Characterization of golimumab, a human monoclonal antibody specific for human tumor necrosis factor α.
We prepared and characterized golimumab (CNTO148), a human IgG1 tumor necrosis factor alpha (TNFα) antagonist monoclonal antibody chosen for clinical development based on its molecular properties. Golimumab was compared with infliximab, adalimumab and etanercept for affinity and in vitro TNFα neutralization. The affinity of golimumab for soluble human TNFα, as determined by surface plasmon resonance, was similar to that of etanercept (18 pM versus 11 pM), greater than that of infliximab (44 pM) and significantly greater than that of adalimumab (127 pM, p=0.018).  The concentration of golimumab necessary to neutralize TNFα-induced E-selectin expression on human endothelial cells by 50% was significantly less than those for infliximab (3.2 fold; p=0.017) and adalimumab (3.3-fold; p=0.008) and comparable to that for etanercept. The conformational stability of golimumab was greater than that of infliximab (primary melting temperature [Tm] 74.8 °C vs. 69.5 °C) as assessed by differential scanning calorimetry.  In addition, golimumab showed minimal aggregation over the intended shelf life when formulated as a high concentration liquid product (100 mg/mL) for subcutaneous administration.  In vivo, golimumab at doses of 1 and 10 mg/kg significantly delayed disease progression in a mouse model of human TNFα-induced arthritis when compared with untreated mice, while infliximab was effective only at 10 mg/kg. Golimumab also significantly reduced histological scores for arthritis severity and cartilage damage, as well as serum levels of pro-inflammatory cytokines and chemokines associated with arthritis. Thus, we have demonstrated that golimumab is a highly stable human monoclonal antibody with high affinity and capacity to neutralize human TNFα in vitro and in vivo.
Centocor Research and Development, Radnor, PA.
David J
DJ
Shealy
Centocor Research and Development, Radnor, PA.
Ann
A
Cai
Centocor Research and Development, Radnor, PA.
Kim
K
Staquet
Centocor Research and Development, Radnor, PA.
Audrey
A
Baker
Centocor Research and Development, Radnor, PA.
Eilyn R
ER
Lacy
Centocor Research and Development, Radnor, PA.
Laura
L
Johns
Centocor Research and Development, Radnor, PA.
Omid
O
Vafa
Centocor Research and Development, Radnor, PA.
George
G
Gunn
Centocor Research and Development, Radnor, PA.
Susan
S
Tam
Centocor Research and Development, Radnor, PA.
Sarah
S
Sague
Centocor Research and Development, Radnor, PA.
Dana
D
Wang
Centocor Research and Development, Radnor, PA.
Mike
M
Brigham-Burke
Centocor Research and Development, Radnor, PA.
Paul
P
Dalmonte
Centocor Research and Development, Radnor, PA.
Eva
E
Emmell
Centocor Research and Development, Radnor, PA.
Bill
B
Pikounis
Centocor Research and Development, Radnor, PA.
Peter J
PJ
Bugelski
Centocor Research and Development, Radnor, PA.
Honghui
H
Zhou
Centocor Research and Development, Radnor, PA.
Bernard J
BJ
Scallon
Centocor Research and Development, Radnor, PA.
Jill
J
Giles-Komar
D000068879:Adalimumab; D000818:Animals; D000911:Antibodies, Monoclonal / Q000302:isolation & purification / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000915:Antibody Affinity; D001168:Arthritis / Q000139:chemically induced / Q000276:immunology*; D002356:Cartilage / Q000187:drug effects* / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism; D000068800:Etanercept; D005786:Gene Expression Regulation / Q000187:drug effects; D006825:Hybridomas; D007074:Immunoglobulin G / Q000302:isolation & purification / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D000069285:Infliximab; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D011487:Protein Conformation; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D019040:E-Selectin; D007074:Immunoglobulin G; D018836:Inflammation Mediators; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; C529000:golimumab; D000069285:Infliximab; D000068879:Adalimumab; D000068800:Etanercept