Object. Adhesion of leukocytes and their migration into the periadventitial space may be critical in the pathophysiology of vasospasm following subarachnoid hemorrhage (SAH). The cell adhesion molecules involved in this process are lymphocyte function—associated antigen—1 (CD11a/CD18) and macrophage antigen—1 (CD11b/CD18), which are present on neutrophils/macrophages, and intercellular adhesion molecule—1 (CD54), which is present in endothelial cells. A humanized monoclonal antibody (mAb), Hu23F2G, targets CD11/CD18 and prevents leukocyte adhesion to endothelial cells. In this study, systemic administration of Hu23F2G prevented vasospasm in the rabbit model of SAH.Methods. Twenty-six New Zealand White rabbits were injected with autologous blood into the cisterna magna to induce SAH, after which they were randomized to receive injections of either Hu23F2G (10 animals) or a placebo at 30 minutes and 24 and 48 hours after SAH (six animals). Control animals underwent sham operations (four animals) or SAH alone (six animals). The animals were killed 72 hours after SAH, their bodies perfused and fixed, and their basilar arteries processed for morphometric analysis. Peripheral white blood cells (WBCs) were counted at 72 hours. The percentages of lumen patency were compared using the Student t-test. The presence of neutrophils and macrophages was confirmed by immunohistochemical analysis in which a rat anti—rabbit anti-CD18 mAb and cresyl violet were used.Treatment with Hu23F2G resulted in the significant prevention of vasospasm. Animals treated with Hu23F2G had 90 ± 7% lumen patency compared with 65 ± 7% in the placebo group (p = 0.025). The percentage of lumen patency in the SAH-only group was 59 ± 10%. The mean WBC count was 16,300 ± 2710/µl in the treatment group, compared with 7000 ± 386/µl in the control group (p = 0.02). Administration of Hu23F2G produced increased numbers of WBCs in 70% of the animals treated.Conclusions. This study supports the concept that leukocyte—endothelial cell interactions play an important role in the pathophysiology of chronic vasospasm after SAH. Systemic therapy with an anti-CD11/CD18 mAb prevents vasospasm after SAH by inhibiting adhesion of neutrophils and macrophages and their migration into the periadventitial space.

01 Oct 2002·Journal of the American College of CardiologyQ1 · MEDICINE

The effect of blockade of the CD11/CD18 integrin receptor on infarct size in patients with acute myocardial infarction treated with direct angioplasty: the results of the HALT-MI study

Q1 · MEDICINE

Article

Author: Raymond J Gibbons ; Paul A Gurbel ; Florence Sheehan ; Nicolas A.F Chronos ; David P Faxon

OBJECTIVEThe purpose of this study was to determine whether Hu23F2G (LeukoArrest), an antibody to the CD11/CD18 integrin receptors, would reduce infarct size in patients undergoing primary angioplasty for an acute myocardial infarction.BACKGROUNDReperfusion injury in acute myocardial infarction has been shown experimentally to be related to neutrophil accumulation. Inhibitors of the CD11/CD18 or CD18 integrin receptors have been shown to reduce infarct size in experimental models.METHODSPatients within 6 h of onset of chest pain with ST-segment elevation were randomized to receive either 0.3 mg/kg or 1.0 mg/kg of Hu23F2G or placebo just before angioplasty of occluded arteries (Thrombolysis in Myocardial Infarction TIMI flow grade 0 or 1). The primary end point was infarct size as measured by sestamibi single-photon emission computed tomography (SPECT) scan five to nine days later.RESULTSFour-hundred and twenty patients were enrolled and received a placebo or the study drug. The groups did not differ in baseline or angiographic characteristics or angioplasty results. Infarct size was 16%, 17.2% and 16.6%, for placebo, 0.3 mg/kg and 1.0 mg/kg, respectively, of the left ventricle (p = NS). No differences were evident in those patients with anterior myocardial infarction or those presenting within 2 h of onset of chest pain. Corrected TIMI frame count was also not different between groups. Clinical events at 30 days were very low, with a mortality of 0.8%, 1.4% and 3.3%, respectively. The drug was well tolerated, with a slight increase in minor infections in the high dose group.CONCLUSIONSThe results of this multicenter, double-blind, placebo-controlled, randomized clinical trial demonstrated that an antibody to CD11/CD18 leukocyte integrin receptor did not reduce infarct size in patients who underwent primary angioplasty.

01 Sep 2001·The American Journal of CardiologyQ3 · MEDICINE

An anti-CD11/CD18 monoclonal antibody in patients with acute myocardial infarction having percutaneous transluminal coronary angioplasty (the FESTIVAL study)

Q3 · MEDICINE

Article

Author: Rusnak, J. M. ; Martin, J. S. ; Saoud, J. B. ; Breisblatt, W. M. ; Holland, A. E. ; Simons, M. ; Peterman, H. S. ; Clements, I. P. ; Kopecky, S. L. ; Gibbons, R. J. ; Feldman, R. L. ; Gessler, C. J. ; Yu, A. S.

Maximal benefits of coronary reperfusion after acute myocardial infarction (AMI) with ST-segment elevation may be attenuated by neutrophil-mediated reperfusion injury. Inflammatory mediators released from potentially viable myocytes cause activation of neutrophils, which traverse the endothelium and enter the myocardium. This process involves interaction between the neutrophil-expressed CD11/CD18 and endothelial-expressed intercellular adhesion molecule-1 (ICAM-1). Preclinical studies have shown that monoclonal antibodies (MAb) to CD18 can limit infarct size and preserve left ventricular function. We sought to determine the initial clinical safety and tolerability of Hu23F2G (LeukArrest), a humanized MAb to CD11/CD18, in patients with AMI who underwent percutaneous transluminal coronary angioplasty (PTCA). Sixty patients with AMI were randomized to low- (0.3 mg/kg) or high-dose (1.0 mg/kg) Hu23F2G or to placebo immediately before PTCA. We found no clinically significant differences in vital signs, physical examination, laboratory evaluation, or need for subsequent cardiac interventions. In Hu23F2G treatment groups, serum concentration of Hu23F2G increased rapidly to 3,234 +/- 1,298 microg/L (low-dose group) and 15,558 +/- 4409 microg/L (high-dose group) between 5 and 60 minutes, then declined over 72 hours to near-baseline values. Myocardial single-photon emission computed tomographic imaging 120 to 260 hours after PTCA showed no statistically significant differences in final left ventricular defect size. Hu23F2G was well tolerated, with no increase in adverse events, including infections. Thus, Hu23F2G appears safe and well tolerated in patients undergoing PTCA for AMI.

100 Deals associated with Rovelizumab

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D08993	Rovelizumab	-	-

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Indication	Highest Phase	Country/Location	Organization	Date
Multiple Sclerosis	Phase 3	US	ICOS Corp.	01 Jan 1999
Shock	Phase 3	US	ICOS Corp.	31 Dec 1998
Myocardial Infarction	Phase 3	US	ICOS Corp.	01 Feb 1997
Central nervous system injury	Phase 3	US	ICOS Corp.	-
Peripheral arterial occlusive disease	Phase 3	US	ICOS Corp.	-
Stroke	Phase 3	US	ICOS Corp.	-
Vascular restenosis	Phase 3	US	ICOS Corp.	-
Vasospasm, Intracranial	Phase 3	US	ICOS Corp.	-

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