# US 2022/0033467 A1 · Modified Monocytes/Macrophage Expressing Chimeric Antigen Receptors and Uses Thereof

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- Number: US 2022/0033467 A1
- Document ID: US20220033467A1
- Status: Published application
- Kind: A1
- Application number: 17/477,461
- Filed: 2021-09-16
- Published: 2022-02-03
- Earliest claimed: 2015-07-28
- Assignees: The Trustees of the University of Pennsylvania
- Applicants: The Trustees of the University of Pennsylvania
- Inventors: Saar GILL; Michael KLICHINSKY; Carl H. JUNE
- Web page: https://patentgrep.com/patent/US20220033467A1

## CPC

- C07K 14/70517: {CD8}
- A61K 40/17: Monocytes; Macrophages
- A61K 40/31: Chimeric antigen receptors [CAR]
- A61K 40/4205: {Her-2/neu/ErbB2, Her-3/ErbB3 or Her 4/ ErbB4}
- A61K 40/4211: {CD19 or B4}
- A61K 40/4255: {Mesothelin [MSLN]}
- A61P 37/02: Immunomodulators
- C07K 14/7051: {T-cell receptor (TcR)-CD3 complex}
- C07K 14/70535: {Fc-receptors, e.g. CD16, CD32, CD64 (CD2314/705F)}
- C07K 14/7056: {Lectin superfamily, e.g. CD23, CD72}
- C07K 16/2803: {against the immunoglobulin superfamily}
- C07K 16/30: from tumour cells
- C07K 16/32: against translation products of oncogenes
- C07K 19/00: Hybrid peptides {, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes}
- C12N 5/0645: {Macrophages, e.g. Kuepfer cells in the liver; Monocytes}
- A61K 35/14: Blood; Artificial blood (perfluorocarbons A61K31/02; umbilical cord blood A61K35/51; haemoglobin A61K38/42)
- 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 2039/505: {comprising antibodies}
- A61K 2039/892: {Reproductive system [uterus, ovaries, cervix, testes]}
- A61P 35/00: Antineoplastic agents
- C07K 2317/622: Single chain antibody (scFv)
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2319/00: Fusion polypeptide
- C07K 2319/02: containing a signal sequence
- C07K 2319/03: containing a transmembrane segment
- C07K 2319/74: containing a fusion for binding to a cell surface receptor
- C12N 2510/00: Genetically modified cells
- 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
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

The present invention includes methods and compositions for treating cancer, whether a solid tumor or a hematologic malignancy. By expressing a chimeric antigen receptor in a monocyte, macrophage or dendritic cell, the modified cell is recruited to the tumor microenvironment where it acts as a potent immune effector by infiltrating the tumor and killing the target cells. One aspect includes a modified cell and pharmaceutical compositions comprising the modified cell for adoptive cell therapy and treating a disease or condition associated with immunosuppression.

## Claims

### Claim at position 1

1-44. (canceled)

### Claim 45

A method of treating a malignancy in a subject, comprising:
administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a modified cell comprising a chimeric antigen receptor (CAR),
wherein the CAR comprises an antigen binding domain, a transmembrane domain and an intracellular domain of a stimulatory and/or co-stimulatory molecule,
wherein the antigen binding domain targets a tumor antigen, and
wherein the modified cell is a human macrophage or human monocyte.

### Claim 46 (depends on 45)

The method of claim 45, wherein the tumor antigen is Receptor tyrosine-protein kinase ERBB2 (HER2), prostate-specific membrane antigen (PSMA), CD19, or mesothelin.

### Claim 47 (depends on 45)

The method of claim 45, wherein the malignancy is or comprises: carcinoma, blastoma, sarcoma, leukemia, a lymphoid malignancy, or melanoma.

### Claim 48 (depends on 45)

The method of claim 45, wherein the antigen binding domain of the CAR comprises an antibody selected from the group consisting of a monoclonal antibody, a polyclonal antibody, a synthetic antibody, human antibody, humanized antibody, single domain antibody, single chain variable fragment, and antigen-binding fragments thereof.

### Claim 49 (depends on 45)

The method of claim 45, wherein the transmembrane domain of the CAR comprises a CD8 or CD28 transmembrane domain.

### Claim 50 (depends on 45)

The method of claim 45, wherein the intracellular domain of the CAR comprises dual signaling domains.

### Claim 51 (depends on 45)

The method of claim 45, wherein the intracellular domain of the CAR comprises a CD3 zeta intracellular domain.

### Claim 52 (depends on 45)

The method of claim 45, wherein the modified cell exhibits targeted effector activity.

### Claim 53 (depends on 52)

The method of claim 52, wherein the targeted effector activity is directed against a target cell comprising the tumor antigen.

### Claim 54 (depends on 52)

The method of claim 52, wherein the targeted effector activity is selected from the group consisting of phagocytosis, targeted cellular cytotoxicity, antigen presentation, and cytokine secretion.

### Claim 55 (depends on 52)

The method of claim 52, wherein the targeted effector activity is enhanced by inhibition of CD47 or SIRPα activity.

### Claim 56 (depends on 45)

The method of claim 45, wherein the pharmaceutical composition further comprises an agent selected from the group consisting of a nucleic acid, an antibiotic, an anti-inflammatory agent, an antibody or antibody fragments thereof, a growth factor, a cytokine, an enzyme, a protein, a peptide, a fusion protein, a synthetic molecule, an organic molecule, a carbohydrate or the like, a lipid, a hormone, a microsome, a derivative or a variation thereof, and any combination thereof.

### Claim 57 (depends on 45)

The method of claim 45, wherein the modified cell exhibits reduced SIRPα activity relative to an unmodified cell.

### Claim 58 (depends on 45)

The method of claim 45, wherein at least 35% of the modified cells in the pharmaceutical composition express the CAR.

### Claim 59 (depends on 45)

The method of claim 45, wherein the modified cell comprises an Ad5f35 adenoviral component.

### Claim 60 (depends on 45)

The method of claim 45, wherein the modified cell is autologous or allogeneic to the patient.

### Claim 61 (depends on 45)

The method of claim 45, wherein the modified cells are administered by injection, aerosol inhalation, ingestion, transfusion, implantation or transplantation.

### Claim 62 (depends on 45)

The method of claim 45, wherein the modified cells are administered transarterially, subcutaneously, intradermally, intratumorally, intranodally, intramedullary, intramuscularly, intravenously, or intraperitoneally.

### Claim 63 (depends on 45)

The method of claim 45, wherein the modified cell is administered to a patient in conjunction with at least one other treatment modality.

### Claim 64 (depends on 63)

The method of claim 63, wherein the at least one other treatment modality is or comprises antiviral therapy, chemotherapy, radiation, an immunosuppressive agent, and/or an antibody therapy.