IP Library › Granted Patent US 12,661,390
Granted Patent B2
US 12,661,390 · App. 17/765,728 · Granted Jun 23, 2026

ADAMTS13 treatment to enhance graft survival

Inventors: Denisa D. Wagner (Dover, MA); Siu Ling Wong (Singapore, SG)
Assignee: THE CHILDREN'S MEDICAL CENTER CORPORATION
A61K38/4886A61K45/06A61P37/06C12Y304/24082
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Quick Facts
Patent No.
US 12,661,390
App. No.
17/765,728
Filed
Mar 31, 2022
Granted
Jun 23, 2026
Kind
B2
Art Unit
1651
USPC
424/94.67
Abstract

The disclosure provides a method for treating and/or preventing graft rejection with A Disintegrin And Metalloproteinase with Thrombospondin type 1 motif, member-13 (ADAMT S13). The disclosure provides a method for increasing ADAMTS13-mediated von Willebrand factor (VWF) cleavage in a subject that received a graft by administering ADAMTS13. The disclosure also provides a method of determining the likelihood that a subject will rejection a graft.

Claims (18)

1 . A method for treating or preventing graft rejection in a subject that received a skin graft, the method comprising administering to the subject in need thereof a therapeutically effective amount of a composition comprising A Disintegrin And Metalloproteinase with Thrombospondin type 1 motif, member-13 (ADAMTS13), wherein administering ADAMTS13 reduces and/or prevents neutrophil extracellular trap (NET) burden in the skin graft.

2 . The method of claim 1 , wherein the subject is administered ADAMTS13 after at least one symptom of graft rejection is present, or wherein the subject is administered ADAMTS13 before a symptom of graft rejection is present.

3 . The method of claim 1 , wherein administering ADAMTS13 reduces and/or prevents at least one of graft deterioration, graft desiccation, graft shrinkage, scab formation, graft hardening, loss of hair, graft dysfunction, organ deterioration, organ damage, organ dysfunction, cell damage, inflammation, swelling, erythema, seroma, severity of pain, infection, neutrophil recruitment, lymphocyte recruitment, platelet aggregation, microthrombosis, generation of angiogenesis or a combination of any thereof as compared to control, the subject without treatment, and/or the subject before transplantation.

4 . The method of claim 3 , wherein the lymphocyte recruitment is T-cell recruitment.

5 . The claim of claim 3 , wherein the level of NET burden is determined by measuring the level of histone modifications, cell-free DNA, citrullinated histone H3 (H3Cit), citrullinated histone H4 (H4Cit), neutrophil elastase (NE), and/or myeloperoxidase (MPO) DNA conjugates.

6 . The method of claim 1 , wherein administering ADAMTS13 results in at least one of increased survival of the graft, improved organ function, increased survival of the subject, or a combination of any thereof as compared to control, the subject without treatment, and/or the subject before transplantation.

7 . The method of claim 1 , wherein the therapeutically effective amount of ADAMTS13 is from about 20 to about 6,000 international units per kilogram body weight.

8 . The method of claim 1 , wherein the composition comprising ADAMTS13 is administered in a single bolus injection, monthly, every two weeks, weekly, twice a week, daily, every twelve hours, every eight hours, every six hours, every four hours, or every two hours, and wherein the composition comprising ADAMTS13 is administered intravenously, subcutaneously, or dermally.

9 . The method of claim 1 , wherein the ADAMTS13 is recombinant ADAMTS13, or wherein the ADAMTS13 is plasma derived.

10 . The method of claim 1 , wherein the subject is a mammal or wherein the subject is a human.

11 . The method of claim 1 , wherein the composition is in a stable aqueous solution ready for administration.

12 . The method of claim 1 , wherein the therapeutically effective amount of the composition comprising ADAMTS13: is administered to the subject within 48 hours after receiving the graft, or is sufficient to maintain an effective level of ADAMTS13 activity in the subject.

13 . The method of claim 1 , wherein the graft is an allograft; an autograft; a xenograft obtained from a pig, a primate, or a cow; an artificially manufactured device; or wherein the graft is transplanted to the subject that is suffering from a wound, a burn, a damaged organ, or an infection, and/or the subject has undergone surgery.

14 . The method of claim 1 , further comprising modifying one or more additional genes or gene products such that the expression and/or function of said additional gene(s) or gene product(s) is reduced or eliminated, wherein said additional gene(s) or gene product(s) are PAD4, H3Cit, H4Cit, MPO, NE, or NLRP3.

15 . The method of claim 14 , wherein the modifying of one or more additional genes comprises: disrupting said gene(s) with a site-specific nuclease; administering an RNA interference (RNAi) molecule or an antisense oligonucleotide; or administering one or more of a small molecule inhibitor, a peptide, an antibody or antibody fragment, and an aptamer.

16 . The method of claim 15 , wherein the site-specific nuclease comprises a Cas protein and a guide RNA, a zinc finger nuclease (ZFN), a TALEN nuclease, or a mega-TALEN nuclease; or wherein the RNAi molecule is a small interfering RNA (siRNA) or a small hairpin RNA (shRNA).

17 . The method of claim 1 , further comprising inhibiting NET formation and/or neutrophil infiltration.

18 . The method of claim 17 , wherein the inhibiting NET formation comprises: administering one or more of a small molecule inhibitor, a peptide, an antibody or antibody fragment, and an aptamer; or by administering, increasing the expression of, and/or activating DNase 1.

Assignments (2)
LICENSE Recorded Dec 18, 2024
From: BOSTON CHILDREN'S HOSPITAL
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 069730/0898 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 7, 2022
From: WAGNER, DENISA D.; WONG, SIU LING
To: THE CHILDREN'S MEDICAL CENTER CORPORATION
Reel/Frame 059531/0651 →
Continuity (2)
Provisional Application 62911019 · Oct 4, 2019
Related Publication 20220339266A1 · Oct 27, 2022
References Cited (70)
US 8623352B2 · Mathiessen et al. · 2014 [cited by applicant]
US 8945895B2 · Hasslacher et al. · 2015 [cited by applicant]
US 11567080B2 · Hata et al. · 2023 [cited by applicant]
US 20050266528A1 · Laemmie et al. · 2005 [cited by applicant]
US 20110086413A1 · Grillberger et al. · 2011 [cited by applicant]
US 20110229455A1 · Mathiessen et al. · 2011 [cited by applicant]
US 20130136732A1 · Wagner · 2013 [cited by examiner]
US 20140271611A1 · Schiviz et al. · 2014 [cited by applicant]
US 20170196945A1 · Wagner · 2017 [cited by examiner]
US 20190161746A1 · Wagner et al. · 2019 [cited by applicant]
JP 2010280571A · 2010 [cited by applicant]
WO 2002042441A2 · 2002 [cited by applicant]
WO 2012006594A1 · 2012 [cited by applicant]
WO 2014151968A1 · 2014 [cited by applicant]
WO 2017119498A1 · 2017 [cited by applicant]
Mangold et al., “Coronary Neutrophil Extracellular Trap Burden and Deoxyribonuclease Activity in ST-Elevation Acute Coronary Syndrome Are Predictors of ST-Segment Resolution and Infarct Size”, Circulation Research, vol.… [cited by examiner]
Rahmel, “Vascularized Composite Allografts: Procurement, Allocation, and Implementation”, Current Transplantation Reports, vol. 1, pp. 173-182. (Year: 2014). [cited by examiner]
Motsch et al., “Microvascular integrity plays an important role for graft survival after experimental skin transplantation”, Transplant Immunology, vol. 33, pp. 204-209. (Year: 2015). [cited by examiner]
Hugenholtz et al. “An unbalance between von Willebrand factor and ADAMTS13 in acute liver failure: Implications for hemostasis and clinical outcome”, Hepatology 58.2: 752-761 (2013). [cited by applicant]
Ko et al. “Plasma ADAMTS13 activity may predict early adverse events in living donor liver transplantation: Observations in 3 cases”, Liver Transplantation 12.5: 859-869 (2006). [cited by applicant]
Kobayashi et al. “Decreased ADAMTS13 Levels in Patients after Living Donor Liver Transplantation”, Thrombosis Research 124.5: 541-545 (2009). [cited by applicant]
Matsui et al. “ADAMTS13 Improving the Cell Engraftment Efficacy in Mouse Model of Bone Marrow Transplantation”, Blood 120.21: Abstract 1077 (2012). [cited by applicant]
Benichou et al. “Immune recognition and rejection of allogeneic skin grafts.” Immunotherapy 3(6) 757-770 (2011). [cited by applicant]
Chauhan et al. “ADAMTS13: a new link between thrombosis and inflammation.” The Journal of experimental medicine 205(9): 2065-2074 (2008). [cited by applicant]
Chen et al. “Inflammation, von Willebrand factor, and ADAMTS13.” Blood 132(2): 141-147 (2018). [cited by applicant]
Cheng et al. “Murine full-thickness skin transplantation.” JoVE (Journal of Visualized Experiments) (119): e55105 (2017). [cited by applicant]
Emil et al. “Hemolytic uremic syndrome in a child with burn injuries.” The Journal of burn care & rehabilitation 19(2): 135-137 (1998). [cited by applicant]
Fuchs et al. “Extracellular DNA traps promote thrombosis.” PNAS107(36): 15880-15885 (2010). [cited by applicant]
Gelman et al. “Cutting edge: Acute lung allograft rejection is independent of secondary lymphoid organs.” The Journal of Immunology 182(7): 3969-3973 (2009). [cited by applicant]
Grassle et al. “von Willebrand factor directly interacts with DNA from neutrophil extracellular traps.” Arteriosclerosis, thrombosis, and vascular biology 34(7): 1382-1389 (2014). [cited by applicant]
Han et al. “A shear-based assay for assessing plasma ADAMTS13 activity and inhibitors in patients with thrombotic thrombocytopenia purpura.” Transfusion 51(7): 1580-1591 (2011). [cited by applicant]
Johnson et al. “Combat-related facial burns: analysis of strategic pitfalls.” Journal of Oral and Maxillofacial Surgery 73(1): 106-111 (2015). [cited by applicant]
Kanitakis et al. “Capillary thrombosis in the skin: a pathologic hallmark of severe/chronic rejection of human vascularized composite tissue allografts?” Transplantation 100(4): 954-957 (2016). [cited by applicant]
Kariya et al., “Direct evidence for activated CD8+ T cell transmigration across portal vein endothelial cells in liver graft rejection.” Journal of gastroenterology 51(10): 985-998 (2016). [cited by applicant]
Kawecki et al. “von Willebrand factor and inflammation.” Journal of Thrombosis and Haemostasis 15(7) 1285-1294 (2017). [cited by applicant]
Kitala et al., “Allogeneic vs. Autologous Skin Grafts in the Therapy of Patients with Burn Injuries: A Retrospective, Open-label Clinical Study with Pair Matching.” Adv Clin Exp Med. 25(5): 923-929 (2016). [cited by applicant]
Kiuchi et al. “Background and Prognostic Implications of Perireperfusion Tissue Injuries in Human Liver Transplants: A Panel Histochemical Study.” Transplantation 66(6): 737-747 (1998). [cited by applicant]
Kokame et al. “VWF73, a region from D1596 to R1668 of von Willebrand factor, provides a minimal substrate for ADAMTS-13.” Blood 103(2): 607-612 (2004). [cited by applicant]
Kokame et al. “FRETS-VWF73, a first fluorogenic substrate for ADAMTS13 assay.” British journal of haematology 129(1): 93-100 (2005). [cited by applicant]
Landsman et al. “Characterization of a cryopreserved split-thickness human skin allograft—TheraSkin.” Advances in skin & wound care 29(9): 399-406 (2016). [cited by applicant]
Lewis et al. “Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation.” Nature chemical biology 11(3): 189-191 (2015). [cited by applicant]
Li et al. “PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps.” Journal of Experimental Medicine 207(9): 1853-1862 (2010). [cited by applicant]
Maile et al. “Lymphopenia-induced homeostatic proliferation of CD8+ T cells is a mechanism for effective allogeneic skin graft rejection following burn injury.” The Journal of Immunology 176(11): 6717-6726 (2006). [cited by applicant]
Mishra et al. “Cutting edge: protein arginine deiminase 2 and 4 regulate NLRP3 inflammasome-dependent IL-1β maturation and ASC speck formation in macrophages.” The Journal of Immunology 203(4): 795-800 (Jul. 2019). [cited by applicant]
Moake. “Thrombotic microangiopathies.” New England Journal of Medicine 347(8): 589-600 (2002). [cited by applicant]
Münzer et al. “Abstract 118: Assembly of the Nlrp3 inflammasome regulates NET formation and is promoted by the vimentin intermediate filament cytoskeletal system.” Arteriosclerosis, Thrombosis, and Vascular Biology 39(S… [cited by applicant]
Nolasco et al. “Hemolytic uremic syndrome—associated Shiga toxins promote endothelial-cell secretion and impair ADAMTS13 cleavage of unusually large von Willebrand factor multimers.” Blood 106(13): 4199-4209 (2005). [cited by applicant]
Otawara et al. “Microfluidic assay measures increased neutrophil extracellular traps circulating in blood after burn injuries.” Scientific Reports 8(1): 1-9 (2018). [cited by applicant]
Öztürk et al. “Can burn injury cause thrombotic thrombocytopenia purpura?” Southern Clinics of Istanbul Eurasia 30(2) 175-177 (2019). [cited by applicant]
Peyvandi et al. “ADAMTS-13 assays in thrombotic thrombocytopeniarpura.” Journal of Thrombosis and Haemostasis 8(4): (2010): 631-640 (2010). [cited by applicant]
Pilon et al. “Administration of low doses of IL-2 combined to rapamycin promotes allogeneic skin graft survival in mice.” American Journal of Transplantation 14(12): 2874-2882 (2014). [cited by applicant]
Plaimauer et al., “Cloning, expression, and functional characterization of the von Willebrand factor-cleaving protease (ADAMTS13).” Blood 100(10): 3626-32 (2002). [cited by applicant]
Plaimauer et al. “Expression and characterization of recombinant human ADAMTS-13.” Seminars in hematology 41(1): 24-33 (2004). [cited by applicant]
Rieger et al. “Relation between ADAMTS13 activity and ADAMTS13 antigen levels in healthy donors and patients with thrombotic microangiopathies (TMA).” Thrombosis and haemostasis 95(02): 212-220 (2006). [cited by applicant]
Saffarzadeh et al. “Neutrophil extracellular traps directly induce epithelial and endothelial cell death: A predominant role of histones.” PloS one 7(2): 1-14 (2012). [cited by applicant]
Sayah et al. “Neutrophil extracellular traps are pathogenic in primary graft dysfunction after lung transplantation.” American journal of respiratory and critical care medicine 191(4): 455-463 (2015). [cited by applicant]
Scozzi et al. “Neutrophil extracellular trap fragments stimulate innate immune responses that prevent lung transplant tolerance.” American Journal of Transplantation 19(4): 1011-1023 (Apr. 2019). [cited by applicant]
Scully et al. “Recombinant ADAMTS-13: first-in-human pharmacokinetics and safety in congenital thrombotic thrombocytopenia purpura.” Blood 130(19): 2055-2063 (2017). [cited by applicant]
Shim et al. “Platelet-VWF complexes are preferred substrates of ADAMTS13 under fluid shear stress.” Blood 111(2): 651-657 (2008). [cited by applicant]
Sorvillo et al. “Plasma peptidylarginine deiminase IV promotes VWF-platelet string formation and accelerates thrombosis after vessel injury.” Circulation research 125(5): 507-519 (Aug. 2019). [cited by applicant]
Sun et al. “Citrullination of NF-κB p65 promotes its nuclear localization and TLR-induced expression of IL-1β and TNFα.” Science immunology 2(12): 1-32 (2017). [cited by applicant]
Suri. “The use of human deoxyribonuclease (rhDNase) in the management of cystic fibrosis.” BioDrugs 19(3): 135-144 (2005). [cited by applicant]
Tillack et al. “T lymphocyte priming by neutrophil extracellular traps links innate and adaptive immune responses.” The Journal of Immunology 188(7): 3150-3159 (2012). [cited by applicant]
Wolf et al. “Comparison between civilian burns and combat burns from Operation Iraqi Freedom and Operation Enduring Freedom.” Annals of surgery 243(6): 786-795 (2006). [cited by applicant]
Wong et al. “Diabetes primes neutrophils to undergo NETosis, which impairs wound healing.” Nature medicine 21(7): 815-819 (2015). [cited by applicant]
Xu et al. “Extracellular histones are major mediators of death in sepsis.” Nature medicine 15(11): 1318-1321 (2009). [cited by applicant]
Hull et al., “Why some organ allografts are tolerated better than others: new insights for an old question.” Current opinion in organ transplantation 24.1: 49-57 (2019). [cited by applicant]
Jansen et al. “Release of extracellular DNA influences renal ischemia reperfusion injury by platelet activation and formation of neutrophil extracellular traps.” Kidney international vol. 91,2 (2017): 352-364. [cited by applicant]
Khodor et al. “Clopidogrel-induced refractory thrombotic thrombocytopenia purpura successfully treated with rituximab.” Hematology/oncology and stem cell therapy 9,2 (2016): 76-79. [cited by applicant]
Savchenko et al. “VWF-mediated leukocyte recruitment with chromatin decondensation by PAD4 increases myocardial ischemia/reperfusion injury in mice.” Blood 123.1 : 141-148 (2014). [cited by applicant]