# US 2025/0375522 A1 · Chimeric checkpoint receptor for the use in treatment of malignant b-cell diseases

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- Number: US 2025/0375522 A1
- Document ID: US20250375522A1
- Status: Published application
- Kind: A1
- Application number: 18/876,596
- Filed: 2023-06-28
- Published: 2025-12-11
- Earliest claimed: 2022-06-29
- Assignees: Universität zu Köln
- Applicants: Universität zu Köln
- Inventors: Markus Chmielewski
- Web page: https://patentgrep.com/patent/US20250375522A1

## CPC

- A61K 40/11: T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
- C07K 14/70521: {CD28, CD152}
- A61K 31/7088: Compounds having three or more nucleosides or nucleotides
- 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)
- A61K 40/31: Chimeric antigen receptors [CAR]
- A61K 40/421: {Immunoglobulin superfamily}
- A61K 40/4211: {CD19 or B4}
- A61K 40/4212: {CD22, BL-CAM, siglec-2 or sialic acid binding Ig-related lectin 2}
- A61K 40/4221: {CD20}
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- C07K 14/00: Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K 14/7051: {T-cell receptor (TcR)-CD3 complex}
- C07K 14/70578: {NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95 (NGF-receptor C07K14/71, TNF-receptor C07K14/7151)}
- C07K 16/2803: {against the immunoglobulin superfamily}
- C07K 16/2827: {against B7 molecules, e.g. CD80, CD86}
- C07K 16/2887: {against CD20}
- C12N 5/0636: {T lymphocytes}
- C12N 15/62: DNA sequences coding for fusion proteins
- C12N 15/85: for animal cells
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- A61K 2239/31: characterized by the route of administration
- A61K 2239/38: characterised by the dose, timing or administration schedule
- A61K 2239/48: Blood cells, e.g. leukemia or lymphoma
- C07K 2317/31: multispecific
- C07K 2317/622: Single chain antibody (scFv)
- C07K 2319/00: Fusion polypeptide
- C07K 2319/03: containing a transmembrane segment
- C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
- 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)
- 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
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

The invention is related to a chimeric checkpoint receptor (CCR) fusion protein, a nucleic acid molecule encoding said fusion protein, a vector comprising said nucleic acid molecule, a host cell comprising said nucleic acid molecule and/or expressing the fusion protein, a method for providing said host cell, a pharmaceutical composition comprising said fusion protein, nucleic acid molecule or host cell, and said products for use as a medicament and in the treatment of B cell lymphoma.

## Claims

### Claim 1

Fusion protein comprising:
a) an extracellular domain comprising a polypeptide with specific affinity to CD80 and/or CD86;
b) a transmembrane domain; and
c) an intracellular domain comprising a co-stimulatory polypeptide.

### Claim 2 (depends on 1)

Fusion protein according to claim 1, wherein the polypeptide with specific affinity to CD80 and/or CD86 has an amino acid sequence which is at least 80% identical to the amino acid sequence of the extracellular domain of human CTLA-4 (SEQ ID NO: 1) or an amino acid sequence which is at least 80% identical to the amino acid sequence of the extracellular domain of human CD28 (SEQ ID NO: 2), or an amino acid sequence which is at least 80% identical to the amino acid sequence of the CD86-binding domain of the anti-CD86 antibody commonly referred to in the art as clone hu3D1 (SEQ ID NO: 5), preferably wherein the polypeptide with specific affinity to CD80 and/or CD86 has an amino acid sequence which is at least 80% identical to the amino acid sequence of the extracellular domain of human CTLA-4 (SEQ ID NO: 1), and/or wherein the transmembrane domain is suitable for insertion and anchoring of the fusion protein in the cell membrane of a mammalian cell, preferably wherein the transmembrane domain comprises the transmembrane region of one or more of the alpha, beta or zeta chain of the T-cell receptor, CTLA-4, CD28, CD3 epsilon, CD45, CD4, CD5, CD8 (e.g., CD8 alpha, CD8 beta), CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154, CD200, KIRDS2, 0X40, CD2, CD27, LFA-1 (CDIIa, CD18), ICOS (CD278), 4-1 BB (CD137), GITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), CD160, CD19,IL2R beta, IL2R gamma, IL7R .alpha., VLA1, ITGAI, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CDIId, ITGAE, CD103, ITGAL, CDIIa, LFA-1, ITGAM, CDIIb, ITGAX, CDIIc, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, TNFR2, DNAM1 (CD226), SFAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAMI, CRTAM, Ly9(CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), SLAMF6 (NTB-A, Ly108). SEAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, and PAG/Cbp, or an amino acid sequence which is at least 80% identical thereto, preferably wherein the transmembrane domain comprises the transmembrane region of human CTLA-4 (SEQ ID NO: 17), or an amino acid sequence which is at least 80% identical thereto, and/or wherein the intracellular domain comprises the intracellular domain or a costimulatory polypeptide of one or more of human 4-1 BB (CD137; SEQ ID NO: 3), CD3 (SEQ ID NO: 25), CD28, ICOS, OX-40, BTLA, CD27, CD30, GITR, Myd88-CD40, KIR2DS2 and HVEM, or an amino acid sequence which is at least 80% identical thereto, preferably wherein the intracellular domain comprises the intracellular domain or a co-stimulatory polypeptide of human 4-1 BB (CD137; SEQ ID NO: 3), or an amino acid sequence which is at least 80% identical thereto, or wherein the intracellular domain comprises the intracellular domain or a co-stimulatory polypeptide of CD3 (SEQ ID NO: 25), or an amino acid sequence which is at least 80% identical thereto, preferably wherein the intracellular domain comprises the intracellular domain or a costimulatory polypeptide of human 4-1 BB (CD137; SEQ ID NO: 3), or an amino acid sequence which is at least 80% identical thereto.

### Claim 3 (depends on 1)

Fusion protein according to claim 1, wherein the extracellular domain comprises a polypeptide comprising the extracellular domain of human CTLA-4 (SEQ ID NO: 1), or an amino acid sequence which is at least 80% identical thereto, and the intracellular domain comprises a co-stimulatory peptide comprising the intracellular domain of human 4-1 BB (CD137; SEQ ID NO: 3), or an amino acid sequence which is at least 80% identical thereto.

### Claim 4 (depends on 1)

Nucleic acid molecule encoding the fusion protein of claim 1.

### Claim 5 (depends on 4)

Vector comprising the nucleic acid molecule of claim 4.

### Claim 6 (depends on 4)

Host cell comprising the nucleic acid molecule of claim 4, preferably wherein the host cell is transduced with the nucleic acid molecule or the vector, or preferably wherein the nucleic acid molecule or the vector of is stably integrated into the genome of the host cell.

### Claim 7 (depends on 1)

Host cell stably or transiently expressing a fusion protein according to claim 1.

### Claim 8 (depends on 6)

Host cell according to claim 6, wherein the host cell stably or transiently expresses a protein comprising an extracellular domain with specific affinity to CD19 and an intracellular co-stimulatory domain, preferably wherein the extracellular domain with specific affinity to CD19 comprises at least an antigen-binding fragment of an anti-CD19 antibody, more preferably wherein the extracellular domain with specific affinity to CD19 comprises an anti-CD19 scFv, or wherein the host cell stably or transiently expresses a protein comprising an extracellular domain with specific affinity to CD20 and an intracellular co-stimulatory domain, preferably wherein the extracellular domain with specific affinity to CD20comprises at least an antigen-binding fragment of an anti-CD20 antibody, more preferably wherein the extracellular domain with specific affinity to CD20 comprises an anti-CD20 scFv.

### Claim 9 (depends on 8)

Host cell according to claim 8, wherein the intracellular costimulatory domain of the fusion protein and/or of the protein comprising an extracellular domain with specific affinity to CD 19 or CD20 comprises an amino acid sequence of the intracellular domain of CD3ζ; (SEQ ID NO: 25), or an amino acid sequence which is at least 80% identical thereto, or an amino acid sequence of the intracellular domain or a co-stimulatory polypeptide of human 4-1 BB (CD137; SEQ ID NO: 3), or an amino acid sequence which is at least 80% identical thereto, preferably wherein the intracellular costimulatory domain of the fusion protein and/or of the protein comprising an extracellular domain with specific affinity to CD 19 or CD20 comprises an amino acid sequence of the intracellular domain of CD3ζ; (SEQ ID NO: 25), or an amino acid sequence which is at least 80% identical thereto.

### Claim 10 (depends on 6)

Host cell according to claim 6, wherein the host cell is a human CD8+ T cell.

### Claim 11 (depends on 6)

Method of providing a host cell of claim 6 comprising:
(1) transducing a host cell with a nucleic acid molecule of or a vector;
(2) cultivating the transduced host cell of in a suitable medium allowing growth of the cell and expression of the fusion protein encoded by said nucleic acid molecule or said vector; and
(3) collecting the host cells from the medium.

### Claim 12 (depends on 11)

Host cell obtainable by the method of claim 11.

### Claim 13 (depends on 1)

Pharmaceutical composition comprising a fusion protein of claim 1, a nucleic acid molecule, a vector, and/or a host cell.

### Claim 14 (depends on 1)

Fusion protein of claim 1, nucleic acid molecule, vector , host cell, or pharmaceutical composition for use as a medicament.

### Claim 15 (depends on 1)

Fusion protein of claim 1, nucleic acid molecule, vector, host cell, or pharmaceutical composition for use in the treatment of B cell lymphoma, preferably for the treatment of non-Hodgkin lymphoma selected from the group comprising marginal zone B cell lymphoma (MZL), mucosa-associated lymphatic tissue lymphoma (MALT), small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL), mantle cell lymphoma (MCL), Burkitt's lymphoma, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia, nodal marginal zone B cell lymphoma (NMZL), splenic marginal zone lymphoma (SMZL), and diffuse large B cell lymphoma (DLBCL), more preferably for the treatment of diffuse large B cell lymphoma (DLBCL).

### Claim 16 (depends on 1)

Kit or kit-in-parts comprising a fusion protein of claim 1, nucleic acid molecule, vector, host cell of any-one-of-claims, or pharmaceutical composition, and a container.