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Antibody evolution from the centre to the periphery: applied to a human antibody fragment recognising the tumour-associated antigen mucin-1.

Jirholt, Pernilla; Borrebaeck, Carl LU and Ohlin, Mats LU (2002) In Journal of Molecular Biology 318(2). p.407-416
Abstract
Mucin-1 has proven to be a suitable target for antibody-based diagnosis and therapy of certain tumours, but no appropriate human antibody or antibody fragment displaying slow dissociation rate kinetics against this target is available. Since a rapid dissociation character prevents an antibody fragment from remaining at the site of the antigen, this fact may prevent the successful application of a human mucin-1 specific antibody in diagnosis and therapy. We have now used iterative antibody libraries to evolve a human antibody fragment originally obtained from a naïve antibody library. A strategy was devised whereby molecular variants displaying slow dissociation kinetics against the repetitive mucin-1 tumour-associated antigen can be... (More)
Mucin-1 has proven to be a suitable target for antibody-based diagnosis and therapy of certain tumours, but no appropriate human antibody or antibody fragment displaying slow dissociation rate kinetics against this target is available. Since a rapid dissociation character prevents an antibody fragment from remaining at the site of the antigen, this fact may prevent the successful application of a human mucin-1 specific antibody in diagnosis and therapy. We have now used iterative antibody libraries to evolve a human antibody fragment originally obtained from a naïve antibody library. A strategy was devised whereby molecular variants displaying slow dissociation kinetics against the repetitive mucin-1 tumour-associated antigen can be selected in vitro. The evolved clones, that allowed for a reduced dissociation from the tumour antigen, carried substitutions in the outer parts of the binding site. This demonstrated the ability of this in vitro evolution technique to mimic the process whereby antibodies evolve in vivo. We have thus devised a strategy through which molecular variants displaying slow dissociation from a repetitive target like the mucin-1 tumour-associated antigen can be obtained in vitro. These or related molecules obtained by this approach will serve as a starting point for the development of fully human antibodies for use in mucin-1 specific tumour therapy of diagnosis. (Less)
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organization
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published
subject
keywords
Antibody Diversity, CA-15-3 Antigen : immunology, Complementarity Determining Regions, Evolution, Molecular, Protein Conformation, Neoplasms : therapy, Neoplasms : immunology, Neoplasms : diagnosis, Molecular Sequence Data, Models, Immunoglobulin Fragments : genetics, Human, Immunoglobulin Fragments : chemistry, Amino Acid Sequence
in
Journal of Molecular Biology
volume
318
issue
2
pages
407 - 416
publisher
Elsevier
external identifiers
  • wos:000175479300016
  • pmid:12051847
  • scopus:0036305825
ISSN
1089-8638
DOI
10.1016/S0022-2836(02)00087-6
language
English
LU publication?
yes
id
9517c541-be1d-429e-bdd4-af285d6b93d7 (old id 108682)
alternative location
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12051847&dopt=Abstract
date added to LUP
2007-07-05 11:07:04
date last changed
2017-09-03 04:43:00
@article{9517c541-be1d-429e-bdd4-af285d6b93d7,
  abstract     = {Mucin-1 has proven to be a suitable target for antibody-based diagnosis and therapy of certain tumours, but no appropriate human antibody or antibody fragment displaying slow dissociation rate kinetics against this target is available. Since a rapid dissociation character prevents an antibody fragment from remaining at the site of the antigen, this fact may prevent the successful application of a human mucin-1 specific antibody in diagnosis and therapy. We have now used iterative antibody libraries to evolve a human antibody fragment originally obtained from a naïve antibody library. A strategy was devised whereby molecular variants displaying slow dissociation kinetics against the repetitive mucin-1 tumour-associated antigen can be selected in vitro. The evolved clones, that allowed for a reduced dissociation from the tumour antigen, carried substitutions in the outer parts of the binding site. This demonstrated the ability of this in vitro evolution technique to mimic the process whereby antibodies evolve in vivo. We have thus devised a strategy through which molecular variants displaying slow dissociation from a repetitive target like the mucin-1 tumour-associated antigen can be obtained in vitro. These or related molecules obtained by this approach will serve as a starting point for the development of fully human antibodies for use in mucin-1 specific tumour therapy of diagnosis.},
  author       = {Jirholt, Pernilla and Borrebaeck, Carl and Ohlin, Mats},
  issn         = {1089-8638},
  keyword      = {Antibody Diversity,CA-15-3 Antigen : immunology,Complementarity Determining Regions,Evolution,Molecular,Protein Conformation,Neoplasms : therapy,Neoplasms : immunology,Neoplasms : diagnosis,Molecular Sequence Data,Models,Immunoglobulin Fragments : genetics,Human,Immunoglobulin Fragments : chemistry,Amino Acid Sequence},
  language     = {eng},
  number       = {2},
  pages        = {407--416},
  publisher    = {Elsevier},
  series       = {Journal of Molecular Biology},
  title        = {Antibody evolution from the centre to the periphery: applied to a human antibody fragment recognising the tumour-associated antigen mucin-1.},
  url          = {http://dx.doi.org/10.1016/S0022-2836(02)00087-6},
  volume       = {318},
  year         = {2002},
}