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Combination inhibitor BMS-986197 demonstrates good activity against HIV in early study
Liz Highleyman, 2016-03-18 07:30:00
A long-acting bio-engineered molecule
with a triple mechanism of action demonstrated potent antiviral activity and worked
against HIV that developed resistance to any one of the three mechanisms in a
laboratory study, and lowered viral load in humanised mice, according to
research presented at the Conference on
Retroviruses and Opportunistic Infections (CROI 2016) last month in Boston.
antiretroviral therapy is highly safe and effective for most people with HIV,
but there is still room for more convenient agents that could help improve
adherence, as well as drugs for people with highly resistant virus.
BMS-986197 is an injectable biologic agent which investigators think could potentially be
self-administered as a long-acting subcutaneous injection; combining different modes
of action in a single agent could avoid the need for multiple injections.
Krystal, formerly of Bristol-Myers
Squibb and now at ViiV Healthcare, presented findings from early laboratory and
animal studies of BMS-986197, which is part of the portfolio of Bristol-Myers
Squibb's investigational HIV agents recently acquired by ViiV.
BMS-986197 is made up of adnectins, small proteins with modifiable
binding loops resembling certain antibody regions. Researchers combined
adnectins targeting the CD4 cell surface receptor and HIV's gp41 protein
subunit, along with a peptide fusion inhibitor, to build a so-called
'combinectin' inhibitor which uses independent mechanisms to interfere with
three routes of HIV entry. Finally, this combinectin was attached to human
serum albumin to improve its pharmacokinetics.
anti-CD4 adnectin appears to allow HIV's gp120 envelope protein to bind to the
receptor, but prevents conformational changes needed for binding to
co-receptors (CCR5 or CXCR4). The second adnectin attacks the N17 sequence of the
HIV gp41 envelope protein subunit. The fusion inhibitor component works
similarly to enfuvirtide (Fuzeon).
or 50% effective concentration, of the anti-CD4 adnectin, the anti-gp41 adnectin
and the fusion inhibitor peptide were 8.5, 5.4 and 0.4 nM (nanoMolar),
respectively. Linking these three inhibitors into a single molecule led to
synergistic effects greater than the sum of the parts. The optimal combination
of the two adnectins increased potency by more than 100-fold, while adding the
fusion inhibitor appeared to increase the barrier to resistance. The addition
of human serum albumin decreased potency but made the combinectin last longer
in the body.
In the laboratory BMS-986197 demonstrated antiviral activity against a
wide range of clinical virus isolates of different subtypes obtained from
people with HIV. It retained potency against viruses that were resistant to any
one of the three separate entry inhibition mechanisms and it showed no loss of potency in human blood
mice with humanised immune systems, BMS-986197 produced dose-dependent
decreases in viral load, and at the highest dose most became undetectable. Cell
receptors remained occupied and pharmacokinetics were consistent over 36 days. In
cynomologous monkeys a subcutaneous injection had a half-life of 30 hours and
the researchers projected a half-life in humans of about 40 hours – potentially
adequate for once-weekly dosing.
is a long-acting (projected weekly
dose) biologic molecule containing three individual inhibitors of HIV-1 entry
that can be dosed subcutaneously," the researchers concluded. "BMS-986197 is effective at lowering viral
loads in a mouse model of infection."