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.
Shealy
David J
DJ
Centocor Research and Development, Radnor, PA.
Cai
Ann
A
Centocor Research and Development, Radnor, PA.
Staquet
Kim
K
Centocor Research and Development, Radnor, PA.
Baker
Audrey
A
Centocor Research and Development, Radnor, PA.
Lacy
Eilyn R
ER
Centocor Research and Development, Radnor, PA.
Johns
Laura
L
Centocor Research and Development, Radnor, PA.
Vafa
Omid
O
Centocor Research and Development, Radnor, PA.
Gunn
George
G
Centocor Research and Development, Radnor, PA.
Tam
Susan
S
Centocor Research and Development, Radnor, PA.
Sague
Sarah
S
Centocor Research and Development, Radnor, PA.
Wang
Dana
D
Centocor Research and Development, Radnor, PA.
Brigham-Burke
Mike
M
Centocor Research and Development, Radnor, PA.
Dalmonte
Paul
P
Centocor Research and Development, Radnor, PA.
Emmell
Eva
E
Centocor Research and Development, Radnor, PA.
Pikounis
Bill
B
Centocor Research and Development, Radnor, PA.
Bugelski
Peter J
PJ
Centocor Research and Development, Radnor, PA.
Zhou
Honghui
H
Centocor Research and Development, Radnor, PA.
Scallon
Bernard J
BJ
Centocor Research and Development, Radnor, PA.
Giles-Komar
Jill
J
Centocor Research and Development, Radnor, PA.
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