The contribution of Fc effector mechanisms in the efficacy of anti-CD154 immunotherapy depends on the nature of the immune challenge.
Blockade of the CD154-CD40 co-stimulatory pathway with anti-CD154 mAbs has shown impressive efficacy in models of autoimmunity and allotransplantation. Clinical benefit was also demonstrated in systemic lupus erythematosus (SLE) and idiopathic thrombocytopenia patients with the humanized anti-CD154 mAb, 5C8 (hu5C8). However, thromboembolic complications that occurred during the course of the hu5C8 clinical trials have proven to be a major setback to the field and safe alternative therapeutics targeting the CD154-CD40 pathway are of great interest. Recently, effector mechanisms have been shown to play a part in anti-CD154 mAb-induced transplant acceptance in murine models, while this issue remains unresolved for humoral-mediated models. Herein, aglycosyl anti-CD154 mAbs with reduced binding to FcgammaR and complement were used as a novel means to test the role of effector mechanisms in non-human primate and murine models not amenable to gene knockout technology. While aglycosyl hu5C8 mAb was relatively ineffective in rhesus renal and islet allotransplantation, it inhibited primary and secondary humoral responses to a protein immunogen in cynomolgus monkeys. Moreover, an aglycosyl, chimeric MR1 mAb (muMR1) prolonged survival and inhibited pathogenic auto-antibody production in a murine model of SLE. Thus, the mechanisms required for efficacy of anti-CD154 mAbs depend on the nature of the immune challenge.
Ferrant
Janine L
JL
Biogen Idec, Inc., 14 Cambridge Center, Cambridge, MA, USA. janine.ferrant-orgettas@biogenidec.com
Benjamin
Christopher D
CD
Cutler
Anne H
AH
Kalled
Susan L
SL
Hsu
Yen-Ming
YM
Garber
Ellen A
EA
Hess
Donna M
DM
Shapiro
Renee I
RI
Kenyon
Norma S
NS
Harlan
David M
DM
Kirk
Allan D
AD
Burkly
Linda C
LC
Taylor
Frederick R
FR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology*; D061067:Antibodies, Monoclonal, Humanized; D019013:CD40 Antigens / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology*; D004195:Disease Models, Animal; D006031:Glycosylation; D006801:Humans; D007116:Immunization, Passive; D007141:Immunoglobulin Fc Fragments / Q000276:immunology; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D016030:Kidney Transplantation / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D008252:Macaca fascicularis; D051379:Mice; D017452:Receptors, IgG / Q000276:immunology*; D013920:Thrombocythemia, Essential / Q000276:immunology / Q000473:pathology / Q000628:therapy; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D019013:CD40 Antigens; D007141:Immunoglobulin Fc Fragments; D017452:Receptors, IgG; C442103:hu5C8 antibody; D023201:CD40 Ligand