# US 10,189,910 B2 · Anti-DPEP3 antibodies and methods of use

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- Number: US 10,189,910 B2
- Document ID: US10189910B2
- Status: Granted
- Kind: B2
- Application number: 15/181,353
- Filed: 2016-06-13
- Published: 2017-02-02
- Granted: 2019-01-29
- Earliest claimed: 2013-12-12
- Assignees: Abbvie Stemcentrx LLC
- Applicants: AbbVie Stemcentrx LLC
- Inventors: Laura Saunders; Deepti Rokkam; David Liu; Mandy Boontanrart
- Web page: https://patentgrep.com/patent/US10189910B2

## CPC

- C07K 16/40: against enzymes
- A61K 31/551: having two nitrogen atoms, e.g. dilazep
- A61K 47/6851: {the antibody targeting a determinant of a tumour cell}
- A61P 35/00: Antineoplastic agents
- C07K 16/30: from tumour cells
- C12Y 304/13019: Membrane dipeptidase (3.4.13.19)
- A61K 2039/505: {comprising antibodies}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- 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 2317/77: Internalization into the cell
- 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
- C12Y: ENZYMES

## Abstract

Provided herein are novel anti-DPEP3 antibodies and antibody drug conjugates (ADC), including derivatives thereof, and methods of using the same to treat proliferative disorders.

## Claims

### Claim 1

An antibody drug conjugate comprising a monoclonal antibody conjugated, linked, or otherwise associated with a cytotoxic agent,
wherein the monoclonal antibody binds human DPEP3 and comprises three complementarity determining regions of a light chain variable region set forth as SEQ ID NO: 205 and three complementarity determining regions of a heavy chain variable region set forth as SEQ ID NO: 207.

### Claim 2 (depends on 1)

The antibody drug conjugate of claim 1, wherein mutating at least one of amino acids E217, R242, Q248, Q372, K375, and E379 of SEQ ID NO: 3 results in loss of binding of the antibody to DPEP3.

### Claim 3 (depends on 1)

The antibody drug conjugate of claim 1, wherein the monoclonal antibody binds to an epitope on human DPEP3 that comprises residues E217, R242, Q248, Q372, K375, and E379.

### Claim 4 (depends on 1)

The antibody drug conjugate of claim 1, wherein the monoclonal antibody is a chimeric, CDR grafted, or humanized antibody.

### Claim 5 (depends on 1)

The antibody drug conjugate of claim 1, comprising the formula Ab-[L-D]n, wherein:
a) Ab comprises the antibody;
b) L comprises an optional linker;
c) D comprises a drug, which is the cytotoxic agent; and
d) n is an integer from about 1 to about 20.

### Claim 6 (depends on 1)

The antibody drug conjugate of claim 1, wherein the cytotoxic agent is a pyrrolobenzodiazepine (PBD).

### Claim 7 (depends on 1)

A pharmaceutical composition comprising (i) the antibody drug conjugate of claim 1 and (ii) a pharmaceutically acceptable carrier.

### Claim 8 (depends on 1)

The antibody drug conjugate of claim 1, wherein the antibody comprises residues 24-34 of SEQ ID NO: 205 for CDRL1, residues 50-56 of SEQ ID NO: 205 for CDRL2, residues 89-97 of SEQ ID NO: 205 for CDRL3, residues 31-35 of SEQ ID NO: 207 for CDRH1, residues 50-65 of SEQ ID NO: 207 for CDRH2 and residues 95-102 of SEQ ID NO: 207 for CDRH3, wherein the CDR residues are numbered according to Kabat.

### Claim 9 (depends on 1)

The antibody drug conjugate of claim 1, wherein the antibody comprises residues 24-34 of SEQ ID NO: 205 for CDRL1, residues 50-56 of SEQ ID NO: 205 for CDRL2, residues 89-97 of SEQ ID NO: 205 for CDRL3, residues 26-32 of SEQ ID NO: 207 for CDRH1, residues 52-56 of SEQ ID NO: 207 for CDRH2 and residues 95-102 of SEQ ID NO: 207 for CDRH3, wherein the CDR residues are numbered according to Chothia.

### Claim 10 (depends on 1)

The antibody drug conjugate of claim 1, wherein the antibody comprises residues 30-36 of SEQ ID NO: 205 for CDRL1, residues 46-55 of SEQ ID NO: 205 for CDRL2, residues 89-96 of SEQ ID NO: 205 for CDRL3, residues 30-35 of SEQ ID NO: 207 for CDRH1, residues 47-58 of SEQ ID NO: 207 for CDRH2 and residues 93-101 of SEQ ID NO: 207 for CDRH3, wherein the CDR residues are numbered according to MacCallum.

### Claim 11 (depends on 1)

The antibody drug conjugate of claim 1, wherein the antibody comprises residues 24-34 of SEQ ID NO: 205 for CDRL1, residues 50-56 of SEQ ID NO: 205 for CDRL2, residues 89-97 of SEQ ID NO: 205 for CDRL3, residues 26-35 of SEQ ID NO: 207 for CDRH1, residues 50-58 of SEQ ID NO: 207 for CDRH2 and residues 95-102 of SEQ ID NO: 207 for CDRH3, wherein the CDR residues are numbered according to AbM.

### Claim 12 (depends on 1)

The antibody drug conjugate of claim 1, wherein the antibody comprises a light chain variable region set forth as SEQ ID NO: 205 and a heavy chain variable region set forth as SEQ ID NO: 207.

### Claim 13 (depends on 1)

The antibody drug conjugate of claim 1, wherein the antibody comprises two light chains and two heavy chains, wherein each of the two light chains comprises a sequence set forth as SEQ ID NO: 224 and each of the two heavy chains comprises a sequence set forth as SEQ ID NO: 225.

### Claim 14 (depends on 1)

The antibody drug conjugate of claim 1, wherein the antibody comprises two light chains, two heavy chains, and two unpaired cysteine residues.

### Claim 15 (depends on 14)

The antibody drug conjugate of claim 14, wherein each of the two light chains comprises an unpaired cysteine residue.

### Claim 16 (depends on 15)

The antibody drug conjugate of claim 15, wherein the two light chains each comprise an unpaired cysteine residue at position C214.

### Claim 17 (depends on 14)

The antibody drug conjugate of claim 14, wherein each of the two heavy chains comprises an unpaired cysteine residue.

### Claim 18 (depends on 17)

The antibody drug conjugate of claim 17, wherein each of the two heavy chains comprise IgG1 comprising an unpaired cysteine residue at position C220.

### Claim 19 (depends on 14)

The antibody drug conjugate of claim 14, wherein the antibody comprises an IgG1 monoclonal antibody comprising (i) a cysteine residue at heavy chain position 220 and a deletion of a cysteine residue at light chain position 214; (ii) a cysteine residue at heavy chain position 220 and a substitution of a cysteine residue at light chain position 214; (iii) a cysteine residue at light chain position 214 and a deletion of a cysteine residue at heavy chain position 220; or (iv) a cysteine residue at light chain position 214 and a substitution of a cysteine residue at heavy chain position 220; and
wherein the antibody comprises native cysteine residues at heavy chain positions 226 and 229.

### Claim 20 (depends on 14)

The antibody drug conjugate of claim 14, wherein each of the two light chains comprises a sequence set forth as SEQ ID NO: 224 and each of the two heavy chains comprises a sequence set forth as SEQ ID NO: 226.

### Claim 21 (depends on 1)

The antibody drug conjugate of claim 1, wherein the antibody is conjugated to the cytotoxic agent.

### Claim 22 (depends on 1)

The antibody drug conjugate of claim 1, wherein the cytotoxic agent is a pyrrolobenzodiazepine having the structure:

### Claim 23 (depends on 1)

The antibody drug conjugate of claim 1, wherein the antibody comprises a light chain variable region set forth as SEQ ID NO: 205 and a heavy chain variable region set forth as SEQ ID NO: 207 and wherein the cytotoxic agent is a pyrrolobenzodiazepine having the structure:

### Claim 24 (depends on 1)

The antibody drug conjugate of claim 1, wherein the antibody comprises two light chains and two heavy chains, wherein each of the two light chains comprises a sequence set forth as SEQ ID NO: 224 and each of the two heavy chains comprises a sequence set forth as SEQ ID NO: 226, and wherein the cytotoxic agent is a pyrrolobenzodiazepine having the structure:

### Claim 25 (depends on 1)

The antibody drug conjugate of claim 1, wherein the antibody drug conjugate has a drug loading of 2.

### Claim 26 (depends on 25)

The antibody drug conjugate of claim 25, comprising a linker.

### Claim 27 (depends on 26)

The antibody drug conjugate of claim 26, wherein the linker is a cleavable linker.

### Claim 28 (depends on 27)

The antibody drug conjugate of claim 27, wherein the linker comprises a maleimide linker.

### Claim 29 (depends on 7)

The pharmaceutical composition of claim 7, comprising a drug to antibody ratio (DAR) of 1, 2, 3, 4, 5, 6, 7 or 8 each ±0.4.

### Claim 30 (depends on 7)

The pharmaceutical composition of claim 7, comprising a drug to antibody ratio (DAR) of 2±0.4.

### Claim 31 (depends on 30)

The pharmaceutical composition of claim 30, comprising less than 30% of non-predominant antibody drug conjugate species.

### Claim 32 (depends on 7)

The pharmaceutical formulation of claim 7, wherein the antibody drug conjugate further comprises a linker and wherein:
(a) the antibody comprises a light chain variable region set forth as SEQ ID NO: 205 and a heavy chain variable region set forth as SEQ ID NO: 207; and
(b) the cytotoxic agent is a pyrrolobenzodiazepine having the structure:

### Claim 33 (depends on 7)

The pharmaceutical composition of claim 7, wherein the antibody drug conjugate further comprises a linker and wherein:
(a) the antibody comprises two light chains and two heavy chains, wherein the two light chains each comprise a sequence set forth as SEQ ID NO: 224 and the two heavy chains each comprise a sequence set forth as SEQ ID NO: 226; and
(b) the cytotoxic agent is a pyrrolobenzodiazepine having the structure:

### Claim 34 (depends on 32)

The pharmaceutical composition of claim 32, comprising a drug to antibody ratio (DAR) of 1, 2, 3, 4, 5, 6, 7 or 8 each ±0.4.

### Claim 35 (depends on 32)

The pharmaceutical composition of claim 32, comprising a drug to antibody ratio (DAR) of 2±0.4.

### Claim 36 (depends on 32)

The pharmaceutical composition of claim 32, comprising less than 30% of non-predominant antibody drug conjugate species.

### Claim 37 (depends on 33)

The pharmaceutical composition of claim 33, comprising a drug to antibody ratio (DAR) of 2±0.4.

### Claim 38 (depends on 33)

The pharmaceutical composition of claim 33, comprising less than 30% of non-predominant antibody drug conjugate species.