an immunogenic fragment thereof, whereby antibodies which are immunoreactive with the SLC34A2 peptide are produced.

### Claim 29 (depends on 27)

A vaccine comprising one or more polypeptide of claim 27, and a pharmaceutically acceptable adjuvant.

### Claim 30 (depends on 29)

The vaccine of claim 29 wherein said vaccine is a tumor or anti-cancer vaccine and further comprises one or more additional tumor antigens.

### Claim 31 (depends on 29)

The vaccine of claim 29 for the treatment or prevention of ovarian cancer.

### Claim 32 (depends on 29)

The vaccine of claim 29, wherein said polypeptide is conjugated to a carrier.

### Claim 33 (depends on 27)

An immunogenic composition comprising one or more polypeptide of claim 27, and a pharmaceutically acceptable adjuvant.

### Claim 34 (depends on 27)

A pharmaceutical composition comprising one or more polypeptide of claim 27, and a pharmaceutically acceptable carrier.

### Claim 35 (depends on 27)

A pharmaceutical composition comprising an SLC34A2 antibody immunoreactive with one or more polypeptide of claim 27, and a pharmaceutically acceptable carrier.

### Claim 36 (depends on 27)

A method for generating antibodies immunoreactive with SLC34A2, comprising immunizing an animal with a polypeptide of claim 27 or a fragment thereof and isolating peptide binding antibodies.

### Claim 37 (depends on 27)

An isolated nucleic acid which encodes one or more polypeptide of claim 27.

### Claim 38 (depends on 37)

A nucleic acid vaccine or DNA vaccine comprising the nucleic acid of claim 37.

### Claim 39

A method for screening or identifying agents or compounds which modulate SLC34A2 wherein the ability of an agent or compound to bind, interact with, or otherwise agonize or antagonize an SLC34A2 peptide selected from the group of any of SEQ ID NOS: 1-8 is determined.

### Claim 40 (depends on 39)

The method of claim 39, wherein the peptide is measured by:
(a) contacting a sample containing peptide with an antibody to the said peptide in combination with a candidate agent or compound under conditions that allow binding of the peptide to the antibody to occur; and
(b) detecting whether binding has occurred between the peptide and the antibody; wherein reduction or enhancement of binding of the antibody indicates that the candidate agent or compound in the sample modulates SLC34A2.

### Claim 41 (depends on 1, 40)

The method of claim 40 wherein the antibody is an antibody according to claim 1.