# US 2019/0169621 A1 · Targeted/immunomodulatory fusion proteins in combination with additional therapeutic agents and methods for making same

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- Number: US 2019/0169621 A1
- Document ID: US20190169621A1
- Status: Published application
- Kind: A1
- Application number: 16/263,157
- Filed: 2019-01-31
- Published: 2019-06-06
- Earliest claimed: 2012-04-30
- Assignees: Biocon Limited
- Applicants: Biocon Limited
- Inventors: NAGARAJ GOVINDAPPA; SREESHA P. SRINIVASA; USHA BUGHANI; RESHMI NAIR
- Web page: https://patentgrep.com/patent/US20190169621A1

## CPC

- C12N 15/62: DNA sequences coding for fusion proteins
- A61K 38/10: Peptides having 12 to 20 amino acids {(A61K38/043 - A61K38/046 take precedence)}
- A61K 38/179: {for growth factors; for growth regulators}
- 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 48/005: {characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered}
- A61P 35/00: Antineoplastic agents
- A61P 37/04: Immunostimulants
- C07K 7/08: having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68)
- C07K 14/00: Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K 14/495: Transforming growth factor [TGF]
- C07K 14/65: Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2
- C07K 14/70532: {B7 molecules, e.g. CD80, CD86}
- C07K 14/70596: {Molecules with a "CD"-designation not provided for elsewhere}
- C07K 14/71: for growth factors; for growth regulators
- C07K 16/2818: {against CD28 or CD152}
- C07K 16/2863: {against receptors for growth factors, growth regulators}
- C07K 16/2866: {against receptors for cytokines, lymphokines, interferons}
- C07K 16/2878: {against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95}
- C07K 16/2887: {against CD20}
- C07K 16/30: from tumour cells
- C07K 16/32: against translation products of oncogenes
- C12N 5/0018: {Culture media for cell or tissue culture (media for specific animal cell type C12N5/06)}
- G01N 33/6854: {Immunoglobulins}
- 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 2121/00: Preparations for use in therapy
- C07K 2317/14: Specific host cells or culture conditions, e.g. components, pH or temperature
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/31: multispecific
- C07K 2317/51: Complete heavy chain or Fd fragment, i.e. VH + CH1
- C07K 2317/515: Complete light chain, i.e. VL + CL
- C07K 2317/732: Antibody-dependent cellular cytotoxicity [ADCC]
- C07K 2319/00: Fusion polypeptide
- C07K 2319/02: containing a signal sequence
- C07K 2319/33: fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
- C12N 2500/22: Zinc; Zn chelators
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- 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
- 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)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

The present invention provides for a composition and a method for treating a subject afflicted with a cancer, wherein the composition comprises therapeutically effective amounts of: (a) an anti-Programmed Death-Ligand 1 (PD-L1) antibody and (b) a targeted/immunomodulatory fusion protein comprising at least one tumor targeting moiety and at least one immunomodulatory moiety that counteracts the immune tolerance of cancer cells.

## Claims

### Claim 1

A composition combining multiple cancer therapeutic agents, the composition comprising an anti-PD-L1 antibody and a chimeric targeted/immunomodulatory fusion polypeptide comprising at least one tumor targeting moiety to target a cancer cell and at least one immunomodulating moiety that counteracts immune tolerance of cancer cell.

### Claim 2 (depends on 1)

The composition according to claim 1, wherein the tumor targeting moiety and the immunomodulating moiety are linked by an amino acid spacer of sufficient length of amino acid residues so that both moieties can successfully bond to their individual target.

### Claim 3 (depends on 1)

The composition according to claim 1, wherein the immunomodulatory moiety specifically binds to Transforming growth factor-beta (TGF-β) and the tumor targeting moiety binds a component of a tumor cell.

### Claim 4 (depends on 3)

The composition according to claim 3, wherein the tumor targeting moiety is an antibody that binds to EGFR1, where in the antibody can be the full antibody, heavy chain or light chain.

### Claim 5 (depends on 1)

The composition according to claim 1, wherein the immunomodulating moiety is bound to either the C-terminus of the heavy or light chain of the tumor targeting antibody.

### Claim 6 (depends on 1)

The composition according to claim 1, wherein the immunomodulatory moiety is an extracellular ligand-binding domain of Transforming growth factor-beta receptor TGF-βRII, TGF-βRIIb, or TGF-βRIII.

### Claim 7 (depends on 1)

The composition of claim 1, wherein the immunomodulatory moiety is an extracellular ligand-binding domain (ECD) of TGF-βRII.

### Claim 8 (depends on 1)

The composition of claim 1 wherein a chimeric targeted/immunomodulatory fusion polypeptide consists of SEQ ID NO: 1 and 9.

### Claim 9

A method for immunotherapy of a subject afflicted with cancer, which method comprises administering to the subject a composition comprising a therapeutically effective amount of an anti-PD-L1 antibody and a chimeric targeted/immunomodulatory fusion polypeptide comprising an immunomodulatory moiety that binds transforming growth factor beta (TGF-β) and a tumor targeting moiety that binds to EGFR1.

### Claim 10 (depends on 9)

The method according to claim 9, wherein the cancer is characterized by overexpression of PD-L1 and/or EGFR1.

### Claim 11 (depends on 10)

The method according to claim 10, wherein the anti-PD-L1 antibody and a chimeric targeted/immunomodulatory fusion polypeptide are administered sequentially in either order or simultaneously.

### Claim 12 (depends on 9)

The method according to claim 9, wherein the immunomodulating moiety is bound to either the C-terminus of the heavy or light chain of the tumor targeting antibody.

### Claim 13 (depends on 9)

The method according to claim 9, wherein the immunomodulatory moiety is an extracellular ligand-binding domain of Transforming growth factor-beta receptor TGF-βRII, TGF-βRIIb, or TGF-βRIII.

### Claim 14 (depends on 9)

The method according to claim 9, wherein the immunomodulatory moiety is an extracellular ligand-binding domain (ECD) of TGF-βRII.

### Claim 15 (depends on 9)

The method according to claim 9, wherein a chimeric targeted/immunomodulatory fusion polypeptide consists of SEQ ID NO: 1 and 9.

### Claim 16 (depends on 15)

The method according to claim 15, wherein the chimeric targeted/immunomodulatory fusion polypeptide is encoded by SEQ ID NOs: 5 to 8.

### Claim 17

A kit for treating cancer comprising a combination of an anti-PD-L1 antibody and a chimeric polypeptide comprising an immunomodulatory moiety that binds to and traps transforming growth factor beta (TGF-β) and a tumor targeting moiety that is an antibody that binds to EGFR1.

### Claim 18

A method for increasing IFNγ release and TGF-β1 trapping in cancer cells, the method comprising introducing to the cancer cells a combination of a therapeutically effective amount of an anti-PD-L1 antibody and a chimeric targeted/immunomodulatory fusion polypeptide comprising an immunomodulatory moiety that binds transforming growth factor beta (TGF-β) and a tumor targeting moiety that binds to EGFR1.

### Claim 19 (depends on 18)

The method according to claim 18, wherein the anti-PD-L1 antibody and a chimeric targeted/immunomodulatory fusion polypeptide are introduced sequentially in either order or simultaneously.

### Claim 20 (depends on 18)

The method according to claim 18, wherein the immunomodulating moiety is bound to the C-terminus of the light chain of the tumor targeting antibody.

### Claim 21 (depends on 18)

The method according to claim 18, wherein the immunomodulatory moiety is an extracellular ligand-binding domain (ECD) of TGF-βRII.

### Claim 22 (depends on 18)

The method according to claim 18, wherein a chimeric targeted/immunomodulatory fusion polypeptide consists of SEQ ID NO: 1 and 9.