# US 2018/0022809 A1 · Anti-pd-l1 antibodies and diagnostic uses thereof

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- Number: US 2018/0022809 A1
- Document ID: US20180022809A1
- Status: Published application
- Kind: A1
- Application number: 15/727,388
- Filed: 2017-10-06
- Published: 2018-01-25
- Earliest claimed: 2014-07-11
- Assignees: Genentech, Inc.; Spring BioScience Corporation; Ventana Medical Systems, Inc.
- Applicants: Genentech, Inc.; Spring BioScience Corporation; Ventana Medical Systems, Inc.
- Inventors: Marcin KOWANETZ; Hartmut KOEPPEN; Zachary BOYD; Zhiming LIAO; Yifei ZHU; Bharathi VENNAPUSA; Patrick C. ROCHE
- Web page: https://patentgrep.com/patent/US20180022809A1

## CPC

- C07K 16/2827: {against B7 molecules, e.g. CD80, CD86}
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 14/70532: {B7 molecules, e.g. CD80, CD86}
- G01N 33/53: Immunoassay; Biospecific binding assay; Materials therefor
- G01N 33/5758: {involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites}
- A61N 2005/1021: {Radioactive fluid}
- 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 2317/54: F(ab')2
- C07K 2317/55: Fab or Fab'
- C07K 2317/622: Single chain antibody (scFv)
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
- G01N 2500/10: involving cells
- G01N 2800/52: Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
- 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)
- A61N: ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY (measurement of bioelectric currents A61B; surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body A61B18/00; anaesthetic apparatus in general A61M; incandescent lamps H01K; infrared radiators for heating H05B)

## Abstract

The invention provides programmed death-ligand 1 (PD-L1) antibodies and methods of using the same.

## Claims

### Claim 1

An isolated antibody that specifically binds to PD-L1, wherein the antibody binds to an epitope comprising amino acid residues 279-290 of human PD-L1 polypeptide (SEQ ID NO: 1).

### Claim 2 (depends on 11)

The antibody of claim 11, wherein the antibody comprises the following hypervariable regions (HVRs):
(a) an HVR-H1 comprising the amino acid sequence of SNGLT (SEQ ID NO: 2);
(b) an HVR-H2 comprising the amino acid sequence of TINKDASAYYASWAKG (SEQ ID NO: 3); and
(c) an HVR-H3 comprising the amino acid sequence of IAFKTGTSI (SEQ ID NO: 4).

### Claim 3 (depends on 2)

The antibody of claim 2, further comprising the following heavy chain variable domain framework regions (FRs):
(a) FR-H1 comprising the amino acid sequence of QSLEESGGRLVKPDETLTITCTVSGIDLS (SEQ ID NO: 5);
(b) FR-H2 comprising the amino acid sequence of WVRQAPGEGLEWIG (SEQ ID NO: 6);
(c) FR-H3 comprising the amino acid sequence of RLTISKPSSTKVDLKITSPTTEDTATYFCGR (SEQ ID NO: 7); and
(d) FR-H4 comprising the amino acid sequence of WGPGTLVTVSS (SEQ ID NO: 8).

### Claim 4 (depends on 2, 3)

The antibody of claim 2 or 3, further comprising the following HVRs:
(a) an HVR-L1 comprising the amino acid sequence of QASESVYSNNYLS (SEQ ID NO: 9);
(b) an HVR-L2 comprising the amino acid sequence of LASTLAS (SEQ ID NO: 10); and
(c) an HVR-L3 comprising the amino acid sequence of IGGKSSSTDGNA (SEQ ID NO: 11).

### Claim 5 (depends on 4)

The antibody of claim 4, further comprising the following light chain variable domain FRs:
(a) FR-L1 comprising the amino acid sequence of AIVMTQTPSPVSAAVGGTVTINC (SEQ ID NO: 12);
(b) FR-L2 comprising the amino acid sequence of WFQQKPGQPPKLLIY (SEQ ID NO: 13);
(c) FR-L3 comprising the amino acid sequence of GVPSRFKGSGSGTQFTLTISGVQCDDAATYYC (SEQ ID NO: 14); and
(d) FR-L4 comprising the amino acid sequence of FGGGTEVVVR (SEQ ID NO: 15

### Claim 6 (depends on 1)

The antibody of claim 1, wherein the antibody comprises the following HVRs:
(a) an HVR-L1 comprising the amino acid sequence of QASESVYSNNYLS (SEQ ID NO: 9);
(b) an HVR-L2 comprising the amino acid sequence of LASTLAS (SEQ ID NO: 10); and
(c) an HVR-L3 comprising the amino acid sequence of IGGKSSSTDGNA (SEQ ID NO: 11).

### Claim 7 (depends on 6)

The antibody of claim 6, further comprising the following light chain variable domain FRs:
(a) FR-L1 comprising the amino acid sequence of AIVMTQTPSPVSAAVGGTVTINC (SEQ ID NO: 12);
(b) FR-L2 comprising the amino acid sequence of WFQQKPGQPPKLLIY (SEQ ID NO: 13);
(c) FR-L3 comprising the amino acid sequence of GVPSRFKGSGSGTQFTLTISGVQCDDAATYYC (SEQ ID NO: 14); and
(d) FR-L4 comprising the amino acid sequence of FGGGTEVVVR (SEQ ID NO: 15).

### Claim 8 (depends on 1)

The antibody of claim 1, comprising (a) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 16; (b) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17; or (c) a VH sequence as in (a) and a VL sequence as in (b).

### Claim 9 (depends on 8)

The antibody of claim 8, comprising a VH sequence of SEQ ID NO: 16.

### Claim 10 (depends on 8)

The antibody of claim 8, comprising a VL sequence of SEQ ID NO: 17.

### Claim 11

An isolated antibody that specifically binds PD-L1, wherein the antibody comprises the following HVRs:
(a) an HVR-H1 comprising the amino acid sequence of SNGLT (SEQ ID NO: 2);
(b) an HVR-H2 comprising the amino acid sequence of TINKDASAYYASWAKG (SEQ ID NO: 3);
(c) an HVR-H3 comprising the amino acid sequence of IAFKTGTSI (SEQ ID NO: 4);
(d) an HVR-L1 comprising the amino acid sequence of QASESVYSNNYLS (SEQ ID NO: 9);
(e) an HVR-L2 comprising the amino acid sequence of LASTLAS (SEQ ID NO: 10); and
(f) an HVR-L3 comprising the amino acid sequence of IGGKSSSTDGNA (SEQ ID NO: 11).

### Claim 12 (depends on 11)

The antibody of claim 11, wherein the antibody further comprises the following heavy chain variable domain and light chain variable domain FRs:
(a) FR-H1 comprising the amino acid sequence of QSLEESGGRLVKPDETLTITCTVSGIDLS (SEQ ID NO: 5);
(b) FR-H2 comprising the amino acid sequence of WVRQAPGEGLEWIG (SEQ ID NO: 6);
(c) FR-H3 comprising the amino acid sequence of RLTISKPSSTKVDLKITSPTTEDTATYFCGR (SEQ ID NO: 7);
(d) FR-H4 comprising the amino acid sequence of WGPGTLVTVSS (SEQ ID NO: 8);
(e) FR-L1 comprising the amino acid sequence of AIVMTQTPSPVSAAVGGTVTINC (SEQ ID NO: 12);
(f) FR-L2 comprising the amino acid sequence of WFQQKPGQPPKLLIY (SEQ ID NO: 13);
(g) FR-L3 comprising the amino acid sequence of GVPSRFKGSGSGTQFTLTISGVQCDDAATYYC (SEQ ID NO: 14); and
(h) FR-L4 comprising the amino acid sequence of FGGGTEVVVR (SEQ ID NO: 15).

### Claim 13 (depends on 11, 12)

The antibody of claim 11 or 12, wherein the antibody comprises a VH sequence of SEQ ID NO: 16 and a VL sequence of SEQ ID NO: 17.

### Claim 14 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13)

An isolated antibody that competes for binding to PD-L1 with the antibody of any one of claims 1-13.

### Claim 15 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13)

An isolated antibody that binds to the same epitope as the antibody of any one of claims 1-13.

### Claim 16 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15)

The antibody of any one of claims 1-15, wherein the antibody is a monoclonal antibody.

### Claim 17 (depends on 16)

The antibody of claim 16, wherein the monoclonal antibody is a rabbit monoclonal antibody.

### Claim 18 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15)

The antibody of any one of claims 1-15, wherein the antibody is an IgG antibody.

### Claim 19 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15)

The antibody of any one of claims 1-15, wherein the antibody is an antibody fragment that specifically binds PD-L1.

### Claim 20 (depends on 19)

The antibody of claim 19, wherein the antibody fragment is selected from the group consisting of Fab, single chain variable fragment (scFv), Fv, Fab′, Fab′-SH, F(ab)2, and diabody.

### Claim 21 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20)

An isolated nucleic acid encoding an isolated antibody of any one of claims 1-20.

### Claim 22 (depends on 21)

A vector comprising the nucleic acid of claim 21.

### Claim 23 (depends on 22)

A host cell comprising the vector of claim 22.

### Claim 24 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20)

An immunoconjugate comprising the antibody of any one of claims 1-20.

### Claim 25 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20)

The antibody of any one of claims 1-20 for use in detecting the presence or expression level of PD-L1 in a biological sample.

### Claim 26 (depends on 25)

The antibody of claim 25, wherein the detecting is by immunohistochemistry (IHC), immunofluorescence (IF), flow cytometry, Enzyme-Linked Immunosorbant Assay (ELISA), or immunoblotting.

### Claim 27 (depends on 26)

The antibody of claim 26, wherein the detecting is by IHC.

### Claim 28 (depends on 25, 26, 27)

The antibody of any one of claims 25-27, wherein the sample comprises a fixed tissue.

### Claim 29 (depends on 28)

The antibody of claim 28, wherein the fixed tissue is a formalin-fixed paraffin-embedded (FFPE) tissue.

### Claim 30 (depends on 25, 26, 27, 28, 29)

The antibody of any one of claims 25-29, wherein the sample is from a subject having, or at risk of, a cancer or an immune dysfunction.

### Claim 31 (depends on 30)

The antibody of claim 30, wherein the immune dysfunction is a T-cell dysfunctional disorder.

### Claim 32 (depends on 31)

The antibody of claim 31, wherein the T-cell dysfunctional disorder is an unresolved acute infection, chronic infection, or tumor immunity.

### Claim 33 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20)

A method of detecting the presence or expression level of PD-L1 in a biological sample comprising contacting the biological sample with the antibody of any one of claims 1-20 and detecting the presence of the bound antibody.

### Claim 34 (depends on 33)

The method of claim 33, wherein the detecting is by IHC, IF, flow cytometry, ELISA, or immunoblotting.

### Claim 35 (depends on 34)

The method of claim 34, wherein the detecting is by IHC.

### Claim 36 (depends on 33, 34, 35)

The method of any one of claims 33-35, wherein the sample comprises a fixed tissue.

### Claim 37 (depends on 36)

The method of claim 36, wherein the fixed tissue is a FFPE tissue.

### Claim 38 (depends on 33, 34, 35, 36, 37)

The method of any one of claims 33-37, wherein the sample is from a subject having, or at risk of, a cancer or an immune dysfunction.

### Claim 39 (depends on 38)

The method of claim 38, wherein the immune dysfunction is a T-cell dysfunctional disorder.

### Claim 40 (depends on 39)

The method of claim 39, wherein the T-cell dysfunctional disorder is an unresolved acute infection, chronic infection, or tumor immunity.

### Claim 41 (depends on 38)

The method of claim 38, wherein the sample is from a subject having a cancer.

### Claim 42 (depends on 33, 34, 35, 36, 37, 38, 39, 40, 41)

The method of any one of claims 33-41, wherein the presence or expression level of PD-L1 in the sample indicates that the subject is likely to respond to treatment with an anti-cancer therapy.

### Claim 43 (depends on 33, 34, 35, 36, 37, 38, 39, 40, 41)

The method of any one of claims 33-41, wherein the presence or expression level of PD-L1 in the sample indicates that the subject is more likely to respond to treatment with an anti-cancer therapy.

### Claim 44 (depends on 33, 34, 35, 36, 37, 38, 39, 40, 41)

The method of any one of claims 33-41, wherein the presence or expression level of PD-L1 in the sample indicates the likelihood that the subject will exhibit benefit from treatment with an anti-cancer therapy.

### Claim 45 (depends on 41, 42, 43, 44)

The method of any one of claims 41-44, wherein the method further comprises selecting an anti-cancer therapy for the subject based on the presence or expression level of PD-L1 in the sample.

### Claim 46 (depends on 41, 42, 43, 44, 45)

The method of any one of claims 41-45, wherein the method further comprises administering a therapeutically effective amount of an anti-cancer therapy to the subject.

### Claim 47 (depends on 38, 41, 42, 43, 44, 45, 46)

The method of any one of claims 38 and 41-46, wherein the cancer is selected from the group consisting of non-small cell lung cancer, squamous cell cancer, small-cell lung cancer, cancer of the peritoneum, hepatocellular cancer, gastrointestinal cancer, pancreatic cancer, glioma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, leukemia, and head and neck cancer.

### Claim 48 (depends on 47)

The method of claim 47, wherein the cancer is non-small cell lung cancer (NSCLC).

### Claim 49 (depends on 48)

The method of claim 48, wherein the NSCLC is adenocarcinoma of the lung or squamous carcinoma of the lung.

### Claim 50 (depends on 38, 41, 42, 43, 44, 45, 46, 47, 48, 49)

The method of any one of claims 38 and 41-49, wherein the sample is a tumor sample.

### Claim 51 (depends on 50)

The method of claim 50, wherein the tumor sample comprises tumor-infiltrating immune cells, tumor cells, stromal cells, or any combination thereof.

### Claim 52 (depends on 51)

The method of claim 51, wherein the tumor sample has a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise about 1% or more of the tumor sample by area.

### Claim 53 (depends on 52)

The method of claim 52, wherein the tumor sample has a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise about 5% or more of the tumor sample by area.

### Claim 54 (depends on 53)

The method of claim 53, wherein the tumor sample has a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise about 10% or more of the tumor sample by area.

### Claim 55 (depends on 50, 51, 52, 53, 54)

The method of any one of claims 50-54, wherein the tumor sample has a detectable expression level of PD-L1 in about 1% or more of the tumor cells in the tumor sample.

### Claim 56 (depends on 55)

The method of claim 55, wherein the tumor sample has a detectable expression level of PD-L1 in about 5% or more of the tumor cells in the tumor sample.

### Claim 57 (depends on 56)

The method of claim 56, wherein the tumor sample has a detectable expression level of PD-L1 in about 10% or more of the tumor cells in the tumor sample.

### Claim 58 (depends on 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57)

The method of any one of claims 46-57, wherein the anti-cancer therapy comprises a PD-1 axis binding antagonist.

### Claim 59 (depends on 58)

The method of claim 58, wherein the PD-1 axis binding antagonist is selected from the group consisting of a PD-L1 binding antagonist, a PD-1 binding antagonist, and a PD-L2 binding antagonist.

### Claim 60 (depends on 59)

The method of claim 59, wherein the PD-1 axis binding antagonist is a PD-L1 binding antagonist.

### Claim 61 (depends on 60)

The method of claim 60, wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to one or more of its ligand binding partners.

### Claim 62 (depends on 61)

The method of claim 61, wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1.

### Claim 63 (depends on 61)

The method of claim 61, wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to B7-1.

### Claim 64 (depends on 61, 62, 63)

The method of any one of claims 61-63, wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to both PD-1 and B7-1.

### Claim 65 (depends on 60, 61, 62, 63, 64)

The method of any one of claims 60-64, wherein the PD-L1 binding antagonist is an antibody.

### Claim 66 (depends on 65)

The method of claim 65, wherein the antibody is selected from the group consisting of: YW243.55.S70, MPDL3280A (atezolizumab), MDX-1105, and MED14736 (durvalumab), and MSB0010718C (avelumab).

### Claim 67 (depends on 59)

The method of claim 59, wherein the PD-1 axis binding antagonist is a PD-1 binding antagonist.

### Claim 68 (depends on 67)

The method of claim 67, wherein the PD-1 binding antagonist inhibits the binding of PD-1 to one or more of its ligand binding partners.

### Claim 69 (depends on 68)

The method of claim 68, wherein the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1.

### Claim 70 (depends on 68)

The method of claim 68, wherein the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L2.

### Claim 71 (depends on 68, 69, 70)

The method of any one of claims 68-70, wherein the PD-1 binding antagonist inhibits the binding of PD-1 to both PD-L1 and PD-L2.

### Claim 72 (depends on 67, 68, 69, 70, 71)

The method of any one of claims 67-71, wherein the PD-1 binding antagonist is an antibody.

### Claim 73 (depends on 72)

The method of claim 72, wherein the antibody is selected from the group consisting of: MDX 1106 (nivolumab), MK-3475 (pembrolizumab), CT-011 (pidilizumab), MEDI-0680 (AMP-514), PDR001, REGN2810, and BGB-108.

### Claim 74 (depends on 67, 68, 69, 70, 71)

The method of any one of claims 67-71, wherein the PD-1 binding antagonist is an Fc-fusion protein.

### Claim 75 (depends on 74)

The method of claim 74, wherein the Fc-fusion protein is AMP-224.

### Claim 76 (depends on 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75)

The method of any one of claims 46-75, further comprising administering to the patient an effective amount of a second therapeutic agent.

### Claim 77 (depends on 76)

The method of claim 76, wherein the second therapeutic agent is selected from the group consisting of a cytotoxic agent, a growth-inhibitory agent, a radiation therapy agent, an anti-angiogenic agent, and combinations thereof.

### Claim 78 (depends on 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77)

The method of any one of claims 33-77, wherein the subject is a human.