IP Library › Granted Patent US 9,914,938
Granted Patent B2
US 9,914,938 · App. 15/652,080 · Granted Mar 13, 2018

Methods and compositions for the activation of gamma-delta T-cells

Inventors: Charles David Pauza (Baltimore, MD); Haishan Li (North Potomac, MD); Tyler Lahusen (Frederick, MD); Mei-Ling Liou (Germantown, MD)
Assignee: American Gene Technologies International, Inc.
C12N15/86A61K38/16C12N5/0636C12N15/113A61K48/00A61K2039/5158C12N5/00C12N2310/14C12N2310/141C12N2310/531
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Quick Facts
Patent No.
US 9,914,938
App. No.
15/652,080
Granted
Mar 13, 2018
Kind
B2
Abstract

The present invention relates generally to methods and compositions for gene therapy and immunotherapy that activate gamma delta T-cells, and in particular, can be used in the treatment of various cancers and infectious diseases.

Claims (477)

1. A viral vector for treating a condition associated with the mevalonate pathway, the viral vector comprising:

a. at least one encoded shRNA capable of inhibiting production of an enzyme of the mevalonate pathway, wherein the shRNA comprises a sequence having at least 90% percent identity with:

i.

(SEQ ID NO: 1)

GTCCTGGAGTACAATGCCATTCTCGAGAATGGCATTGTACTC

CAGGACTTTTT;

ii.

(SEQ ID NO: 2)

GCAGGATTTCGTTCAGCACTTCTCGAGAAGTGCTGAACGAA

ATCCTGCTTTTT;

iii.

(SEQ ID NO: 3)

GCCATGTACATGGCAGGAATTCTCGAGAATTCCTGCCATGTA

CATGGCTTTTT;

or

iv.

(SEQ ID NO: 4)

GCAGAAGGAGGCTGAGAAAGTCTCGAGACTTTCTCAGCCTC

CTTCTGCTTTTT;

or

b. at least one encoded microRNA capable of inhibiting production of an enzyme of the mevalonate pathway, wherein the microRNA comprises a sequence having at least 90% percent identity with:

i.

(SEQ ID NO: 5)

AAGGTATATTGCTGTTGACAGTGAGCGACACTTTCTCAGCCT

CCTTCTGCGTGAAGCCACAGATGGCAGAAGGAGGCTGAGAA

AGTGCTGCCTACTGCCTCGGACTTCAAGGGGCT;

ii.

(SEQ ID NO: 6)

AAGGTATATTGCTGTTGACAGTGAGCGACACTTTCTCAGCCT

CCTTCTGCGTGAAGCCACAGATGGCAGAAGGGCTGAGAAAG

TGCTGCCTACTGCCTCGGACTTCAAGGGGCT;

iii.

(SEQ ID NO: 7)

TGCTGTTGACAGTGAGCGACTTTCTCAGCCTCCTTCTGCGTG

AAGCCACAGATGGCAGAAGGAGGCTGAGAAAGTTGCCTACT

GCCTCGGA;

iv.

(SEQ ID NO: 8)

CCTGGAGGCTTGCTGAAGGCTGTATGCTGACTTTCTCAGCCT

CCTTCTGCTTTTGGCCACTGACTGAGCAGAAGGGCTGAGAA

AGTCAGGACACAAGGCCTGTTACTAGCACTCA;

v.

(SEQ ID NO: 9)

CATCTCCATGGCTGTACCACCTTGTCGGGACTTTCTCAGCCT

CCTTCTGCCTGTTGAATCTCATGGCAGAAGGAGGCGAGAAA

GTCTGACATTTTGGTATCTTTCATCTGACCA;

or

vi.

(SEQ ID NO: 10)

GGGCCTGGCTCGAGCAGGGGGCGAGGGATACTTTCTCAGCC

TCCTTCTGCTGGTCCCCTCCCCGCAGAAGGAGGCTGAGAAA

GTCCTTCCCTCCCAATGACCGCGTCTTCGTCG.

2. The viral vector of claim 1 , wherein:

a. the shRNA comprises a sequence having at least 95% percent identity with:

i.

(SEQ ID NO: 1)

GTCCTGGAGTACAATGCCATTCTCGAGAATGGCATTGTACTC

CAGGACTTTTT;

ii.

(SEQ ID NO: 2)

GCAGGATTTCGTTCAGCACTTCTCGAGAAGTGCTGAACGAA

ATCCTGCTTTTT;

iii.

(SEQ ID NO: 3)

GCCATGTACATGGCAGGAATTCTCGAGAATTCCTGCCATGTA

CATGGCTTTTT;

or

iv.

(SEQ ID NO: 4)

GCAGAAGGAGGCTGAGAAAGTCTCGAGACTTTCTCAGCCTC

CTTCTGCTTTTT;

or

b. the microRNA comprises a sequence having at least 95% percent identity with:

i.

(SEQ ID NO: 5)

AAGGTATATTGCTGTTGACAGTGAGCGACACTTTCTCAGCCT

CCTTCTGCGTGAAGCCACAGATGGCAGAAGGAGGCTGAGAAA

GTGCTGCCTACTGCCTCGGACTTCAAGGGGCT;

ii.

(SEQ ID NO: 6)

AAGGTATATTGCTGTTGACAGTGAGCGACACTTTCTCAGCCT

CCTTCTGCGTGAAGCCACAGATGGCAGAAGGGCTGAGAAAGT

GCTGCCTACTGCCTCGGACTTCAAGGGGCT;

iii.

(SEQ ID NO: 7)

TGCTGTTGACAGTGAGCGACTTTCTCAGCCTCCTTCTGCGTG

AAGCCACAGATGGCAGAAGGAGGCTGAGAAAGTTGCCTACTG

CCTCGGA;

iv.

(SEQ ID NO: 8)

CCTGGAGGCTTGCTGAAGGCTGTATGCTGACTTTCTCAGCCT

CCTTCTGCTTTTGGCCACTGACTGAGCAGAAGGGCTGAGAAA

GTCAGGACACAAGGCCTGTTACTAGCACTCA;

v.

(SEQ ID NO: 9)

CATCTCCATGGCTGTACCACCTTGTCGGGACTTTCTCAGCCT

CCTTCTGCCTGTTGAATCTCATGGCAGAAGGAGGCGAGAAAG

TCTGACATTTTGGTATCTTTCATCTGACCA;

or

vi.

(SEQ ID NO: 10)

GGGCCTGGCTCGAGCAGGGGGCGAGGGATACTTTCTCAGCC

TCCTTCTGCTGGTCCCCTCCCCGCAGAAGGAGGCTGAGAAA

GTCCTTCCCTCCCAATGACCGCGTCTTCGTCG.

3. The viral vector of claim 1 , wherein:

a. the shRNA comprises:

i.

(SEQ ID NO: 1)

GTCCTGGAGTACAATGCCATTCTCGAGAATGGCATTGTACTC

CAGGACTTTTT;

ii.

(SEQ ID NO: 2)

GCAGGATTTCGTTCAGCACTTCTCGAGAAGTGCTGAACGAAA

TCCTGCTTTTT;

iii.

(SEQ ID NO: 3)

GCCATGTACATGGCAGGAATTCTCGAGAATTCCTGCCATGTA

CATGGCTTTTT;

or

iv.

(SEQ ID NO: 4)

GCAGAAGGAGGCTGAGAAAGTCTCGAGACTTTCTCAGCCTCC

TTCTGCTTTTT;

or

b. the microRNA comprises:

i.

(SEQ ID NO: 5)

AAGGTATATTGCTGTTGACAGTGAGCGACACTTTCTCAGCCT

CCTTCTGCGTGAAGCCACAGATGGCAGAAGGAGGCTGAGAAA

GTGCTGCCTACTGCCTCGGACTTCAAGGGGCT;

ii.

(SEQ ID NO: 6)

AAGGTATATTGCTGTTGACAGTGAGCGACACTTTCTCAGCCT

CCTTCTGCGTGAAGCCACAGATGGCAGAAGGGCTGAGAAAGT

GCTGCCTACTGCCTCGGACTTCAAGGGGCT;

iii.

(SEQ ID NO: 7)

TGCTGTTGACAGTGAGCGACTTTCTCAGCCTCCTTCTGCGTG

AAGCCACAGATGGCAGAAGGAGGCTGAGAAAGTTGCCTACTG

CCTCGGA;

iv.

(SEQ ID NO: 8)

CCTGGAGGCTTGCTGAAGGCTGTATGCTGACTTTCTCAGCCT

CCTTCTGCTTTTGGCCACTGACTGAGCAGAAGGGCTGAGAAA

GTCAGGACACAAGGCCTGTTACTAGCACTCA;

v.

(SEQ ID NO: 9)

CATCTCCATGGCTGTACCACCTTGTCGGGACTTTCTCAGCCT

CCTTCTGCCTGTTGAATCTCATGGCAGAAGGAGGCGAGAAAG

TCTGACATTTTGGTATCTTTCATCTGACCA;

or

vi.

(SEQ ID NO: 10)

GGGCCTGGCTCGAGCAGGGGGCGAGGGATACTTTCTCAGCCT

CCTTCTGCTGGTCCCCTCCCCGCAGAAGGAGGCTGAGAAAGT

CCTTCCCTCCCAATGACCGCGTCTTCGTCG.

4. The viral vector of claim 1 , wherein the enzyme is farnesyl diphosphate synthase (FDPS).

5. The viral vector of claim 1 , wherein the viral vector is a lentiviral vector or an adeno-associated virus vector.

6. The viral vector of claim 1 , wherein the viral vector is a lentiviral vector.

7. A lentiviral particle produced by a packaging cell and capable of infecting a target cell, the lentiviral particle comprising: an envelope protein capable of infecting a target cell, and:

a. an encoded shRNA capable of inhibiting production of an enzyme of the mevalonate pathway, wherein the shRNA comprises a sequence having at least 90% percent identity with:

i.

(SEQ ID NO: 1)

GTCCTGGAGTACAATGCCATTCTCGAGAATGGCATTGTACTC

CAGGACTTTTT;

ii.

(SEQ ID NO: 2)

GCAGGATTTCGTTCAGCACTTCTCGAGAAGTGCTGAACGAAA

TCCTGCTTTTT;

iii.

(SEQ ID NO: 3)

GCCATGTACATGGCAGGAATTCTCGAGAATTCCTGCCATGTA

CATGGCTTTTT;

or

iv.

(SEQ ID NO: 4)

GCAGAAGGAGGCTGAGAAAGTCTCGAGACTTTCTCAGCCTCC

TTCTGCTTTTT;

or

b. an encoded microRNA capable of inhibiting production of an enzyme of the mevalonate pathway, wherein the microRNA comprises a sequence having at least 90% percent identity with:

i.

(SEQ ID NO: 5)

AAGGTATATTGCTGTTGACAGTGAGCGACACTTTCTCAGCCT

CCTTCTGCGTGAAGCCACAGATGGCAGAAGGAGGCTGAGAAA

GTGCTGCCTACTGCCTCGGACTTCAAGGGGCT;

ii.

(SEQ ID NO: 6)

AAGGTATATTGCTGTTGACAGTGAGCGACACTTTCTCAGCCT

CCTTCTGCGTGAAGCCACAGATGGCAGAAGGGCTGAGAAAGT

GCTGCCTACTGCCTCGGACTTCAAGGGGCT;

iii.

(SEQ ID NO: 7)

TGCTGTTGACAGTGAGCGACTTTCTCAGCCTCCTTCTGCGTG

AAGCCACAGATGGCAGAAGGAGGCTGAGAAAGTTGCCTACTG

CCTCGGA;

iv.

(SEQ ID NO: 8)

CCTGGAGGCTTGCTGAAGGCTGTATGCTGACTTTCTCAGCCT

CCTTCTGCTTTTGGCCACTGACTGAGCAGAAGGGCTGAGAAA

GTCAGGACACAAGGCCTGTTACTAGCACTCA;

v.

(SEQ ID NO: 9)

CATCTCCATGGCTGTACCACCTTGTCGGGACTTTCTCAGCCT

CCTTCTGCCTGTTGAATCTCATGGCAGAAGGAGGCGAGAAAG

TCTGACATTTTGGTATCTTTCATCTGACCA;

or

vi.

(SEQ ID NO: 10)

GGGCCTGGCTCGAGCAGGGGGCGAGGGATACTTTCTCAGCCT

CCTTCTGCTGGTCCCCTCCCCGCAGAAGGAGGCTGAGAAAGT

CCTTCCCTCCCAATGACCGCGTCTTCGTCG.

8. The lentiviral particle of claim 7 , wherein:

a. the encoded shRNA comprises a sequence having at least 95% percent identity with:

i.

(SEQ ID NO: 1)

GTCCTGGAGTACAATGCCATTCTCGAGAATGGCATTGTACTC

CAGGACTTTTT;

ii.

(SEQ ID NO: 2);

GCAGGATTTCGTTCAGCACTTCTCGAGAAGTGCTGAACGAAA

TCCTGCTTTTT

iii.

(SEQ ID NO: 3);

GCCATGTACATGGCAGGAATTCTCGAGAATTCCTGCCATGTA

CATGGCTTTTT

or

iv.

(SEQ ID NO: 4);

GCAGAAGGAGGCTGAGAAAGTCTCGAGACTTTCTCAGCCTCC

TTCTGCTTTTT

or

b. the microRNA comprises a sequence having at least 95% percent identity with:

i.

(SEQ ID NO: 5)

AAGGTATATTGCTGTTGACAGTGAGCGACACTTTCTCAGCCT

CCTTCTGCGTGAAGCCACAGATGGCAGAAGGAGGCTGAGAAA

GTGCTGCCTACTGCCTCGGACTTCAAGGGGCT;

ii.

(SEQ ID NO: 6)

AAGGTATATTGCTGTTGACAGTGAGCGACACTTTCTCAGCCT

CCTTCTGCGTGAAGCCACAGATGGCAGAAGGGCTGAGAAAGT

GCTGCCTACTGCCTCGGACTTCAAGGGGCT;

iii.

(SEQ ID NO: 7)

TGCTGTTGACAGTGAGCGACTTTCTCAGCCTCCTTCTGCGTG

AAGCCACAGATGGCAGAAGGAGGCTGAGAAAGTTGCCTACTG

CCTCGGA;

iv.

(SEQ ID NO: 8)

CCTGGAGGCTTGCTGAAGGCTGTATGCTGACTTTCTCAGCCT

CCTTCTGCTTTTGGCCACTGACTGAGCAGAAGGGCTGAGAAA

GTCAGGACACAAGGCCTGTTACTAGCACTCA;

v.

(SEQ ID NO: 9)

CATCTCCATGGCTGTACCACCTTGTCGGGACTTTCTCAGCCT

CCTTCTGCCTGTTGAATCTCATGGCAGAAGGAGGCGAGAAAG

TCTGACATTTTGGTATCTTTCATCTGACCA;

or

vi.

(SEQ ID NO: 10)

GGGCCTGGCTCGAGCAGGGGGCGAGGGATACTTTCTCAGCCT

CCTTCTGCTGGTCCCCTCCCCGCAGAAGGAGGCTGAGAAAGT

CCTTCCCTCCCAATGACCGCGTCTTCGTCG.

9. The lentiviral particle of claim 7 , wherein:

a. the shRNA comprises:

i.

(SEQ ID NO: 1)

GTCCTGGAGTACAATGCCATTCTCGAGAATGGCATTGTACTC

CAGGACTTTTT;

ii.

(SEQ ID NO: 2)

GCAGGATTTCGTTCAGCACTTCTCGAGAAGTGCTGAACGAAA

TCCTGCTTTTT;

iii.

(SEQ ID NO: 3)

GCCATGTACATGGCAGGAATTCTCGAGAATTCCTGCCATGTA

CATGGCTTTTT;

or

iv.

(SEQ ID NO: 4)

GCAGAAGGAGGCTGAGAAAGTCTCGAGACTTTCTCAGCCTCC

TTCTGCTTTTT;

or

b. the microRNA comprises:

i.

(SEQ ID NO: 5)

AAGGTATATTGCTGTTGACAGTGAGCGACACTTTCTCAGCCT

CCTTCTGCGTGAAGCCACAGATGGCAGAAGGAGGCTGAGAAA

GTGCTGCCTACTGCCTCGGACTTCAAGGGGCT;

ii.

(SEQ ID NO: 6)

AAGGTATATTGCTGTTGACAGTGAGCGACACTTTCTCAGCCT

CCTTCTGCGTGAAGCCACAGATGGCAGAAGGGCTGAGAAAGT

GCTGCCTACTGCCTCGGACTTCAAGGGGCT;

iii.

(SEQ ID NO: 7)

TGCTGTTGACAGTGAGCGACTTTCTCAGCCTCCTTCTGCGTG

AAGCCACAGATGGCAGAAGGAGGCTGAGAAAGTTGCCTACTG

CCTCGGA;

iv.

(SEQ ID NO: 8)

CCTGGAGGCTTGCTGAAGGCTGTATGCTGACTTTCTCAGCCT

CCTTCTGCTTTTGGCCACTGACTGAGCAGAAGGGCTGAGAAA

GTCAGGACACAAGGCCTGTTACTAGCACTCA;

v.

(SEQ ID NO: 9)

CATCTCCATGGCTGTACCACCTTGTCGGGACTTTCTCAGCCT

CCTTCTGCCTGTTGAATCTCATGGCAGAAGGAGGCGAGAAAG

TCTGACATTTTGGTATCTTTCATCTGACCA;

or

vi.

(SEQ ID NO: 10)

GGGCCTGGCTCGAGCAGGGGGCGAGGGATACTTTCTCAGCCT

CCTTCTGCTGGTCCCCTCCCCGCAGAAGGAGGCTGAGAAAGT

CCTTCCCTCCCAATGACCGCGTCTTCGTCG.

10. The lentiviral particle of claim 7 , wherein the envelope protein targets an endocytic compartment of the target cell.

11. The lentiviral particle of claim 7 , wherein the target cell is a cancer cell selected from one or more of a carcinoma, a leukemia, a lymphoma, a sarcoma, a myeloma, or a mesothelioma.

12. The lentiviral particle of claim 7 , wherein the target cell is capable of activating a gamma delta T cell following infection with the lentiviral particle.

13. The lentiviral particle of claim 7 , wherein the enzyme is FDPS.

14. A pharmaceutical combination for treating a condition associated with the mevalonate pathway, the pharmaceutical combination comprising: a lentiviral particle that is produced by a packaging cell and is capable of infecting a target cell, wherein the lentiviral particle comprises an envelope protein capable of infecting a target cell, and

a. an encoded shRNA capable of inhibiting production of an enzyme of the mevalonate pathway, wherein the shRNA comprises a sequence having at least 90% percent identity with:

i.

(SEQ ID NO: 1)

GTCCTGGAGTACAATGCCATTCTCGAGAATGGCATTGTACTC

CAGGACTTTTT;

ii.

(SEQ ID NO: 2)

GCAGGATTTCGTTCAGCACTTCTCGAGAAGTGCTGAACGAAA

TCCTGCTTTTT;

iii.

(SEQ ID NO: 3)

GCCATGTACATGGCAGGAATTCTCGAGAATTCCTGCCATGTA

CATGGCTTTTT;

or

iv.

(SEQ ID NO: 4)

GCAGAAGGAGGCTGAGAAAGTCTCGAGACTTTCTCAGCCTCC

TTCTGCTTTTT;

or

b. an encoded microRNA capable of inhibiting production of an enzyme of the mevalonate pathway, wherein the microRNA comprises a sequence having at least 90% percent identity with:

i.

(SEQ ID NO: 5)

AAGGTATATTGCTGTTGACAGTGAGCGACACTTTCTCAGCCT

CCTTCTGCGTGAAGCCACAGATGGCAGAAGGAGGCTGAGAAA

GTGCTGCCTACTGCCTCGGACTTCAAGGGGCT;

ii.

(SEQ ID NO: 6)

AAGGTATATTGCTGTTGACAGTGAGCGACACTTTCTCAGCCT

CCTTCTGCGTGAAGCCACAGATGGCAGAAGGGCTGAGAAAGT

GCTGCCTACTGCCTCGGACTTCAAGGGGCT;

iii.

(SEQ ID NO: 7)

TGCTGTTGACAGTGAGCGACTTTCTCAGCCTCCTTCTGCGTG

AAGCCACAGATGGCAGAAGGAGGCTGAGAAAGTTGCCTACTG

CCTCGGA;

iv.

(SEQ ID NO: 8)

CCTGGAGGCTTGCTGAAGGCTGTATGCTGACTTTCTCAGCCT

CCTTCTGCTTTTGGCCACTGACTGAGCAGAAGGGCTGAGAAA

GTCAGGACACAAGGCCTGTTACTAGCACTCA;

v.

(SEQ ID NO: 9)

CATCTCCATGGCTGTACCACCTTGTCGGGACTTTCTCAGCCT

CCTTCTGCCTGTTGAATCTCATGGCAGAAGGAGGCGAGAAAG

TCTGACATTTTGGTATCTTTCATCTGACCA;

or

vi.

(SEQ ID NO: 10)

GGGCCTGGCTCGAGCAGGGGGCGAGGGATACTTTCTCAGCCT

CCTTCTGCTGGTCCCCTCCCCGCAGAAGGAGGCTGAGAAAGT

CCTTCCCTCCCAATGACCGCGTCTTCGTCG;

and

c. an aminobisphosphonate compound; separately or together.

15. The pharmaceutical combination of claim 14 , wherein the encoded shRNA comprises a sequence having at least 95% percent identity with:

i.

(SEQ ID NO: 1)

GTCCTGGAGTACAATGCCATTCTCGAGAATGGCATTGTACTC

CAGGACTTTTT;

ii.

(SEQ ID NO: 2)

GCAGGATTTCGTTCAGCACTTCTCGAGAAGTGCTGAACGAAA

TCCTGCTTTTT;

iii.

(SEQ ID NO: 3)

GCCATGTACATGGCAGGAATTCTCGAGAATTCCTGCCATGTA

CATGGCTTTTT;

or

iv.

(SEQ ID NO: 4)

GCAGAAGGAGGCTGAGAAAGTCTCGAGACTTTCTCAGCCTCC

TTCTGCTTTTT;

or

b. the microRNA comprises a sequence having at least 95% percent identity with:

i.

(SEQ ID NO: 5)

AAGGTATATTGCTGTTGACAGTGAGCGACACTTTCTCAGCCT

CCTTCTGCGTGAAGCCACAGATGGCAGAAGGAGGCTGAGAAA

GTGCTGCCTACTGCCTCGGACTTCAAGGGGCT;

ii.

(SEQ ID NO: 6)

AAGGTATATTGCTGTTGACAGTGAGCGACACTTTCTCAGCCT

CCTTCTGCGTGAAGCCACAGATGGCAGAAGGGCTGAGAAAGT

GCTGCCTACTGCCTCGGACTTCAAGGGGCT;

iii.

(SEQ ID NO: 7)

TGCTGTTGACAGTGAGCGACTTTCTCAGCCTCCTTCTGCGTG

AAGCCACAGATGGCAGAAGGAGGCTGAGAAAGTTGCCTACTG

CCTCGGA;

iv.

(SEQ ID NO: 8)

CCTGGAGGCTTGCTGAAGGCTGTATGCTGACTTTCTCAGCCT

CCTTCTGCTTTTGGCCACTGACTGAGCAGAAGGGCTGAGAAA

GTCAGGACACAAGGCCTGTTACTAGCACTCA;

v.

(SEQ ID NO: 9)

CATCTCCATGGCTGTACCACCTTGTCGGGACTTTCTCAGCCT

CCTTCTGCCTGTTGAATCTCATGGCAGAAGGAGGCGAGAAAG

TCTGACATTTTGGTATCTTTCATCTGACCA;

or

vi.

(SEQ ID NO: 10)

GGGCCTGGCTCGAGCAGGGGGCGAGGGATACTTTCTCAGCCT

CCTTCTGCTGGTCCCCTCCCCGCAGAAGGAGGCTGAGAAAGT

CCTTCCCTCCCAATGACCGCGTCTTCGTCG.

16. The pharmaceutical combination of claim 14 , wherein:

a. the shRNA comprises:

i.

(SEQ ID NO: 1)

GTCCTGGAGTACAATGCCATTCTCGAGAATGGCATTGTACTC

CAGGACTTTTT;

ii.

(SEQ ID NO: 2)

GCAGGATTTCGTTCAGCACTTCTCGAGAAGTGCTGAACGAAA

TCCTGCTTTTT;

iii.

(SEQ ID NO: 3)

GCCATGTACATGGCAGGAATTCTCGAGAATTCCTGCCATGTA

CATGGCTTTTT;

or

iv.

(SEQ ID NO: 4)

GCAGAAGGAGGCTGAGAAAGTCTCGAGACTTTCTCAGCCTCC

TTCTGCTTTTT;

or

b. the microRNA comprises:

i.

(SEQ ID NO: 5)

AAGGTATATTGCTGTTGACAGTGAGCGACACTTTCTCAGCCT

CCTTCTGCGTGAAGCCACAGATGGCAGAAGGAGGCTGAGAAA

GTGCTGCCTACTGCCTCGGACTTCAAGGGGCT;

ii.

(SEQ ID NO: 6)

AAGGTATATTGCTGTTGACAGTGAGCGACACTTTCTCAGCCT

CCTTCTGCGTGAAGCCACAGATGGCAGAAGGGCTGAGAAAGT

GCTGCCTACTGCCTCGGACTTCAAGGGGCT;

iii.

(SEQ ID NO: 7)

TGCTGTTGACAGTGAGCGACTTTCTCAGCCTCCTTCTGCGTG

AAGCCACAGATGGCAGAAGGAGGCTGAGAAAGTTGCCTACTG

CCTCGGA;

iv.

(SEQ ID NO: 8)

CCTGGAGGCTTGCTGAAGGCTGTATGCTGACTTTCTCAGCCT

CCTTCTGCTTTTGGCCACTGACTGAGCAGAAGGGCTGAGAAA

GTCAGGACACAAGGCCTGTTACTAGCACTCA;

v.

(SEQ ID NO: 9)

CATCTCCATGGCTGTACCACCTTGTCGGGACTTTCTCAGCCT

CCTTCTGCCTGTTGAATCTCATGGCAGAAGGAGGCGAGAAAG

TCTGACATTTTGGTATCTTTCATCTGACCA;

or

vi.

(SEQ ID NO: 10)

GGGCCTGGCTCGAGCAGGGGGCGAGGGATACTTTCTCAGCCT

CCTTCTGCTGGTCCCCTCCCCGCAGAAGGAGGCTGAGAAAGT

CCTTCCCTCCCAATGACCGCGTCTTCGTCG.

17. The pharmaceutical combination of claim 14 , wherein the aminobisphosphonate compound comprises zoledronic acid.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 31, 2026
From: PAUZA, CHARLES DAVID; LI, HAISHAN; LAHUSEN, TYLER; LIOU, MEI-LING
To: AMERICAN GENE TECHNOLOGIES INTERNATIONAL INC.
Reel/Frame 075486/0017 →
Continuity (3)
Continuation PCTUS2017013399 · Jan 13, 2017
Provisional Application 62279474 · Jan 15, 2016
Related Publication 20170335344A1 · Nov 23, 2017