Prevention of cerebral vasospasm by a humanized anti-CD11/CD18 monoclonal antibody administered after experimental subarachnoid hemorrhage in nonhuman primates

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  • 1 Department of Neurological Surgery and Division of Interventional Neuroradiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; and ICOS Corporation, Bothell, Washington
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Object. Leukocyte—endothelial cell interactions occurring in the first hours after subarachnoid hemorrhage (SAH) initiate changes in the endothelium and vessel wall that lead to an influx of leukocytes and the development of chronic vasospasm days later. Upregulation of intercellular adhesion molecule—1 (ICAM-1), also called CD54, appears to be a crucial step in this process. There is increasing experimental evidence that blocking the interaction between ICAM-1, which is expressed on endothelium, and integrins such as lymphocyte function—associated antigen—1 (CD11a/CD18) and macrophage antigen—1 (complement receptor 3, CD11b/CD18), which are expressed on the surface of leukocytes, prevents not only inflammation of vessel walls but also chronic vasospasm. The authors extend their previous work with monoclonal antibody (mAb) blockade of leukocyte migration to a nonhuman primate model of chronic, posthemorrhagic cerebral vasospasm.

Methods. Before surgery was performed, six young adult male cynomolgus monkeys underwent baseline selective biplane common carotid and vertebrobasilar artery cerebral angiography via a transfemoral route. On Day 0, a right frontosphenotemporal craniectomy was performed with arachnoid microdissection and placement of 2 to 3 ml of clotted autologous blood in the ipsilateral basal cisterns. The animals were given daily intravenous infusions of 2 mg/kg of either a humanized anti-CD11/CD18 or a placebo mAb beginning 30 to 60 minutes postoperatively. The monkeys were killed on Day 7 after a repeated selective cerebral angiogram was obtained. The area of contrast-containing vessels observed in each hemisphere on anteroposterior angiographic views was calculated for the angiograms obtained on Day 7 and expressed as a percentage of the area on baseline angiograms (percent control areal fraction). Review of flow cytometry and enzyme immunoassay data confirmed the presence of the anti-CD11/CD18 antibody in the serum and bound to leukocytes in the peripheral blood of treated animals. Comparisons of the groups revealed 53 ± 4.8% control vascular areal fraction in the placebo group (two animals) and 95.8 ± 9.4% in the anti-CD11/CD18—treated group (three animals), a statistically significant difference (p = 0.043, t-test).

Conclusions. These results show that blockade of leukocyte migration into the subarachnoid space by an anti-CD11/CD18 mAb is effective in preventing experimental cerebral vasospasm in nonhuman primates, despite the unaltered presence of hemoglobin in the subarachnoid space. These experimental data support the hypothesis that inflammation plays a role in cerebral vasospasm after SAH.

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Contributor Notes

Address reprint requests to: Rafael J. Tamargo, M.D., Department of Neurological Surgery, The Johns Hopkins Hospital, Meyer 8–181, 600 North Wolfe Street, Baltimore, Maryland 21287. email: rtamarg@jhmi.edu.
  • 1.

    Ahn YM, , Gajdusek C, & London S, et al: Sustained arterial narrowing after prolonged exposure to perivascular endothelin. Neurosurgery 50:843849, 2002 Ahn YM, Gajdusek C, London S, et al: Sustained arterial narrowing after prolonged exposure to perivascular endothelin. Neurosurgery 50:843–849, 2002

    • Search Google Scholar
    • Export Citation
  • 2.

    Akopov SE, , Grigorian GS, & Ovanessian GA: Deactivation of NO by polymorphonuclear leukocytes in patients with ischemic cerebral infarction. Stroke 27:23372338, 1996 (Letter) Akopov SE, Grigorian GS, Ovanessian GA: Deactivation of NO by polymorphonuclear leukocytes in patients with ischemic cerebral infarction. Stroke 27:2337–2338, 1996 (Letter)

    • Search Google Scholar
    • Export Citation
  • 3.

    Akopov SE, , Grigorian MR, & Gabrielian ES: The endothelium-dependent relaxation of human middle cerebral arteries: effects of activated neutrophils. Experientia 48:3436, 1992 Akopov SE, Grigorian MR, Gabrielian ES: The endothelium-dependent relaxation of human middle cerebral arteries: effects of activated neutrophils. Experientia 48:34–36, 1992

    • Search Google Scholar
    • Export Citation
  • 4.

    Akopov SE, , Pogossian SS, & Toromanian EN, et al: Increased nitric oxide deactivation by polymorphonuclear leukocytes in patients with intermittent claudication. J Vasc Surg 25:704712, 1997 Akopov SE, Pogossian SS, Toromanian EN, et al: Increased nitric oxide deactivation by polymorphonuclear leukocytes in patients with intermittent claudication. J Vasc Surg 25:704–712, 1997

    • Search Google Scholar
    • Export Citation
  • 5.

    Aversano T, , Zhou W, & Nedelman M, et al: A chimeric IgG4 monoclonal antibody directed against CD18 reduces infarct size in a primate model of myocardial ischemia and reperfusion. J Am Coll Cardiol 25:781788, 1995 Aversano T, Zhou W, Nedelman M, et al: A chimeric IgG4 monoclonal antibody directed against CD18 reduces infarct size in a primate model of myocardial ischemia and reperfusion. J Am Coll Cardiol 25:781–788, 1995

    • Search Google Scholar
    • Export Citation
  • 6.

    Baker KF, , Zervas NT, & Pile-Spellman J, et al: Angiographic evidence of basilar artery constriction in the rabbit: a new model of vasospasm. Surg Neurol 27:107112, 1987 Baker KF, Zervas NT, Pile-Spellman J, et al: Angiographic evidence of basilar artery constriction in the rabbit: a new model of vasospasm. Surg Neurol 27:107–112, 1987

    • Search Google Scholar
    • Export Citation
  • 7.

    Bavbek M, , Polin R, & Kwan AL, et al: Monoclonal antibodies against ICAM-1 and CD 18 attenuate cerebral vasospasm after experimental subarachnoid hemorrhage in rabbits. Stroke 29:19301936, 1998 Bavbek M, Polin R, Kwan AL, et al: Monoclonal antibodies against ICAM-1 and CD 18 attenuate cerebral vasospasm after experimental subarachnoid hemorrhage in rabbits. Stroke 29:1930–1936, 1998

    • Search Google Scholar
    • Export Citation
  • 8.

    Bowen JD, , Petersdorf SH, & Richards TL, et al: Phase I study of a humanized anti-CD11/CD18 monoclonal antibody in multiple sclerosis. Clin Pharmacol Ther 64:339346, 1998 Bowen JD, Petersdorf SH, Richards TL, et al: Phase I study of a humanized anti-CD11/CD18 monoclonal antibody in multiple sclerosis. Clin Pharmacol Ther 64:339–346, 1998

    • Search Google Scholar
    • Export Citation
  • 9.

    Chyatte D: Anti-inflammatory agents and cerebral vasospasm. Neurosurg Clin N Am 1:433450, 1990 Chyatte D: Anti-inflammatory agents and cerebral vasospasm. Neurosurg Clin N Am 1:433–450, 1990

    • Search Google Scholar
    • Export Citation
  • 10.

    Chyatte D: Prevention of chronic cerebral vasospasm in dogs with ibuprofen and high-dose methylprednisolone. Stroke 20:10211026, 1989 Chyatte D: Prevention of chronic cerebral vasospasm in dogs with ibuprofen and high-dose methylprednisolone. Stroke 20:1021–1026, 1989

    • Search Google Scholar
    • Export Citation
  • 11.

    Chyatte D, , Rusch N, & Sundt TM Jr: Prevention of chronic experimental cerebral vasospasm with ibuprofen and high-dose methylprednisolone. J Neurosurg 59:925932, 1983 Chyatte D, Rusch N, Sundt TM Jr: Prevention of chronic experimental cerebral vasospasm with ibuprofen and high-dose methylprednisolone. J Neurosurg 59:925–932, 1983

    • Search Google Scholar
    • Export Citation
  • 12.

    Clatterbuck RE, , Oshiro EM, & Hoffman PA, et al: Inhibition of vasospasm with lymphocyte function-associated antigen—1 monoclonal antibody in a femoral artery model in rats. J Neurosurg 97:676682, 2002 Clatterbuck RE, Oshiro EM, Hoffman PA, et al: Inhibition of vasospasm with lymphocyte function-associated antigen—1 monoclonal antibody in a femoral artery model in rats. J Neurosurg 97:676–682, 2002

    • Search Google Scholar
    • Export Citation
  • 13.

    Crompton MR: The pathogenesis of cerebral infarction following the rupture of cerebral berry aneurysms. Brain 87:491510, 1964 Crompton MR: The pathogenesis of cerebral infarction following the rupture of cerebral berry aneurysms. Brain 87:491–510, 1964

    • Search Google Scholar
    • Export Citation
  • 14.

    Ehrenreich H, , Anderson RW, & Fox CH, et al: Endothelins, peptides with potent vasoactive properties, are produced by human macrophages. J Exp Med 172:17411748, 1990 Ehrenreich H, Anderson RW, Fox CH, et al: Endothelins, peptides with potent vasoactive properties, are produced by human macrophages. J Exp Med 172:1741–1748, 1990

    • Search Google Scholar
    • Export Citation
  • 15.

    Espinosa F, , Weir B, & Boisvert D, et al: Chronic cerebral vasospasm after large subarachnoid hemorrhage in monkeys. J Neurosurg 57:224232, 1982 Espinosa F, Weir B, Boisvert D, et al: Chronic cerebral vasospasm after large subarachnoid hemorrhage in monkeys. J Neurosurg 57:224–232, 1982

    • Search Google Scholar
    • Export Citation
  • 16.

    Espinosa F, , Weir B, & Overton T, et al: A randomized placebo-controlled double-blind trial of nimodipine after SAH in monkeys. Part 1: Clinical and radiological findings. J Neurosurg 60:11671175, 1984 Espinosa F, Weir B, Overton T, et al: A randomized placebo-controlled double-blind trial of nimodipine after SAH in monkeys. Part 1: Clinical and radiological findings. J Neurosurg 60:1167–1175, 1984

    • Search Google Scholar
    • Export Citation
  • 17.

    Espinosa F, , Weir B, & Shnitka R, et al: A randomized placebo-controlled double-blind trial of nimodipine after SAH in monkeys. Part 2: Pathological findings. J Neurosurg 60:11761185, 1984 Espinosa F, Weir B, Shnitka R, et al: A randomized placebo-controlled double-blind trial of nimodipine after SAH in monkeys. Part 2: Pathological findings. J Neurosurg 60:1176–1185, 1984

    • Search Google Scholar
    • Export Citation
  • 18.

    Gundersen HJG, , Bendtsen TF, & Korbo L, et al: Some new, simple and efficient stereological methods and their use in pathological research and diagnosis. APMIS 96:379394, 1988 Gundersen HJG, Bendtsen TF, Korbo L, et al: Some new, simple and efficient stereological methods and their use in pathological research and diagnosis. APMIS 96:379–394, 1988

    • Search Google Scholar
    • Export Citation
  • 19.

    Handa Y, , Kabuto M, & Kobayashi H, et al: The correlation between immunological reaction in the arterial wall and the time course of the development of cerebral vasospasm in a primate model. Neurosurgery 28:542549, 1991 Handa Y, Kabuto M, Kobayashi H, et al: The correlation between immunological reaction in the arterial wall and the time course of the development of cerebral vasospasm in a primate model. Neurosurgery 28:542–549, 1991

    • Search Google Scholar
    • Export Citation
  • 20.

    Handa Y, , Kubota T, & Kaneko M, et al: Expression of intercellular adhesion molecule 1 (ICAM-1) on the cerebral artery following subarachnoid hemorrhage in rats. Acta Neurochir 132:9297, 1995 Handa Y, Kubota T, Kaneko M, et al: Expression of intercellular adhesion molecule 1 (ICAM-1) on the cerebral artery following subarachnoid hemorrhage in rats. Acta Neurochir 132:92–97, 1995

    • Search Google Scholar
    • Export Citation
  • 21.

    Handa Y, , Weir BKA, & Nosko M, et al: The effect of timing of clot removal on chronic vasospasm in a primate model. J Neurosurg 67:558564, 1987 Handa Y, Weir BKA, Nosko M, et al: The effect of timing of clot removal on chronic vasospasm in a primate model. J Neurosurg 67:558–564, 1987

    • Search Google Scholar
    • Export Citation
  • 22.

    Hoshi T, , Shimizu T, & Kito K, et al: [Immunological study of late cerebral vasospasm in subarachnoid hemorrhage. Detection of immunoglobulins, C3, and fibrinogen in cerebral arterial walls by immunofluorescence method.] Neurol Med Chir 24:647654, 1984 (Jpn) Hoshi T, Shimizu T, Kito K, et al: [Immunological study of late cerebral vasospasm in subarachnoid hemorrhage. Detection of immunoglobulins, C3, and fibrinogen in cerebral arterial walls by immunofluorescence method.] Neurol Med Chir 24:647–654, 1984 (Jpn)

    • Search Google Scholar
    • Export Citation
  • 23.

    Hughes JT, & Schianchi PM: Cerebral artery spasm. A histological study at necropsy of the blood vessels in cases of subarachnoid hemorrhage. J Neurosurg 48:515525, 1978 Hughes JT, Schianchi PM: Cerebral artery spasm. A histological study at necropsy of the blood vessels in cases of subarachnoid hemorrhage. J Neurosurg 48:515–525, 1978

    • Search Google Scholar
    • Export Citation
  • 24.

    Kasuya H, & Shimizu T: Activated complement components C3a and C4a in cerebrospinal fluid and plasma following subarachnoid hemorrhage. J Neurosurg 71:741746, 1989 Kasuya H, Shimizu T: Activated complement components C3a and C4a in cerebrospinal fluid and plasma following subarachnoid hemorrhage. J Neurosurg 71:741–746, 1989

    • Search Google Scholar
    • Export Citation
  • 25.

    Kobayashi H, , Hayashi M, & Kobayashi S, et al: Cerebral vasospasm and vasoconstriction caused by endothelin. Neurosurgery 28:673679, 1991 Kobayashi H, Hayashi M, Kobayashi S, et al: Cerebral vasospasm and vasoconstriction caused by endothelin. Neurosurgery 28:673–679, 1991

    • Search Google Scholar
    • Export Citation
  • 26.

    Megyesi JF, , Vollrath B, & Cook DA, et al: In vivo animal models of cerebral vasospasm: a review. Neurosurgery 46:448461, 2000 Megyesi JF, Vollrath B, Cook DA, et al: In vivo animal models of cerebral vasospasm: a review. Neurosurgery 46:448–461, 2000

    • Search Google Scholar
    • Export Citation
  • 27.

    Okada T, , Harada T, & Bark DH, et al: A rat femoral artery model of vasospasm. Neurosurgery 27:349356, 1990 Okada T, Harada T, Bark DH, et al: A rat femoral artery model of vasospasm. Neurosurgery 27:349–356, 1990

    • Search Google Scholar
    • Export Citation
  • 28.

    Oshiro EM, , Hoffman PA, & Dietsch GN, et al: Inhibition of experimental vasospasm with anti-intercellular adhesion molecule-1 monoclonal antibody in rats. Stroke 28:20312038, 1997 Oshiro EM, Hoffman PA, Dietsch GN, et al: Inhibition of experimental vasospasm with anti-intercellular adhesion molecule-1 monoclonal antibody in rats. Stroke 28:2031–2038, 1997

    • Search Google Scholar
    • Export Citation
  • 29.

    Ostergaard JR, , Kristensen BO, & Svehag SE, et al: Immune complexes and complement activation following rupture of intracranial saccular aneurysms. J Neurosurg 66:891897, 1987 Ostergaard JR, Kristensen BO, Svehag SE, et al: Immune complexes and complement activation following rupture of intracranial saccular aneurysms. J Neurosurg 66:891–897, 1987

    • Search Google Scholar
    • Export Citation
  • 30.

    Pellettieri L, , Carlson CA, & Lindholm L: Is the vasospasm following subarachnoid hemorrhage an immunoreactive disease? Experientia 37:11701171, 1981 Pellettieri L, Carlson CA, Lindholm L: Is the vasospasm following subarachnoid hemorrhage an immunoreactive disease? Experientia 37:1170–1171, 1981

    • Search Google Scholar
    • Export Citation
  • 31.

    Pellettieri L, , Nilsson B, & Carlsson CA, et al: Serum immunocomplexes in patients with subarachnoid hemorrhage. Neurosurgery 19:767771, 1986 Pellettieri L, Nilsson B, Carlsson CA, et al: Serum immunocomplexes in patients with subarachnoid hemorrhage. Neurosurgery 19:767–771, 1986

    • Search Google Scholar
    • Export Citation
  • 32.

    Peterson JW, , Kwun BD, & Hackett JD, et al: The role of inflammation in experimental cerebral vasospasm. J Neurosurg 72:767774, 1990 Peterson JW, Kwun BD, Hackett JD, et al: The role of inflammation in experimental cerebral vasospasm. J Neurosurg 72:767–774, 1990

    • Search Google Scholar
    • Export Citation
  • 33.

    Petruk KC, , Weir BKA, & Marriott MR, et al: Clinical grade, regional cerebral blood flow and angiographical spasm in the monkey after subarachnoid and subdural hemorrhage. Stroke 4:431445, 1973 Petruk KC, Weir BKA, Marriott MR, et al: Clinical grade, regional cerebral blood flow and angiographical spasm in the monkey after subarachnoid and subdural hemorrhage. Stroke 4:431–445, 1973

    • Search Google Scholar
    • Export Citation
  • 34.

    Polin RS, , Bavbek M, & Shaffrey ME, et al: Detection of soluble Eselectin, ICAM-1, VCAM-1, and L-selectin in the cerebrospinal fluid of patients after subarachnoid hemorrhage. J Neurosurg 89:559567, 1998 Polin RS, Bavbek M, Shaffrey ME, et al: Detection of soluble Eselectin, ICAM-1, VCAM-1, and L-selectin in the cerebrospinal fluid of patients after subarachnoid hemorrhage. J Neurosurg 89:559–567, 1998

    • Search Google Scholar
    • Export Citation
  • 35.

    Rose LM, , Richards TL, & Peterson J, et al: Resolution of CNS lesions following treatment of experimental allergic encephalomyelitis in macaques with monoclonal antibody to the CD18 leukocyte integrin. Mult Scler 2:259266, 1997 Rose LM, Richards TL, Peterson J, et al: Resolution of CNS lesions following treatment of experimental allergic encephalomyelitis in macaques with monoclonal antibody to the CD18 leukocyte integrin. Mult Scler 2:259–266, 1997

    • Search Google Scholar
    • Export Citation
  • 36.

    Rousseaux P, , Scherpereel B, & Bernard MH, et al: Fever and cerebral vasospasm in ruptured intracranial aneurysms. Surg Neurol 14:459465, 1980 Rousseaux P, Scherpereel B, Bernard MH, et al: Fever and cerebral vasospasm in ruptured intracranial aneurysms. Surg Neurol 14:459–465, 1980

    • Search Google Scholar
    • Export Citation
  • 37.

    Rusnak JM, , Kopecky SL, & Clements IP, et al: An anti-CD11/CD18 monoclonal antibody in patients with acute myocardial infarction having percutaneous transluminal coronary angioplasty (the FESTIVAL study). Am J Cardiol 88:482487, 2001 Rusnak JM, Kopecky SL, Clements IP, et al: An anti-CD11/CD18 monoclonal antibody in patients with acute myocardial infarction having percutaneous transluminal coronary angioplasty (the FESTIVAL study). Am J Cardiol 88:482–487, 2001

    • Search Google Scholar
    • Export Citation
  • 38.

    Sessa WC, , Kaw S, & Hecker M, et al: The biosynthesis of endothelin-1 by human polymorphonuclear leukocytes. Biochem Biophys Res Commun 174:613618, 1991 Sessa WC, Kaw S, Hecker M, et al: The biosynthesis of endothelin-1 by human polymorphonuclear leukocytes. Biochem Biophys Res Commun 174:613–618, 1991

    • Search Google Scholar
    • Export Citation
  • 39.

    Sills AK Jr, , Clatterbuck RE, & Thompson RC, et al: Endothelial cell expression of intercellular adhesion molecule 1 in experimental posthemorrhagic vasospasm. Neurosurgery 41:453461, 1997 Sills AK Jr, Clatterbuck RE, Thompson RC, et al: Endothelial cell expression of intercellular adhesion molecule 1 in experimental posthemorrhagic vasospasm. Neurosurgery 41:453–461, 1997

    • Search Google Scholar
    • Export Citation
  • 40.

    Suzuki R, , Masaoka H, & Hirata Y, et al: The role of endothelin-1 in the origin of cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage. J Neurosurg 77:96100, 1992 Suzuki R, Masaoka H, Hirata Y, et al: The role of endothelin-1 in the origin of cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage. J Neurosurg 77:96–100, 1992

    • Search Google Scholar
    • Export Citation
  • 41.

    Thai QA, , Oshiro EM, & Tamargo RJ: Inhibition of experimental vasospasm in rats with the periadventitial administration of ibuprofen using controlled-release polymers. Stroke 30:140147, 1999 Thai QA, Oshiro EM, Tamargo RJ: Inhibition of experimental vasospasm in rats with the periadventitial administration of ibuprofen using controlled-release polymers. Stroke 30:140–147, 1999

    • Search Google Scholar
    • Export Citation
  • 42.

    Weir B, , Disney L, & Grace M, et al: Daily trends in white blood cell count and temperature after subarachnoid hemorrhage from aneurysm. Neurosurgery 25:161165, 1989 Weir B, Disney L, Grace M, et al: Daily trends in white blood cell count and temperature after subarachnoid hemorrhage from aneurysm. Neurosurgery 25:161–165, 1989

    • Search Google Scholar
    • Export Citation

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