Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
8
pubmed:dateCreated
2000-5-9
pubmed:abstractText
Rituxan (Rituximab) is a chimeric mAb with human IgG1 constant domains used in the therapy of non-Hodgkin's B cell lymphomas. This Ab targets B cells by binding to the cell-surface receptor, CD20. In our investigation of the mechanism of B cell depletion mediated by Rituximab, we first constructed mutants of Rituximab defective in complement activation but with all other effector functions intact. Our results demonstrate that the previously described C1q binding motif in murine IgG2b constituting residues E318, K320, and K322 is not applicable to a human IgG1 when challenged with either human, rabbit, or guinea pig complement. Alanine substitution at positions E318 and K320 in Rituximab had little or no effect on C1q binding and complement activation, whereas alanine substitution at positions D270, K322, P329, and P331 significantly reduced the ability of Rituximab to bind C1q and activate complement. We have also observed that concentrations of complement approaching physiological levels are able to rescue >60% of the activity of these mutant Abs with low affinity for C1q. These data localize the C1q binding epicenter on human IgG1 and suggest that there are species-specific differences in the C1q binding site of Igs.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
AIM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
0022-1767
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
164
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
4178-84
pubmed:dateRevised
2011-11-17
pubmed:meshHeading
pubmed-meshheading:10754313-Alanine, pubmed-meshheading:10754313-Amino Acid Substitution, pubmed-meshheading:10754313-Animals, pubmed-meshheading:10754313-Antibodies, Monoclonal, pubmed-meshheading:10754313-Antibodies, Monoclonal, Murine-Derived, pubmed-meshheading:10754313-Antibody Affinity, pubmed-meshheading:10754313-Antibody-Dependent Cell Cytotoxicity, pubmed-meshheading:10754313-Aspartic Acid, pubmed-meshheading:10754313-Binding Sites, Antibody, pubmed-meshheading:10754313-Complement C1q, pubmed-meshheading:10754313-Guinea Pigs, pubmed-meshheading:10754313-Humans, pubmed-meshheading:10754313-Immunoglobulin Fc Fragments, pubmed-meshheading:10754313-Immunoglobulin G, pubmed-meshheading:10754313-Lysine, pubmed-meshheading:10754313-Mice, pubmed-meshheading:10754313-Peptide Mapping, pubmed-meshheading:10754313-Phenylalanine, pubmed-meshheading:10754313-Rabbits, pubmed-meshheading:10754313-Recombinant Fusion Proteins
pubmed:year
2000
pubmed:articleTitle
Mapping of the C1q binding site on rituxan, a chimeric antibody with a human IgG1 Fc.
pubmed:affiliation
Departments of Analytical Chemistry, Immunology, QC Clinical Development, BioAnalytical Technology, and Protein Engineering, Genentech, South San Francisco, CA 94080, USA.
pubmed:publicationType
Journal Article, Comparative Study