PMID- 22487721
OWN - NLM
STAT- MEDLINE
DCOM- 20120622
LR  - 20201219
IS  - 1872-9142 (Electronic)
IS  - 0161-5890 (Linking)
VI  - 51
IP  - 2
DP  - 2012 Jun
TI  - Structural basis for high selectivity of anti-CCL2 neutralizing antibody CNTO 
      888.
PG  - 227-33
LID - 10.1016/j.molimm.2012.03.022 [doi]
AB  - Human CC chemokine ligand 2 (CCL2), also known as monocyte chemoattractant 
      protein-1 (MCP-1), is a member of the beta chemokine family whose actions are 
      mediated through the G-protein-coupled receptor CCR2. Binding of CCL2 to its 
      receptor CCR2 triggers calcium mobilization and chemotaxis. CCL2 is implicated in 
      the pathogenesis of certain inflammatory diseases and cancer. CNTO 888, a 
      neutralizing human anti-CCL2 antibody, was derived by antibody phage display. The 
      antibody binds human CCL2 with high affinity (K(D)=22 pM) and inhibits CCL2 
      binding to its receptor. The crystal structure of the CNTO 888 Fab alone and in 
      complex with the monomeric form of CCL2 (P8A variant) was determined at 2.6 A and 
      2.8 A resolution, respectively. CNTO 888 recognizes a conformational epitope 
      encompassing residues 18-24 and 45-51 that overlaps the mapped receptor binding 
      site. The epitope of CNTO 888 does not overlap with the dimerization site of 
      CCL2, and thus its inhibitory activity is not expected to result from 
      interference with the oligomeric state of CCL2. Comparison of the 
      X-ray-determined epitopes of CNTO 888 and another CCL2-neutralizing antibody, 
      11K2, provides insight into the molecular basis of antibody selectivity and 
      functional inhibition.
CI  - Copyright (c) 2012 Elsevier Ltd. All rights reserved.
FAU - Obmolova, Galina
AU  - Obmolova G
AD  - Discovery Research, Janssen R&D LLC, 145 King of Prussia Road, Radnor, PA 19087, 
      USA.
FAU - Teplyakov, Alexey
AU  - Teplyakov A
FAU - Malia, Thomas J
AU  - Malia TJ
FAU - Grygiel, Tami L R
AU  - Grygiel TL
FAU - Sweet, Raymond
AU  - Sweet R
FAU - Snyder, Linda A
AU  - Snyder LA
FAU - Gilliland, Gary L
AU  - Gilliland GL
LA  - eng
PT  - Journal Article
DEP - 20120407
PL  - England
TA  - Mol Immunol
JT  - Molecular immunology
JID - 7905289
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Antibodies, Neutralizing)
RN  - 0 (Broadly Neutralizing Antibodies)
RN  - 0 (CCL2 protein, human)
RN  - 0 (Chemokine CCL2)
RN  - 6TC1BB2EV9 (carlumab)
SB  - IM
MH  - Amino Acid Sequence
MH  - Antibodies, Monoclonal/*chemistry
MH  - Antibodies, Monoclonal, Humanized
MH  - Antibodies, Neutralizing/*chemistry
MH  - *Antibody Specificity
MH  - Broadly Neutralizing Antibodies
MH  - Chemokine CCL2/*chemistry
MH  - Humans
MH  - Molecular Sequence Data
MH  - Protein Structure, Secondary
MH  - Protein Structure, Tertiary
MH  - Sequence Alignment
EDAT- 2012/04/11 06:00
MHDA- 2012/06/23 06:00
CRDT- 2012/04/11 06:00
PHST- 2012/02/10 00:00 [received]
PHST- 2012/03/07 00:00 [accepted]
PHST- 2012/04/11 06:00 [entrez]
PHST- 2012/04/11 06:00 [pubmed]
PHST- 2012/06/23 06:00 [medline]
AID - S0161-5890(12)00198-8 [pii]
AID - 10.1016/j.molimm.2012.03.022 [doi]
PST - ppublish
SO  - Mol Immunol. 2012 Jun;51(2):227-33. doi: 10.1016/j.molimm.2012.03.022. Epub 2012 
      Apr 7.