Super Potent Bispecific Llama VHH Antibodies Neutralize HIV via a Combination of gp41 and gp120 Epitopes
Résumé
Broad and potent neutralizing llama single domain antibodies (VHH) against HIV-1
targeting the CD4 binding site (CD4bs) have previously been isolated upon llama immunization.
Here we describe the epitopes of three additional VHH groups selected from phage libraries. The 2E7
group binds to a new linear epitope in the first heptad repeat of gp41 that is only exposed in the
fusion-intermediate conformation. The 1B5 group competes with co-receptor binding and the 1F10
group interacts with the crown of the gp120 V3 loop, occluded in native Env. We present biophysical
and structural details on the 2E7 interaction with gp41. In order to further increase breadth and
potency, we constructed bi-specific VHH. The combination of CD4bs VHH (J3/3E3) with 2E7 group
VHH enhanced strain-specific neutralization with potencies up to 1400-fold higher than the mixture
of the individual VHHs. Thus, these new bivalent VHH are potent new tools to develop therapeutic
approaches or microbicide intervention.