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Title: 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 » 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.« less

Authors:
 [1];  [1];  [1];  [1];  [2];  [1]
  1. Specifica Inc., Santa Fe, NM (United States)
  2. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Publication Date:
Research Org.:
Los Alamos National Lab. (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. doi:10.3389/fimmu.2018.00395.
D'Angelo, Sara, Ferrara, Fortunato, Naranjo, Leslie, Erasmus, M. Frank, Hraber, Peter, and Bradbury, Andrew R. M. Thu . "Many Routes to an Antibody Heavy-Chain CDR3: Necessary, Yet Insufficient, for Specific Binding". United States. doi: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},
journal = {Frontiers in Immunology},
number = ,
volume = 9,
place = {United States},
year = {Thu Mar 08 00:00:00 EST 2018},
month = {Thu Mar 08 00:00:00 EST 2018}
}

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