Immunoprotective primary mesenchymal stem cells and methods

Patent metadata

Field	Value
Publication number	US-10357562-B2
Application number	US-201514802247-A
Country	US
Kind code	B2
Filing date	Jul 17, 2015
Priority date	Mar 14, 2013
Publication date	Jul 23, 2019
Grant date	Jul 23, 2019

Abstract

Immunoprotective primary mesenchymal stems cells (IP-MSC) which episomally express multiple immunoreactive polypeptides that specifically target a pathogen (e.g., an infectious species of virus, bacterium, or parasite) or toxin are described herein. The IP-MSC express two or more (e.g., 2 to about 100) immunoreactive polypeptides (e.g., full antibodies, single-chain antibodies (ScFV), Fab or F(ab)2 antibody fragments, diabodies, tribodies, and the like), and optionally one or more other immunomodulating polypeptides, e.g., a cytokine such as an interleukin (e.g., IL-2, IL-4, IL-6, IL-7, IL-9, and IL-12), an interferon (e.g., IFNα, IFNβ, or IFNω), and the like, which can enhance the effectiveness of the immunoreactive polypeptides.

First claim

We claim:

1. Immunoprotective primary mesenchymal stems cells (IP-MSC) that episomally express multiple immunoreactive polypeptides that specifically target and bind to an antigenic polypeptide of a viral pathogen; the IP-MSC being transfected with one or more episomal vectors expressibly encoding the multiple immunoreactive polypeptides; the one or more episomal vectors also including an inducible apoptosis gene; wherein the antigenic polypeptide is selected from the group consisting of: influenza hemagglutinin 1 (HA1); influenza hemagglutinin 2 (HA2); influenza neuraminidase (NA); Lassa virus (LASV) glycoprotein 1 (gp1); LASV glycoprotein 2 (gp2); LASV nucleocapsid-associated protein (NP); LASV L protein; LASV Z protein; SARS virus S protein; Ebola virus GP2; measles virus fusion 1 (F1) protein; HIV-1 transmembrane (TM) protein; HIV-1 glycoprotein 41 (gp41); HIV-1 glycoprotein 120 (gp120); hepatitis C virus (HCV) envelope glycoprotein 1 (E1); HCV envelope glycoprotein 2 (E2); HCV nucleocapsid protein (p22); West Nile virus (WNV) envelope glycoprotein (E); Japanese encephalitis virus (JEV) envelope glycoprotein (E); yellow fever virus (YFV) envelope glycoprotein (E); tick-borne encephalitis virus (TBEV) envelope glycoprotein (E); hepatitis G virus (HGV) envelope glycoprotein 1 (E1); respiratory synctival virus (RSV) fusion (F) protein; herpes simplex virus 1 (HSV-1) gD protein; HSV-1 gG protein; HSV-2 gD protein; HSV-2 gG protein; hepatitis B virus (HBV) core protein; and Epstein-Barr virus (EBV) glycoprotein 125 (gp125); and the IP-MSC are prepared from adipose-derived mesenchymal stem cells; and wherein the immunoreactive polypeptides comprise an antibody or an antibody fragment that includes the complementarity determining regions of the antibody; wherein the antibody fragment is selected from the group consisting of an antibody single-chain variable antibody fragment (ScFV), a monovalent antibody antigen-binding fragment (Fab), a divalent antibody antigen-binding fragment (F(ab′)2), a diabody, and a tribody; and wherein the one or more episomal vectors are non-infective, non-integrative circular episomal vectors.

2. The IP-MSC of claim 1 , wherein the IP-MSC episomally express 2 to about 100 of the immunoreactive polypeptides.

3. The IP-MSC of claim 1 , wherein the IP-MSC also express one or more other immunomodulating agents.

4. The IP-MSC of claim 3 , wherein the one or more immunomodulating agents are selected from interleukins and interferons.

5. The IP-MSC of claim 3 , wherein the one or more immunomodulating agents are selected from IL-2, IL-4, IL-6, IL-7, IL-9, IL-12, and an interferon.

6. Immunoprotective primary mesenchymal stems cells (IP-MSC) that episomally express multiple immunoreactive polypeptides that specifically target and bind to an antigenic polypeptide of a viral pathogen; the IP-MSC being transfected with one or more episomal vectors expressibly encoding the immunoreactive polypeptides, and the one or more episomal vectors also encoding an inducible apoptosis gene; wherein the immunoreactive polypeptides comprise an antibody; and the antigenic polypeptide is selected from the group consisting of influenza hemagglutinin 1 (HA1), influenza hemagglutinin 2 (HA2), influenza neuraminidase (NA), Lassa virus (LASV) glycoprotein 1 (gp1), LASV glycoprotein 2 (gp2), LASV nucleocapsid-associated protein (NP), LASV L protein, LASV Z protein, SARS virus S protein, Ebola virus GP2, measles virus fusion 1 (F1) protein, HIV-1 transmembrane (TM) protein, HIV-1 glycoprotein 41 (gp41), HIV-1 glycoprotein 120 (gp120), hepatitis C virus (HCV) envelope glycoprotein 1 (E1), HCV envelope glycoprotein 2 (E2), HCV nucleocapsid protein (p22), West Nile virus (WNV) envelope glycoprotein (E), Japanese encephalitis virus (JEV) envelope glycoprotein (E), yellow fever virus (YFV) envelope glycoprotein (E), tick-borne encephalitis virus (TBEV) envelope glycoprotein (E), hepatitis G virus (HGV) envelope glycoprotein 1 (E1), respiratory synctival virus (RSV) fusion (F) protein, herpes simplex virus 1 (HSV-1) gD protein, HSV-1 gG protein, HSV-2 gD protein, HSV-2 gG protein, hepatitis B virus (HBV) core protein, and Epstein-Barr virus (EBV) glycoprotein 125 (gp125); and the IP-MSC are prepared from adipose-derived mesenchymal stem cells; and wherein the one or more episomal vectors are non-infective, non-integrative circular episomal vectors.

7. The IP-MSC of claim 6 , wherein the one or more episomal vectors further encode a tetracycline-controlled transcriptional activation system for activation of the inducible apoptosis gene.

8. The IP-MSC of claim 1 , wherein the one or more episomal vectors further encode a tetracycline-controlled transcriptional activation system for activation of the inducible apoptosis gene.

Assignees

• The Administrators Of The Tulane Educational Fund
• Autoimmune Tech Llc

Inventors

• Garry Robert Francis
• Branco Luis Manuel
• Bunnell Bruce Alan
• Wilson Russell B
• Hopkins Samuel E

Classifications

• A61P39/02

  Antidotes · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• C07K2317/76

  Antagonist effect on antigen, e.g. neutralization or inhibition of binding · CPC title