IP Library › Granted Patent US 12,343,403
Granted Patent B2
US 12,343,403 · App. 16/486,632 · Granted Jul 1, 2025

Targeted ligand-payload based drug delivery for cell therapy

Inventors: Philip S. Low (West Lafayette, IN); Madduri Srinivasarao (West Lafayette, IN); Boning Zhang (West Lafayette, IN)
Assignee: Purdue Research Foundation
A61K47/66A61K40/10A61K40/11A61K40/31A61K40/4211A61K47/6901C07K14/7051C12N9/90C12N15/62A61K38/00A61K2239/31A61K2239/38A61K2239/48C07K2319/03C07K2319/20C07K2319/912C12Y502/01008
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,343,403
App. No.
16/486,632
Granted
Jul 1, 2025
Kind
B2
Abstract

A drug delivery platform providing flexible fine tune of cell therapy is disclosed herein. Particularly, an engineered fusion protein is coupled with a high affinity ligand carrying at least one payload of drug to be internalized by the transplanted cell to observe or regulate transplanted cell therapy effects.

Claims (54)

1. A drug delivery platform for cell therapy comprising:

an engineered protein on a target cell for transplant, wherein the engineered protein is selected from the group consisting of SEQ ID NOS: 1 and 2;

a small molecule ligand conjugated to a linker, wherein the small molecule ligand has intrinsic high affinity to the engineered protein; and

at least one payload of drug conjugated to the linker, wherein the at least one payload of drug is associated with the target cell when the small molecule ligand binds to the engineered protein.

2. The drug delivery platform according to claim 1 , wherein the target cell for transplant is a CAR T cell expressing amino acid sequence selected from SEQ ID NOS: 3 and 4.

3. The drug delivery platform according to claim 1 , wherein the small molecule ligand conjugate has the formula I

4. The drug delivery platform according to claim 1 , wherein the target cell for transplant is a stem cell, a progenitor cell, an immune cell, a chimeric antigen receptor (CAR) T cell or a transplanted cell designed to synthesize a biochemical that is deficient in a patient.

5. The drug delivery platform according to claim 1 , wherein the small molecule ligand is further conjugated to a fluorescent dye or radioactive probe.

6. The drug delivery platform according to claim 1 , wherein the small molecule ligand is further conjugated to a regulator of endogenous gene expression.

7. The drug delivery platform according to claim 1 , wherein the small molecule ligand is further conjugated to a regulator of a transduced transgene expression.

8. The drug delivery platform according to claim 1 , wherein the at least one payload of drug is an imaging agent.

9. The drug delivery platform according to claim 8 , wherein the imaging agent is selected from the group consisting of fluorescent dye rhodamine, fluorescein, and S0456.

10. The drug delivery platform according to claim 2 , wherein imaging agent is selected from the group consisting of radioisotope chelating imaging moieties, EC 20 chelating head, NOTA and DOTA.

11. The drug delivery platform according to claim 1 , wherein the at least one payload of drug is a cytotoxic drug.

12. The drug delivery platform according to claim 3 , wherein the cytotoxic drug is selected from the group consisting of tubulysin, DM1, DM4, and an auristatin.

13. The drug delivery platform according to claim 1 , wherein the at least one payload of drug is a modulator of gene expression.

14. The drug delivery platform according to claim 13 , wherein the modulator is selected from the group consisting of Dasatinib, MEK1/2 inhibitor, and PI3K inhibitor.

15. The drug delivery platform according to claim 13 , wherein the modulator is selected from the group consisting of HDAC inhibitor, kinase inhibitor and metabolic inhibitor.

16. The drug delivery platform according to claim 13 , wherein the modulator is selected from the group consisting of GSK3 beta inhibitor, MAO-B inhibitor and Cdk5 inhibitor.

17. The drug delivery platform according to claim 13 , wherein the modulator is an RORγt agonist.

18. The drug delivery platform according to claim 13 , wherein the modulator is a siRNA.

19. The drug delivery platform according to claim 13 , wherein the modulator is a phosphatase inhibitor.

20. The drug delivery platform according to claim 14 , wherein the phosphatase inhibitor is against SHP1/2 or TC-PTP.

21. The drug delivery platform according to claim 1 , wherein the at least one payload of drug is a modulator of the cell's activity.

22. The drug delivery platform according to claim 1 , wherein the linker to connect the small molecule ligand and the at least one payload of drug is selected from the group consisting of:

23. The drug delivery platform according to claim 1 , wherein the small molecule ligand is selected from the group consisting of FK506, FK506 derivatives, synthetic ligand of FKBP (SLF), SLF derivatives, folic acid (FA), and FA derivatives.

24. The drug delivery platform according to claim 1 , wherein the small molecule ligand is FK506 or its derivative.

25. A drug delivery platform for cell therapy comprising:

an engineered protein on a target cell for transplant, wherein the engineered protein is selected from the group consisting of SEQ ID NOS: 12, 13, 14, and 15;

a small molecule ligand conjugated to a linker, wherein the small molecule ligand has intrinsic high affinity to the engineered protein; and

at least one payload of drug conjugated to the linker, wherein the at least one payload of drug is associated with the target cell when the small molecule ligand binds to the engineered protein.

26. The drug delivery platform according to claim 25 , wherein the at least one payload of drug is an imaging agent.

27. The drug delivery platform according to claim 26 , wherein the imaging agent is selected from the group consisting of fluorescent dye rhodamine, fluorescein, and S0456.

28. The drug delivery platform according to claim 26 , wherein imaging agent is selected from the group consisting of radioisotope chelating imaging moieties, EC 20 chelating head, NOTA and DOTA.

29. The drug delivery platform according to claim 25 , wherein the at least one payload of drug is a cytotoxic drug.

30. The drug delivery platform according to claim 29 , wherein the cytotoxic drug is selected from the group consisting of tubulysin, DM1, DM4, and an auristatin.

31. The drug delivery platform according to claim 25 , wherein the at least one payload of drug is a modulator of gene expression.

32. The drug delivery platform according to claim 31 , wherein the modulator is selected from the group consisting of Dasatinib, MEK1/2 inhibitor, and PI3K inhibitor.

33. The drug delivery platform according to claim 31 , wherein the modulator is selected from the group consisting of HDAC inhibitor, kinase inhibitor and metabolic inhibitor.

34. The drug delivery platform according to claim 31 , wherein the modulator is selected from the group consisting of GSK3 beta inhibitor, MAO-B inhibitor and Cdk5 inhibitor.

35. The drug delivery platform according to claim 31 , wherein the modulator is an RORγt agonist.

36. The drug delivery platform according to claim 31 , wherein the modulator is a siRNA.

37. The drug delivery platform according to claim 31 , wherein the modulator is a phosphatase inhibitor.

38. The drug delivery platform according to claim 37 , wherein the phosphatase inhibitor is against SHP1/2 or TC-PTP.

39. The drug delivery platform according to claim 25 , wherein the at least one payload of drug is a modulator of the cell's activity.

40. The drug delivery platform according to claim 25 , wherein the linker to connect the small molecule ligand and the at least one payload of drug is selected from the group consisting of

41. The drug delivery platform according to claim 25 , wherein the small molecule ligand is selected from the group consisting of FK506, FK506 derivatives, synthetic ligand of FKBP (SLF), SLF derivatives, folic acid (FA), and FA derivatives.

42. The drug delivery platform according to claim 25 , wherein the small molecule ligand is FK506 or its derivative.

43. The drug delivery platform according to claim 25 , wherein the target cell for transplant is a CAR T cell expressing amino acid sequence selected from SEQ ID NOS: 3 and 4.

44. The drug delivery platform according to claim 25 , wherein the small molecule ligand conjugate has formula I

45. The drug delivery platform according to claim 25 , wherein the target cell for transplant is a stem cell, a progenitor cell, an immune cell, a chimeric antigen receptor (CAR) T cell or a transplanted cell designed to synthesize a biochemical that is deficient in a patient.

46. The drug delivery platform according to claim 25 , wherein the small molecule ligand is further conjugated to a fluorescent dye or radioactive probe.

47. The drug delivery platform according to claim 25 , wherein the small molecule ligand is further conjugated to a regulator of endogenous gene expression.

48. The drug delivery platform according to claim 25 , wherein the small molecule ligand is further conjugated to a regulator of a transduced transgene expression.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 9, 2020
From: LOW, PHILIP S.; SRINIVASARAO, MADDURI; ZHANG, BONING
To: PURDUE RESEARCH FOUNDATION
Reel/Frame 053724/0948 →
Continuity (2)
Provisional Application 62460118 · Feb 17, 2017
Related Publication 20200054676A1 · Feb 20, 2020
References Cited (73)
US 11034752B2 · Irvine · 2021 [cited by examiner]
US 20030185840A1 · Ioannides et al. · 2003 [cited by applicant]
US 20070077197A1 · Wedeking et al. · 2007 [cited by applicant]
US 20080260812A1 · Matsuyama · 2008 [cited by examiner]
US 20120076728A1 · Wu et al. · 2012 [cited by applicant]
US 20190359697A1 · Young · 2019 [cited by examiner]
US 20190365806A1 · Jeker · 2019 [cited by examiner]
AU 2018221171 · 2024 [cited by applicant]
CA 3053534A1 · 2018 [cited by applicant]
CN 118634339 · 2024 [cited by applicant]
EP 3583218A1 · 2019 [cited by applicant]
EP 3583218A4 · 2020 [cited by applicant]
JP 2020508042 · 2020 [cited by applicant]
JP 7288402B2 · 2023 [cited by applicant]
KR 102595249B1 · 2023 [cited by applicant]
WO WO9718307A1 · 1997 [cited by examiner]
WO WO2011079227A1 · 2011 [cited by examiner]
WO WO2016098078A2 · 2016 [cited by applicant]
WO WO2016164745A1 · 2016 [cited by applicant]
WO WO2017123956A1 · 2017 [cited by examiner]
WO WO2018152451A1 · 2018 [cited by applicant]
Nam et al. Structural basis for the function and regulation of the receptor protein tyrosine phosphatase CD45(JEM, 2005, 201:441-452) (Year: 2005). [cited by examiner]
Wilbowo et al. Structures of human folate receptors reveal biological trafficking states and diversity in folate and antifolate recognition (PNAS, 2013, 110:15180-15188) (Year: 2013). [cited by examiner]
Suen, W. L. L.; Chau, Y. Size-Dependent Internalisation of Folate-Decorated Nanoparticles via the Pathways of Clathrin and Caveolae-Mediated Endocytosis in ARPE-19 Cells J. Pharm. Pharmacol. 2014, 66, 564-573 (Year: 201… [cited by examiner]
Zhang B, Napoleon JV, Liu X, et al. Sensitive manipulation of CAR T cell activity using a chimeric endocytosing receptor. Journal for Immuno Therapy of Cancer, 2020;8:e000756. (Year: 2020). [cited by examiner]
Doucette et al., Point Mutations Alter the Cellular Distribution of the Human Folate Receptor in Cultured Chinese Hamster Ovary Cells. J. Nutr. 134: 308-316, 2004 (Year: 2004). [cited by examiner]
“European Application Serial No. 18754879.7, Response filed May 25, 2021 to Extended European Search Report mailed Nov. 26, 2020”, 11 pgs. [cited by applicant]
“European Application Serial No. 18754879.7, Response filed Aug. 16, 2022 to Communication Pursuant to Article 94(3) EPC mailed Jul. 18, 2022”, 74 pgs. [cited by applicant]
“Japanese Application Serial No. 2019-544016, Final Notification of Reasons for Refusal mailed Oct. 25, 2022” (w/ English Translation), 10 pgs. [cited by applicant]
“Japanese Application Serial No. 2019-544016, Response filed Jun. 29, 2022 to Notification of Reasons for Refusal mailed Mar. 29, 2022”, 11 pgs. [cited by applicant]
Shillingford, Jonathan M., et al., J. Am Soc Nephrol, vol. 23, No. 10, (2012), 1674-1681. [cited by applicant]
“Chinese Application Serial No. 201880024308.6, Voluntary Amendment filed May 15, 2020”, (w/ English Translation of Claims), 5 pgs. [cited by applicant]
“European Application Serial No. 18754879.7, Extended European Search Report mailed Nov. 26, 2020”, 8 pgs. [cited by applicant]
Xia, Wei, et al., “Folate-Targeted Therapies for Cancer”, [cited by applicant]
Zhou, Xiaoou, et al., “Improving the safety of T-Cell therapies using an inducible caspase-9 gene”, [cited by applicant]
“Japanese Application Serial No. 2019-544016, Notification of Reasons for Refusal mailed Mar. 29, 2022”, (w/ English translation), 10 pgs. [cited by applicant]
“Improving the Safety of T Cell Therapies using an Inducible Caspase-9 Gene”, Exp Hematol.,44 (11), (2016), 1013-1019. [cited by applicant]
“European Application Serial No. 18754879.7, Communication Pursuant to Article 94(3) EPC mailed Jul. 18, 2022”, 4 pgs. [cited by applicant]
“European Application Serial No. 18754879.7, Response to Communication pursuant to Rules 161(2) and 162 EPC filed Apr. 17, 2020”, 19 pgs. [cited by applicant]
“International Application Serial No. PCT/US2018/018557, International Preliminary Report on Patentability mailed Aug. 29, 2019”, 9 pgs. [cited by applicant]
“International Application Serial No. PCT/US2018/018557, International Search Report mailed Jul. 2, 2018”, 6 pgs. [cited by applicant]
“International Application Serial No. PCT/US2018/018557, Written Opinion mailed Jul. 2, 2018”, 7 pgs. [cited by applicant]
Di Stasi, Antonio, et al., “Inducible Apoptosis as a Safety Switch for Adoptive Cell Therapy”, [cited by applicant]
James, John R., et al., “Biophysical mechanism of T-cell receptor triggering in a reconstituted system”, HHMI Author Manuscript, published as: Nature, vol. 487, No. 7405, 65-69, (Jul. 5, 2012), 18 pgs. [cited by applicant]
Shillingford, Jonathan M., et al., “Folate-Conjugated Rapamycin Slows Progression of Polycystic Kidney Disease”, [cited by applicant]
Sun, Jie, et al., “The quest for spatio-temporal control of CAR T cells”, [cited by applicant]
“Australian Application Serial No. 2018221171, First Examination Report mailed Oct. 31, 2023”, 5 pgs. [cited by applicant]
“Canadian Application Serial No. 3,053,534, Office Action mailed Jun. 20, 2023”, 6 pgs. [cited by applicant]
“Canadian Application Serial No. 3,053,534, Response filed Oct. 20, 2023 to Office Action mailed Jun. 20, 2023”, w/ current English claims, 25 pgs. [cited by applicant]
“Chinese Application Serial No. 201880024308.6, Office Action mailed Jan. 20, 2023”, w/ English Translation, 14 pgs. [cited by applicant]
“Chinese Application Serial No. 201880024308.6, Office Action mailed Jul. 27, 2023”, w/ English Claims, 8 pgs. [cited by applicant]
“Chinese Application Serial No. 201880024308.6, Response filed May 12, 2023 to Office Action mailed Jan. 20, 2023”, w/ English claims, 17 pgs. [cited by applicant]
“Chinese Application Serial No. 201880024308.6, Response filed Oct. 7, 2023 to Office Action mailed Jul. 27, 2023”, w/ English claims, 13 pgs. [cited by applicant]
“Japanese Application Serial No. 2019-544016, Final Notification of Reasons for Refusal mailed Apr. 4, 2023”, w/ English Translation, 5 pgs. [cited by applicant]
“Japanese Application Serial No. 2019-544016, Office Action mailed Mar. 14, 2023”, 3 pgs. [cited by applicant]
“Japanese Application Serial No. 2019-544016, Response filed Mar. 22, 2023 to Final Notification of Reasons for Refusal mailed Oct. 25, 2022”, w/ English claims, 8 pgs. [cited by applicant]
“Japanese Application Serial No. 2019-544016, Response Filed Apr. 4, 2023 to Final Notification of Reasons for Refusal mailed Apr. 4, 2023”, w/ English claims, 7 pgs. [cited by applicant]
“Japanese Application Serial No. 2023-047827, Voluntary Amendment filed May 25, 2023”, w/ English claims, 11 pgs. [cited by applicant]
“Japanese Application Serial No. 2023-047827, Voluntary Amendment filed Jul. 10, 2023”, w/ English claims, 16 pgs. [cited by applicant]
“Korean Application Serial No. 10-2019-7026818, Notice of Preliminary Rejection mailed Jul. 24, 2023”, w/ English translation, 13 pgs. [cited by applicant]
“Korean Application Serial No. 10-2019-7026818, Response filed Sep. 13, 2023 to Notice of Preliminary Rejection mailed Jul. 24, 2023”, w/ English claims, 42 pgs. [cited by applicant]
“New Zealand Application Serial No. 756957, Voluntary Amendment filed Feb. 9, 2023”, 22 pgs. [cited by applicant]
“New Zealand Application Serial No. 797259, Voluntary Amendment filed Feb. 23, 2023”, 27 pgs. [cited by applicant]
Porter, D.L., et al., “Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia”, The New England Journal of Medicine 365:725-33. 2011., (Aug. 25, 2011), 9 pgs. [cited by applicant]
“Australian Application Serial No. 2018221171, Response filed Dec. 22, 2023 to First Examination Report mailed Oct. 31, 2023”, 33 pgs. [cited by applicant]
“Chinese Application Serial No. 201880024308.6, Decision of Rejection mailed Jan. 4, 2024”, w English Claims, 16 pgs. [cited by applicant]
“Indian Application Serial No. 201917036615, First Examination Report mailed Feb. 16, 2024”, 8 pgs. [cited by applicant]
“Japanese Application Serial No. 2023-047827, Notification of Reasons for Rejection mailed Apr. 2, 2024”, W English Translation, 12 pgs. [cited by applicant]
“Japanese Application Serial No. 2023-047827, Response filed Aug. 9, 2024 to Notification of Reasons for Rejection mailed Apr. 2, 2024”, W English Claims, 14 pgs. [cited by applicant]
“Chinese Application Serial No. 202410423409.8, Notification to Make Rectification (210302) mailed Jul. 31, 2024”, w Machine English translation, 3 pgs. [cited by applicant]
“Indian Application Serial No. 201917036615, Response filed Aug. 2, 2024 to First Examination Report mailed Feb. 16, 2024”, w English claims, 58 pgs. [cited by applicant]
“Japanese Application Serial No. 2023-047827, Final Notification of Reasons for Rejection mailed Nov. 26, 2024”, W English Translation, 10 pgs. [cited by applicant]
“Chinese Application Serial No. 202410423409.8, Office Action mailed Nov. 27, 2024”, w English Claims, 8 pgs. [cited by applicant]
Cited By (1)
US 12,622,973