# US 2013/0280276 A1 · Antibody targeting osteoclast-related protein siglec-15

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- Number: US 2013/0280276 A1
- Document ID: US20130280276A1
- Status: Published application
- Kind: A1
- Application number: 13/877,779
- Filed: 2011-10-04
- Published: 2013-10-24
- Earliest claimed: 2010-10-05
- Assignees: Daiichi Sankyo Company, Limited
- Inventors: Ichiro Watanabe; Yoshiharu Hiruma; Eisuke Tsuda; Tatsuji Matsuoka; Toshiaki Ohtsuka; Tohru Takahashi; Toshinori Agatsuma; Sandra Miller; Robert Mühlbacher; Kathrin-Ladetzki Baehs; Steffen Runz; Ulrike Schubert; Ingrid Schuster; Dirk Ponsel
- Web page: https://patentgrep.com/patent/US20130280276A1

## CPC

- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61P 19/00: Drugs for skeletal disorders
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 19/10: for osteoporosis
- C07K 16/2803: {against the immunoglobulin superfamily}
- A61K 2039/505: {comprising antibodies}
- C07K 2317/21: from primates, e.g. man
- C07K 2317/55: Fab or Fab'
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- 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

An isolated antibody capable of binding Siglec-15 which inhibits osteoclast formation and/or osteoclastic bone resorption, or a functional fragment thereof. The heavy chain of the antibody comprises a CDRH1 comprising a sequence having at least 80% sequence identity to SEQ ID NO: 106, a CDRH2 comprising a sequence having at least 80% sequence identity to SEQ ID NO: 107, and a CDRH3 comprising a sequence having at least 80% sequence identity to one of SEQ ID NOS: 35, 45, 55, 65 or 80. The light chain of the antibody comprises a CDRL1 comprising a sequence having at least 80% sequence identity to SEQ ID NO: 73 or 83, a CDRL2 comprising a sequence having at least 80% sequence identity to SEQ ID NO: 108, and a CDRL3 comprising a sequence having at least 80% sequence identity to one of SEQ ID NOS: 40, 50, 60, 70, 90, 100 or 109.

## Claims

### Claim 1

An isolated antibody capable of binding Siglec-15 which inhibits osteoclast formation and/or osteoclastic bone resorption, or a functional fragment thereof comprising (a) a heavy chain comprising a CDRH1 comprising a sequence having at least 80% sequence identity to SEQ ID NO: 106, a CDRH2 comprising a sequence having at least 80% sequence identity to SEQ ID NO: 107, and a CDRH3 comprising a sequence having at least 80% sequence identity to one of SEQ ID NOS: 80, 55, 65, 35 or 45; and (b) a light chain comprising a CDRL1 comprising a sequence having at least 80% sequence identity to SEQ ID NO: 83 or 73, a CDRL2 comprising a sequence having at least 80% sequence identity to SEQ ID NO: 108, and a CDRL3 comprising a sequence having at least 80% sequence identity to one of SEQ ID NOS: 90, 60, 100, 70, 40, 50 or 109.

### Claim 2 (depends on 1)

The isolated antibody or functional fragment thereof according to claim 1, wherein the CDRH1 comprises a sequence having at least 80% sequence identity to one of SEQ ID NOS: 78, 53, 63, 33 or 43.

### Claim 3 (depends on 1)

The isolated antibody or functional fragment thereof according to claim 1, wherein the CDRH2 comprises a sequence having at least 80% sequence identity to one of SEQ ID NOS: 104, 54, 94, 64, 34, 44 or 79.

### Claim 4 (depends on 1)

The isolated antibody or functional fragment thereof according to claim 1, wherein the CDR11 comprises a sequence having at least 80% sequence identity to one of SEQ ID NOS: 88, 58, 68, 38 or 48.

### Claim 5 (depends on 1)

The isolated antibody or functional fragment thereof according claim 1, wherein the CDRL2 comprises a sequence having at least 80% sequence identity to one of SEQ ID NOS: 89, 59, 69, 39 or 49.

### Claim 6 (depends on 1)

The isolated antibody or functional fragment thereof according to claim 1, wherein the sequences of CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 in the antibody comprise:
a) SEQ ID NOS: 103, 104, 105, 88, 89 and 90, respectively or sequences with at least 80%, 90% or 95% sequence identity thereto;
b) SEQ ID NOS: 53, 54, 55, 58, 59 and 60, respectively or sequences with at least 80%, 90% or 95% sequence identity thereto;
c) SEQ ID NOS: 93, 94, 95, 98, 99 and 100, respectively or sequences with at least 80%, 90% or 95% sequence identity thereto;
d) SEQ ID NOS: 63, 64, 65, 68, 69 and 70, respectively or sequences with at least 80%, 90% or 95% sequence identity thereto;
e) SEQ ID NOS: 33, 34, 35, 38, 39 and 40, respectively or sequences with at least 80%, 90% or 95% sequence identity thereto;
f) SEQ ID NOS: 43, 44, 45, 48, 49 and 50, respectively or sequences with at least 80%, 90% or 95% sequence identity thereto; or
g) SEQ ID NOS: 78, 79, 80, 88, 89 and 90, respectively or sequences with at least 80%, 90% or 95% sequence identity thereto.

### Claim 7 (depends on 1)

The isolated antibody or functional fragment thereof according to claim 1, wherein the antibody comprises:
a heavy chain variable region selected from the group consisting of
a1) an amino acid sequence comprising: amino acid residues 20 to 140 of SEQ ID NO: 102, amino acid residues 20 to 137 of SEQ ID NO: 52, amino acid residues 20 to 138 of SEQ ID NO: 92, amino acid residues 20 to 136 of SEQ ID NO: 62, amino acid residues 20 to 136 of SEQ ID NO: 32, amino acid residues 20 to 135 of SEQ ID NO: 42, or amino acid residues 20 to 138 of SEQ ID NO: 77;
a2) an amino acid sequence having at least 90% sequence identity with the amino acid sequence of a1);
a3) an amino acid sequence having at least 95% sequence identity with the amino acid sequence of a1); and
a4) an amino acid sequence including addition, deletion or substitution of one or several amino acid residues in the amino acid sequence of a1); and
a light chain variable region selected form the group consisting of
b1) an amino acid sequence comprising: amino acid residues 20 to 134 of SEQ ID NO: 87, amino acid residues 20 to 129 of SEQ ID NO: 57, amino acid residues 20 to 133 of SEQ ID NO: 97, amino acid residues 20 to 129 of SEQ ID NO: 67, amino acid residues 20 to 129 of SEQ ID NO: 37, or amino acid residues 20 to 129 of SEQ ID NO: 47;
b2) an amino acid sequence having at least 90% sequence identity with the amino acid sequence of b1);
b3) an amino acid sequence having at least 95% sequence identity with the amino acid sequence of b1); and
b4) an amino acid sequence including addition, deletion or substitution of one or several amino acid residues in the amino acid sequence of b1).

### Claim 8 (depends on 1)

The isolated antibody or functional fragment thereof according claim 1, wherein the antibody comprises:
a heavy chain selected from the group consisting of
a1) an amino acid sequence comprising the sequence of one of SEQ ID NOS: 102, 52, 92, 62, 32, 42 or 77;
a2) an amino acid sequence having at least 90% sequence identity with the amino acid sequence of a1);
a3) an amino acid sequence having at least 95% sequence identity with the amino acid sequence of a1); and
a4) an amino acid sequence including addition, deletion or substitution of one or several amino acid residues in the amino acid sequence of a1); and
a light chain selected from the group consisting of
b1) an amino acid sequence comprising the sequence of one of SEQ ID NOS: 87, 57, 97, 67, 37 or 47;
b2) an amino acid sequence having at least 90% sequence identity with the amino acid sequence of b1);
b3) an amino acid sequence having at least 95% sequence identity with the amino acid sequence of b1); and
b4) an amino acid sequence including addition, deletion or substitution of one or several amino acid residues in the amino acid sequence of b1).

### Claim 9 (depends on 1)

The isolated antibody or functional fragment thereof according to claim 1, wherein the antibody comprises a heavy chain consisting of an amino acid sequence comprising SEQ ID NO: 102, and a light chain consisting of an amino acid sequence comprising SEQ ID NO: 87.

### Claim 10 (depends on 1)

The isolated antibody or functional fragment thereof according to claim 1, wherein the antibody comprises a heavy chain consisting of an amino acid sequence comprising SEQ ID NO: 52, and a light chain consisting of an amino acid sequence comprising SEQ ID NO: 57.

### Claim 11 (depends on 1)

The isolated antibody or functional fragment thereof according to claim 1, wherein the antibody comprises a heavy chain consisting of an amino acid sequence comprising SEQ ID NO: 92, and a light chain consisting of an amino acid sequence comprising SEQ ID NO: 97.

### Claim 12 (depends on 1)

The isolated antibody or functional fragment thereof according to claim 1 wherein the antibody comprises a heavy chain consisting of an amino acid sequence comprising SEQ ID NO: 62, and a light chain consisting of an amino acid sequence comprising SEQ ID NO: 67.

### Claim 13 (depends on 1)

The isolated antibody or functional fragment thereof according claim 1, wherein the antibody comprises a heavy chain consisting of an amino acid sequence comprising SEQ ID NO: 32, and a light chain consisting of an amino acid sequence comprising SEQ ID NO: 37.

### Claim 14 (depends on 1)

The isolated antibody or functional fragment thereof according to claim 1, wherein the antibody comprises a heavy chain consisting of an amino acid sequence comprising SEQ ID NO: 42, and a light chain consisting of an amino acid sequence comprising SEQ ID NO: 47.

### Claim 15 (depends on 1)

The isolated antibody or functional fragment thereof according to claim 1, wherein the antibody comprises a heavy chain consisting of an amino acid sequence comprising SEQ ID NO: 77, and a light chain consisting of an amino acid sequence comprising SEQ ID NO: 87.

### Claim 16 (depends on 1)

The isolated antibody or functional fragment thereof according to claim 1, wherein the functional fragment is selected from the group consisting of Fab. F(ab′)2, Fab′ and Fv.

### Claim 17 (depends on 1)

The isolated antibody or functional fragment thereof according to claim 1, wherein the functional fragment is a scFv.

### Claim 18

(canceled)

### Claim 19

(canceled)

### Claim 20 (depends on 1)

A method for treating a patient suffering from abnormal bone metabolism comprising administering a therapeutically effective amount of the isolated antibody or functional fragment thereof according to claim 1.

### Claim 21 (depends on 1)

A pharmaceutical composition comprising at least one antibody or functional fragment thereof according to claim 1.

### Claim 22 (depends on 21)

The pharmaceutical composition according to claim 21, wherein the composition is a therapeutic and/or preventive agent for abnormal bone metabolism.

### Claim 23 (depends on 1)

A pharmaceutical composition for treating and/or preventing abnormal bone metabolism comprising at least one antibody or functional fragments thereof according to claim 1, and at least one member selected from the group consisting of bisphosphonates, active vitamin D3, calcitonin and derivatives thereof, hormone preparations such as estradiol, SERMs (selective estrogen receptor modulators), ipriflavone, vitamin K2 (menatetrenone), calcium preparations. PTH (parathyroid hormone) preparations, nonsteroidal anti-inflammatory agents, soluble TNF receptor preparations, anti-TNF-α antibodies or functional fragments of the antibodies, anti-PTHrP (parathyroid hormone-related protein) antibodies or functional fragments of the antibodies, IL-1 receptor antagonists, anti-IL-6 receptor antibodies or functional fragments of the antibodies, anti-RANKL antibodies or functional fragments of the antibodies and OCIF (osteoclastogenesis inhibitory factor).

### Claim 24 (depends on 20)

The method of claim 20, wherein the abnormal hone metabolism is selected from the group consisting of: osteoporosis, bone destruction accompanying rheumatoid arthritis, cancerous hypercalcemia, bone destruction accompanying multiple myeloma or cancer metastasis to bone, giant cell tumor, tooth loss due to periodontitis, osteolysis around a prosthetic joint, bone destruction in chronic osteomyelitis, Paget's disease of bone, renal osteodystrophy and osteogenesis imperfecta.

### Claim 25 (depends on 24)

The method according to claim 24, characterized in that the abnormal bone metabolism is osteoporosis, bone destruction accompanying rheumatoid arthritis or bone destruction accompanying cancer metastasis to bone.

### Claim 26 (depends on 25)

The method according to claim 25, characterized in that the osteoporosis is postmenopausal osteoporosis, senile osteoporosis, secondary osteoporosis due to the use of a therapeutic agent such as a steroid or an immunosuppressant, or osteoporosis accompanying rheumatoid arthritis.

### Claim 27 (depends on 1)

A polynucleotide which comprises:
a) a nucleotide sequence that encodes the antibody or functional fragment thereof according to claim 1; or
b) a nucleotide sequence of a polynucleotide which hybridizes to a polynucleotide consisting of a nucleotide sequence complementary to the nucleotide sequence of a) under stringent conditions.

### Claim 28 (depends on 27)

The polynucleotide according to claim 27, wherein the nucleotide sequences encoding CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 comprise:
a) nucleotides 148 to 162 of SEQ ID NO: 101, nucleotides 205 to 261 of SEQ ID NO: 101, nucleotides 358 to 387 of SEQ ID NO: 101, nucleotides 124 to 165 of SEQ ID NO: 86, nucleotides 211 to 231 of SEQ ID NO: 86 and nucleotides 328 to 363 of SEQ ID NO: 86, respectively;
b) nucleotides 148 to 162 of SEQ ID NO: 51, nucleotides 205 to 255 of SEQ ID NO: 51, nucleotides 352 to 378 of SEQ ID NO: 51, nucleotides 124 to 156 of SEQ ID NO: 56, nucleotides 202 to 222 of SEQ ID NO: 56 and nucleotides 319 to 348 of SEQ ID NO: 56, respectively;
c) nucleotides 148 to 162 of SEQ ID NO: 91, nucleotides 205 to 255 of SEQ ID NO: 91, nucleotides 352 to 381 of SEQ ID NO: 91, nucleotides 124 to 165 of SEQ ID NO: 96, nucleotides 211 to 231 of SEQ ID NO: 96 and nucleotides 328 to 360 of SEQ ID NO: 96, respectively;
d) nucleotides 148 to 162 of SEQ ID NO: 61, nucleotides 205 to 255 of SEQ ID NO: 61, nucleotides 352 to 375 of SEQ ID NO: 61, nucleotides 124 to 156 of SEQ ID NO: 66, nucleotides 202 to 222 of SEQ ID NO: 66 and nucleotides 319 to 348 of SEQ ID NO: 66, respectively;
e) nucleotides 148 to 162 of SEQ ID NO: 31, nucleotides 205 to 255 of SEQ ID NO: 31, nucleotides 352 to 375 of SEQ ID NO: 31, nucleotides 124 to 156 of SEQ ID NO: 36, nucleotides 202 to 222 of SEQ ID NO: 36 and nucleotides 319 to 348 of SEQ ID NO: 36, respectively;
f) nucleotides 148 to 162 of SEQ ID NO: 41 nucleotides 205 to 255 of SEQ ID NO: 41, nucleotides 352 to 372 of SEQ ID NO: 4E nucleotides 124 to 156 of SEQ ID NO: 46, nucleotides 202 to 222 of SEQ ID NO: 46 and nucleotides 319 to 348 of SEQ ID NO: 46, respectively; or
g) nucleotides 148 to 162 of SEQ ID NO: 76, nucleotides 205 to 255 of SEQ ID NO: 76, nucleotides 352 to 381 of SEQ ID NO: 76, nucleotides 124 to 165 of SEQ ID NO: 86, nucleotides 211 to 231 of SEQ ID NO: 86 and nucleotides 328 to 363 of SEQ ID NO: 86, respectively.

### Claim 29 (depends on 27)

The polynucleotide according to claim 27, wherein the polynucleotide comprises:
a nucleotide sequence encoding a heavy chain variable region selected from the group consisting of
a1) a nucleotide sequence comprising: nucleotides 58 to 420 of SEQ ID NO: 101, nucleotides 58 to 411 of SEQ ID NO: 51, nucleotides 58 to 414 of SEQ ID NO: 91, nucleotides 58 to 408 of SEQ ID NO: 61, nucleotides 58 to 408 of SEQ ID NO: 3E nucleotides 58 to 405 of SEQ ID NO: 41 or nucleotides 58 to 414 of SEQ ID NO: 76;
a2) a nucleotide sequence of a polynucleotide which hybridizes to a polynucleotide consisting of a nucleotide sequence complementary to the nucleotide sequence of a1) under stringent conditions; and
a3) a nucleotide sequence including addition, deletion or substitution of one or several nucleotides in the nucleotide sequence of a1); and
a nucleotide sequence encoding a light chain variable region selected from the group consisting of
b1) a nucleotide sequence comprising: nucleotides 58 to 402 of SEQ ID NO: 86, nucleotides 58 to 387 of SEQ ID NO: 56, nucleotides 58 to 399 of SEQ ID NO: 96, nucleotides 58 to 387 of SEQ ID NO: 66, nucleotides 58 to 387 of SEQ ID NO: 36 or nucleotides 58 to 387 of SEQ ID NO: 46;
b2) a nucleotide sequence of a polynucleotide which hybridizes to a polynucleotide consisting of a nucleotide sequence complementary to the nucleotide sequence of b1) under stringent conditions; and
b3) a nucleotide sequence including addition, deletion or substitution of one or several nucleotides in the nucleotide sequence of b1).

### Claim 30 (depends on 29)

The polynucleotide according to claim 29, wherein the polynucleotide comprises:
a nucleotide sequence encoding a heavy chain selected from the group consisting of
a1) a nucleotide sequence the sequence of one of SEQ ID NOS: 101, 51, 91, 61, 31, 41 or 76;
a2) a nucleotide sequence of a polynucleotide which hybridizes to a polynucleotide consisting of a nucleotide sequence complementary to the nucleotide sequence of a1) under stringent conditions; and
a3) a nucleotide sequence including addition, deletion or substitution of one or several nucleotides in the nucleotide sequence of a1); and
a nucleotide sequence encoding a light chain selected from the group consisting of
b1) a nucleotide sequence comprising the sequence of one of SEQ ID NOS: 86, 56, 96, 66, 36 or 46;
b2) a nucleotide sequence of a polynucleotide which hybridizes to a polynucleotide consisting of a nucleotide sequence complementary to the nucleotide sequence of b1) under stringent condition; and
b3) a nucleotide sequence including addition, deletion or addition of one or several nucleotides in the nucleotide sequence of b1).

### Claim 31 (depends on 27)

A vector comprising at least one polynucleotide according to claim 27.

### Claim 32 (depends on 27)

A transformed cell comprising at least one polynucleotide according claim 27.

### Claim 33 (depends on 31)

A transformed cell comprising at least one vector according to claim 31.

### Claim 34 (depends on 1)

A method of producing the isolated antibody or functional fragment of claim 1, comprising (i) culturing a transformed cell that comprises at least one polynucleotide encoding (a) a heavy chain comprising a CDRH1 comprising a sequence having at least 80% sequence identity to SEQ ID NO: 106, a CDRH2 comprising a sequence having at least 80% sequence identity to SEQ ID NO: 107, and a CDRH3 comprising a sequence having at least 80% sequence identity to one of SEQ ID NOS: 80, 55, 65, 35 or 45; and (b) a light chain comprising a CDRL1 comprising a sequence having at least 80% sequence identity to SEQ ID NO: 83 or 73, a CDRL2 comprising a sequence having at least 80% sequence identity to SEQ ID NO: 108, and a CDRL3 comprising a sequence having at least 80% sequence identity to one of SEQ Ill NOS: 90, 60, 100, 70, 40, 50 or 109, (ii) collecting culturing materials, and (iii) purifying said antibodies from said culturing materials.

### Claim 35 (depends on 22)

The pharmaceutical composition according to claim 22, wherein the abnormal bone metabolism is selected from the group consisting of: osteoporosis, bone destruction accompanying rheumatoid arthritis, cancerous hypercalcemia, bone destruction accompanying multiple myeloma or cancer metastasis to bone, giant cell tumor, tooth loss due to periodontitis, osteolysis around a prosthetic joint, bone destruction in chronic osteomyelitis, Paget's disease of bone, renal osteodystrophy and osteogenesis imperfecta.

### Claim 36 (depends on 23)

The pharmaceutical composition according to claim 23, wherein the abnormal bone metabolism is selected from the group consisting of: osteoporosis, bone destruction accompanying rheumatoid arthritis, cancerous hypercalcemia, bone destruction accompanying multiple myeloma or cancer metastasis to bone, giant cell tumor, tooth loss due to periodontitis, osteolysis around a prosthetic joint, bone destruction in chronic osteomyelitis, Paget's disease of bone, renal osteodystrophy and osteogenesis imperfecta.

### Claim 37 (depends on 35)

The pharmaceutical composition according to claim 35, characterized in that the abnormal bone metabolism is osteoporosis, bone destruction accompanying rheumatoid arthritis or bone destruction accompanying cancer metastasis to bone.

### Claim 38 (depends on 36)

The pharmaceutical composition according to claim 36, characterized in that the abnormal bone metabolism is osteoporosis, bone destruction accompanying rheumatoid arthritis or bone destruction accompanying cancer metastasis to bone.

### Claim 39 (depends on 37)

The pharmaceutical composition according to claim 37, characterized in that the osteoporosis is postmenopausal osteoporosis, senile osteoporosis, secondary osteoporosis due to the use of a therapeutic agent such as a steroid or an immunosuppressant, or osteoporosis accompanying rheumatoid arthritis.

### Claim 40 (depends on 38)

The pharmaceutical composition according to claim 38, characterized in that the osteoporosis is postmenopausal osteoporosis, senile osteoporosis, secondary osteoporosis due to the use of a therapeutic agent such as a steroid or an immunosuppressant, or osteoporosis accompanying rheumatoid arthritis.