# US 12,005,073 B2 · Methods for modulating regulatory T cells, regulatory b cells, and immune responses using modulators of the april-taci interaction

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- Number: US 12,005,073 B2
- Document ID: US12005073B2
- Status: Granted
- Kind: B2
- Application number: 16/612,938
- Filed: 2018-06-20
- Published: 2021-04-22
- Granted: 2024-06-11
- Earliest claimed: 2017-06-20
- Assignees: Dana-Farber Cancer Institute, Inc.
- Applicants: Dana-Farber Cancer Institute, Inc.
- Inventors: Kenneth C. Anderson; Yu-Tzu Tai
- Web page: https://patentgrep.com/patent/US12005073B2

## CPC

- C07K 16/2875: {against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154 (against NGF C07K16/22, against TNF C07K16/241)}
- A61K 31/7105: Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
- A61K 39/00: Medicinal preparations containing antigens or antibodies (materials for immunoassay G01N33/53)
- A61K 39/39: characterised by the immunostimulating additives, e.g. chemical adjuvants
- C12N 15/113: Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 2039/505: {comprising antibodies}
- A61K 2039/577: {tolerising response}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
- C12N 2310/11: Antisense
- C12N 2310/141: MicroRNAs, miRNAs
- C12N 2310/20: involving clustered regularly interspaced short palindromic repeats [CRISPR]
- 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)
- 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 is based, in part, on methods for modulating regulatory T cells, regulatory B cells, and immune responses using modulators of the APRIL-TACI interaction.

## Claims

### Claim 1

An in vitro or ex vivo method of selectively decreasing the number and/or inhibitory immune activity of Tregs and/or Bregs comprising contacting the Tregs and/or Bregs with 1) an immune checkpoint therapy comprising an anti-PD-1 antibody, an anti-PD-L1 antibody, and/or an anti-PD-L2 antibody, and 2) an antibody that blocks the interaction of TACI receptor protein expressed by the Tregs and/or Bregs with APRIL ligand and selectively decreases the number and/or inhibitory immune activity of the Tregs and/or Bregs, wherein the antibody that blocks the interaction of TACI receptor protein expressed by the Tregs and/or Bregs with APRIL ligand is an anti-APRIL antibody or an anti-TACI antibody.

### Claim 2 (depends on 1)

The method of claim 1, wherein the antibody that blocks the interaction of TACI receptor protein expressed by the Tregs and/or Bregs with APRIL ligand is an anti-APRIL antibody.

### Claim 3 (depends on 1)

The method of claim 1, wherein the antibody that blocks the interaction of TACI receptor protein expressed by the Tregs and/or Bregs with APRIL ligand is an anti-TACI antibody.

### Claim 4 (depends on 1)

The method of claim 1, wherein the antibody that blocks the interaction of TACI receptor protein expressed by the Tregs and/or Bregs with APRIL ligand downregulates the interaction between the TACI receptor protein expressed by the Tregs and/or Bregs with APRIL ligand.

### Claim 5 (depends on 1)

The method of claim 1, wherein expression of IL10, PD-L1, and/or one or more growth or survival genes selected from the group consisting of MCLA, Bc1-2, Bc1-xL, CCND1, CCND2, and BIRC3, is decreased.

### Claim 6 (depends on 1)

The method of claim 1, wherein the anti-PD-1 antibody, anti-PD-L1 antibody, and/or anti-PD-L2 antibody and/or the antibody that blocks the interaction of TACI receptor protein expressed by the Tregs and/or Bregs with APRIL ligand is murine, chimeric, humanized, composite, or human.

### Claim 7 (depends on 1)

The method of claim 1, wherein the anti-PD-1 antibody, anti-PD-L1 antibody, and/or anti-PD-L2 antibody and/or the antibody that blocks the interaction of TACI receptor protein expressed by the Tregs and/or Bregs with APRIL ligand is detectably labeled, comprises an Fc domain, and/or is selected from the group consisting of Fv, Fav, F(ab′)2, Fab′, dsFv, scFv, sc(Fv)2, and diabodies fragments.

### Claim 8 (depends on 1)

The method of claim 1, wherein the anti-PD-1 antibody, anti-PD-L1 antibody, and/or anti-PD-L2 antibody and/or the antibody that blocks the interaction of TACI receptor protein expressed by the Tregs and/or Bregs with APRIL ligand is conjugated to a cytotoxic agent.

### Claim 9 (depends on 8)

The method of claim 8, wherein the cytotoxic agent is selected from the group consisting of a chemotherapeutic agent, a biologic agent, a toxin, and a radioactive isotope.

### Claim 10 (depends on 1)

The method of claim 1, further comprising:
a) contacting the Tregs and/or Bregs with a STING agonist;
b) contacting the Tregs and/or Bregs with an immune checkpoint inhibitor, wherein the immune checkpoint is selected from the group consisting of CTLA-4, PD-1, VISTA, B7-H2, B7-H3, PD-L1, B7-H4, B7-H6, ICOS, HVEM, PD-L2, CD160, gp49B, PIR-B, KIR family receptors, TIM-1, TIM-3, TIM-4, LAG-3, GITR, 4-IBB, OX-40, BTLA, SIRPalpha (CD47), CD48, 2B4 (CD244), B7.1, B7.2, ILT-2, ILT-4, TIGIT, HHLA2, butyrophilins, IDO, IDO2, and A2aR; and/or
c) contacting the Tregs and/or Bregs in the presence of cancer cells.

### Claim 11 (depends on 10)

The method of claim 10, wherein the antibody that blocks the interaction of TACI receptor protein expressed by the Tregs and/or Bregs with APRIL ligand, either alone or in further combination with A) the STING agonist and/or B) the immune checkpoint inhibitor, contacts the Tregs and/or Bregs in the presence of Tcons and i) does not significantly modulate the number of the Tcons and/or ii) modulates immunomodulatory cytokine production in the Tregs and/or Bregs.

### Claim 12 (depends on 10)

The method of claim 10, wherein the antibody that blocks the interaction of TACI receptor protein expressed by the Tregs and/or Bregs with APRIL ligand, either alone or in further combination with the A) the STING agonist and/or B) the immune checkpoint inhibitor, contacts the Tregs and/or Bregs in the presence of Tcons and cancer cells, and the antibody that blocks the interaction of TACI receptor protein expressed by the Tregs and/or Bregs with APRIL ligand, either alone or in further combination with the immune checkpoint inhibitor, reduces i) the number of proliferating cancer cells and/or ii) reduces the volume or size of a tumor comprising the cancer cells.

### Claim 13 (depends on 10)

The method of claim 10, wherein the Tregs comprise CD4+CD25+, CD4+FOXP3+, CD4+FoxP3+IL10+, CD4+FoxP3highIL10high and/or CD4+CD25highFOXP3+Tregs.

### Claim 14 (depends on 10)

The method of claim 10, wherein the Bregs comprise CD19+CD24highCD38high Bregs.

### Claim 15 (depends on 10)

The method of claim 10, wherein the Tcons comprise CD4+CD25−Tcons.

### Claim 16 (depends on 10)

The method of claim 10, wherein the Tregs and/or Bregs are in the presence of cancer cells, wherein the cancer cells are multiple myeloma cells.

### Claim 17 (depends on 1)

The method of claim 1, wherein
a) the Tregs comprise CD4+CD25+, CD4+FOXP3+, CD4+FoxP3+IL10+, CD4+FoxP3highIL10high and/or CD4+CD25highFOXP3+Tregs;
b) the Bregs comprise CD19+CD24highCD38high Bregs; and
c) the Tcons comprise CD4+CD25−Tcons.

### Claim 18 (depends on 2)

The method of claim 2, wherein
a) the Tregs comprise CD4+CD25+, CD4+FOXP3+, CD4+FoxP3+IL10+, CD4+FoxP3highIL10high and/or CD4+CD25highFOXP3+Tregs;
b) the Bregs comprise CD19+CD24highCD38high Bregs; and
c) the Tcons comprise CD4+CD25−Tcons.

### Claim 19 (depends on 3)

The method of claim 3, wherein
a) the Tregs comprise CD4+CD25+, CD4+FOXP3+, CD4+FoxP3+IL10+, CD4+FoxP3highIL10high and/or CD4+CD25highFOXP3+Tregs;
b) the Bregs comprise CD19+CD24highCD38high Bregs; and
c) the Tcons comprise CD4+CD25−Tcons.

### Claim 20 (depends on 1)

The method of claim 1, wherein the Tregs and/or Bregs are in the presence of cancer cells, wherein the cancer cells are multiple myeloma cells.