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Accelerating target deconvolution for therapeutic antibody candidates using highly parallelized genome editing

Mattsson, Jenny LU ; Ekdahl, Ludvig LU ; Junghus, Fredrik LU ; Ajore, Ram LU ; Erlandsson, Eva LU ; Niroula, Abhishek LU ; Pertesi, Maroulio LU ; Frendéus, Björn LU ; Teige, Ingrid LU and Nilsson, Björn LU (2021) In Nature Communications 12. p.1-8
Abstract

Therapeutic antibodies are transforming the treatment of cancer and autoimmune diseases. Today, a key challenge is finding antibodies against new targets. Phenotypic discovery promises to achieve this by enabling discovery of antibodies with therapeutic potential without specifying the molecular target a priori. Yet, deconvoluting the targets of phenotypically discovered antibodies remains a bottleneck; efficient deconvolution methods are needed for phenotypic discovery to reach its full potential. Here, we report a comprehensive investigation of a target deconvolution approach based on pooled CRISPR/Cas9. Applying this approach within three real-world phenotypic discovery programs, we rapidly deconvolute the targets of 38 of 39 test... (More)

Therapeutic antibodies are transforming the treatment of cancer and autoimmune diseases. Today, a key challenge is finding antibodies against new targets. Phenotypic discovery promises to achieve this by enabling discovery of antibodies with therapeutic potential without specifying the molecular target a priori. Yet, deconvoluting the targets of phenotypically discovered antibodies remains a bottleneck; efficient deconvolution methods are needed for phenotypic discovery to reach its full potential. Here, we report a comprehensive investigation of a target deconvolution approach based on pooled CRISPR/Cas9. Applying this approach within three real-world phenotypic discovery programs, we rapidly deconvolute the targets of 38 of 39 test antibodies (97%), a success rate far higher than with existing approaches. Moreover, the approach scales well, requires much less work, and robustly identifies antibodies against the major histocompatibility complex. Our data establish CRISPR/Cas9 as a highly efficient target deconvolution approach, with immediate implications for the development of antibody-based drugs.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Antibodies/metabolism, CRISPR-Cas Systems/genetics, Cell Line, Tumor, Cell Survival/genetics, Clustered Regularly Interspaced Short Palindromic Repeats/genetics, Gene Editing, Humans
in
Nature Communications
volume
12
article number
1277
pages
1 - 8
publisher
Nature Publishing Group
external identifiers
  • pmid:33627649
  • scopus:85101554959
ISSN
2041-1723
DOI
10.1038/s41467-021-21518-4
language
English
LU publication?
yes
id
857305dd-d0f4-4cf3-a288-1dd7d31cea2b
date added to LUP
2022-10-04 15:06:32
date last changed
2024-06-13 19:52:05
@article{857305dd-d0f4-4cf3-a288-1dd7d31cea2b,
  abstract     = {{<p>Therapeutic antibodies are transforming the treatment of cancer and autoimmune diseases. Today, a key challenge is finding antibodies against new targets. Phenotypic discovery promises to achieve this by enabling discovery of antibodies with therapeutic potential without specifying the molecular target a priori. Yet, deconvoluting the targets of phenotypically discovered antibodies remains a bottleneck; efficient deconvolution methods are needed for phenotypic discovery to reach its full potential. Here, we report a comprehensive investigation of a target deconvolution approach based on pooled CRISPR/Cas9. Applying this approach within three real-world phenotypic discovery programs, we rapidly deconvolute the targets of 38 of 39 test antibodies (97%), a success rate far higher than with existing approaches. Moreover, the approach scales well, requires much less work, and robustly identifies antibodies against the major histocompatibility complex. Our data establish CRISPR/Cas9 as a highly efficient target deconvolution approach, with immediate implications for the development of antibody-based drugs.</p>}},
  author       = {{Mattsson, Jenny and Ekdahl, Ludvig and Junghus, Fredrik and Ajore, Ram and Erlandsson, Eva and Niroula, Abhishek and Pertesi, Maroulio and Frendéus, Björn and Teige, Ingrid and Nilsson, Björn}},
  issn         = {{2041-1723}},
  keywords     = {{Antibodies/metabolism; CRISPR-Cas Systems/genetics; Cell Line, Tumor; Cell Survival/genetics; Clustered Regularly Interspaced Short Palindromic Repeats/genetics; Gene Editing; Humans}},
  language     = {{eng}},
  pages        = {{1--8}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Accelerating target deconvolution for therapeutic antibody candidates using highly parallelized genome editing}},
  url          = {{http://dx.doi.org/10.1038/s41467-021-21518-4}},
  doi          = {{10.1038/s41467-021-21518-4}},
  volume       = {{12}},
  year         = {{2021}},
}