Download A novel HIV-Envelope specific bi-specific killer engager (BiKE

A novel HIV-Envelope specific bi-specific killer engager (BiKE) enhances natural killer cell
response to HIV-infected targets
Zachary Davis, PhD; Todd Lenvik, Louis Hansen, Ashley Haase, MD; Timothy Schacker, MD;
Jeffrey Miller, MD
While advancements in efficacy and use of anti-retroviral drugs have substantially ameliorated
the health and longevity of HIV-infected individuals, these drugs are merely a stop-gap to
prevent progression to AIDS and to limit further transmission of the virus. Due to HIV’s errorprone replicative process which frequently results in alterations to the proteins that constitute its
viral envelope, the normal antibody response to HIV is unable to keep pace with viral mutation
and is therefore insufficient to target and clear the virus. In recent years, a clone of anti-HIV Env
antibody (VRC01) was identified and isolated from the serum of HIV-infected patients that has
broad binding specificity to a wide variety of primary HIV strains. However, this antibody clone,
while exhibiting a strong neutralizing capacity, showed little to no ability to mediate an ADCC
response necessary to eliminate infected cells. Cellular responses to HIV-infected cells are also
dampened by viral alterations of surface expressed ligands on infected cells. Natural killer (NK)
cells, which mediate cytotoxic and cytokine secreting functions in response to recognition of
germ-line encoded ligands do respond to HIV-infected cells but exhibit significantly diminished
responses due to HIV’s selective retention of MHC-I, which act as inhibitory ligands to NK
expressed inhibitory receptors, and down-modulation of co-activation ligands. However, NK can
mediate ADCC through the low affinity Fc receptor, CD16, which when triggered is able to
overcome inhibition by NK inhibitory receptors in order to respond to antibody coated targets. As
such, the VRC01 antibody clone is a prime candidate for inclusion our a bi-specific killer
engager (BiKE) platform in combination with an anti-CD16 component which would allow for NK
targeting and killing of HIV-infected cells expressing HIV Env on their membranes. Here we
show our novel construct binds directly to HIV-infected cells and engages CD16 on NK cells to
trigger NK cytotoxic and cytokine secreting functions.