Antibody PRO 140 Suppresses HIV Viral Load with Once-weekly Dosing
Subcutaneous injections of PRO
140, a humanized monoclonal antibody that blocks
the CCR5 co-receptor and inhibits HIV entry into cells,
reduced viral load significantly more than placebo,
according to a study described in the May
15, 2010 Journal of Infectious Diseases.
PRO 140 worked well when administered once-weekly, offering
proof-of-concept for an antiretroviral therapy that
can be taken less often than current drugs.
HIV uses 2 co-receptors, designated CCR5 and CXCR4, along with
the CD4 cell surface receptor to enter cells. Maraviroc
(Selzentry) is the first approved drug that prevents HIV entry
by blocking CCR5. PRO 140 works by a similar principle, but uses
monoclonal (all identical) antibodies, rather than a drug molecule,
to block the co-receptor.
Jacobson from Drexel University College of Medicine and colleagues
conducted the first clinical trial to evaluate whether subcutaneous
(under the skin) administration of PRO 140 would inhibit HIV.
Prior studies have shown that intravenously administered PRO 140
has potent antiviral activity, but subcutaneous administration
would be much more practical and allow patients to administer
the drug themselves at home.
investigators designed a randomized double-blind, placebo-controlled
study that included 44 patients with HIV viral load > 5000
copies/mL (median 25,100 copies/mL) and CD4 cell counts > 300
cells/mm3 (median 410 cells/mm3); 15 were treatment-experienced,
the rest had not previously used ART. Tropism testing showed that
participants had exclusively CCR5-using virus, and they had not
been on antiretroviral therapy (ART) for at least the past 12
were randomly assigned to receive subcutaneous injections of placebo
or 3 doses of PRO 140: 162 mg once-weekly for 3 weeks, 324 mg
once-weekly for 3 weeks, or 324 mg every other week for 2 doses.
Investigators monitored PRO 140 serum concentrations, antiviral
activity, and safety over 58 days of follow-up.
PRO 140 demonstrated potent and prolonged antiretroviral activity.
antiviral effects were observed following the first dose,
and viral load decreased with continued dosing.
of patients in the 324 mg once-weekly arm and 75% in the 324
mg every other week arm achieved > 1 log decrease in viral
load (compared with none in the placebo group).
maximum viral load reductions according to dose were as follows
(all statistically significant relative to placebo):
mg once-weekly: 0.99 log;
mg once-weekly: 1.65 log;
mg every other week: 1.37 log;
maximum viral load reduction increased to 1.60 logs when 3
patients later determined to have CXCR4-tropic virus (that
is, they should not have been eligible for the study) were
cell count increased in all PRO 140 dose groups, but the changes
were not statistically significant.
140 was generally well-tolerated, with no drug-related serious
adverse events or dose-limiting toxicities.
site reactions reported by more than 5% of participants were
induration or hard swelling (20%), pain (9%), and irritation
reactions were mild, transient, and self-resolving, and occurred
with similar frequency in the PRO 140 and placebo groups.
load remained suppressed between successive PRO 140 doses,
including the every other week interval.
mean PRO 140 half-life in the body was 3.4 days for the 162
mg once-weekly dose and 3.7 days for 324 mg once-weekly.
on these findings, the study authors concluded, "This trial
demonstrates proof of concept for a monoclonal antibody administered
subcutaneously in HIV-1 infected individuals."
PRO 140 offers the potential for significant dose-dependent HIV-1
RNA suppression and infrequent patient self-administration,"
load reductions and antiviral response rates increased as the
total amount of PRO 140 administered over 3 weeks was increased
from 486 mg (162 mg weekly) to 648 mg (324 mg biweekly) to 932
mg (324 mg weekly)," they elaborated in their discussion.
trough [lowest] concentrations increased after repeat subcutaneous
dosing, a loading dose potentially could be used to increase the
initial rate of virologic suppression," they continued. "After
an initial loading dose, potent virologic suppression and steady-state
trough concentrations of PRO 140 might be attainable with subcutaneous
maintenance doses similar to those examined here."
University College of Medicine, Philadelphia, PA; AIDS Research
Consortium of Atlanta, Atlanta, GA; Quest Clinical Research, San
Francisco, CA; University of Alabama, Birmingham, AL; Montefiore
Medical Center and Einstein/Montefiore Center for AIDS Research,
Bronx, NY; Progenics Pharmaceuticals, Tarrytown, NY.
Jacobson, MA Thompson, JP Lalezari, and others. Anti-HIV-1 Activity
of Weekly or Biweekly Treatment with Subcutaneous PRO 140, a CCR5
Monoclonal Antibody. Journal of Infectious Diseases 201(10): 1481-1487
May 15 2010.