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PH1-derived bivalent bibodies and trivalent tribodies bind differentially to shed and tumour cell-associated MUC1

Steve Schoonooghe UGent, Ingrid Burvenich, Liesbet Vervoort UGent, Filip De Vos UGent, Nico Mertens UGent and Johan Grooten UGent (2010) PROTEIN ENGINEERING DESIGN & SELECTION. 23(9). p.721-728
abstract
Most adenocarcinomas express altered MUC1 as a tumour-associated antigen. Due to suboptimal glycosylation in tumour-associated MUC1, the apomucin core is exposed, revealing new epitopes for antibody-directed immunotherapy. The human PH1 Fab binds specifically to this MUC1 apomucin. We describe the engineering and functional characterization of bi- and trivalent recombinant antibody derivatives from the PH1 Fab. Bi- and tribodies were made using the disulfide-stabilized Fab fragment as a heterodimerization scaffold with PH1 single-chain variable fragments fused to either one or both Fab-chain C-termini. Immunoassays revealed 27- and 165-fold improved dissociation constants (K(D) = 30 and 5 nM) of the PH1 bi- and tribodies compared with the parental Fab (K(D) = 820 nM). Unexpectedly, major differences were seen in the ability of the antibody constructs to bind shed and tumour cell-tethered MUC1. While the tribody did not discriminate between both MUC1 forms, the bibody demonstrated preferential interaction with membrane-bound MUC1 compared with shed MUC1. This preferential recognition of membrane-bound MUC1, along with the high serum stability of the bibody, its intermediate size and efficient internalization by MUC1(+) cells, makes the human PH1-derived bibody a valuable candidate as a cancer-targeting therapeutic.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
MUC1, trivalent, bivalent, antibody derivatives, antibodies, ANTIBODY DERIVATIVES, MONOCLONAL-ANTIBODY, BREAST-CANCER, EXPRESSION, ANTIGEN, AFFINITY, FRAGMENTS, CARCINOMA, MINIBODY, MUCINS
journal title
PROTEIN ENGINEERING DESIGN & SELECTION
Protein Eng. Des. Sel.
volume
23
issue
9
pages
721 - 728
Web of Science type
Article
Web of Science id
000280919300004
JCR category
BIOTECHNOLOGY & APPLIED MICROBIOLOGY
JCR impact factor
3.023 (2010)
JCR rank
47/158 (2010)
JCR quartile
2 (2010)
ISSN
1741-0126
DOI
10.1093/protein/gzq044
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
1089023
handle
http://hdl.handle.net/1854/LU-1089023
date created
2010-12-17 12:29:29
date last changed
2010-12-17 14:03:50
@article{1089023,
  abstract     = {Most adenocarcinomas express altered MUC1 as a tumour-associated antigen. Due to suboptimal glycosylation in tumour-associated MUC1, the apomucin core is exposed, revealing new epitopes for antibody-directed immunotherapy. The human PH1 Fab binds specifically to this MUC1 apomucin. We describe the engineering and functional characterization of bi- and trivalent recombinant antibody derivatives from the PH1 Fab. Bi- and tribodies were made using the disulfide-stabilized Fab fragment as a heterodimerization scaffold with PH1 single-chain variable fragments fused to either one or both Fab-chain C-termini. Immunoassays revealed 27- and 165-fold improved dissociation constants (K(D) = 30 and 5 nM) of the PH1 bi- and tribodies compared with the parental Fab (K(D) = 820 nM). Unexpectedly, major differences were seen in the ability of the antibody constructs to bind shed and tumour cell-tethered MUC1. While the tribody did not discriminate between both MUC1 forms, the bibody demonstrated preferential interaction with membrane-bound MUC1 compared with shed MUC1. This preferential recognition of membrane-bound MUC1, along with the high serum stability of the bibody, its intermediate size and efficient internalization by MUC1(+) cells, makes the human PH1-derived bibody a valuable candidate as a cancer-targeting therapeutic.},
  author       = {Schoonooghe, Steve and Burvenich, Ingrid and Vervoort, Liesbet and De Vos, Filip and Mertens, Nico and Grooten, Johan},
  issn         = {1741-0126},
  journal      = {PROTEIN ENGINEERING DESIGN \& SELECTION},
  keyword      = {MUC1,trivalent,bivalent,antibody derivatives,antibodies,ANTIBODY DERIVATIVES,MONOCLONAL-ANTIBODY,BREAST-CANCER,EXPRESSION,ANTIGEN,AFFINITY,FRAGMENTS,CARCINOMA,MINIBODY,MUCINS},
  language     = {eng},
  number       = {9},
  pages        = {721--728},
  title        = {PH1-derived bivalent bibodies and trivalent tribodies bind differentially to shed and tumour cell-associated MUC1},
  url          = {http://dx.doi.org/10.1093/protein/gzq044},
  volume       = {23},
  year         = {2010},
}

Chicago
Schoonooghe, Steve, Ingrid Burvenich, Liesbet Vervoort, Filip De Vos, Nico Mertens, and Johan Grooten. 2010. “PH1-derived Bivalent Bibodies and Trivalent Tribodies Bind Differentially to Shed and Tumour Cell-associated MUC1.” Protein Engineering Design & Selection 23 (9): 721–728.
APA
Schoonooghe, S., Burvenich, I., Vervoort, L., De Vos, F., Mertens, N., & Grooten, J. (2010). PH1-derived bivalent bibodies and trivalent tribodies bind differentially to shed and tumour cell-associated MUC1. PROTEIN ENGINEERING DESIGN & SELECTION, 23(9), 721–728.
Vancouver
1.
Schoonooghe S, Burvenich I, Vervoort L, De Vos F, Mertens N, Grooten J. PH1-derived bivalent bibodies and trivalent tribodies bind differentially to shed and tumour cell-associated MUC1. PROTEIN ENGINEERING DESIGN & SELECTION. 2010;23(9):721–8.
MLA
Schoonooghe, Steve, Ingrid Burvenich, Liesbet Vervoort, et al. “PH1-derived Bivalent Bibodies and Trivalent Tribodies Bind Differentially to Shed and Tumour Cell-associated MUC1.” PROTEIN ENGINEERING DESIGN & SELECTION 23.9 (2010): 721–728. Print.