Granted Patent
B2
US 12,644,888 · App. 17/626,679 · Granted Jun 2, 2026
Methods for treating cerebral vasospasm with a PD-1 agonist
Inventors:
Michael Lim (Reisterstown, MD); Christopher Jackson (Baltimore, MD); Rafael J. Tamargo (Baltimore, MD); John Choi (Palo Alto, CA)
Assignee:
The Johns Hopkins University
G01N33/56972A61K38/1774A61K39/3955A61P9/10C07K14/70532A61K2039/505C07K2319/00G01N2333/70532G01N2800/2871G01N2800/52
View Patent ↗
Loading inventors, assignments & file history…
Abstract
The present invention relates to the field of inflammation. More specifically, the present invention provides compositions and methods for treating cerebral inflammation and associated sequelae thereof including cerebral vasospasm. In one embodiment, a method for treating cerebral vasospasm in a patient comprises the step of administering to the patient a PD-1 agonist, wherein a blood sample obtained from the patient comprises elevated PD-1 expression on monocytes relative to a control.
Claims (18)
1 . A method comprising:
a. measuring programmed death-1 (PD-1) expression on monocytes in a blood sample obtained from a patient, wherein the patient has suffered a hemorrhagic or ischemic stroke; and
b. treating the patient with soluble PD-L1 if the PD-1 expression is increased relative to a control.
2 . The method of claim 1 , wherein the PD-1 expression on monocytes is measured using flow cytometry.
3 . The method of claim 1 , wherein the soluble PD-L1 is a PD-L1 fusion protein.
4 . The method of claim 1 , wherein the patient suffers from an aneurysmal subarachnoid hemorrhage.
5 . The method of claim 1 , wherein the patient has cerebral vasospasm.
6 . The method of claim 1 , wherein the patient has suffered a brain injury.
7 . A method comprising administering to a patient having an increased PD-1 expression on monocytes relative to a control soluble PD-L1, wherein the patient has suffered a hemorrhagic or ischemic stroke.
8 . The method of claim 7 , wherein the soluble PD-L1 is a PD-L1 fusion protein.
9 . The method of claim 7 , wherein the patient suffers from an aneurysmal subarachnoid hemorrhage.
10 . The method of claim 7 , wherein the patient has cerebral vasospasm.
11 . The method of claim 7 , wherein the patient has suffered a brain injury.
12 . The method of claim 7 , wherein the patient has or is suspected of having a monocyte-cerebral inflammation.
13 . A method for treating cerebral vasospasm in a patient comprising the step of administering to the patient soluble PD-1, wherein a blood sample obtained from the patient comprises elevated PD-1 expression on monocytes relative to a control.
14 . The method of claim 13 , wherein the patient has suffered a brain injury.
15 . The method of claim 13 , wherein the patient has suffered a stroke.
16 . The method of claim 13 , wherein the patient has suffered a myocardial infarction.
Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jul 12, 2022
From: LIM, MICHAEL; JACKSON, CHRISTOPHER; TAMARGO, RAFAEL J.; CHOI, JOHN
To: THE JOHNS HOPKINS UNIVERSITY
Reel/Frame 060487/0064 →
Continuity (2)
Provisional Application
62873439
· Jul 12, 2019
References Cited (60)
US 4103687A
· Ishii
· 1978
[cited by applicant]
US 6004986A
· Arthur et al.
· 1999
[cited by applicant]
US 7867491B2
· Yang et al.
· 2011
[cited by applicant]
US 8586038B2
· Yang et al.
· 2013
[cited by applicant]
US 8927697B2
· Davis et al.
· 2015
[cited by applicant]
US 9181342B2
· Davis
· 2015
[cited by applicant]
US 9683043B2
· Davis et al.
· 2017
[cited by applicant]
US 9701749B2
· Shibayama et al.
· 2017
[cited by applicant]
US 20120269806A1
· Sykes
· 2012
[cited by examiner]
WO 2002064022
· 2002
[cited by applicant]
WO 2006127587
· 2006
[cited by applicant]
Han et al., PD-L1 (Programmed Death Ligand 1) Protects Against Experimental Intracerebral Hemorrhage-Induced Brain Injury, Stroke, vol. 48, No. 8, pp. 2255-2262 (2017).
[cited by applicant]
Han, R., et al. PD-L1 (Programmed Death Ligand 1) Protects Against Experimental Intracerebral Hemorrhage-Induced Brain Injury. Stroke. vol. 48, No. 8, Aug. 1, 2017, pp. 2255-2262.
[cited by applicant]
Ren, X. Programmed Death-1 Pathway Limits Central Nervous System Inflammation and Neurologic Deficits in Murine Experimental Stroke. Stroke. vol. 41. No. 9, Sep. 1, 2011, pp. 2578-2583.
[cited by applicant]
Chen, et al., Enhanced Expression of PD-L1 on Microglia after Surgical Brain Injury Exerts Self-Protection from Inflammation and Promotes Neurological Repair. Neurochemical Research (2019) 44: 2470-2481.
[cited by applicant]
Wang, et al., PDL1 Fusion Protein Protects Against Experimental Cerebral Malaria via Repressing Over-Reactive CD8+ T Cell Responses. Frontiers in Immunology (2018) 9:3157, pp. 1-13.
[cited by applicant]
Zhang, et al., Association Between Programmed Cell Death-1 and CD4+ T Cell Alternations in Different Phases of Ischemic Stroke Patients (2018) 12: 170, pp. 1-11.
[cited by applicant]
Jedrzejowska-Szypulka,H. et al., “Neutralization of interleukin-1beta reduces vasospasm and alters cerebral blood vessel density following experimental subarachnoid hemorrhage in rats,” Curr. Neurovasc Res., 6(2):95-103…
[cited by applicant]
Yuan et al., “Programmed death (PD)-1 attenuates macrophage activation and brain inflammation via regulation of fibrinogen-like protein 2 (Fgl-2) after intracerebral hemorrhage in mice,” Immunol. Lett., 179: 114-121 (20…
[cited by applicant]
Ferro, et al., Update on subarachnoid haemorrhage. J Neurol 255, 465-479 (2008).
[cited by applicant]
Charpentier, et al., Multivariate analysis of predictors of cerebral vasospasm occurrence after aneurysmal subarachnoid hemorrhage. Stroke 130, 1402-8 (1999).
[cited by applicant]
Hijdra, et al., Prediction of delayed cerebral ischemia, rebleeding, and outcome after aneurysmal subarachnoid hemorrhage. Stroke 19, 1250-6 (1988).
[cited by applicant]
Chaichana, et al., Haptoglobin 2-2 Genotype Determines Chronic Vasospasm After Experimental Subarachnoid Hemorrhage. Stroke 38, 3266-3271 (2007).
[cited by applicant]
Barber, et al., Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682-687 (2005).
[cited by applicant]
Fife, et al., The role of the PD-1 pathway in autoimmunity and peripheral tolerance. Annals of the New York Academy of Sciences 1217, 45-59 (2011).
[cited by applicant]
Dong, et al., Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion. Nat Med 8, 793-800 (2002).
[cited by applicant]
Topalian, et al., Immune Checkpoint Blockade: A Common Denominator Approach to Cancer Therapy. Cancer Cell 27, 450-461 (2015).
[cited by applicant]
Gaetani, et al., Cisternal CSF levels of cytokines after subarachnoid hemorrhage. Taylor & Francis 20, 337-342 (2016).
[cited by applicant]
Kaynar, et al., Detection of soluble intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in both cerebrospinal fluid and serum of patients after aneurysmal subarachnoid hemorrhage. Journal of Neurosu…
[cited by applicant]
Polin, et al., Detection of soluble E-selectin, ICAM-1, VCAM-1, and Lselectin in the cerebrospinal fluid of patients after subarachnoid hemorrhage. Journal of Neurosurgery 89, 559-567 (2019).
[cited by applicant]
Kikuchi, et al., Cytokine production in cerebrospinal fluid after subarachnoid haemorrhage. Taylor & Francis 17, 106-108 (2016).
[cited by applicant]
Xie, et al., Increase ICAM-1 and LFA-1 expression by cerebrospinal fluid of subarachnoid hemorrhage patients: Involvement of TNF-alpha Brain Research 1512, 89-96 (2013).
[cited by applicant]
Schneider, et al., Functional analysis of Pro-inflammatory properties within the cerebrospinal fluid after subarachnoid hemorrhage in vivo and in vitro. J Neuroinflammation 9, 330-2 (2012).
[cited by applicant]
Barrow, et al., The role of inflammation and potential use of sex steroids in intracranial aneurysms and subarachnoid hemorrhage. Surg Neurol Int 9, 150-2 (2018).
[cited by applicant]
Froehler, et al., Vasospasm after subarachnoid hemorrhage in haptoglobin 2-2 mice can be prevented with a glutathione peroxidase mimetic. Journal of Clinical Neuroscience 17, 1169-1172 (2010).
[cited by applicant]
Schallner, et al., Microglia regulate blood clearance in subarachnoid hemorrhage by heme oxygenase-1. J. Clin. Invest. 125, 2609-2625 (2015).
[cited by applicant]
Kubota, et al., The kinetics of lymphocyte subsets and macrophages in subarachnoid space after subarachnoid hemorrhage in rats. Am Heart Assoc 24, 1993-2000 (1993).
[cited by applicant]
Provencio, et al., CSF Neutrophils Are Implicated in the Development of Vasospasm in Subarachnoid Hemorrhage. Neurocrit Care 12, 244-251 (2009).
[cited by applicant]
Spitzer, et al., Activation of Cytotoxic Natural Killer Cells After Aneurysmal Subarachnoid Hemorrhage. World Neurosurgery 101, 666-676.e1 (2017).
[cited by applicant]
Huang, et al., PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis. Proceedings of the National Academy of Sciences 106, 6303-6308 (2009).
[cited by applicant]
Loftus, et al., Beta-Blockade use for Traumatic Injuries and Immunomodulation. Shock 46, 341-351 (2016).
[cited by applicant]
Bunc, et al., The influence of noradrenergic blockage on vasospasm and the quantity of cerebral dopamine ß-hydroxylase following subarachnoid haemorrhage in rabbits. Wien Klin Wochenschr 115, 652-659 (2003).
[cited by applicant]
Chalouhi, et al., Beta-blocker therapy and impact on outcome after aneurysmal subarachnoid hemorrhage: a cohort study. Journal of Neurosurgery 125, 730-736 (2019).
[cited by applicant]
Chang, et al., Beta Blockade and Clinical Outcomes in Aneurysmal Subarachnoid Hemorrhage. TONEUJ 10, 155-163 (2016).
[cited by applicant]
Stansfield, et al., Clinical significance of monocyte heterogeneity. Clin Trans Med 4, 2527-2 (2015).
[cited by applicant]
Mildner, et al., Genomic Characterization of Murine Monocytes Reveals C/EFPBeta Transcription Factor Dependence of Ly6C-cells. Immunity 46, 849-862.e7 (2017).
[cited by applicant]
Prinz, et al., Tickets to the brain: Role of CCR2 and CX3CR1 in myeloid cell entry in the CNS. Journal of Neuroimmunology 224, 80-84 (2010).
[cited by applicant]
Huo, et al., Role of vascular cell adhesion molecule-1 and fibronectin connecting segment-1 in monocyte rolling and adhesion on early atherosclerotic lesions. Circ Res 87, 153-159 (2000).
[cited by applicant]
Yednock, et al., Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha4beta1 integrin. Nature 356, 63-66 (1992).
[cited by applicant]
De Rooij, et al., Incidence of subarachnoid haemorrhage: a systematic review with emphasis on region, age, gender and time trends. J Neurol Neurosurg Psychiatry, 78, 1365-1372 (2007).
[cited by applicant]
Ingall, et al., A Multinational Comparison of Subarachnoid Hemorrhage Epidemiology in the Who Monica Stroke Study. Stroke, 31, 1054-1061 (2000).
[cited by applicant]
Rincon, et al., The epidemiology of admissions of nontraumatic subarachnoid hemorrhage in the United States. Neurosurgery, 72, 217-22 (2013).
[cited by applicant]
Dabus, et al., Current options for the management of aneurysmal subarachnoid hemorrhage-induced cerebral vasospasm: a comprehensive review of the literature. Interv Neurol, 2, 30-51 (2013).
[cited by applicant]
Lynes, et al., Current Options and Future Directions in Immune Therapy for Glioblastoma. Front Oneal. 2018; 8:578; DOI: 10.3389/fonc.2018.00578.
[cited by applicant]
Arrieta et al., Expression of PD-1/PD-LI and PD-L2 in peripheral T-cells from non-small cell lung cancer patients. Oncotarget. 2017; 8(60):101994-102005; DOI: 10.18632/oncotarget.22025.
[cited by applicant]
Bodhankar, et al., PD-LI mAb Treats Ischemic Stroke by Controlling CNS Inflammation. Stroke. 2015; 46(10): 2926-; DOI: 10.1161/STROKEAHA.115.010592.
[cited by applicant]
Yu, et al., Therapeutic Antibodies in Stroke. Transl. Stroke Res. 2013; 4:477-; DOI 10.1007 Is 12975-013-0281-2.
[cited by applicant]