# US 11,028,174 B1 · Bifunctional molecules targeting PD-L1 and TGF-β

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- Number: US 11,028,174 B1
- Document ID: US11028174B1
- Status: Granted
- Kind: B1
- Application number: 17/006,517
- Filed: 2020-08-28
- Granted: 2021-06-08
- Earliest claimed: 2020-07-28
- Assignees: Lepu Biopharma Co., Ltd.
- Applicants: Lepu Biopharma Co., Ltd.
- Inventors: Wenci Gong; Yiwei Tou
- Web page: https://patentgrep.com/patent/US11028174B1

## CPC

- C07K 16/2827: {against B7 molecules, e.g. CD80, CD86}
- A61P 35/00: Antineoplastic agents
- C07K 14/71: for growth factors; for growth regulators
- C07K 16/22: against growth factors {; against growth regulators}
- A61K 2039/505: {comprising antibodies}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/31: multispecific
- C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- C07K 2317/565: Complementarity determining region [CDR]
- 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 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
- C07K 2319/32: fusions with soluble part of a cell surface receptor, "decoy receptors"
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)

## Abstract

Provided are anti-PD-L1 antibodies with superior activities in blocking the PD-1 and PD-L1 interactions. Also provided are multifunctional molecules that include the anti-PD-L1 antibodies or fragments thereof fused to an extracellular domain of human TGF-beta receptor type-2.

## Claims

### Claim 1

A multifunctional molecule, comprising an anti-PD-L1 (programmed death-ligand 1) antibody or fragment thereof and an extracellular domain of human TGF-β RII (TGF-beta receptor type-2),
wherein the anti-PD-L1 antibody or fragment thereof has specificity to the human PD-L1 protein and comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2 and a VH CDR3, and a light chain variable region (VL) comprising a VL CDR1, a VL CDR2, and a VL CDR3,
wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3, respectively, comprise the amino acid sequences of
SEQ ID NO:13-18,
wherein the human TGF-β RII extracellular domain comprises the amino acid sequence of SEQ ID NO:72 and is fused to the anti-PD-L1 antibody or fragment thereof.

### Claim 2 (depends on 1)

The multifunctional molecule of claim 1, wherein anti-PD-L1 antibody or fragment thereof comprises a heavy chain that comprises the VH and a separate light chain comprising the VL.

### Claim 3 (depends on 2)

The multifunctional molecule of claim 2, wherein the TGF-β RII extracellular domain is fused to the heavy chain of the anti-PD-L1 antibody or fragment thereof.

### Claim 4 (depends on 3)

The multifunctional molecule of claim 3, wherein the TGF-β RII extracellular domain is fused to the C-terminus of the heavy chain of the anti-PD-L1 antibody or fragment thereof.

### Claim 5 (depends on 3)

The multifunctional molecule of claim 3, wherein the TGF-β RII extracellular domain is fused to the heavy chain of the anti-PD-L1 antibody or fragment thereof through a peptide linker.

### Claim 6 (depends on 1)

The multifunctional molecule of claim 1, wherein the TGF-β RII extracellular domain comprises SEQ ID NO:72 and includes at least a partial deletion of amino acid residues 24-48 of SEQ ID NO:71.

### Claim 7 (depends on 1)

The multifunctional molecule of claim 1, wherein the TGF-β RII extracellular domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO:61, and 73-78, wherein for SEQ ID NO:74, X is any amino acid except K, S, or N.

### Claim 8 (depends on 1)

The multifunctional molecule of claim 1, which includes at least 30 amino acid residues between SEQ ID NO:72 and the anti-PD-L1 antibody or fragment thereof.

### Claim 9 (depends on 1)

The multifunctional molecule of claim 1, which includes an alpha helix motif between SEQ ID NO:72 and the anti-PD-L1 antibody or fragment thereof.

### Claim 10 (depends on 1)

The multifunctional molecule of claim 1, wherein the VH comprises an amino acid sequence selected from the group consisting of SEQ ID NO:31-37, and the VL comprises an amino acid sequence selected from the group consisting of SEQ ID NO:38-43.

### Claim 11 (depends on 10)

The multifunctional molecule of claim 10, wherein the VH comprises the amino acid sequence of SEQ ID NO:34, and the VL comprises the amino acid sequence of SEQ ID NO:43.

### Claim 12 (depends on 1)

The multifunctional molecule of claim 1, which comprises a light chain comprising the VL and a light chain constant region, and a heavy chain comprising the VH, a heavy chain constant region, a peptide linker, and the TGF-β RII extracellular domain.

### Claim 13 (depends on 12)

The multifunctional molecule of claim 12, wherein the heavy chain constant region comprises the amino acid sequence of SEQ ID NO:59.

### Claim 14 (depends on 1)

A method for treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of the multifunctional molecule of claim 1.

### Claim 15 (depends on 14)

The method of claim 14, wherein the cancer is a solid tumor.

### Claim 16 (depends on 14)

The method of claim 14, wherein the cancer is selected from the group consisting of bladder cancer, liver cancer, colon cancer, rectal cancer, endometrial cancer, leukemia, lymphoma, pancreatic cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, urethral cancer, head and neck cancer, gastrointestinal cancer, stomach cancer, oesophageal cancer, ovarian cancer, renal cancer, melanoma, prostate cancer and thyroid cancer.