# US 2019/0375852 A1 · Combination Of T-Cell Redirecting Multifunctional Antibodies With Immune Checkpoint Modulators And Uses Thereof

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- Number: US 2019/0375852 A1
- Document ID: US20190375852A1
- Status: Published application
- Kind: A1
- Application number: 16/462,710
- Filed: 2017-11-29
- Published: 2019-12-12
- Earliest claimed: 2016-11-29
- Inventors: Horst LINDHOFER; Peter RUF
- Web page: https://patentgrep.com/patent/US20190375852A1

## CPC

- A61K 39/39: characterised by the immunostimulating additives, e.g. chemical adjuvants
- C07K 16/3084: {against tumour-associated gangliosides}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- A61P 37/04: Immunostimulants
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 16/2809: {against the T-cell receptor (TcR)-CD3 complex}
- C07K 16/2818: {against CD28 or CD152}
- C07K 16/30: from tumour cells
- C07K 16/468: {Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies}
- A61K 2039/507: {Comprising a combination of two or more separate antibodies}
- A61K 2039/585: {wherein the target is cancer}
- C07K 2317/31: multispecific
- C07K 2317/52: Constant or Fc region; Isotype
- C07K 2317/72: Increased effector function due to an Fc-modification
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- 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

## Abstract

The present invention provides a combination of (i) an immune checkpoint modulator and (ii) a T-cell redirecting multifunctional antibody, or an antigen binding fragment thereof, for use in therapeutic treatment of a cancer disease. The T-cell redirecting multifunctional antibody comprises (a) a specificity against a T cell surface antigen; (b) a specificity against a cancer- and/or tumor-associated antigen; and (c) a binding site for human FcRI, FcγRIIa and/or FcγRIII, wherein the antibody, or the antigen binding fragment thereof, binds with a higher affinity to human FcγRI, FcγRIIa and/or FcγRIII than to human FcγRIIb.

## Claims

### Claim 1

A combination of
(i) an immune checkpoint modulator and
(ii) a T-cell redirecting multifunctional antibody, or an antigen binding fragment0 thereof, comprising:
(a) a specificity against a T cell surface antigen;
(b) a specificity against a cancer- and/or tumor-associated antigen; and
(c) a binding site for human FcγRI, FcγRIIa and/or FcγRIII, wherein the antibody, or the antigen binding fragment thereof, binds with a higher affinity to human FcγRI, FcγRIIa and/or FcγRIII than to human FcγRIII.

### Claim 2

(canceled)

### Claim 3 (depends on 1)

The combination according to claim 1, wherein the immune checkpoint modulator and the T-cell redirecting multifunctional antibody, or the antigen binding fragment thereof, are directed to distinct targets.

### Claim 4 (depends on 1)

The combination according to claim 1, wherein the T-cell redirecting multifunctional antibody, or the antigen binding fragment thereof, induces increased expression of an immune checkpoint molecule.

### Claim 5 (depends on 1)

The combination according to claim 1, wherein the combination mediates sustained T-cell activation as compared to the T-cell activation induced by (i) the immune checkpoint modulator alone, or (ii) the T-cell redirecting multifunctional antibody, or the antigen binding fragment thereof, alone.

### Claim 6 (depends on 1)

The combination according to claim 1, wherein the T cell surface antigen is selected from the group consisting of CD2, CD3, CD4, CD5, CD6, CD8, CD28, CD40L and CD44.

### Claim at position 7

-9. (canceled)

### Claim 10 (depends on 1)

The combination according to claim 1, wherein the cancer- and/or tumor-associated antigen is not an immune checkpoint molecule and/or a ligand thereof.

### Claim 11 (depends on 1)

The combination according to claim 1, wherein the cancer- and/or tumor-associated antigen is selected from the group consisting of EpCAM, HER2/neu, CEA, MAGE, proteoglycan, VEGF, EGFR, mTOR, PIK3CA, RAS, alpha(v)beta(3)-integrin, HLA, HLA-DR, ASC, carbonic anhydrase, CD1, CD2, CD4, CD6, CD7, CD8, CD11, CD13, CD14, CD19, CD20, CD21, CD22, CD23, CD24, CD30 CD33, CD37, CD38, CD40, CD41, CD47, CD52, CD138, c-erb-2, CALLA, MHCII, CD44v3, CD44v6, p97, GM1, GM2, GM3, GD1a, GD1b, GD2, GD3, GT1b, GT3, GQ1, NY-ESO-1, NFX2, SSX2, SSX4, Trp2, gp100, tyrosinase, MUC-1, telomerase, survivin, p53, CA125, Wue antigen, Lewis Y antigen, HSP-27, HSP-70, HSP-72, HSP-90, Pgp, MCSP, EphA2 and cell surface targets GC182, GT468 or GT512.

### Claim at position 10

-16. (canceled)

### Claim 17 (depends on 1)

The combination according to claim 1, wherein the antibody, or the antigen binding fragment thereof, comprises an Fc moiety.

### Claim at position 12

-19. (canceled)

### Claim 20 (depends on 1)

The combination according to claim 1, wherein the antibody, or the antigen binding fragment thereof, comprises a mouse IgG2a/rat IgG2b Fc region.

### Claim at position 14

-27. (canceled)

### Claim 28 (depends on 1)

The combination according to claim 1, wherein the antibody, or the antigen binding fragment thereof, is selected from the group consisting of catumaxomab, lymphomun, ertumaxomab, ektomab, preferably the antibody is catumaxomab and/or ektomab.

### Claim 29 (depends on 1)

The combination according to claim 1, wherein the immune checkpoint modulator is an activator or an inhibitor of one or more immune checkpoint point molecule(s) selected from CD27, CD28, CD40, CD122, CD137, OX40, GITR, ICOS, A2AR, B7-H3, B7-H4, BTLA, CD40, CTLA-4, IDO, KIR, LAG3, PD-1, PD-L1, PD-L2, TIM-3, VISTA, CEACAM1, GARP, PS, CSF1R, CD94/NKG2A, TDO, GITR, TNFR and/or FasR/DcR3; or an activator or an inhibitor of one or more ligands thereof.

### Claim at position 17

-34. (canceled)

### Claim 35 (depends on 1)

The combination according to claim 1, wherein more than one immune checkpoint modulator is used, in particular at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 distinct immune checkpoint modulators are used, preferably 2, 3, 4 or 5 distinct immune checkpoint modulators are used, more preferably 2, 3 or 4 distinct immune checkpoint modulators are used, even more preferably 2 or 3 distinct immune checkpoint modulators are used and most preferably 2 distinct immune checkpoint modulators are used.

### Claim at position 19

-53. (canceled)

### Claim 54 (depends on 1)

The combination according to claim 1, further comprising
(iii) a glucocorticoid.

### Claim at position 21

-58. (canceled)

### Claim 59

A kit comprising
(i) an immune checkpoint modulator and
(ii) a T-cell redirecting multifunctional antibody, or an antigen binding fragment thereof, comprising:
(a) a specificity against a T cell surface antigen;
(b) a specificity against a cancer- and/or tumor-associated antigen; and
(c) a binding site for human FcγRI, FcγRIIa and/or FcγRIII, wherein the antibody, or the antigen binding fragment thereof, binds with a higher affinity to human FcγRI, FcγRIIa and/or FcγRIII than to human FcγRIIb;
for use in therapeutic treatment of a cancer disease, in particular in a human subject.

### Claim at position 23

-66. (canceled)

### Claim 67

A composition comprising
(i) an immune checkpoint modulator and
(ii) a T-cell redirecting multifunctional antibody, or an antigen binding fragment thereof, comprising:
(a) a specificity against a T cell surface antigen;
(b) a specificity against a cancer- and/or tumor-associated antigen; and
(c) a binding site for human FcγRI, FcγRIIa and/or FcγRIII, wherein the antibody, or the antigen binding fragment thereof, binds with a higher affinity to human FcγRI, FcγRIIa and/or FcγRIII than to human FcγRIIb.

### Claim at position 25

-73. (canceled)

### Claim 74

A method for therapeutically treating cancer or initiating, enhancing or prolonging an anti-tumor-response in a subject in need thereof comprising administering to the subject
(i) an immune checkpoint modulator and
(ii) a T-cell redirecting multifunctional antibody, or an antigen binding fragment thereof, comprising:
(a) a specificity against a T cell surface antigen;
(b) a specificity against a cancer- and/or tumor-associated antigen; and
(c) a binding site for human FcγRI, FcγRIIa and/or FcγRIII, wherein the antibody, or the antigen binding fragment thereof, binds with a higher affinity to human FcγRI, FcγRIIa and/or FcγRIII than to human FcγRIIb.

### Claim at position 27

-80. (canceled)

### Claim 81

A method of prolonging T-cell activation in a subject comprising administering to a subject a combination of:
(i) an immune checkpoint modulator and
(ii) a T-cell redirecting multifunctional antibody, or an antigen binding fragment thereof, comprising:
(a) a specificity against a T cell surface antigen;
(b) a specificity against a cancer- and/or tumor-associated antigen; and
(c) a binding site for human FcγRI, FcγRIIa and/or FcγRIII, wherein the antibody, or the antigen binding fragment thereof, binds with a higher affinity to human FcγRI, FcγRIIa and/or FcγRIII than to human FcγRIIb.

### Claim 82

A combination therapy for therapeutically treating cancer, wherein the combination therapy comprises administration of
(i) an immune checkpoint modulator and
(ii) a T-cell redirecting multifunctional antibody, or an antigen binding fragment thereof, comprising:
(a) a specificity against a T cell surface antigen;
(b) a specificity against a cancer- and/or tumor-associated antigen; and
(c) a binding site for human FcγRI, FcγRIIa and/or FcγRIII, wherein the antibody, or the antigen binding fragment thereof, binds with a higher affinity to human FcγRI, FcγRIIa and/or FcγRIII than to human FcγRIIb.

### Claim at position 30

-88. (canceled)

### Claim 89 (depends on 74)

The method of claim 74, wherein the immune checkpoint modulator is administered after the T-cell redirecting multifunctional antibody, or the antigen-binding fragment thereof.

### Claim 90 (depends on 74)

The method of claim 74, wherein the immune checkpoint modulator is administered at least 6 hours after the T-cell redirecting multifunctional antibody, or the antigen-binding fragment thereof.

### Claim 91 (depends on 74)

The method of claim 74, wherein the immune checkpoint modulator is administered no more than 96 hours after the T-cell redirecting multifunctional antibody, or the antigen-binding fragment thereof.

### Claim 92 (depends on 74)

The method of claim 74, wherein (i) the first administration of the immune checkpoint modulator is applied 12-96 hours after the final administration of the T-cell redirecting multifunctional antibody, or the antigen-binding fragment thereof.

### Claim 93 (depends on 74)

The method of claim 74, wherein the T-cell redirecting multifunctional antibody, or the antigen binding fragment thereof, is administered according to an escalating dosage regimen.