TNFRSF-BINDING AGENTS AND USES THEREOF

• US 20160256527A1
• Filed: 02/03/2016
• Published: 09/08/2016
• Est. Priority Date: 02/03/2015
• Status: Active Grant

• Current Assignee: OncoMed Pharmaceuticals, Incorporated (Mereo BioPharma Group Plc)
• Original Assignee: OncoMed Pharmaceuticals, Incorporated (Mereo BioPharma Group Plc)
• Inventors: GURNEY, Austin L.
• Granted Patent: US 9,724,390 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 38/19 Cytokines; Lymphokines; Interferons
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 14/00 Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
• CPC Class Codes: C07K 14/52 Cytokines; Lymphokines; Interferons
• CPC Class Codes: C07K 14/525 Tumour necrosis factor [TNF]
• CPC Class Codes: C07K 14/7151 for tumor necrosis factor [TNF], for lymphotoxin [LT]
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 2317/31 multispecific
• CPC Class Codes: C07K 2317/55 Fab or Fab'
• CPC Class Codes: C07K 2317/622 Single chain antibody (scFv)
• CPC Class Codes: C07K 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2319/30 Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
• CPC Class Codes: C12N 15/00 Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor mutants or genetically engineered microorganisms, per se C12N1/00, C12N5/00, C12N7/00; new plants per se A01H; plant reproduction by tissue culture techniques A01H4/00; new animals per se A01K67/00; use of medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases, gene therapy A61K48/00
• CPC Class Codes: C12N 15/62 : DNA sequences coding for fusion proteins
• CPC Class Codes: C12Q 1/68 : involving nucleic acids

Abstract

Polypeptides and agents that bind a TNF receptor superfamily protein are disclosed, particularly agents that specifically bind GITR, OX40, or CD40. The polypeptides or agents may include fusion polypeptides, particularly polypeptides comprising GITRL, OX40L, or CD40L and/or bispecific agents. Also disclosed are methods of using the polypeptides or agents for inducing and/or enhancing the immune response, as well as methods for the treatment of diseases such as cancer.

Claims

1-213. -213. (canceled)

214. A polypeptide comprising a first, second, and third copy of the extracellular domain of a human tumor necrosis factor receptor ligand superfamily (TNFSF) protein or a fragment thereof capable of binding a receptor of the TNFSF protein, wherein at least one of the first, second, or third copies of the extracellular domain or a fragment thereof comprises the stalk region of the TNFSF protein.

215. The polypeptide of claim 214, wherein the TNFSF protein is selected from the group consisting of glucocorticoid-induced tumor necrosis factor receptor ligand (GITRL), CD40 ligand (CD40L), OX40 ligand (OX40L), 4-1BB ligand, APRIL, BAFF, CD27 ligand, CD30 ligand, EDA, EDA-A1, EDA-A2, Fas ligand, LIGHT, lymphotoxin, lymphotoxin beta, lymphotoxin-alpha, TL1A, TNF-alpha, TRAIL, TRANCE, and TWEAK.

216. The polypeptide of claim 215, wherein the TNFSF protein is

a) GITRL and the polypeptide comprises SEQ ID NO:

5 or SEQ ID NO;

66;

b) OX40L and the polypeptide comprises SEQ ID NO;

44, SEQ ID NO;

69, SEQ ID NO;

70, SEQ ID NO;

71, or SEQ ID NO;

72;

or

c) CD40L and the polypeptide comprises SEQ ID NO;

85, or SEQ ID NO;

97.

217. The polypeptide of claim 214, wherein the TNFSF protein is

a) GITRL and the stalk region comprises LQLETAK (SEQ ID NO:

32);

b) OX40L and the stalk region is selected from the group consisting of;

QVSHRYP (SEQ ID NO;

55), ALQVSHRYP (SEQ ID NO;

74), SHRYP (SEQ ID NO;

75), and HRYP (SEQ ID NO;

76);

or

c) CD40L and the stalk region is selected from the group consisting of;

MQKGDQ (SEQ ID NO;

98), FEMQKGDQ (SEQ ID NO;

99), EMQKGDQ (SEQ ID NO;

100), QKGDQ (SEQ ID NO;

101), and KGDQ (SEQ ID NO;

102).

218. The polypeptide of claim 216, which further comprises a human Fc region or an immunoglobulin heavy chain.

219. The polypeptide of claim 218, wherein the human Fc region is selected from the group consisting of:

SEQ ID NO;

10, SEQ ID NO;

11, SEQ ID NO;

12, SEQ ID NO;

13, and SEQ ID NO;

14.

220. The polypeptide of claim 218, which comprises SEQ ID NO:

7.

221. The polypeptide of claim 216, wherein the TNFSF protein is GITR and which activates GITR and/or induces GITR activity.

222. The polypeptide of claim 214, which:

(a) increases cell-mediated immunity;

(b) increases T-cell activity;

(c) increases cytolytic T-cell (CTL) activity;

(d) increases natural killer (NK) cell activity;

(e) decreases or inhibits regulatory T-cell (Treg) activity; and

/or

(f) decreases or inhibits myeloid-derived suppressor cell (MDSC) activity.

224. A bispecific agent comprising:

a) the polypeptide of claim 214, and

b) an antigen-binding site from an antibody.

225. The bispecific agent of claim 224, wherein the agent is a homodimer or a heterodimer.

228. A pharmaceutical composition comprising the polypeptide of claim 214 and a pharmaceutically acceptable carrier.

229. A polynucleotide comprising a polynucleotide that encodes the polypeptide of claim 214.

230. An isolated cell comprising or producing the polypeptide of claim 214.

231. A method of treating cancer in a subject, a method of inducing, activating, promoting, increasing, enhancing, or prolonging an immune response in a subject, method of inhibiting the growth of a tumor in a subject, method of increasing T-cell activity in a subject, method of increasing cytolytic T-cell (CTL) activity in a subject, method of increasing natural killer (NK) activity in a subject, method of decreasing or inhibiting regulatory T-cell (Treg) activity in a subject, or a method of decreasing or inhibiting myeloid-derived suppressor cell (MDSC) activity in a subject, comprising administering to a subject a therapeutically effective amount of the polypeptide of claim 214.

232. The method of claim 231, wherein the cancer is selected from the group consisting of colorectal cancer, colon cancer, ovarian cancer, pancreatic cancer, lung cancer, liver cancer, breast cancer, kidney cancer, prostate cancer, gastrointestinal cancer, melanoma, cervical cancer, bladder cancer, glioblastoma, head and neck cancer, lymphoma and leukemia.

233. The method of claim 231, which further comprises administering at least one additional therapeutic agent.

234. The method of claim 233, wherein the additional therapeutic agent is a chemotherapeutic agent or an agent that stimulates the immune response.

235. The method of claim 233, wherein the additional therapeutic agent is an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, or an anti-TIGIT antibody.

223. A polypeptide encoded by the plasmid deposited with ATCC and assigned designation number PTA-122112.

226. A bispecific agent comprising:

a) a first arm comprising a polypeptide comprising a first, second, and third copy of the extracellular domain of a human tumor necrosis factor receptor ligand superfamily (TNFSF) protein or a fragment thereof, and

b) a second arm comprising an antigen-binding site from an antibody.

227. The bispecific agent of claim 226, wherein the TNFSF protein is GITRL, OX40L, or CD40L.

236. A method of decreasing or inhibiting regulatory T-cell (Treg) activity or myeloid-derived suppressor cell (MDSC) activity in a subject, or a method of increasing T-cell activity, cytolytic T-cell (CTL) activity, or natural killer (NK) activity in a subject, comprising administering to the subject a therapeutically effective amount of a polypeptide comprising a first, second, and third copy of the extracellular domain of a human tumor necrosis factor receptor ligand superfamily (TNFSF) protein or a fragment thereof capable of binding a receptor of the TNFSF protein.

237. A method of claim 236, wherein the TNFSF protein is GITRL, OX40L, or CD40L.