# US 12,110,337 B2 · Anti-CD27 antibodies and uses thereof

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- Number: US 12,110,337 B2
- Document ID: US12110337B2
- Status: Granted
- Kind: B2
- Application number: 17/045,143
- Filed: 2019-04-03
- Published: 2021-05-27
- Granted: 2024-10-08
- Earliest claimed: 2018-04-04
- Assignees: Bristol-Myers Squibb Company
- Applicants: Bristol-Myers Squibb Company
- Inventors: Li-Sheng Lu; Mark J. Selby; Alan J. Korman; Shrikant Deshpande; Mohan Srinivasan; Jun Zhang; Haichun Huang; Guodong Chen; Richard Y. Huang; Ekaterina Deyanova
- Web page: https://patentgrep.com/patent/US12110337B2

## CPC

- C07K 16/2878: {against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95}
- A61K 39/39541: {against normal tissues, cells}
- A61P 35/00: Antineoplastic agents
- 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 2317/74: Inducing cell proliferation
- C07K 2317/75: Agonist effect on antigen
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- 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

## Abstract

This disclosure provides isolated antibodies that bind specifically to CD27 with high affinity. The disclosure provides methods for treating a subject afflicted with a cancer comprising administering to the subject a therapeutically effective amount of an anti-CD27 antibody as monotherapy or in combination with a checkpoint inhibitor, such as an anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibody.

## Claims

### Claim 1

An agonist monoclonal antibody or an antigen-binding portion thereof that specifically binds to human CD27, wherein the antibody or portion thereof comprises:
(a) a heavy chain variable region (VH) comprising a CDR1 comprising consecutively linked amino acids having the sequence set forth as SEQ ID NO: 2, a CDR2 comprising consecutively linked amino acids having the sequence set forth as SEQ ID NO: 3, and a CDR3 comprising consecutively linked amino acids having the sequence set forth as SEQ ID NO: 4; and
(b) a light chain variable region (VL) comprising a CDR1 comprising consecutively linked amino acids having the sequence set forth as SEQ ID NO: 5, a CDR2 comprising consecutively linked amino acids having the sequence set forth as SEQ ID NO: 6, and a CDR3 comprising consecutively linked amino acids having the sequence set forth as SEQ ID NO: 7.

### Claim 2 (depends on 1)

The agonist monoclonal antibody or antigen-binding portion thereof of claim 1 that specifically binds to an epitope located within discontinuous regions spanning approximately amino acid residues 21-41 and 52-57 of human CD27, the sequence of which is set forth as SEQ ID NO: 1, as determined by hydrogen-deuterium exchange mass spectrometry (HDX-MS) and/or fast photochemical oxidation of proteins (FPOP) epitope mapping.

### Claim 3 (depends on 1)

The agonist monoclonal antibody or antigen-binding portion thereof of claim 1, which comprises a VH comprising consecutively linked amino acids having the sequence set forth as SEQ ID NO: 8; and/or a VL comprising consecutively linked amino acids having the sequence set forth as SEQ ID NO: 9.

### Claim 4 (depends on 1)

The agonist monoclonal antibody or antigen-binding portion thereof of claim 1, which comprises a heavy chain comprising consecutively linked amino acids having the sequence set forth as SEQ ID NO: 12 and/or a light chain comprising consecutively linked amino acids having the sequence set forth as SEQ ID NO: 13.

### Claim 5

An agonist monoclonal antibody that specifically binds to human CD27 and does not block binding to its CD70 ligand, wherein the monoclonal antibody is the monoclonal antibody designated BMS-986215, which comprises a heavy chain comprising consecutively linked amino acids having the sequence set forth as SEQ ID NO: 12 and a light chain comprising consecutively linked amino acids having the sequence set forth as SEQ ID NO: 13.

### Claim 6 (depends on 1)

The agonist monoclonal antibody or antigen-binding portion thereof of claim 1, which does not block binding to its CD70 ligand as measured by surface plasmon resonance (SPR) or flow cytometry.

### Claim 7 (depends on 1)

The agonist monoclonal antibody or antigen-binding portion thereof of claim 1, which comprises a heavy chain constant region which is of a human IgG1, IgG2, IgG3, or IgG4 isotype.

### Claim 8 (depends on 7)

The agonist monoclonal antibody or antigen-binding portion thereof of claim 7, which is of a human IgG1 isotype.

### Claim 9 (depends on 1)

The antigen-binding portion of claim 1, which is an antibody fragment or a single chain antibody, wherein the antibody fragment is selected from the group consisting of a Fab, F(ab′)2, a Fd and a Fv fragment;
and wherein the single chain antibody is selected from the group consisting of a single-chain variable fragment (scFv), a divalent scFv (di-scFv), a diabody, a minibody;
and any combination thereof of said antibody fragment or single chain antibody.

### Claim 10 (depends on 3)

The agonist monoclonal antibody or antigen-binding portion thereof of claim 3, which has one or more characteristics chosen from:
(a) does not specifically bind to rat CD27 and/or mouse CD27 as measured by SPR or flow cytometry;
(b) does not specifically bind to one or more TNF receptor superfamily members selected from the group consisting of CD30, HVEM, DR5, 4-1BB, CD40, OX40, GITR, and any combination thereof;
(c) does not specifically bind to one or more human tissues at concentrations up to 10 μg/mL, wherein the human tissues are selected from the group consisting of thyroid, lung, skin, uterus, prostate, liver, kidney, pancreas, adrenal, pituitary, placenta, testis, cerebrum, cerebellum, heart, peripheral nerve, and any combination thereof;
(d) is capable of inducing proliferation and/or IFN-γ secretion in a CHO-svCD3-CD32A assay;
(e) is capable of inducing proliferation of CD4+CD45RO+memory T cells;
(f) is capable of increasing IL-2 release from staphylococcus enterotoxin B (SEB)-stimulated human peripheral blood mononuclear cells (PBMCs);
(g) is capable of increasing IL-2 release at least two-fold when combined with an anti-Programmed Death-1 (anti-PD-1) antibody;
(h) is capable of reversing Treg-mediated suppression of co-cultured CD4+responder T cells in the presence of monocyte-derived dendritic cells (MDDC) and soluble OKT3; and
(i) is capable of potentiating the proliferation of human T cells and induction of IFN-γ secretion by soluble CD70.

### Claim 11 (depends on 3)

The agonist monoclonal antibody or antigen-binding portion thereof of claim 3, wherein the monoclonal antibody or antigen-binding portion thereof:
(a) binds to human CD27 with a KD of about 100 nM or lower as determined by surface plasmon resonance (SPR); and/or
(b) induces NF-κB and MAPK signaling in naïve and pre-activated human T cells stimulated by an anti-CD3 Ab and an anti-CD28 antibody with an EC50 of about 0.5 nM or lower.

### Claim 12 (depends on 3)

The agonist monoclonal antibody or antigen-binding portion thereof of claim 3, wherein the monoclonal antibody or antigen-binding portion thereof:
(a) binds to human T cells with an EC50 of about 0.1 nM or lower as determined by flow cytometry; and/or
(b) binds to cynomolgus T cells with EC50 of about 0.5 nM or lower as determined by flow cytometry.

### Claim 13 (depends on 3)

The agonist monoclonal antibody or antigen-binding portion thereof of claim 3, which:
(a) is a human antibody or a fragment thereof;
(b) is a chimeric antibody or a fragment thereof;
(c) induces proliferation and/or IFN-γ secretion in a CHO-svCD3-CD32A assay with an EC50 of about 0.05 nM or lower;
(d) induces proliferation of CD4+CD45RO+memory T cells with an EC50 of about 0.01 nM or lower and/or induces IFN-γ secretion with an EC50 of about 0.05 nM or lower;
(e) increases IL-2 release from SEB-stimulated human PBMCs by greater than about 50% in the presence of a cross-linker, or by at least about two-fold when combined with an anti-PD-1 antibody;
(f) reverses Treg-mediated suppression of co-cultured CD4+responder T cells in the presence of MDDC and soluble OKT by at least about 70%; or
(g) potentiates the proliferation of human T cells by soluble CD70 with an EC50 of about 0.01 nM or lower,
and/or potentiates the induction of IFN-γ secretion by soluble CD70 with an EC50 of about 0.01 nM or lower.

### Claim 14 (depends on 11)

The agonist monoclonal antibody or antigen-binding portion thereof of claim 11, wherein the monoclonal antibody or antigen-binding portion thereof:
(a) binds to human CD27 with a KD of between about 40 nM and about 45 nM at about 37° C. and/or between about 13 nM and 16 nM at about 25° C.; and/or
(b) induces NF-κB and MAPK signaling with an EC50 of between about 0.02 nM and about 0.25 nM.

### Claim 15 (depends on 12)

The agonist monoclonal antibody or antigen-binding portion thereof of claim 12, wherein the monoclonal antibody or antigen-binding portion thereof binds to human T cells with an EC50 of between about 0.025 nM and about 0.075 nM, and/or binds to cynomolgus T cells with EC50 of between about 0.025 nM and about 0.4 nM.

### Claim 16 (depends on 13)

The agonist monoclonal antibody or antigen-binding portion thereof of claim 13, which:
(a) induces proliferation and/or IFN-γ secretion in a CHO-svCD3-CD32A assay with an EC50 of between about 0.001 nM and about 0.03 nM;
(b) induces proliferation of CD4+CD45RO+memory T cells with an EC50 of between about 0.004 nM to about 0.006 nM and/or induces IFN-γ secretion in CD4+CD45RO+memory T cells with an EC50 of between about 0.005 nM and about 0.03 nM, and/or
(c) potentiates the proliferation of human T cells by soluble CD70 with an EC50 of between about 0.001 nM and about 0.01 nM and/or potentiates the induction of IFN-γ secretion by soluble CD70 with an EC50 of between about 0.001 nM and about 0.01 nM.

### Claim 17 (depends on 1)

A composition comprising
the agonist monoclonal antibody or antigen-binding portion thereof of claim 1
and
a pharmaceutically acceptable carrier.

### Claim 18 (depends on 17)

The composition of claim 17, further comprising an additional antibody or an antigen-binding portion thereof, optionally wherein the additional antibody or antigen-binding portion thereof is chosen from an anti-PD-1 antibody, anti-Programmed Death Ligand-1 (PD-L1) antibody, anti-Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) antibody, anti-Lymphocyte Activation Gene-3 (LAG-3) antibody, anti-B and T lymphocyte attenuator (BTLA) antibody, anti-T cell Immunoglobulin and Mucin domain-3 (TIM-3) antibody, anti-Killer Immunoglobulin-like Receptor (KIR) antibody, anti-Killer cell Lectin-like Receptor G1 (KLRG-1) antibody, anti-adenosine A2a receptor (A2aR) antibody, anti-Natural Killer Cell Receptor 2B4 (CD244) antibody, anti-CD160 antibody, T cell Immunoreceptor with Ig and ITIM domains (TIGIT) antibody, V-domain Ig Suppressor of T cell Activation (VISTA) antibody, nivolumab, pembrolizumab, cemiplimab, atezolizumab, durvalumab, avelumab, the antibody designated BMS-936559, an anti-Inducible T cell Co-Stimulator (ICOS) antibody, anti-CD137 (4-1BB) antibody, anti-CD134 (OX40) antibody, anti-CD27 antibody, anti-Glucocorticoid-Induced TNFR-Related protein (GITR) antibody, anti-Herpes Virus Entry Mediator (HVEM) antibody, and any combination thereof.

### Claim 19 (depends on 1)

A kit for treating a subject afflicted with a cancer or for inhibiting growth of tumor cells in a subject, the kit comprising:
(a) one or more dosages ranging from about 0.1 to about 20 mg/kg body weight of the monoclonal antibody or antigen-binding portion thereof of claim 1; and
(b) instructions for using the one or more dosages in a method for treating a subject afflicted with a cancer.

### Claim 20 (depends on 19)

The kit of claim 19, further comprising one or more dosages of an additional therapeutic agent.

### Claim 21 (depends on 1)

An immunoconjugate comprising the agonist monoclonal antibody or antigen-binding portion thereof of claim 1, linked to a therapeutic agent.

### Claim 22 (depends on 1)

A bispecific molecule comprising the agonist monoclonal antibody or antigen-binding portion thereof of claim 1, linked to a binding domain that has a different binding specificity than the monoclonal antibody or antigen binding portion thereof.

### Claim 23 (depends on 21)

The immunoconjugate of claim 21, wherein the therapeutic agent is a cytotoxin or a radioactive isotope.

### Claim 24 (depends on 21)

A composition comprising the immunoconjugate of claim 21 and a pharmaceutically acceptable carrier.

### Claim 25 (depends on 22)

A composition comprising the bispecific molecule of claim 22 and a pharmaceutically acceptable carrier.