Many Routes to an Antibody Heavy-Chain CDR3: Necessary, Yet Insufficient, for Specific Binding

D'Angelo, Sara; Ferrara, Fortunato; Naranjo, Leslie; Erasmus, M. Frank; Hraber, Peter; Bradbury, Andrew R.  M.

doi:10.3389/fimmu.2018.00395

Title: Many Routes to an Antibody Heavy-Chain CDR3: Necessary, Yet Insufficient, for Specific Binding

Journal Article · Thu Mar 08 00:00:00 EST 2018 · Frontiers in Immunology

DOI:https://doi.org/10.3389/fimmu.2018.00395· OSTI ID:1430019

D'Angelo, Sara ^[1]; Ferrara, Fortunato ^[1]; Naranjo, Leslie ^[1]; Erasmus, M. Frank ^[1]; Hraber, Peter ^[2]; Bradbury, Andrew R. M. ^[1]

Specifica Inc., Santa Fe, NM (United States)
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

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.

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Research Organization:: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: USDOE; National Inst. of Health (NIH) (United States)

Grant/Contract Number:: AC52-06NA25396; 1-U54-DK093500-01

OSTI ID:: 1430019

Report Number(s):: LA-UR-17-30898

Journal Information:: Frontiers in Immunology, Vol. 9; ISSN 1664-3224

Publisher:: Frontiers Research FoundationCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 43 works

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Seeking high-priority mutations enabling successful antibody-breeding: systematic analysis of a mutant that gained over 100-fold enhanced affinity Oyama, Hiroyuki; Kiguchi, Yuki; Morita, Izumi Scientific Reports, Vol. 10, Issue 1 https://doi.org/10.1038/s41598-020-61529-7	journal	March 2020
Immunosenescence and human vaccine immune responses Crooke, Stephen N.; Ovsyannikova, Inna G.; Poland, Gregory A. Immunity & Ageing, Vol. 16, Issue 1 https://doi.org/10.1186/s12979-019-0164-9	journal	September 2019
ASAP - A Webserver for Immunoglobulin-Sequencing Analysis Pipeline Avram, Oren; Vaisman-Mentesh, Anna; Yehezkel, Dror Frontiers in Immunology, Vol. 9 https://doi.org/10.3389/fimmu.2018.01686	journal	July 2018

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