# US 11,993,661 B2 · Constructs targeting prostate-specific membrane antigen (PSMA) and uses thereof

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- Number: US 11,993,661 B2
- Document ID: US11993661B2
- Status: Granted
- Kind: B2
- Application number: 17/253,589
- Filed: 2019-06-17
- Published: 2022-06-16
- Granted: 2024-05-28
- Earliest claimed: 2018-06-18
- Assignees: Eureka Therapeutics, Inc.
- Applicants: Eureka Therapeutics, Inc.
- Inventors: Hong Liu; Hongruo Yun; Xiaomei Ge; Zhiyuan Yang; Lianxing Liu; Pengbo Zhang; Yixiang Xu; Shan Li; Lucas Horan
- Web page: https://patentgrep.com/patent/US11993661B2

## CPC

- C07K 16/3069: {Reproductive system, e.g. ovaria, uterus, testes, prostate}
- A61K 40/11: T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
- A61K 40/31: Chimeric antigen receptors [CAR]
- A61K 40/4276: {Prostate specific membrane antigen [PSMA]}
- A61P 35/00: Antineoplastic agents
- C07K 14/7051: {T-cell receptor (TcR)-CD3 complex}
- C07K 14/70521: {CD28, CD152}
- C07K 16/2809: {against the T-cell receptor (TcR)-CD3 complex}
- G01N 33/57555: of the prostate
- A61K 2039/507: {Comprising a combination of two or more separate antibodies}
- A61K 2039/585: {wherein the target is cancer}
- A61K 2239/28: Expressing multiple CARs, TCRs or antigens
- A61K 2239/38: characterised by the dose, timing or administration schedule
- A61K 2239/58: Prostate
- C07K 2317/21: from primates, e.g. man
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/31: multispecific
- C07K 2317/52: Constant or Fc region; Isotype
- C07K 2317/622: Single chain antibody (scFv)
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2317/75: Agonist effect on antigen
- 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
- C07K 2319/02: containing a signal sequence
- C07K 2319/03: containing a transmembrane segment
- C07K 2319/33: fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
- 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)

## Abstract

The present application provides constructs comprising an antibody moiety that specifically binds to PSMA (e.g., PSMA expressed on the surface of a cell). Also provided are methods of making and using these constructs.

## Claims

### Claim 1

An anti-prostate specific membrane antigen (PSMA) construct comprising an anti-PSMA antibody moiety specifically recognizing an extracellular domain of PSMA comprising the amino acid sequence of SEQ ID NO: 44, wherein the anti-PSMA antibody moiety comprises:
a) a heavy chain variable domain (VH) comprising a heavy chain complementarity determining region (CDR-H) 1 comprising the amino acid sequence of SEQ ID NO: 1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 3, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; and a light chain variable domain (VL) comprising a light chain complementarity determining region (CDR-L) 1 comprising the amino acid sequence of SEQ ID NO: 7, a CDR-L2 comprising the amino acid sequence GNS, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 9; or
b) a VH comprising a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 2, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 6; and a VL comprising a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 8, a CDR-L2 comprising the amino acid sequence SNN, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10.

### Claim 2 (depends on 1)

The anti-PSMA construct of claim 1, wherein the anti-PSMA antibody moiety comprises:
i) a VH comprising the amino acid sequence of SEQ ID NO: 16, or an amino acid sequence having at least about 85% sequence identity to SEQ ID NO: 16, and a VL comprising the amino acid sequence of SEQ ID NO: 18, or an amino acid sequence having at least about 85% sequence identity to SEQ ID NO: 18; or
ii) a Vu comprising the amino acid sequence of SEQ ID NO: 17, or an amino acid sequence having at least about 85% sequence identity to SEQ ID NO: 17, and a VL comprising the amino acid sequence of SEQ ID NO: 19, or an amino acid sequence having at least about 85% sequence identity to SEQ ID NO: 19.

### Claim 3 (depends on 1)

The anti-PSMA construct of claim 1, wherein the anti-PSMA antibody moiety is chimeric, human, humanized, or semi-synthetic.

### Claim 4 (depends on 1)

The anti-PSMA construct of claim 1, wherein the anti-PSMA antibody moiety is a full-length antibody, a Fab, a Fab′, a F(ab′)2, an Fv, or a single chain Fv (scFv).

### Claim 5 (depends on 4)

The anti-PSMA construct of claim 4, wherein the anti-PSMA antibody moiety is an scFv.

### Claim 6 (depends on 5)

The anti-PSMA construct of claim 5, wherein the scFv comprises:
i) the amino acid sequence of SEQ ID NO: 20, or an amino acid sequence that has at least about 85% sequence identity to SEQ ID NO: 20; or
ii) the amino acid sequence of SEQ ID NO: 21, or an amino acid sequence that has at least about 85% sequence identity to SEQ ID NO: 21.

### Claim 7 (depends on 4)

The anti-PSMA construct of claim 4, wherein the anti-PSMA moiety is a full-length antibody, and wherein the full-length antibody comprises:
i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 39 or an amino acid sequence having at least about 85% sequence identity to SEQ ID NO: 39, and a light chain comprising the amino acid sequence of SEQ ID NO: 40 or an amino acid sequence having at least about 85% sequence identity to SEQ ID NO: 40; or
ii) a heavy chain comprising the amino acid sequence of SEQ ID NO: 41 or an amino acid sequence having at least about 85% sequence identity to SEQ ID NO: 41, and a light chain comprising the amino acid sequence of SEQ ID NO: 42 or an amino acid having at least about 85% sequence identity to SEQ ID NO: 42.

### Claim 8 (depends on 1)

The anti-PSMA construct of claim 1, wherein the anti-PSMA construct is monospecific.

### Claim 9 (depends on 1)

The anti-PSMA construct of claim 1, wherein the anti-PSMA construct is multi specific.

### Claim 10 (depends on 9)

The anti-PSMA construct of claim 9, wherein the anti-PSMA construct is a tandem scFv, a diabody (Db), a single chain diabody (scDb), a dual-affinity retargeting (DART) antibody, a F(ab′)2, a dual variable domain (DVD) antibody, a knob-into-hole (KiH) antibody, a dock and lock (DNL) antibody, a chemically cross-linked antibody, a heteromultimeric antibody, or a heteroconjugate antibody.

### Claim 11 (depends on 9)

The anti-PSMA construct of claim 9, wherein the anti-PSMA construct further comprises a second antibody moiety specifically recognizing a second antigen.

### Claim 12 (depends on 11)

The anti-PSMA construct of claim 11, wherein the second antigen is an antigen on the surface of a B cell, a natural killer cell, a dendritic cell, a macrophage, a monocyte, a neutrophil, or a T cell.

### Claim 13 (depends on 1)

The anti-PSMA construct of claim 1, wherein the anti-PSMA construct is a chimeric antigen receptor (CAR) comprising:
(a) an extracellular domain comprising the anti-PSMA antibody moiety;
(b) a transmembrane domain; and
(c) an intracellular signaling domain.

### Claim 14 (depends on 13)

The anti-PSMA construct of claim 13, wherein the intracellular signaling domain comprises a primary immune cell signaling sequence of CD3ζ, TCRζ, FcRγ, FcRβ, CD3γ, CD3δ, CD3ε, CD5, CD22, CD79a, CD79b, or CD66d, and/or wherein the intracellular signaling domain further comprise a costimulatory signaling sequence of CD28, 4-1BB, ICOS, or OX40.

### Claim 15 (depends on 1)

The anti-PSMA construct of claim 1, wherein the anti-PSMA construct is a chimeric antibody-T cell receptor (TCR) construct (caTCR) comprising:
(a) an extracellular domain comprising the anti-PSMA antibody moiety; and
(b) a TCR module (TCRM) comprising a first TCR domain (TCRD) comprising a first TCR transmembrane domain (TCR-TM) and a second TCRD comprising a second TCR-TM, wherein the TCRM facilitates recruitment of at least one TCR-associated signaling molecule.

### Claim 16 (depends on 15)

The anti-PSMA construct of claim 15, wherein the first TCR-TM and the second TCR-TM are from a γ/δ TCR.

### Claim 17 (depends on 2)

The anti-PSMA construct of claim 2, wherein the anti-PSMA construct comprises:
i) a first polypeptide chain comprising the amino acid sequence of SEQ ID NO: 31, and a second polypeptide chain comprising the amino acid sequence of SEQ ID NO: 32;
ii) a first polypeptide chain comprising the amino acid sequence of SEQ ID NO: 34, and a second polypeptide chain comprising the amino acid sequence of SEQ ID NO;
iii) a first polypeptide chain comprising the amino acid sequence of SEQ ID NO: 165, and a second polypeptide chain comprising the amino acid sequence of SEQ ID NO: 166;
iv) a first polypeptide chain comprising the amino acid sequence of SEQ ID NO: 167, and a second polypeptide chain comprising the amino acid sequence of SEQ ID NO: 168;
v) a first polypeptide chain comprising the amino acid sequence of SEQ ID NO: 169, and a second polypeptide chain comprising the amino acid sequence of SEQ ID NO: 170;
vi) a first polypeptide chain comprising the amino acid sequence of SEQ ID NO: 171, and a second polypeptide chain comprising the amino acid sequence of SEQ ID NO: 172;
vii) a first polypeptide chain comprising the amino acid sequence of SEQ ID NO: 173, and a second polypeptide chain comprising the amino acid sequence of SEQ ID NO: 174;
viii) a first polypeptide chain comprising the amino acid sequence of SEQ ID NO: 175, and a second polypeptide chain comprising the amino acid sequence of SEQ ID NO: 176;
ix) a first polypeptide chain comprising the amino acid sequence of SEQ ID NO: 177, and a second polypeptide chain comprising the amino acid sequence of SEQ ID NO: 178;
x) a first polypeptide chain comprising the amino acid sequence of SEQ ID NO: 179, and a second polypeptide chain comprising the amino acid sequence of SEQ ID NO: 180;
xi) a polypeptide chain comprising the amino acid sequence of SEQ ID NO: 29;
xii) a polypeptide chain comprising the amino acid sequence of SEQ ID NO: 30; or
xiii) a polypeptide chain comprising the amino acid sequence of any one of SEQ ID NOs: 37, 38, 55-84, 93, and 184-186.

### Claim 18 (depends on 15)

The anti-PSMA construct of claim 15, wherein the TCR-associated signaling molecule is selected from the group consisting of CD3δε, CD3γε, and CD3ζζ, and/or wherein the caTCR lacks a functional primary immune cell signaling domain.

### Claim 19 (depends on 1)

The anti-PSMA construct of claim 1, wherein the anti-PSMA construct is a chimeric signaling receptor (CSR) comprising:
i) a ligand-binding module comprising the anti-PSMA antibody moiety;
ii) a transmembrane module; and
iii) a co-stimulatory immune cell signaling module that is capable of providing a co-stimulatory signal to an effector cell,
wherein the CSR lacks a functional primary immune cell signaling domain.

### Claim 20 (depends on 19)

The anti-PSMA construct of claim 19, wherein:
(i) the CSR lacks any primary immune cell signaling sequences;
(ii) the transmembrane module of the CSR and the co-stimulatory immune cell signaling module of the CSR are from different molecules;
(iii) the transmembrane module of the CSR comprises a transmembrane domain of CD28, CD3ε, CD3ζ, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD27, CD30, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154, 4-1BB, OX40, or the α, β, δ, or γ chain of a TCR; and/or
(iv) the co-stimulatory immune cell signaling module is from the intracellular domain of a co-stimulatory receptor of a TCR selected from the group consisting of 4-1BB, CD27, CD28, CD30, OX40, ICOS, and CD40.

### Claim 21 (depends on 1)

The anti-PSMA construct of claim 1, wherein the anti-PSMA antibody moiety is conjugated to an effector molecule, wherein the effector molecule is a detectable label or a therapeutic agent selected from the group consisting of a drug, a toxin, a radioisotope, a protein, a peptide, and a nucleic acid.

### Claim 22 (depends on 1)

A nucleic acid or a vector encoding the anti-PSMA construct of claim 1.

### Claim 23 (depends on 22)

A host cell comprising the nucleic acid or the vector of claim 22.

### Claim 24 (depends on 23)

A method of producing an anti-PSMA construct, comprising culturing the host cell of claim 23 under a condition where the anti-PSMA construct is expressed, and recovering the anti-PSMA construct produced by the host cell.

### Claim 25 (depends on 1)

A pharmaceutical composition comprising the anti-PSMA construct of claim 1, and a pharmaceutical acceptable carrier.