A Phase 1, Open Label, Dose-escalation Study of the Safety, Pharmacokinetics and Antiretroviral Activity of 3BNC117

The proposed study is a first-in-man phase I study that aims to evaluate the safety, tolerability and pharmacokinetics of 3BNC117 in HIV-infected and HIV-uninfected subjects, and its antiretroviral activity in HIV-infected subjects.

In preclinical studies carried out in humanized mice and non-human primates, 3BNC117 alone or in combination with other neutralizing antibodies led to protection from HIV-1 or SHIV infection and also to sustained suppression of HIV-1 plasma viremia. The aims of this protocol are to evaluate the safety, tolerability and pharmacokinetics profile of 3BNC117 in both HIV-infected and HIV-uninfected subjects,and its antiretroviral activity in HIV-infected subjects.

Eligibility Criteria:
Inclusion Criteria:

* Group 1 (HIV-uninfected):

  * Adult males and females, age 18 to 65
  * Amenable to HIV risk reduction counseling and agrees to maintaining behavior consistent with low risk of HIV exposure;
  * If a sexually active male or female, participating in sexual activity that could lead to pregnancy, agrees to use an effective method of contraception throughout the study.
* Groups 2-5 (HIV-infected):

  * Age 18 to 65
  * HIV infection confirmed by ELISA and immunoblot
  * Groups 2A-D - on ART with HIV-1 plasma RNA levels below 100,000 copies/ml, or off ART for at least 8 weeks with HIV-1 plasma RNA level between 2,000-100,000 copies/ml by standard assays on 2 occasions at least 1 week apart;
  * Group 2E - Untreated HIV-infected (not on ART for at least 8 weeks): HIV-1 RNA plasma levels between 2,000 - 100,000 copies/ml;
  * Group 3 - Untreated HIV controllers (not on ART for at least 8 weeks): HIV-1 RNA plasma level of \< 2,000 copies/ml by standard assays, on 2 occasions, at least 1 week apart, and ART-naive.
  * Group 4 - ART treated with HIV-1 RNA plasma level of \> 20 copies/ml by standard assays on 2 occasions, at least 1 week apart, while on combination antiretroviral therapy;
  * Groups 5A and 5B - ART treated with HIV-1 RNA plasma level of \< 20 copies/ml by standard assays on 2 occasions, at least 1 week apart, while on combination antiretroviral therapy;
  * Current CD4 cell count \> 300 cells/µl
  * If sexually active male and female, participating in sexual activity that could lead to pregnancy, agrees to use an effective method of contraception throughout the study.

Exclusion criteria:

* Group 1 (HIV-uninfected):

  * Confirmed HIV-1 or HIV-2 infection;
  * History of immunodeficiency or autoimmune disease; use of systemic corticosteroids, immunosuppressive anti-cancer, or other medications considered significant by the trial physician within the last 6 months;
  * Any clinically significant acute or chronic medical condition that in the opinion of the investigator would preclude participation;
  * Within the 12 months prior to enrollment, the volunteer has a history of sexually transmitted disease;
  * Hepatitis B (surface antigen, HbsAg) or hepatitis C (HCV antibodies);
  * Laboratory abnormalities in the parameters listed below:

    * Absolute neutrophil count ≤ 2,000
    * Hemoglobin ≤ 12 gm/dL if female; ≤ 13.5 gm/dL if male
    * Platelet count ≤ 140,000
    * ALT ≥ 1.25 x ULN
    * AST ≥ 1.25 x ULN
    * Total bilirubin ≥ 1.1 ULN
    * Creatinine ≥ 1.1 x ULN
    * Coagulation parameters (PT, PTT, INR) ≥ 1.1 x ULN
  * Pregnancy or breastfeeding;
  * Any vaccination within 14 days prior to 3BNC117 administration;
  * Receipt of any experimental HIV vaccine in the past or monoclonal antibody therapy of any kind in the past;
  * Participation in another clinical study of an investigational product currently or within past 12 weeks, or expected participation during this study.
* Groups 2-5 (HIV-infected):

  * History of AIDS-defining illness
  * History of systemic corticosteroids, immunosuppressive anti-cancer, or other medications considered significant by the trial physician within the last 6 months;
  * Any clinically significant acute or chronic medical condition, other than HIV infection, that in the opinion of the investigator would preclude participation;
  * Hepatitis B (surface antigen, HbsAg) or hepatitis C (HCV antibodies);
  * Laboratory abnormalities in the parameters listed below:

    * Absolute neutrophil count ≤ 1,300
    * Hemoglobin ≤ 10 gm/dL
    * Platelet count ≤ 125,000
    * ALT ≥ 2.0 x ULN
    * AST ≥ 2.0 x ULN
    * Total bilirubin ≥ 1.1 ULN
    * Creatinine ≥ 1.1 x ULN
    * Coagulation parameters ≥ 1.1 x ULN;
  * Current antiretroviral regimen includes either maraviroc or enfuvirtide;
  * Pregnancy or breastfeeding;
  * Any vaccination within 14 days prior to 3BNC117 administration;
  * Receipt of any experimental HIV vaccine or monoclonal antibody therapy of any kind in the past;
  * Participation in another clinical study of an investigational product currently or within past 12 weeks, or expected participation during this study.