Sartorisu-Sowmya eBook - 16

NIAD

DECIPHERING THE IMMUNE RESPONSE TO VIRAL INFECTION

A healthy volunteer receives an intravenous infusion
of mAb114 - an experimental treatment for Ebola
virus disease - in a Phase 1 clinical trial held at the NIH
Clinical Center in Bethesda, Maryland.

16 | GENengnews.com

PhD, chief of the Biodefense Research
Section, and colleagues have developed
a therapeutic mAb (mAb114) derived
from blood drawn from an Ebola survivor
11 years after infection.
Sullivan and team first verified the
presence of circulating antibodies against
the EBOV's surface glycoprotein (GP).
Then, they sorted the patient's memory B
cells, immortalized individual clones, and
chose one with specific properties they
had determined from previous research
to increase mAb potency. After cloning
its gene, purifying mAb protein, and
testing in a rhesus macaque model, they
found mAb114 could protect against
infection even when given five days after
challenge.
Seeking to identify the structural and
molecular basis for mAb114's striking
activity, Sullivan and colleagues at
Dartmouth College obtained crystals
and solved the ternary structure of the
mAb/GP complex. Sullivan explained
that the GP, found in abundance on

the virus surface, consists of a trimer of
monomers with two subunits, GP1 and
GP2. They found the mAb binds to a novel
site of vulnerability on GP1, attesting to
the value of identifying natural defenses
targeted by the host immune system.
Subsequently, Julie E. Ledgerwood, DO,
chief, clinical trials program at the VRC,
and her team, led by Martin Gaudinski,
MD, medical director at the VRC,
completed the first-in-human open labelPhase I trial of mAb114. Ledgerwood
reported (Lancet 2019) that even after
a single 30-minute intravenous infusion
(and patient monitoring for 24 weeks),
the mAb was well tolerated, showed
linear pharmacokinetics, and was rapidly
infused, making it suitable for rapid
deployment as a treatment for outbreaks.
Thus, one of the striking features of
mAb114 is that a single infusion, rather
than several over multiple days, protects
the subject.
Ridgeback Biotherapeutics is leading
further clinical development of mAb114.
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