Nussenzweig: Phase 1 studies of the pharmacokinetics, safety, and bioactivity of 3BNC117-LS and
10-1074-LS among adults in the US and sub-Saharan Africa
Despite signifi cant efforts over the last 30 years, and exceptional recent scientifi c advances, it seems highly
unlikely that we will be able to develop an effective active anti-HIV vaccine in the near future. In the interim,
there is a need for HIV prophylaxis methods that are effective in controlling new infections, deliverable in areas
most in need (such as sub-Saharan Africa), and economically feasible in these regions. Passive immunization
with broadly neutralizing monoclonal antibodies (bNAbs) is being considered in this context. Passive
bNAb immunization has been shown to prevent SHIV infection in rhesus macaque models, can be delivered
subcutaneously (enabling self-administration in some settings), and the antibodies have a long half-life. This
is particularly true of antibodies such as the two that will be investigated in this grant, 3BNC117-LS and
10-1074-LS, which have been specifi cally modifi ed to have increased half-lives in vivo. This grant will be used
to evaluate the safety, tolerability, pharmacokinetic profi le, and antiretroviral effects of two human anti-HIV
neutralizing antibodies given in combination in humans, with the long-term goal of achieving high levels of
effi cacy in preventing HIV acquisition.
3BNC117-LS and 10-1074-LS are broad and potent anti-HIV neutralizing antibodies recognizing the HIV-1
envelope CD4 binding site and the V3 loop of the HIV-1 envelope, respectively. Two amino acid substitutions
(the LS mutation) were introduced in the Fc region of the parental antibodies to extend their half-lives. Both
the parental and LS-modifi ed antibodies provide broad coverage of diverse HIV-1 strains, and the parental
antibodies showed favorable safety profi les in phase I trials. The LS mutation alters the binding properties of
the antibodies for the neonatal Fc receptor (FcRN). It thereby enhances antibody re-cycling and prolongs the
half-lives by 3- to 4-fold. The increased half-lives should be dose sparing and allow for quarterly or biannual
This proposal builds on the research performed under OPP1092074 (awarded to M. Nussenzweig, Rockefeller
University), and enables the development and evaluation of a combination of 3NBC117-LS and 10-1074-LS
for passive immunoprophylaxis in sub-Saharan Africa. It includes phase 1 studies in the US and in sub-Saharan
Africa, as well as overall management and oversight of product development. Data generated from
these studies will support phase 2b effi cacy studies in sub-Saharan Africa. Two studies will be conducted at
the Rockefeller University, and the other will be conducted in four sub-Saharan African sites. The ultimate goal
is to develop a commercially viable product for sub-Saharan African countries that can be delivered subcutaneously
once every 3-6 months.
The grant is led by Michel Nussenzweig at Rockefeller University. Drs. Connie Celum (University of Washington, Seattle) and Julie McElrath (Fred
Hutchinson Cancer Research Center, Seattle) are partner investigators for the proposed phase 1b study in Africa. The Product Development Center
at the International AIDS Vaccine Initiative (IAVI) will manage the production of 10-1074-LS and will assist with regulatory submissions in the US and
Africa; these activities are funded under separate awards to IAVI.
1.) Phase 1a: First-in-Human Studies in the US. Two phase 1, dose-escalation studies to assess the safety, pharmacokinetics, and antiretroviral
activity of 10-1074-LS alone and in combination with 3BNC117-LS in HIV-uninfected and HIV-infected individuals will be conducted. The
antibodies will be administered intravenously or subcutaneously.
2.) Phase 1b: Study in sub-Saharan African Sites. This will be a phase 1b, placebo-controlled study of the safety, tolerability, and pharmacokinetics/
pharmacodynamics of 10-1074-LS and 3BNC117-LS administered in combination subcutaneously to HIV-uninfected individuals in Kenya,
Uganda, and South Africa.