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In vitro evolution of antibodies inspired by in vivo evolution

Persson, Helena; Kirik, Ufuk LU ; Thörnqvist, Linnea LU ; Greiff, Lennart LU ; Levander, Fredrik LU and Ohlin, Mats LU (2018) In Frontiers in Immunology 9(JUN).
Abstract

In vitro generation of antibodies often requires variable domain sequence evolution to adapt the protein in terms of affinity, specificity, or developability. Such antibodies, including those that are of interest for clinical development, may have their origins in a diversity of immunoglobulin germline genes. Others and we have previously shown that antibodies of different origins tend to evolve along different, preferred trajectories. Apart from substitutions within the complementary determining regions, evolution may also, in a germline gene-origin-defined manner, be focused to residues in the framework regions, and even to residues within the protein core, in many instances at a substantial distance from the antibody's... (More)

In vitro generation of antibodies often requires variable domain sequence evolution to adapt the protein in terms of affinity, specificity, or developability. Such antibodies, including those that are of interest for clinical development, may have their origins in a diversity of immunoglobulin germline genes. Others and we have previously shown that antibodies of different origins tend to evolve along different, preferred trajectories. Apart from substitutions within the complementary determining regions, evolution may also, in a germline gene-origin-defined manner, be focused to residues in the framework regions, and even to residues within the protein core, in many instances at a substantial distance from the antibody's antigen-binding site. Examples of such germline origin-defined patterns of evolution are described. We propose that germline gene-preferred substitution patterns offer attractive alternatives that should be considered in efforts to evolve antibodies intended for therapeutic use with respect to appropriate affinity, specificity, and product developability. We also hypothesize that such germline gene-origin-defined in vitro evolution hold potential to result in products with limited immunogenicity, as similarly evolved antibodies will be parts of conventional, in vivo-generated antibody responses and thus are likely to have been seen by the immune system in the past.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Affinity maturation, Antibody, Antibody therapeutics, Developability, Evolution, Humanization, Immunoglobulin germline gene, Somatic hypermutation
in
Frontiers in Immunology
volume
9
issue
JUN
publisher
Frontiers Media S. A.
external identifiers
  • scopus:85048823650
DOI
10.3389/fimmu.2018.01391
language
English
LU publication?
yes
id
e9fe7385-7498-4367-902e-0fec76ce6975
date added to LUP
2018-07-05 10:56:59
date last changed
2019-04-10 04:10:53
@article{e9fe7385-7498-4367-902e-0fec76ce6975,
  abstract     = {<p>In vitro generation of antibodies often requires variable domain sequence evolution to adapt the protein in terms of affinity, specificity, or developability. Such antibodies, including those that are of interest for clinical development, may have their origins in a diversity of immunoglobulin germline genes. Others and we have previously shown that antibodies of different origins tend to evolve along different, preferred trajectories. Apart from substitutions within the complementary determining regions, evolution may also, in a germline gene-origin-defined manner, be focused to residues in the framework regions, and even to residues within the protein core, in many instances at a substantial distance from the antibody's antigen-binding site. Examples of such germline origin-defined patterns of evolution are described. We propose that germline gene-preferred substitution patterns offer attractive alternatives that should be considered in efforts to evolve antibodies intended for therapeutic use with respect to appropriate affinity, specificity, and product developability. We also hypothesize that such germline gene-origin-defined in vitro evolution hold potential to result in products with limited immunogenicity, as similarly evolved antibodies will be parts of conventional, in vivo-generated antibody responses and thus are likely to have been seen by the immune system in the past.</p>},
  articleno    = {1391},
  author       = {Persson, Helena and Kirik, Ufuk and Thörnqvist, Linnea and Greiff, Lennart and Levander, Fredrik and Ohlin, Mats},
  keyword      = {Affinity maturation,Antibody,Antibody therapeutics,Developability,Evolution,Humanization,Immunoglobulin germline gene,Somatic hypermutation},
  language     = {eng},
  month        = {06},
  number       = {JUN},
  publisher    = {Frontiers Media S. A.},
  series       = {Frontiers in Immunology},
  title        = {In vitro evolution of antibodies inspired by in vivo evolution},
  url          = {http://dx.doi.org/10.3389/fimmu.2018.01391},
  volume       = {9},
  year         = {2018},
}