# US 10,501,542 B2 · CTLA4 binders

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- Number: US 10,501,542 B2
- Document ID: US10501542B2
- Status: Granted
- Kind: B2
- Application number: 15/353,886
- Filed: 2016-11-17
- Published: 2017-05-18
- Granted: 2019-12-10
- Earliest claimed: 2015-11-18
- Assignees: Merck Sharp & Dohme Corp.
- Applicants: Merck Sharp & Dohme Corp.
- Inventors: Juha Punnonen; Maribel Beaumont; Marie-Ange Buyse; Carlo Boutton; Bruno Dombrecht; Bjorn Victor; Robert A. Kastelein
- Web page: https://patentgrep.com/patent/US10501542B2

## CPC

- C07K 16/2818: {against CD28 or CD152}
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 31/10: Antimycotics
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 37/04: Immunostimulants
- C07K 14/765: Serum albumin, e.g. HSA
- C07K 16/18: against material from animals or humans
- A61K 2039/505: {comprising antibodies}
- A61K 2039/54: {characterised by the route of administration}
- A61K 2039/545: {characterised by the dose, timing or administration schedule}
- C07K 2317/22: from camelids, e.g. camel, llama or dromedary
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/31: multispecific
- C07K 2317/32: specific for a neo-epitope on a complex, e.g. antibody-antigen or ligand-receptor
- 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 2317/35: Valency
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/569: Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
- C07K 2317/62: comprising only variable region components
- 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 2319/31: fusions, other than Fc, for prolonged plasma life, e.g. albumin
- 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

The present invention provides molecules, such as ISVDs and Nanobodies, that bind to CTLA4 or human serum albumin. These molecules have been engineered so as to reduce the incidence of binding by pre-existing antibodies in the bodies of a subject administered such a molecule. Methods for increasing immune response, treating cancer and/or treating an infectious disease with such molecules are provided.

## Claims

### Claim 1

A CTLA4 binder comprising one or more immunoglobulin single variable domains (ISVDs) that bind to human CTLA4
wherein the one or more ISVDs independently comprises the amino acid sequence: XVQLVESGGGVVQPGGSLRLSCAASGGTFSFYGMG WFRQAPGKEREFVADIRTSAGRTYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTALYYCAAEPSGISGWDYWGQG TLVTVSS (SEQ ID NO: 60); and
optionally comprising a half-life extender and/or a C-terminal extender.

### Claim 2

A CTLA4 binder comprising one or more immunoglobulin single variable domains (ISVDs) that bind to human CTLA4
wherein the one or more ISVDs independently comprises the amino acid sequence selected from SEQ ID NOs: 93-109; and
optionally lacking the signal sequence amino acids AAADYKDHDGDYKDHDIDYKDDDDKGAAHHHHHH (amino acids 120-153 of each of SEQ ID Nos: 93-109) thereof.

### Claim 3 (depends on 1)

The CTLA4 binder of claim 1, wherein the CTLA4 binder comprises a half-life extender.

### Claim 4 (depends on 3)

The CTLA4 binder of claim 3, wherein the half-life extender is an ISVD that binds to human serum albumin.

### Claim 5 (depends on 4)

The CTLA4 binder of claim 4 wherein the ISVD that binds to human serum albumin is ALB11002, which has the amino acid sequence set forth in SEQ ID NO: 66.

### Claim 6 (depends on 1)

The CTLA4 binder of claim 1 comprising:
an ISVD that binds to human CTLA4 comprising the amino acid sequence set forth in SEQ ID NO: 60; a peptide linker; an ISVD that binds to human CTLA4 comprising the amino acid sequence set forth in SEQ ID NO: 60; a peptide linker; a half-life extender; and, optionally, a C-terminal extension alanine.

### Claim 7 (depends on 1)

A CTLA4 binder of claim 1 comprising:
an ISVD that binds to human CTLA4 comprising the amino acid sequence set forth in SEQ ID NO: 60; a peptide linker; a half-life extender; and, optionally, a C-terminal extension alanine.

### Claim 8 (depends on 6)

The CTLA4 binder of claim 6 wherein each peptide linker comprises the amino acid sequence GGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 65).

### Claim 9 (depends on 1)

An injection device or vessel that comprises the CTLA4 binder of claim 1 and further comprising a therapeutic agent.

### Claim 10 (depends on 1)

The CTLA4 binder of claim 1, wherein the CTLA4 binder comprises at least two ISVDs that bind human CTLA4.

### Claim 11

A CTLA4 binder comprising one or more immunoglobulin single variable domains (ISVDs) that bind to human CTLA4 which comprises the amino acid sequence:
(SEQ ID NO: 62)
DVQLVESGGGVVQPGGSLRLSCAASGGTFSFYGMG
WFRQAPGKEREFVADIRTSAGRTYYADSVKGRFTISRDNSKNTVYLQMN
SLRPEDTALYYCAAEPSGISGWDYWGQGTLVTVSSGGGGSGGGGSGGGG
SGGGGSGGGGSGGGGSGGGGSEVQLVESGGGVVQPGGSLRLSCAASGGT
FSFYGMGWFRQAPGKEREFVADIRTSAGRTYYADSVKGRFTISRDNSKN
TVYLQMNSLRPEDTALYYCAAEPSGISGWDYWGQGTLVTVSSGGGGSGG
GGSGGGGSGGGGSGGGGSGGGGSGGGGSEVQLVESGGGVVQPGNSLRLS
CAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSDTLYADSVKGRFTI
SRDNAKTTLYLQMNSLRPEDTALYYCTIGGSLSRSSQGTLVTVSSA.

### Claim 12 (depends on 11)

A pharmaceutical composition comprising the CTLA4 binder of claim 11 and a pharmaceutically acceptable carrier.

### Claim 13 (depends on 12)

A pharmaceutical composition comprising the CTLA4 binder of claim 12 and a pharmaceutically acceptable carrier.

### Claim 14

A CTLA4 binder consisting of SEQ ID NO: 62.

### Claim 15

A CTLA4 binder comprising one or more immunoglobulin single variable domains (ISVDs) that bind to human which comprises
the amino acid sequence:
(SEQ ID NO: 64)
DVQLVESGGGVVQPGGSLRLSCAASGGTFSFYGMG
WERQAPGKEREEVADIRTSAGRTYYADSVKGRFTISRDNSKNTVYLQMN
SLRPEDTALYYCAAEPSGISGWDYWGQGTLVTVSSGGGGSGGGGSGGGG
SGGGGSGGGGSGGGGSGGGGSEVQLVESGGGVVQPGNSLRLSCAASGET
FSSFGMSWVRQAPGKGLEWVSSISGSGSDTLYADSVKGRFTISRDNAKT
TLYLQMNSLRPEDTALYYCTIGGSLSRSSQGTLVTVSSA.