Dissociation of efficacy and cytokine release mediated by an Fc-modified anti-CD3 mAb in a chronic experimental autoimmune encephalomyelitis model.
Humanization and modification of the Fc region of anti-human CD3 mAbs have greatly expanded their potential use in chronic T cell mediated diseases. However, low levels of cytokine release and immunogenicity may still impact a chronic dosing strategy. We investigated the use of an Fc-modified murine chimeric anti-mouse CD3 (N297A) in the chronic MOG(35-55)-induced EAE mouse model of MS. Two daily doses of 10 microg at the onset of clinical symptoms led to both a reduction in T cell numbers in the blood and a significant, prolonged reduction in the symptoms. Histological examination of the spinal cords at the peak of efficacy confirmed a reduction of infiltrating T cells in the CNS. Analysis of the cerebral spinal fluid from EAE mice showed biologically active levels of N297A. Analysis of the cytokine/chemokine levels in cerebrospinal fluid showed a decrease in GM-CSF, IL-6 and IP-10. The combination of N297A dosing with cyclosporine A (CSA) pretreatment showed a significant decrease of TNFalpha, IL-6 and IP-10 without effect on clinical efficacy. However, pretreatment of CSA significantly reduced the immunogenic response observed following a second course of N297A treatment. Therefore, the side effects of an Fc-modified anti-CD3 mAb may be modulated without affecting efficacy.
Belmar
Nicole A
NA
PDL BioPharma 1400 Seaport Blvd Redwood City, CA 94063, USA. nicole.belmar@facetbiotech.com
Lombardo
John R
JR
Chao
Debra T
DT
Li
Olga
O
Ma
Xiaohong
X
Pong-Afar
Melody
M
Law
Debbie A
DA
Starling
Gary C
GC
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001812:Blood-Brain Barrier; D017252:CD3 Complex / Q000276:immunology*; D018925:Chemokines / Q000096:biosynthesis; D016572:Cyclosporine / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000628:therapy*; D005260:Female; D007141:Immunoglobulin Fc Fragments / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013116:Spinal Cord / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D018925:Chemokines; D016207:Cytokines; D007141:Immunoglobulin Fc Fragments; D016572:Cyclosporine