Resolution of CNS lesions following treatment of experimental allergic encephalomyelitis in macaques with monoclonal antibody to the CD18 leukocyte integrin

Department of Pathology, University of Washington School of Medicine, Seattle 98195, USA.
Multiple Sclerosis (Impact Factor: 4.82). 02/1997; 2(6):259-66. DOI: 10.1177/135245859700200601
Source: PubMed


Experimental allergic encephalomyelitis (EAE) in macaques is an acute inflammatory and demyelinating disease of the central nervous system (CNS) which has been studied extensively as a model of the human demyelinating disease multiple sclerosis (MS). The in vivo administration of monoclonal antibodies against CD18, the common beta-chain of a leukocyte integrin, at the onset of clinical disease, significantly prolonged the survival of nine of 11 macaques (82%) and in some cases completely reversed the clinical appearance of disease. Treatment with anti-CD18 mAbs dramatically reduced the extent of inflammation in brain lesions as determined by magnetic resonance imaging (MRI). These improvements confirm that anti-CD18 mAbs are powerful anti-inflammatory agents in vivo and suggest that such mAbs may provide effective treatment of both demyelinating and inflammatory CNS diseases in man.

2 Reads

  • The Neuroscientist 01/1998; 4(1):4-8. DOI:10.1177/107385849800400107 · 6.84 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Accumulating evidence points toward a significant role for the microvascular endothelium in the pathogenesis of several neurologic conditions. This review highlights those biochemical, anatomical, and physiological features of the endothelium thought to be dysfunctional in these disease states, and elaborates on novel treatment modalities that target the endothelium.
    Journal of Neuroscience Research 02/1998; 51(4):423-30. DOI:10.1002/(SICI)1097-4547(19980215)51:43.0.CO;2-E · 2.59 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To evaluate the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of a humanized anti-CD11/CD18 monoclonal antibody (Hu23F2G) in patients with multiple sclerosis. In this phase I uncontrolled dose escalation study, patients (n = 24) with primary or secondary progressive multiple sclerosis received single intravenous infusions of Hu23F2G (0.01 to 4.0 mg/kg). Study parameters included safety, pharmacology, immunogenicity, and brain magnetic resonance imaging (MRI). Hu23F2G had few adverse effects, but 2 cases of urinary tract infection and 2 cases of gingivitis did occur. Transient leukocytes developed in some subjects receiving > or = 1.0 mg/kg. The pharmacokinetic response was nonlinear, with the area under the curve increasing out of proportion to the increase in dose. The mean terminal half-life increased with dose and was 21.9 (SD, 12.8) hours at the 4.0 mg/kg dose. High saturation (> 80%) of CD11/CD18 on circulating leukocytes was achieved with doses > or = 0.2 mg/kg. The duration of high leukocyte saturation was dose-dependent, persisting for more than a week at the 4.0 mg/kg dose. A marked decrease in leukocyte migration in response to cutaneous inflammation was observed. Antibodies against Hu23F2G were not detected. The neurologic examinations were stable except for 1 subject who had worsening weakness associated with an infection. No significant changes were noted on brain MRI scans. Hu23F2G was tolerated at doses that achieved high degrees of leukocyte CD11/CD118 saturation with in vivo inhibition of leukocyte migration. Because this phase I study was not designed to determine the clinical efficacy of Hu23F2G, further studies are needed.
    Clinical Pharmacology &#38 Therapeutics 10/1998; 64(3):339-46. DOI:10.1016/S0009-9236(98)90183-7 · 7.90 Impact Factor
Show more