Methods of tumour therapy with a combination medicament comprising il-12 and an agent for blockade of t-cell inhibitory molecules

Patent metadata

Field	Value
Publication number	US-2019201493-A1
Application number	US-201916357756-A
Country	US
Kind code	A1
Filing date	Mar 19, 2019
Priority date	Oct 11, 2011
Publication date	Jul 4, 2019
Grant date	—

Abstract

The invention relates to a combination medicament for treatment of malignant neoplastic disease. The combination medicament comprises an IL-12 polypeptide having a biological activity of IL-12 or a nucleic acid expression vector comprising a sequence encoding such IL-12 polypeptide, and a non-agonist blockade of T-cell inhibitory molecules, including non -agonist LAG-3 ligand, non-agonist TIM-3 ligand, non-agonist BLTA ligand, non-agonist TIGIT ligand, non-agonist VISTA ligand, non-agonist B7/H3 ligand, non-agonist CTLA-4 ligand or non-agonist PD-1 ligand, particularly an anti-CTLA-4 or anti-PD-1 immunoglobulin G.

First claim

We Claim:

1 . A method of treating a patient suffering from a malignant primary tumor selected from the group consisting of glioma and glioblastoma multiforme, the method comprising
a. the administration into a malignant primary tumor, into the vicinity of a malignant primary tumor, or to the lymph node associated with a malignant primary tumor, an effective amount of
aa. a recombinant IL-12 polypeptide or
bb. a polypeptide comprising
i. a polypeptide sequence at least 95% identical to the sequence of human p35 (SEQ ID NO:5), and
ii. a polypeptide sequence at least 95% identical to the sequence of human p40 (SEQ ID NO:6) and
iii. a human immunoglobulin G crystallisable fragment

and b. the systemic administration of an effective amount of a non-agonist CTLA-4 antibody,
thereby treating the malignant primary tumor.

2 . The method of claim 1 , wherein the recombinant IL-12 polypeptide comprises a human immunoglobulin G subgroup 4 crystallisable fragment.

3 . The method of claim 1 , wherein the recombinant IL-12 polypeptide comprises:
a. an immunoglobulin G crystallisable fragment and a recombinant or synthetic human IL-12 sequence, or b. a sequence at least 95% identical to SEQ ID NO:1.

4 . The method of claim 1 , wherein the non-agonist CTLA-4 antibody is a gamma immunoglobulin that binds to CTLA-4.

5 . The method of claim 1 , wherein the recombinant IL-12 polypeptide is provided as a dosage form for intratumoural injection.

6 . The method of claim 1 , wherein the non-agonist CTLA-4 antibody is provided as a dosage form for intravenous injection.

7 . The method of claim 1 , wherein the recombinant IL-12 polypeptide is a fusion protein comprising the human p40 p35 subunits and the crystallisable fragment of human 1gG4,
said recombinant IL-12 polypeptide is provided as a dosage form for intratumoural delivery, and wherein said non-agonist CTLA-4 antibody is an immunoglobulin G provided as a dosage form for systemic delivery.

8 . The method of claim 1 , wherein the malignant primary tumor is glioblastoma multiforme.

9 . The method of claim 1 , wherein the method of treatment is a method of inhibiting growth of the malignant primary tumor.

10 . The method of claim 1 , wherein the method of treatment is a method of reducing the size of the malignant primary tumor.

11 . The method of claim 1 , wherein the CTLA-4 antibody is ipilimumab or tremelimumab.

12 . A method of treating a patient suffering from a malignant primary tumor selected from the group consisting of glioma and glioblastoma multiforme, the method comprising
a. the administration into a malignant primary tumor, into the vicinity of a malignant primary tumor, or to the lymph node associated with a malignant primary tumor, an effective amount of
aa. a recombinant IL-12 polypeptide or
bb. a polypeptide comprising
i. a polypeptide sequence at least 95% identical to the sequence of human p35 (SEQ ID NO:5), and
ii. a polypeptide sequence at least 95% identical to the sequence of human p40 (SEQ ID NO:6) and
iii. a human immunoglobulin G crystallisable fragment

and b. the systemic administration of an effective amount of a non-agonist LAG-3 ligand, non-agonist TIM-3 ligand, non-agonist BLTA ligand, non-agonist TIGIT ligand, non-agonist VISTA ligand, non-agonist B7/H3 ligand, non-agonist CTLA-4 ligand or non -agonist PD-1 ligand,
thereby treating the malignant primary tumor.

13 . The method of claim 12 , wherein the non-agonist LAG-3 ligand, non-agonist TIM-3 ligand, non-agonist BLTA ligand, non-agonist TIGIT ligand, non-agonist VISTA ligand, non-agonist B7/H3 ligand, non-agonist CTLA-4 ligand or non-agonist PD-1 ligand is a non -agonist antibody.

14 . A method of treating a patient suffering from a malignant primary tumor selected from the group consisting of glioma, glioblastoma multiforme, meningioma, melanoma, pancreatic cancer, breast cancer, lung cancer, prostate cancer and bladder cancer, the method comprising
a. the administration into a malignant primary tumor, into the vicinity of a malignant primary tumor, or to the lymph node associated with a malignant primary tumor, an effective amount of
aa. a recombinant IL-12 polypeptide or
bb. a polypeptide comprising
i. a polypeptide sequence at least 95% identical to the sequence of human p35 (SEQ ID NO:5), and
ii. a polypeptide sequence at least 95% identical to the sequence of human p40 (SEQ ID NO:6) and
iii. a human immunoglobulin G crystallisable fragment

and b. the systemic administration of an effective amount of a non-agonist LAG-3 ligand, non-agonist TIM-3 ligand, non-agonist BLTA ligand, non-agonist TIGIT ligand, non-agonist VISTA ligand, non-agonist B7/H3 ligand, non-agonist CTLA-4 ligand or non -agonist PD-1 ligand,
thereby treating the malignant primary tumor.

Assignees

• Univ Zuerich

Inventors

• Becher Burkhard
• Vom Berg Johannes

Classifications

• A61K9/0019

  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) · CPC title

• C07K16/2818

  against CD28 or CD152 · CPC title

• A61K39/3955

  against proteinaceous materials, e.g. enzymes, hormones, lymphokines · CPC title

• C07K2317/21

  from primates, e.g. man · CPC title

• A61K39/39516

  from serum, plasma · CPC title