A humanized anti-human CD154 monoclonal antibody blocks CD154-CD40 mediated human B cell activation.
Humanized anti-CD154 antibody, IDEC-131, had a slightly, but reproducibly, better binding affinity for CD154 (Kd = 5.6 nM), compared to the parent antibody 24-31 (Kd = 8.5 nM). Otherwise it was indistinguishable from the murine parent antibody in its ability to bind to CD154, block CD154 binding to CD40 and inhibit T cell-dependent B cell differentiation. The latter activity was independent of FcR binding as the Fab'1 fragment of IDEC-131 had an equivalent biological activity to that of the whole antibody. IDEC-131 blocked soluble CD154 from inducing proliferation of purified B cells, and blocked T cell dependent anti-tetanus toxoid specific antibody production by human B cells in vitro. IDEC-131, gamma1, kappa, had strong Fc gammaRI, Fc gammaRII and C1q binding, but was unable to induce complement dependent (CDC) or antibody dependent cell-cytotoxicity (ADCC) of activated peripheral blood T cells, which express relatively low levels of CD154. IDEC-131 antibody inhibited both primary and secondary antibody responses to ovalbumin in cynomolgus monkeys at a dose of 5 mg/kg. In non-immunized animals, treatment with IDEC-131 at 50 mg/kg weekly for 13 weeks induced no change in any of the measured lymphocyte subsets, including B cells, CD4+ and CD8+ T cells. Similarly, a safety study in chimpanzees showed no discernible safety related issues at 20 mg/kg, including B and T cell subsets. These results show that the humanized anti-CD154 antibody, IDEC-131, has retained the affinity and functional activity of its murine parent antibody, is unlikely to deplete CD154 positive lymphocytes in humans, and is safe and effective in blocking antibody production in monkeys. Based on its safety and efficacy profile, IDEC-131 is being developed for therapy of systemic lupus erythematosus.
Brams
P
P
IDEC Pharmaceuticals Corporation, San Diego, CA 92121, USA.
Black
A
A
Padlan
E A
EA
Hariharan
K
K
Leonard
J
J
Chambers-Slater
K
K
Noelle
R J
RJ
Newman
R
R
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000502:physiology*; D001483:Base Sequence; D019013:CD40 Antigens / Q000502:physiology*; D023201:CD40 Ligand / Q000502:physiology*; D016466:CHO Cells; D002454:Cell Differentiation; D006224:Cricetinae; D005260:Female; D005803:Genes, Immunoglobulin; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics; D008213:Lymphocyte Activation; D008252:Macaca fascicularis; D008297:Male; D008969:Molecular Sequence Data; D002679:Pan troglodytes
D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D007135:Immunoglobulin Variable Region; D023201:CD40 Ligand