Many Routes to an Antibody Heavy-Chain CDR3: Necessary, Yet Insufficient, for Specific Binding
Abstract
Because of its great potential for diversity, the immunoglobulin heavy-chain complementarity-determining region 3 (HCDR3) is taken as an antibody molecule’s most important component in conferring binding activity and specificity. For this reason, HCDR3s have been used as unique identifiers to investigate adaptive immune responses in vivo and to characterize in vitro selection outputs where display systems were employed. Here, we show that many different HCDR3s can be identified within a target-specific antibody population after in vitro selection. For each identified HCDR3, a number of different antibodies bearing differences elsewhere can be found. In such selected populations, all antibodies with the same HCDR3 recognize the target, albeit at different affinities. In contrast, within unselected populations, the majority of antibodies with the same HCDR3 sequence do not bind the target. In one HCDR3 examined in depth, all target-specific antibodies were derived from the same VDJ rearrangement, while non-binding antibodies with the same HCDR3 were derived from many different V and D gene rearrangements. Careful examination of previously published in vivo datasets reveals that HCDR3s shared between, and within, different individuals can also originate from rearrangements of different V and D genes, with up to 26 different rearrangements yielding the same identical HCDR3more »
- Authors:
-
- Specifica Inc., Santa Fe, NM (United States)
- Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
- Publication Date:
- Research Org.:
- Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
- Sponsoring Org.:
- USDOE; National Inst. of Health (NIH) (United States)
- OSTI Identifier:
- 1430019
- Report Number(s):
- LA-UR-17-30898
Journal ID: ISSN 1664-3224
- Grant/Contract Number:
- AC52-06NA25396; 1-U54-DK093500-01
- Resource Type:
- Journal Article: Accepted Manuscript
- Journal Name:
- Frontiers in Immunology
- Additional Journal Information:
- Journal Volume: 9; Journal ID: ISSN 1664-3224
- Publisher:
- Frontiers Research Foundation
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; Biological Science
Citation Formats
D'Angelo, Sara, Ferrara, Fortunato, Naranjo, Leslie, Erasmus, M. Frank, Hraber, Peter, and Bradbury, Andrew R. M. Many Routes to an Antibody Heavy-Chain CDR3: Necessary, Yet Insufficient, for Specific Binding. United States: N. p., 2018.
Web. doi:10.3389/fimmu.2018.00395.
D'Angelo, Sara, Ferrara, Fortunato, Naranjo, Leslie, Erasmus, M. Frank, Hraber, Peter, & Bradbury, Andrew R. M. Many Routes to an Antibody Heavy-Chain CDR3: Necessary, Yet Insufficient, for Specific Binding. United States. https://doi.org/10.3389/fimmu.2018.00395
D'Angelo, Sara, Ferrara, Fortunato, Naranjo, Leslie, Erasmus, M. Frank, Hraber, Peter, and Bradbury, Andrew R. M. 2018.
"Many Routes to an Antibody Heavy-Chain CDR3: Necessary, Yet Insufficient, for Specific Binding". United States. https://doi.org/10.3389/fimmu.2018.00395. https://www.osti.gov/servlets/purl/1430019.
@article{osti_1430019,
title = {Many Routes to an Antibody Heavy-Chain CDR3: Necessary, Yet Insufficient, for Specific Binding},
author = {D'Angelo, Sara and Ferrara, Fortunato and Naranjo, Leslie and Erasmus, M. Frank and Hraber, Peter and Bradbury, Andrew R. M.},
abstractNote = {Because of its great potential for diversity, the immunoglobulin heavy-chain complementarity-determining region 3 (HCDR3) is taken as an antibody molecule’s most important component in conferring binding activity and specificity. For this reason, HCDR3s have been used as unique identifiers to investigate adaptive immune responses in vivo and to characterize in vitro selection outputs where display systems were employed. Here, we show that many different HCDR3s can be identified within a target-specific antibody population after in vitro selection. For each identified HCDR3, a number of different antibodies bearing differences elsewhere can be found. In such selected populations, all antibodies with the same HCDR3 recognize the target, albeit at different affinities. In contrast, within unselected populations, the majority of antibodies with the same HCDR3 sequence do not bind the target. In one HCDR3 examined in depth, all target-specific antibodies were derived from the same VDJ rearrangement, while non-binding antibodies with the same HCDR3 were derived from many different V and D gene rearrangements. Careful examination of previously published in vivo datasets reveals that HCDR3s shared between, and within, different individuals can also originate from rearrangements of different V and D genes, with up to 26 different rearrangements yielding the same identical HCDR3 sequence. On the basis of these observations, we conclude that the same HCDR3 can be generated by many different rearrangements, but that specific target binding is an outcome of unique rearrangements and VL pairing: the HCDR3 is necessary, albeit insufficient, for specific antibody binding.},
doi = {10.3389/fimmu.2018.00395},
url = {https://www.osti.gov/biblio/1430019},
journal = {Frontiers in Immunology},
issn = {1664-3224},
number = ,
volume = 9,
place = {United States},
year = {Thu Mar 08 00:00:00 EST 2018},
month = {Thu Mar 08 00:00:00 EST 2018}
}
Web of Science
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High-throughput sequencing of natively paired antibody chains provides evidence for original antigenic sin shaping the antibody response to influenza vaccination
journal, March 2014
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Identifying functional anti-Staphylococcus aureus antibodies by sequencing antibody repertoires of patient plasmablasts
journal, May 2014
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- Clinical Immunology, Vol. 152, Issue 1-2
Non-progressing cancer patients have persistent B cell responses expressing shared antibody paratopes that target public tumor antigens
journal, February 2018
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- Clinical Immunology, Vol. 187
Specific binder for Lightning-Link® biotinylated proteins from an antibody phage library
journal, September 2013
- Ferrara, Fortunato; Naranjo, Leslie A.; D'Angelo, Sara
- Journal of Immunological Methods, Vol. 395, Issue 1-2
The Remarkable Flexibility of the Human Antibody Repertoire; Isolation of Over One Thousand Different Antibodies to a Single Protein, BLyS
journal, November 2003
- Edwards, Bryan M.; Barash, Steven C.; Main, Sarah H.
- Journal of Molecular Biology, Vol. 334, Issue 1
Expressed Murine and Human CDR-H3 Intervals of Equal Length Exhibit Distinct Repertoires that Differ in their Amino Acid Composition and Predicted Range of Structures
journal, December 2003
- Zemlin, Michael; Klinger, Martin; Link, Jason
- Journal of Molecular Biology, Vol. 334, Issue 4
Comprehensive Interrogation of a Minimalist Synthetic CDR-H3 Library and Its Ability to Generate Antibodies with Therapeutic Potential
journal, May 2013
- Mahon, Ciara M.; Lambert, Matthew A.; Glanville, Jacob
- Journal of Molecular Biology, Vol. 425, Issue 10
Non-immunized natural human heavy chain CDR3 repertoires allow the isolation of high affinity peptides mimicking a human influenza hemagglutinin epitope
journal, March 2008
- Deroo, Sabrina; Fischer, Aurélie; Beaupain, Nadia
- Molecular Immunology, Vol. 45, Issue 5
Deep sequencing in library selection projects: what insight does it bring?
journal, August 2015
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