# US 10,870,702 B2 · Methods of assessing and treating cancer in subjects having dysregulated lymphatic systems

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- Number: US 10,870,702 B2
- Document ID: US10870702B2
- Status: Granted
- Kind: B2
- Application number: 16/155,726
- Filed: 2018-10-09
- Published: 2019-02-07
- Granted: 2020-12-22
- Earliest claimed: 2016-09-26
- Assignees: Ensemlble Group Holdings
- Applicants: Ensemble Group Holdings
- Inventors: Michael David Kuo; Ching-Yu Huang
- Web page: https://patentgrep.com/patent/US10870702B2

## CPC

- C07K 16/2818: {against CD28 or CD152}
- A61B 5/418: {lymph vessels, ducts or nodes}
- A61B 6/032: {Transmission computed tomography [CT]}
- A61B 6/037: {Emission tomography}
- A61K 31/4375: the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
- A61P 35/00: Antineoplastic agents
- C07K 16/22: against growth factors {; against growth regulators}
- A61K 2039/505: {comprising antibodies}
- A61K 2039/507: {Comprising a combination of two or more separate antibodies}
- A61K 2039/545: {characterised by the dose, timing or administration schedule}
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- 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)
- A61B: DIAGNOSIS; SURGERY; IDENTIFICATION (usefulness limited to only animals A61D)
- 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

## Abstract

Provided herein is a method for determining cancer treatment using an immune modulating therapy in a subject in need thereof. The method comprises assessing whether a lymphatic system in a subject is dysregulated. When the lymphatic system is dysregulated, a treatment for the lymphatic system is determined before a therapeutic amount of an immune modulating therapy is administered to treat cancer in the subject. Alternatively, when the lymphatic system is dysregulated, an immune modulating therapy is selected to treat cancer in the subject, which immune modulating therapy is independent of immune-cell priming, antigen trafficking, antigen presentation, and any combination thereof. The subject may also be treated for cancer accordingly.

## Claims

### Claim 1

A method to treat cancer in a subject in need of inhibition of lymphangiogenesis, comprising:
a. assessing whether the lymphatic system in the subject is dysregulated;
b. administering to the subject a therapeutically effective amount of a first monoclonal antibody chosen from pembrolizumab, nivolumab, or a combination thereof, thereby inducing an immune modifying effect in the subject; and
c. further administering to the subject a therapeutically effective amount of a second monoclonal antibody, before or concurrent with the administration of the first monoclonal antibody, wherein the second monoclonal antibody binds to the extracellular domain of VEGFR-3, and wherein the second monoclonal antibody inhibits the lymphangiogenesis in the subject.

### Claim 2

A method to treat cancer in a subject in need of inhibition of lymphangiogenesis, comprising:
a. selecting a subject with a condition of a dysregulated lymphatic system comprising lymphangiogenesis;
b. administering to the subject a therapeutically effective amount of a first monoclonal antibody chosen from pembrolizumab, nivolumab, or a combination thereof, thereby inducing an immune modifying effect in the subject; and
c. further administering to the subject a therapeutically effective amount of a second monoclonal antibody, before or concurrent with the administration of the first monoclonal antibody, wherein the second monoclonal antibody binds to the extracellular domain of VEGFR-3, and wherein the second monoclonal antibody inhibits the lymphangiogenesis in the subject.

### Claim 3 (depends on 2)

The method of claim 2, wherein the second monoclonal antibody is a chimeric or humanized antibody.

### Claim 4 (depends on 2)

The method of claim 2, wherein the second monoclonal antibody is administered before the first therapeutic antibody.

### Claim 5 (depends on 2)

The method of claim 2, wherein the second therapeutic antibody is administered concurrently with the first therapeutic antibody.

### Claim 6 (depends on 2)

The method of claim 2, wherein the dysregulated lymphatic system is further characterized by one or more conditions chosen from abnormal lymphatic development, lymphatic proliferation, lymphangiogenesis, impaired lymphatic vessel function, dysregulated lymphatic vessel function, augmented tumor cell lymphatic infiltration, lymphangitic carcinomatosis, abnormal functioning or homeostatic regulation, lymphatic remodeling, physical pressure upon lymphatics, altered tumoral lymphatic development, altered tumoral lymphangiogenesis, and output blockage of lymphatic structures in lymphatic organs.

### Claim 7 (depends on 2)

The method of claim 2, wherein the cancer is chosen form lung cancer, breast cancer, a cancer of the gastrointestinal tract, a cancer of unknown origin, head and neck cancer, bladder cancer, prostate cancer, skin cancer, kidney cancer, a primary brain tumor, ocular tumor, sarcoma, a cancer of primary soft tissue, mesenchymal cancer, bone cancer, a tumor of the lymphatic system, and leukemia.

### Claim 8 (depends on 7)

The method of claim 7, wherein the cancer is lung cancer, and the method further comprises administering one or more drugs chosen from afatinib dimaleate, alectinib, bevacizumab, carboplatin, ceritinib, crizotinib, docetaxel, doxorubicin, erlotinib, etoposide, everolimus, gefitinib, gemcitabine, mechlorethamine, methotrexate, necitumumab, nivolumab, osimertinib, paclitaxel, paclitaxel albumin-stabilized nanoparticles, pembrolizumab, pemetrexed, ramucirumab, topotecan, vinorelbine, pharmaceutically acceptable salts thereof, and combinations thereof.