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A novel promiscuous class of camelid single-domain antibody contributes to the antigen-binding repertoire.
Tijdschriftbijdrage - Tijdschriftartikel
It is well established that, in addition to conventional Abs, camelids (such as Camelus dromedarius and Lama glama) possess unique
homodimericHchainAbs (HCAbs) devoid ofLchains.The Ag-binding site of theseHCAbs consists of a single variable domain, referred
to as VHH. It is widely accepted that these VHHs, with distinct framework-2 imprints evolved within the V(H) clan III-family 3, are
exclusively present onHCAbs. In this study, we report the finding of a distinct leader signal sequence linked to variable genes displaying
a high degree of homology to the clan II, human VH(4) family that contributes to the HCAb Ag-binding diversity. Although the VHH
framework-2 imprints are clearly absent, theirVH(4)-D-JH recombination products can be rearranged to theHchains of both classical
andHCAbs.This suggests that for theseVdomains the presence of aLchain to constitute theAg-binding site is entirelyoptional.As such,
the capacity of this promiscuous VH(4) family to participate in two distinct Ab formats significantly contributes to the breadth of the
camelid Ag-binding repertoire. This was illustrated by the isolation of stable, dendritic cell-specificVH(4) single domains fromaVH(4)-
HCAbphage display library. The high degree of homology with humanVH(4) sequences is promising in that itmay circumvent the need
for "humanization" of such single-domain Abs in therapeutic applications.
homodimericHchainAbs (HCAbs) devoid ofLchains.The Ag-binding site of theseHCAbs consists of a single variable domain, referred
to as VHH. It is widely accepted that these VHHs, with distinct framework-2 imprints evolved within the V(H) clan III-family 3, are
exclusively present onHCAbs. In this study, we report the finding of a distinct leader signal sequence linked to variable genes displaying
a high degree of homology to the clan II, human VH(4) family that contributes to the HCAb Ag-binding diversity. Although the VHH
framework-2 imprints are clearly absent, theirVH(4)-D-JH recombination products can be rearranged to theHchains of both classical
andHCAbs.This suggests that for theseVdomains the presence of aLchain to constitute theAg-binding site is entirelyoptional.As such,
the capacity of this promiscuous VH(4) family to participate in two distinct Ab formats significantly contributes to the breadth of the
camelid Ag-binding repertoire. This was illustrated by the isolation of stable, dendritic cell-specificVH(4) single domains fromaVH(4)-
HCAbphage display library. The high degree of homology with humanVH(4) sequences is promising in that itmay circumvent the need
for "humanization" of such single-domain Abs in therapeutic applications.
Tijdschrift: J Immunol
ISSN: 0022-1767
Volume: 184
Pagina's: 5696-5704
Jaar van publicatie:2010
Trefwoorden:Camelid single-domain antibody, homodimeric H chain Abs, L chain, VHH