# US 2025/0145705 A1 · Gprc5d antibody and application thereof

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- Number: US 2025/0145705 A1
- Document ID: US20250145705A1
- Status: Published application
- Kind: A1
- Application number: 18/726,077
- Filed: 2022-12-30
- Published: 2025-05-08
- Earliest claimed: 2021-12-31
- Assignees: Shandong Simcere Biopharmaceutical Co., Ltd.
- Applicants: Shandong Simcere Biopharmaceutical Co., Ltd.
- Inventors: Yayuan FU; Jingli LIAO; Bowei YIN; Zhuoxiao CAO; Renhong TANG; Jinsheng REN
- Web page: https://patentgrep.com/patent/US20250145705A1

## CPC

- A61P 35/00: Antineoplastic agents
- C07K 16/28: against receptors, cell surface antigens or cell surface determinants
- A61K 35/17: Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes (when activated by a specific antigen A61K39/00)
- G01N 33/6854: {Immunoglobulins}
- 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 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- 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)
- 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)
- 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 invention relates to an antibody against G protein coupled receptor C5 family subtype D (GPRC5D) and an application of the antibody. Specifically, disclosed are an antibody specifically binding to GPRC5D or an antigen-binding fragment thereof, and an encoding nucleic acid thereof, an expression vector and an expression cell, a preparation method, a pharmaceutical composition, and a use thereof in the preparation of a pharmaceutical composition for treating diseases, for example, a use in treating tumors. The present invention has important significance for the development of GPRC5D antibody treatment drugs and detection reagents.

## Claims

### Claim 1

An antibody or an antigen-binding fragment thereof that specifically binds to G protein coupled receptor C5 family subtype D (GPRC5D), wherein the antibody or the antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, and wherein
(1) the light chain variable region comprises LCDR1, LCDR2 and LCDR3, the LCDR1 has any of a sequence of the following LCDR1, or a sequence with 1, 2, 3 or more amino acid insertions, deletions and/or substitutions compared with the sequence, the LCDR2 has any of a sequence of the following LCDR2, or a sequence with 1, 2, 3 or more amino acid insertions, deletions and/or substitutions compared with the sequence, and the LCDR3 has any of a sequence of the following LCDR3, or a sequence with 1, 2, 3 or more amino acid insertions, deletions and/or substitutions compared with the sequence:
No.
LCDR1
LCDR2
LCDR3
L1
SEQ ID NO: 35
SEQ ID NO: 36
SEQ ID NO: 37
L2
SEQ ID NO: 38
SEQ ID NO: 39
SEQ ID NO: 37
L3
SEQ ID NO: 46
SEQ ID NO: 47
SEQ ID NO: 48
L4
SEQ ID NO: 49
SEQ ID NO: 50
SEQ ID NO: 48
L5
SEQ ID NO: 57
SEQ ID NO: 58
SEQ ID NO: 59
L6
SEQ ID NO: 60
SEQ ID NO: 61
SEQ ID NO: 59
L7
SEQ ID NO: 68
SEQ ID NO: 69
SEQ ID NO: 70
L8
SEQ ID NO: 71
SEQ ID NO: 72
SEQ ID NO: 70
L9
SEQ ID NO: 79
SEQ ID NO: 80
SEQ ID NO: 81
L10
SEQ ID NO: 82
SEQ ID NO: 83
SEQ ID NO: 81
L11
SEQ ID NO: 90
SEQ ID NO: 91
SEQ ID NO: 92
L12
SEQ ID NO: 93
SEQ ID NO: 94
SEQ ID NO: 92
L13
SEQ ID NO: 101
SEQ ID NO: 102
SEQ ID NO: 103
L14
SEQ ID NO: 104
SEQ ID NO: 105
SEQ ID NO: 103
L15
SEQ ID NO: 112
SEQ ID NO: 113
SEQ ID NO: 114
L16
SEQ ID NO: 115
SEQ ID NO: 116
SEQ ID NO: 114
L17
SEQ ID NO: 217
SEQ ID NO: 102
SEQ ID NO: 103
L18
SEQ ID NO: 227
SEQ ID NO: 102
SEQ ID NO: 103
L19
SEQ ID NO: 228
SEQ ID NO: 102
SEQ ID NO: 103
L20
SEQ ID NO: 229
SEQ ID NO: 102
SEQ ID NO: 103
L21
SEQ ID NO: 230
SEQ ID NO: 102
SEQ ID NO: 103
and,
(2) the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3, the HCDR1 has any of a sequence of the following HCDR1, or a sequence with 1, 2, 3 or more amino acid insertions, deletions and/or substitutions compared with the sequence, the HCDR2 has any of a sequence of the following HCDR2, or a sequence with 1, 2, 3 or more amino acid insertions, deletions and/or substitutions compared with the sequence, and the HCDR3 has any of a sequence of the following HCDR3, or a sequence with 1, 2, 3 or more amino acid insertions, deletions and/or substitutions compared with the sequence:
No.
HCDR1
HCDR2
HCDR3
H1
SEQ ID NO: 29
SEQ ID NO: 30
SEQ ID NO: 31
H2
SEQ ID NO: 32
SEQ ID NO: 33
SEQ ID NO: 34
H3
SEQ ID NO: 40
SEQ ID NO: 41
SEQ ID NO: 42
H4
SEQ ID NO: 43
SEQ ID NO: 44
SEQ ID NO: 45
H5
SEQ ID NO: 51
SEQ ID NO: 52
SEQ ID NO: 53
H6
SEQ ID NO: 54
SEQ ID NO: 55
SEQ ID NO: 56
H7
SEQ ID NO: 62
SEQ ID NO: 63
SEQ ID NO: 64
H8
SEQ ID NO: 65
SEQ ID NO: 66
SEQ ID NO: 67
H9
SEQ ID NO: 73
SEQ ID NO: 74
SEQ ID NO: 75
H10
SEQ ID NO: 76
SEQ ID NO: 77
SEQ ID NO: 78
H11
SEQ ID NO: 84
SEQ ID NO: 85
SEQ ID NO: 86
H12
SEQ ID NO: 87
SEQ ID NO: 88
SEQ ID NO: 89
H13
SEQ ID NO: 95
SEQ ID NO: 96
SEQ ID NO: 97
H14
SEQ ID NO: 98
SEQ ID NO: 99
SEQ ID NO: 100
H15
SEQ ID NO: 106
SEQ ID NO: 107
SEQ ID NO: 108
H16
SEQ ID NO: 109
SEQ ID NO: 110
SEQ ID NO: 111
H17
SEQ ID NO: 40
SEQ ID NO: 142
SEQ ID NO: 42
H18
SEQ ID NO: 40
SEQ ID NO: 143
SEQ ID NO: 42
H19
SEQ ID NO: 51
SEQ ID NO: 158
SEQ ID NO: 53
H20
SEQ ID NO: 51
SEQ ID NO: 159
SEQ ID NO: 53
preferably, the antibody or the antigen-binding fragment thereof comprises sequences of six CDRs in the following combination of a light chain variable region and a heavy chain variable region: L1+H1, L2+H2, L3+H3, L4+H4, L5+H5, L6+H6, L7+H7, L8+H8, L9+H9, L10+H10, L11+H11, L12+H12, L13+H13, L14+H14, L15+H15, L16+H16, L3+H17, L3+H18, L5+H19, L5+H20, L17+H13, L18+H13, L19+H13, L20+H13 or L21+H13, or sequences of six CDRs having 1, 2, 3 or more amino acid insertions, deletions and/or substitutions compared with the sequences of six CDRs.

### Claim 2 (depends on 1)

The antibody or the antigen-binding fragment thereof of claim 1, wherein:
(1) the light chain variable region sequence comprises a sequence as shown in any one of SEQ ID NOs: 14, 16, 18, 20, 22, 24, 26, 28, 118-120, 130-131, 144-145, 160-163, 172-175, 184-187, 196-197, 206-208, 218-221 and 231-233, or a sequence having 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or higher identity to the sequence;
and,
(2) the heavy chain variable region sequence comprises a sequence as shown in any one of SEQ ID NOs: 13, 15, 17, 19, 21, 23, 25, 27, 121-125, 132-137, 146-152, 164-166, 176-178, 188-190, 198-201, 209-212, 222 and 234-238, or a sequence having 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or higher identity to the sequence;
preferably, the antibody or the antigen-binding fragment thereof has a light chain variable region and a heavy chain variable region as follows:
(1) the light chain variable region and the heavy chain variable region comprise sequences as shown in SEQ ID NO: 14 and SEQ ID NO: 13 respectively;
(2) the light chain variable region and the heavy chain variable region comprise sequences as shown in SEQ ID NO: 16 and SEQ ID NO: 15 respectively;
(3) the light chain variable region and the heavy chain variable region comprise sequences as shown in SEQ ID NO: 18 and SEQ ID NO: 17 respectively;
(4) the light chain variable region and the heavy chain variable region comprise sequences as shown in SEQ ID NO: 20 and SEQ ID NO: 19 respectively;
(5) the light chain variable region and the heavy chain variable region comprise sequences as shown in SEQ ID NO: 22 and SEQ ID NO: 21 respectively;
(6) the light chain variable region and the heavy chain variable region comprise sequences as shown in SEQ ID NO: 24 and SEQ ID NO: 23 respectively;
(7) the light chain variable region and the heavy chain variable region comprise sequences as shown in SEQ ID NO: 26 and SEQ ID NO: 25 respectively;
(8) the light chain variable region and the heavy chain variable region comprise sequences as shown in SEQ ID NO: 28 and SEQ ID NO: 27 respectively;
(9) the light chain variable region comprises a sequence as shown in any one of SEQ ID NOs: 118-120, and the heavy chain variable region comprises a sequence as shown in any one of SEQ ID NOs: 121-125;
(10) the light chain variable region comprises a sequence as shown in any one of SEQ ID NOs: 130-131, and the heavy chain variable region comprises a sequence as shown in any one of SEQ ID NOs: 132-137;
(11) the light chain variable region comprises a sequence as shown in any one of SEQ ID NOs: 144-145, and the heavy chain variable region comprises a sequence as shown in any one of SEQ ID NOs: 146-152;
(12) the light chain variable region comprises a sequence as shown in any one of SEQ ID NOs: 160-163, and the heavy chain variable region comprises a sequence as shown in any one of SEQ ID NOs: 164-166;
(13) the light chain variable region comprises a sequence as shown in any one of SEQ ID NOs: 172-175, and the heavy chain variable region comprises a sequence as shown in any one of SEQ ID NOs: 176-178;
(14) the light chain variable region comprises a sequence as shown in any one of SEQ ID NOs: 184-187, and the heavy chain variable region comprises a sequence as shown in any one of SEQ ID NOs: 188-190;
(15) the light chain variable region comprises a sequence as shown in any one of SEQ ID NOs: 196-197, and the heavy chain variable region comprises a sequence as shown in any one of SEQ ID NOs: 198-201;
(16) the light chain variable region comprises a sequence as shown in any one of SEQ ID NOs: 206-208, and the heavy chain variable region comprises a sequence as shown in any one of SEQ ID NOs: 209-212;
(17) the light chain variable region comprises a sequence as shown in any one of SEQ ID NOs: 218-221, and the heavy chain variable region comprises a sequence as shown in SEQ ID NO: 222;
(18) the light chain variable region comprises a sequence as shown in any one of SEQ ID NOs: 231-233, and the heavy chain variable region comprises a sequence as shown in any one of SEQ ID NOs: 234-238;
or (19) the light chain variable region comprises a sequence having 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or higher identity to the light chain variable region as shown in any one of the above (1) to (18), and the heavy chain variable region comprises a sequence having 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or higher identity to the heavy chain variable region as shown in any one of the above (1) to (18).

### Claim 3 (depends on 1)

The antibody or the antigen-binding fragment thereof of claim 1, wherein the antibody or the antigen-binding fragment thereof is chimeric, humanized or fully human.

### Claim 4 (depends on 1)

The antibody or the antigen-binding fragment thereof of claim 1, wherein the antibody or the antigen-binding fragment thereof can bind to human or monkey GPRC5D.

### Claim 5 (depends on 1)

The antibody or the antigen-binding fragment thereof of claim 1, wherein, the antigen-binding fragment is selected from one or more of F (ab) 2, Fab′, Fab, Fv, scFv, nanobody or affibody.

### Claim 6 (depends on 1)

The antibody or the antigen-binding fragment thereof of claim 1, wherein the antibody or the antigen-binding fragment thereof further comprises a constant region sequence of any one of human or murine antibody IgG1, IgG2, IgG3, IgG4, IgA, IgM, IgE and IgD; preferably, the antibody or the antigen-binding fragment thereof comprises a constant region sequence of human or murine antibody IgG1, IgG2, IgG3 or IgG4, or comprises a sequence having 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or higher identity to the constant region sequence of human or murine antibody IgG1, IgG2, IgG3 or lgG4; furthermore, the antibody or the antigen-binding fragment thereof is further coupled with a therapeutic agent or a tracer;
preferably, the therapeutic agent is selected from a radioisotope, a chemotherapeutic drug or an immunomodulator, and the tracer is selected from a radiological contrast agent, a paramagnetic ion, a metal, a fluorescent tag, a chemiluminescence tag, an ultrasonic contrast agent and a photosensitizer; and more preferably, the cytotoxic agent is selected from alkaloids, methotrexate, anthracycline antibiotics, taxanes, pyrrolobenzodiazepine or toxin compounds.

### Claim 7 (depends on 1)

A multispecific antigen-binding molecule, wherein the multispecific antigen-binding molecule comprises the antibody or the antigen-binding fragment thereof of claim 1, and an additional antigen-binding molecule binding to an antigen other than GPRC5D or binding to a different GPRC5D epitope than that of the antibody or the antigen-binding fragment thereof of claim 1;
preferably, the additional antigen-binding molecule is an antibody or an antigen-binding fragment thereof;
preferably, the multispecific antigen-binding molecule can be bispecific, trispecific or tetraspecific;
preferably, the multispecific antigen-binding molecule can be bivalent, trivalent, tetravalent, pentavalent or hexavalent.

### Claim 8 (depends on 1)

A chimeric antigen receptor (CAR), wherein the chimeric antigen receptor comprises at least a signal peptide, an extracellular antigen-binding domain, a hinge region, a transmembrane domain and an intracellular signaling domain, and the extracellular antigen-binding domain comprises the GPRC5D antibody or the antigen-binding fragment thereof of claim 1, or the multispecific antigen-binding molecule, which comprises the antibody or the antigen-binding fragment thereof of claim 1, and an additional antigen-binding molecule binding to an antigen other than GPRC5D or binding to a different GPRC5D epitope than that of the antibody or the antigen-binding fragment thereof of claim 1.

### Claim 9 (depends on 8)

An immune effector cell, wherein the immune effector cell expresses the chimeric antigen receptor of claim 8, or comprises a nucleic acid fragment encoding the chimeric antigen receptor of claim 8; preferably, the immune effector cell is selected from a T cell, an NK cell, an NKT cell, a DNT cell, a monocyte, a macrophage, a dendritic cell or a mast cell, and the T cell is preferably selected from a cytotoxic T cell (CTL), a regulatory T cell or a helper T cell; and preferably, the immune effector cell is an autologous immune effector cell or an allogeneic immune effector cell.

### Claim 10 (depends on 1)

An isolated nucleic acid fragment, wherein the nucleic acid fragment encodes the antibody or the antigen-binding fragment thereof of claim 1; the multispecific antigen-binding molecule, which comprises the antibody or the antigen-binding fragment thereof of claim 1, and an additional antigen-binding molecule binding to an antigen other than GPRC5D or binding to a different GPRC5D epitope than that of the antibody or the antigen-binding fragment thereof of claim 1; or the chimeric antigen receptor, which comprises at least a signal peptide, an extracellular antigen-binding domain, a hinge region, a transmembrane domain and an intracellular signaling domain, wherein the extracellular antigen-binding domain comprises the GPRC5D antibody or the antigen-binding fragment thereof of claim 1, or the multispecific antigen-binding molecule.

### Claim 11 (depends on 10)

A vector, wherein the vector comprises the nucleic acid fragment of claim 10.

### Claim 12 (depends on 11)

A host cell, wherein the host cell comprises the vector of claim 11; preferably, the cell is a prokaryotic cell or a eukaryotic cell, such as a bacterial (for example, Escherichia coli) cell, a fungal (for example, yeast) cell, an insect cell or a mammalian cell (for example, a CHO cell line or a 293T cell line).

### Claim 13 (depends on 1, 7, 12)

A method for preparing the antibody or the antigen-binding fragment thereof of claim 1; or the multispecific antigen-binding molecule of claim 7, which comprises the antibody or the antigen-binding fragment thereof of claim 1, and an additional antigen-binding molecule binding to an antigen other than GPRC5D or binding to a different GPRC5D epitope than that of the antibody or the antigen-binding fragment thereof of claim 1; wherein, the method comprises culturing the cell of claim 12 comprising a vector which comprises a nucleic acid fragment encoding the antibody or the antigen binding fragment thereof, or the multi-specific antigen binding molecule, and isolating the antibody, the antigen-binding fragment or the multispecific antigen-binding molecule expressed by the cell.

### Claim 14 (depends on 8)

A method for preparing the aforementioned immune effector cell, wherein the method comprises introducing a nucleic acid fragment encoding the CAR of claim 8 into the immune effector cell, optionally, the method further comprises enabling the immune effector cell to express the CAR of claim 8.

### Claim 15 (depends on 1, 9, 10)

A pharmaceutical composition, wherein the pharmaceutical composition comprises the antibody or the antigen-binding fragment thereof of claim 1; the multispecific antigen-binding molecule, which comprises the antibody or the antigen-binding fragment thereof of claim 1, and an additional antigen-binding molecule binding to an antigen other than GPRC5D or binding to a different GPRC5D epitope than that of the antibody or the antigen-binding fragment thereof of claim 1; the immune effector cell of claim 9 expressing a chimeric antigen receptor which comprises at least a signal peptide, an extracellular antigen-binding domain, a hinge region, a transmembrane domain and an intracellular signaling domain, wherein the extracellular antigen-binding domain comprises the GPRC5D antibody or the antigen-binding fragment thereof of claim 1, or the multispecific antigen-binding molecule; the nucleic acid fragment of claim 10 encoding the antibody or the antigen-binding fragment thereof, the multispecific antigen-binding molecule or the chimeric antigen receptor; or the vector comprising the nucleic acid fragment; optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, a diluent or an auxiliary agent; and optionally, the pharmaceutical composition further comprises an additional anti-tumor agent.

### Claim 16 (depends on 1)

A method for treating a tumor or a cancer, wherein the method comprises administering to a subject an effective amount of the antibody or the antigen-binding fragment thereof of claim 1; the multispecific antigen-binding molecule which comprises the antibody or the antigen-binding fragment thereof of claim 1, and an additional antigen-binding molecule binding to an antigen other than GPRC5D or binding to a different GPRC5D epitope than that of the antibody or the antigen-binding fragment thereof of claim 1; the immune effector cell expressing a chimeric antigen receptor which comprises at least a signal peptide, an extracellular antigen-binding domain, a hinge region, a transmembrane domain and an intracellular signaling domain, wherein the extracellular antigen-binding domain comprises the GPRC5D antibody or the antigen-binding fragment thereof of claim 1, or the multispecific antigen-binding molecule, the nucleic acid fragment encoding the antibody or the antigen-binding fragment thereof, the multispecific antigen-binding molecule or the chimeric antigen receptor; or the vector comprising the nucleic acid fragment;
preferably, the tumor or the cancer is a GPRC5D-expressing tumor or cancer, preferably a B-cell lymphoma, and more preferably multiple myeloma (MM).

### Claim 17

(canceled)

### Claim 18 (depends on 1)

A kit, wherein the kit comprises the antibody or the antigen-binding fragment thereof of claim 1, the multispecific antigen-binding molecule, which comprises the antibody or the antigen-binding fragment thereof of claim 1, and an additional antigen-binding molecule binding to an antigen other than GPRC5D or binding to a different GPRC5D epitope than that of the antibody or the antigen-binding fragment thereof of claim 1; the immune effector cell expressing a chimeric antigen receptor which comprises at least a signal peptide, an extracellular antigen-binding domain, a hinge region, a transmembrane domain and an intracellular signaling domain, wherein the extracellular antigen-binding domain comprises the GPRC5D antibody or the antigen-binding fragment thereof of claim 1, or the multispecific antigen-binding molecule; the nucleic acid fragment encoding the antibody or the antigen-binding fragment thereof, the multispecific antigen-binding molecule or the chimeric antigen receptor; or the vector comprising the nucleic acid fragment.

### Claim 19 (depends on 1)

A method for detecting GPRC5D expression in a biological sample, wherein the method comprises contacting the biological sample with the antibody or the antigen-binding fragment thereof of claim 1 under conditions that allow the formation of a complex from the antibody or the antigen-binding fragment thereof and GPRC5D; preferably, the method further comprises detecting the formation of the complex, thereby indicating the presence or expression level of GPRC5D in the sample.

### Claim 20 (depends on 1)

Use of the antibody or the antigen-binding fragment thereof of claim 1 in the preparation of a reagent for detecting GPRC5D.