Linked Life Data

18232715

Source:http://linkedlifedata.com/resource/pubmed/id/18232715

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
8
pubmed:dateCreated
2008-2-19
pubmed:abstractText
A new isoform of the light chain of a fully human monoclonal immunoglobulin gamma2 (IgG2) antibody panitumumab against human epidermal growth factor receptor (EGFR) was generated by in vitro aging. The isoform was attributed to the isomerization of aspartate 92 located between phenylalanine 91 and histidine 93 residues in the antigen-binding region. The isomerization rate increased with increased temperature and decreased pH. A size-exclusion chromatography binding assay was used to show that one antibody molecule was able to bind two soluble extracellular EGFR molecules in solution, and isomerization of one or both Asp-92 residues deactivated one or both antigen-binding regions, respectively. In addition, isomerization of Asp-92 showed a decrease in in vitro potency as measured by a cell proliferation assay with a 32D cell line that expressed the full-length human EGFR. The data indicate that antibodies containing either one or two isomerized residues were not effective in inhibiting EGFR-mediated cell proliferation, and that two unmodified antigen binding regions were needed to achieve full efficacy. For comparison, the potency of an intact IgG1 antibody cetuximab against the same receptor was correlated with the bioactivity of its individual antigen-binding fragments. The intact IgG1 antibody with two antigen-binding fragments was also much more active in suppressing cell proliferation than the individual fragments, similar to the IgG2 results. These results indicated that avidity played a key role in the inhibition of cell proliferation by these antibodies against the human EGFR, suggesting that their mechanisms of action are similar.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0006-2960
pubmed:author
pubmed:issnType
Print
pubmed:day
26
pubmed:volume
47
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2518-30
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:18232715-Alkylation, pubmed-meshheading:18232715-Amino Acid Sequence, pubmed-meshheading:18232715-Antibodies, Monoclonal, pubmed-meshheading:18232715-Antibody Affinity, pubmed-meshheading:18232715-Antibody Formation, pubmed-meshheading:18232715-Aspartic Acid, pubmed-meshheading:18232715-Cells, Cultured, pubmed-meshheading:18232715-Chromatography, High Pressure Liquid, pubmed-meshheading:18232715-Humans, pubmed-meshheading:18232715-Immunoglobulin Light Chains, pubmed-meshheading:18232715-Immunoglobulin gamma-Chains, pubmed-meshheading:18232715-Isomerism, pubmed-meshheading:18232715-Models, Molecular, pubmed-meshheading:18232715-Molecular Sequence Data, pubmed-meshheading:18232715-Oxidation-Reduction, pubmed-meshheading:18232715-Protein Isoforms, pubmed-meshheading:18232715-Protein Processing, Post-Translational, pubmed-meshheading:18232715-Receptor, Epidermal Growth Factor, pubmed-meshheading:18232715-Structure-Activity Relationship, pubmed-meshheading:18232715-Transferases
pubmed:year
2008
pubmed:articleTitle
Isomerization of a single aspartyl residue of anti-epidermal growth factor receptor immunoglobulin gamma2 antibody highlights the role avidity plays in antibody activity.
pubmed:affiliation
Department of Pharmaceutics, Process and Product Development, Amgen, Inc., Thousand Oaks, California 91320, USA. drehder@amgen.com
pubmed:publicationType
Journal Article, Comparative Study, Evaluation Studies