Conjugates for immunotherapy

Patent metadata

Field	Value
Publication number	US-2017202902-A1
Application number	US-201515321316-A
Country	US
Kind code	A1
Filing date	Jun 26, 2015
Priority date	Jun 27, 2014
Publication date	Jul 20, 2017
Grant date	—

Abstract

The current invention pertains to a molecular conjugate comprising an antagonist of a cell surface receptor specific to a target cell and an immune effector, such as a T cell modulator, conjugated to the antagonist. The target cell can be a cell responsible for development of a disease in a subject, for example, a cancer cell. In certain embodiments, the immune effector is an immune effector protein or an immune effector fragment thereof. The current invention also pertains to a method of treating a disease in a subject, the method comprising administering to the subject a pharmaceutically effective amount of the molecular conjugates of the current invention to the subject. The methods of the current invention can be used to treat cancer, such as breast cancer, ovarian cancer, prostate cancer, lung cancer, pancreatic cancer, or melanoma.

First claim

1 . A molecular conjugate comprising:
a) an antagonist of a cell surface receptor specific to a target cell; and b) an immune effector conjugated to the antagonist.

2 . The molecular conjugate of claim 1 , wherein the target cell is a cancer cell.

3 . The molecular conjugate of claim 1 , wherein the immune effector is a T cell modulator.

4 . The molecular conjugate of claim 1 , wherein two or more antagonist molecules are conjugated to the immune effector molecule.

5 . The molecular conjugate of claim 4 , wherein the two or more antagonist molecules are a single type of antagonist molecule.

6 . The molecular conjugate of claim 4 , wherein the two or more antagonist molecules are two or more different types of antagonist molecules.

7 . The molecular conjugate of claim 1 , wherein two or more immune effector molecules are conjugated to the antagonist molecule.

8 . The molecular conjugate of claim 7 , wherein the two or more immune effector molecules are a single type of immune effector molecule.

9 . The molecular conjugate of claim 7 , wherein the two or more immune effector molecules are two or more different types of effector molecules.

10 . The molecular conjugate of claim 1 , wherein the immune effector is one or more molecules selected from CD86, 41BBL, OX40, IL-15, Anti-Programmed Death-1 (PD1), anti-B7-Hl, IL-12, Anti-CD40, CD40 ligand, IL-7, Anti-CD137 (anti-4-1BB), Anti-TGF-beta, Anti-IL-10 Receptor or Anti-IL-10, FMS-like Tyrosine Kinase 3 Ligand (Flt3L), Anti-Glucocorticoid-Induced TNF Receptor (GITR), chemokine (C-C motif) ligand 21 (CCL21), Anti-OX40, Anti-B7-H4, Anti-Lymphocyte Activation Gene-3 (LAG-3), CD258 (also referred to as LIGHT or TNFSF14), delta opioid receptor (DOR), or Anti-CTLA4 or an immune effector fragment of any of the foregoing.

11 . The molecular conjugate of claim 2 , wherein the cell surface receptor is selected from luteinizing hormone release hormone (LHRH) receptor, delta opioid receptor (DOR), melanocortin 1 receptor (MCR1), cell surface associated mucin 1 (MUC1), latent membrane protein 2 (LMP2), epidermal growth factor receptor variant III (EGFRvIII), human epidermal growth factor receptor 2 (HER-2/neu), prostate specific membrane antigen (PSMA), ganglioside antigen 2 (GD2), melanoma antigen recognized by T-cells 1 (MelanA/MART1), Ras mutant, glycoprotein 100, Proteinase3 (PR1), bcr-abl, tyrosinase, Androgen receptor, RhoC, transient receptor potential channel 2(TRP-2), prostate stem cell antigen (PSCA), leukocyte specific protein tyrosine kinase (LCK), high molecular weight melanoma-associated antigen (HMWMAA), A-kinase anchor protein 4 (AKAP-4), Angiopoietin-1 receptor (Tie 2), vascular endothelial growth factor receptor 2 (VEGFR2), fibroblast activation protein (FAP), platelet derived growth factor receptor b (PDGFR-b), parathyroid hormone related protein, leuteinizing hormone related protein, alpha(V)Beta(3)Integrin, six transmembrane antigen of the prostate (STEAP), mesothelin, endoglin, KCNK9, or guanylyl cyclase C (GC-C).

12 . (canceled)

13 . The molecular conjugate of claim 1 , wherein the cell surface receptor is luteinizing hormone release hormone (LHRH) receptor, delta opioid receptor (DOR), or melanocortin 1 receptor (MCR1).

14 . The molecular conjugate of claim 13 , wherein the antagonist is a gonadotropin-releasing hormone antagonist (GnRH antagonist) or a delta opioid receptor (DOR) antagonist.

15 . (canceled)

16 . The molecular conjugate of claim 1 , wherein the antagonist is a luteinizing hormone releasing hormone (LHRH) antagonist, and the immune effector is:
(a) CD86, 41BBL, OX40L, or a combination of two or three of the foregoing, or (b) CD40L. 41BB, CCL21, IL-12, or a combination of two or more of the foregoing.

17 . (canceled)

18 . The molecular conjugate of claim 1 , wherein the antagonist is a delta opioid receptor antagonist, and the immune effector is a T-cell modulator.

19 . (canceled)

20 . The molecular conjugate of claim 18 , wherein the T-cell modulator is anti-PD1, anti-PDL1, CD127L, OX40L, CD86, or a combination of two or more of the foregoing.

21 . The molecular conjugate of claim 1 , further comprising an imaging agent.

22 . A composition comprising a molecular conjugate comprising:
a) an antagonist of a cell surface receptor specific to a target cell, and b) an immune effector conjugated to the antagonist; and a pharmaceutically acceptable carrier.

23 - 24 . (canceled)

25 . A method of treating a disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a molecular conjugate according to claim 1 .

26 - 36 . (canceled)

37 . A method for delivering a molecular conjugate to a cell, the method comprising administering to the cell in vitro or in vivo a molecular conjugate of claim 1 .

38 - 39 . (canceled)

Assignees

• H Lee Moffitt Cancer Ct & Res
• Univ South Florida

Inventors

• Mclaughlin Mark
• Morse David L
• Pilon-Thomas Shari
• Antonia Scott

Classifications

• A61K47/646

  the entire peptide or protein drug conjugate elicits an immune response, e.g. conjugate vaccines · CPC title

• A61K2039/60

  characteristics by the carrier linked to the antigen · CPC title

• A61K38/00

  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) · CPC title

• C07K2319/00

  Fusion polypeptide · CPC title

• A61K49/0032

  Methine dyes, e.g. cyanine dyes · CPC title