# US 10,308,688 B2 · T-cell redirecting bispecific antibodies for treatment of disease

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- Number: US 10,308,688 B2
- Document ID: US10308688B2
- Status: Granted
- Kind: B2
- Application number: 15/064,128
- Filed: 2016-03-08
- Published: 2016-06-23
- Granted: 2019-06-04
- Earliest claimed: 2012-08-14
- Assignees: IBC Pharmaceuticals, Inc.
- Applicants: IBC Pharmaceuticals, Inc.
- Inventors: Chien-Hsing Chang; David M. Goldenberg; Edmund A. Rossi; Diane Rossi
- Web page: https://patentgrep.com/patent/US10308688B2

## CPC

- C07K 14/001: {by chemical synthesis}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 38/1709: {from mammals}
- A61K 38/195: {Chemokines, e.g. RANTES}
- A61K 38/21: Interferons {[IFN]}
- A61K 38/212: {IFN-alpha}
- A61K 38/215: {IFN-beta}
- A61K 38/217: {IFN-gamma}
- A61K 38/45: Transferases (2)
- A61K 39/395: Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/42: Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein (oligopeptides having up to five amino acids {A61K47/183}; polyamino acids A61K47/34)
- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- A61K 47/64: Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65)
- A61P 35/00: Antineoplastic agents
- C07K 14/4702: {Regulators; Modulating activity}
- C07K 16/18: against material from animals or humans
- C07K 16/2803: {against the immunoglobulin superfamily}
- C07K 16/2806: {against CD2}
- C07K 16/2809: {against the T-cell receptor (TcR)-CD3 complex}
- C07K 16/2812: {against CD4}
- C07K 16/2815: {against CD8}
- C07K 16/2818: {against CD28 or CD152}
- C07K 16/2827: {against B7 molecules, e.g. CD80, CD86}
- C07K 16/283: {against Fc-receptors, e.g. CD16, CD32, CD64 (CD23 C07K16/2851)}
- C07K 16/2833: {against MHC-molecules, e.g. HLA-molecules}
- C07K 16/2842: {against integrin beta1-subunit-containing molecules, e.g. CD29, CD49}
- C07K 16/2845: {against integrin beta2-subunit-containing molecules, e.g. CD11, CD18}
- C07K 16/2851: {against the lectin superfamily, e.g. CD23, CD72}
- C07K 16/2863: {against receptors for growth factors, growth regulators}
- C07K 16/2866: {against receptors for cytokines, lymphokines, interferons}
- C07K 16/2875: {against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154 (against NGF C07K16/22, against TNF C07K16/241)}
- C07K 16/2878: {against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95}
- C07K 16/2884: {against CD44}
- C07K 16/2887: {against CD20}
- C07K 16/289: {against CD45}
- C07K 16/2893: {against CD52}
- C07K 16/2896: {against molecules with a "CD"-designation, not provided for elsewhere}
- C07K 16/30: from tumour cells
- C07K 16/3007: {Carcino-embryonic Antigens}
- C07K 16/3053: {Skin, nerves, brain}
- C07K 16/3076: {against structure-related tumour-associated moieties}
- C07K 16/3092: {against tumour-associated mucins}
- C07K 16/32: against translation products of oncogenes
- C07K 16/40: against enzymes
- C07K 16/44: against material not provided for elsewhere {, e.g. haptens, metals, DNA, RNA, amino acids}
- C07K 16/468: {Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies}
- C12N 9/12: transferring phosphorus containing groups, e.g. kinases (2.7)
- C12Y 207/11011: cAMP-dependent protein kinase (2.7.11.11)
- 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 2039/572: {cytotoxic response}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/31: multispecific
- C07K 2317/35: Valency
- C07K 2317/53: Hinge
- C07K 2317/54: F(ab')2
- C07K 2317/55: Fab or Fab'
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/622: Single chain antibody (scFv)
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2317/732: Antibody-dependent cellular cytotoxicity [ADCC]
- 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 2317/94: Stability, e.g. half-life, pH, temperature or enzyme-resistance
- C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
- C07K 2319/33: fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
- C07K 2319/40: containing a tag for immunodetection, or an epitope for immunisation
- C07K 2319/735: containing a domain for self-assembly, e.g. a viral coat protein (includes phage display)
- C07K 2319/74: containing a fusion for binding to a cell surface receptor
- C07K 2319/75: containing a fusion for activation of a cell surface receptor, e.g. thrombopoeitin, NPY and other peptide hormones
- C12Y 207/11001: Non-specific serine/threonine protein kinase (2.7.11.1), i.e. casein kinase or checkpoint kinase
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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)
- C12Y: ENZYMES
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The present invention concerns compositions and methods of use of T-cell redirecting complexes, with at least one binding site for a T-cell antigen and at least one binding site for an antigen on a diseased cell or pathogen. Preferably, the complex is a DNL™ complex. More preferably, the complex comprises a bispecific antibody (bsAb). Most preferably, the bsAb is an anti-CD3×anti-CD19 bispecific antibody, although antibodies against other T-cell antigens and/or disease-associated antigens may be used. The complex is capable of targeting effector T cells to induce T-cell-mediated cytotoxicity of cells associated with a disease, such as cancer, autoimmune disease or infectious disease. The cytotoxic immune response is enhanced by co-administration of interferon-based agents that comprise interferon-α, interferon-β, interferon-λ1, interferon-λ2 or interferon-λ3.

## Claims

### Claim 1

A method of inducing a T-cell mediated immune response against a Trop-2 positive human cancer cell comprising administering a T-cell redirecting complex, comprising a bispecific antibody with one first antibody fragment that binds to human CD3 and at least one second antibody fragment that binds to human Trop-2, to a human subject to induce a T-cell mediated immune response against the Trop-2 positive cancer cell, wherein the first antibody fragment is a fragment of the Okt3 antibody and the second antibody fragment is a fragment of the hRS7 antibody.

### Claim 2 (depends on 1)

The method of claim 1, further comprising administering interferon-a to the subject.

### Claim 3 (depends on 2)

The method of claim 2, wherein the interferon-a increases the efficacy of the T-cell redirecting complex.

### Claim 4 (depends on 3)

The method of claim 3, wherein the combination of interferon-a and T-cell redirecting complex is more effective than interferon-a alone and T-cell redirecting complex alone.

### Claim 5 (depends on 2)

The method of claim 2, wherein the interferon-a is administered before, simultaneously with, or after the T-cell redirecting complex.

### Claim 6 (depends on 2)

The method of claim 2, wherein the interferon-a is administered as free interferon, PEGylated interferon, an interferon fusion protein or interferon conjugated to an antibody.

### Claim 7 (depends on 1)

The method of claim 1, wherein the T-cell redirecting complex is administered intravenously.

### Claim 8 (depends on 1)

The method of claim 1, wherein the T-cell redirecting complex is administered subcutaneously.

### Claim 9 (depends on 1)

The method of claim 1, wherein administration of the T-cell redirecting complex to the subject induces an effector T-cell mediated immune response against Trop-2 positive cancer cells.

### Claim 10 (depends on 1)

The method of claim 1, wherein the complex ligates T cells to Trop-2 positive cancer cells and activates the T cells to kill the cancer cells.

### Claim 11 (depends on 1)

The method of claim 1, wherein the antibody fragment is selected from the group consisting of F(ab′)2, F(ab)2, F(ab′), F(ab) and scFv antibody fragments.