Combination Therapy With 3BNC117 and 10-1074 in HIV-Infected Individuals

Recent advances in antibody cloning technologies have led to the discovery of a number of
highly potent and HIV-specific broadly neutralizing monoclonal antibodies (bNAbs) from B
cells of HIV-infected individuals. It has been shown that certain bNAbs can prevent
acquisition of the virus, suppress viral replication, delay and/or prevent plasma viral
rebound following treatment interruption in Simian Immunodeficiency virus (SIV)-infected
animals and block cell-to-cell transmission of laboratory-adapted HIV in vitro. In light of
these encouraging outcomes, a number of clinical trials have been conducted in recent years
in order to explore the feasibility of achieving sustained virologic suppression using a
single bNAb in HIV-infected individuals following analytical treatment interruption (ATI).
Despite the fact that repeated administration of a single bNAb was safe and well-tolerated,
the vast majority of study subjects experienced plasma viral rebound following ATI, clearly
demonstrating that successful passive immunotherapy will require different approach,
including the use of a combination of 2 or more bNAbs to achieve extended periods of
virologic suppression.

Given a major emphasis on current HIV research lies in the possibility of achieving ART-free
virologic remission, it is of great interest to investigate whether a combination of potent
HIV- specific bNAbs, such as 3BNC117 and 10-1074, can prevent plasma viral rebound in
infected individuals upon discontinuation of ART or suppress viral replication in subjects
who are not taking ART.

- INCLUSION CRITERIA:

General Inclusion Criteria for both Groups:

1. Age 18-65 years old.

2. HIV-1 infection and clinically stable.

3. General good health and has an identified primary health care provider for medical
management of HIV infection and is willing to maintain a relationship with a primary
health care provider for medical management of HIV infection while participating in
the study.

4. CD4+ T cell count >450 cells/mm(3) at screening.

5. Laboratory values within pre-defined limits at screening:

1. Absolute neutrophil count >1,000/mm(3).

2. Hemoglobin levels >10.0 g/dL for men and >9.0 g/dL for women.

3. Platelet count >100,000/mm(3).

4. Estimated or a measured glomerular filtration rate >60 mL/min/1.73m(2) as
determined by the National Institutes of Health (NIH) Clinical Center laboratory.

5. AST and ALT levels of <2.5 times upper limit of normal (ULN), direct bilirubin
within the normal range for the NIH Clinical Center laboratory.

6. Willingness to have samples stored for future research.

Inclusion criteria specific for Group 1:

7. Institution of ART within 12 weeks of being diagnosed with primary HIV-1 infection

8. Primary HIV-1 infection is defined as meeting at least one of the following criteria:

1. Detectable plasma HIV-1 RNA levels of >2000 copies/mL with a negative result from
an HIV-1 EIA, or

2. Positive result from an HIV-1 EIA with a negative or indeterminate result from an
HIV-1 western blot or another confirmatory antibody test that subsequently
evolves to a confirmed positive result, or

3. Negative result from an HIV-1 EIA within the past 4 months and HIV-1 RNA levels
of >400,000 copies/mL, in the setting of a potential exposure to HIV-1.

4. Negative result from an HIV-1 EIA within 6 months prior to a positive result from
an HIV-1 EIA and an HIV-1 western blot or another confirmatory antibody test.

5. Presence of low level of HIV antibodies as determined by having a positive EIA or
a positive Western blot with a non-reactive detuned EIA according to a serologic
testing algorithm for recent infection.

9. Documentation of continuous ART treatment with suppression of plasma viral level below
the limit of detection for greater than or equal to 1 years. Individuals with blips
(i.e., detectable viral levels on ART) prior to screening may be included provided
they satisfy the following criteria:

1. The blips are <400 copies/mL, and

2. Succeeding viral levels return to levels below the limit of detection on
subsequent testing.

10. Willingness to undergo ATI

11. Willingness for both male and female subjects to agree to use barrier protection
methods or abstinence during the ATI phase of the study to decrease the risk of HIV
transmission.

Inclusion criteria specific for Group 2:

12. No ART within 24 months of screening.

13. HIV plasma viremia between 200 and 5,000 copies/mL at screening AND at least two
documented viral level greater than or equal to 200 copies/mL in the 12 months prior
to screening.

At the screening visit, subjects considering enrollment in Group 2 will be advised that
current guidelines recommend treatment of all individuals with HIV infection regardless of
viral levels and CD4 counts.

Reproductive Risks

Contraception: The effects of 3BNC117 and 10-1074 on the developing human fetus are
unknown. For this reason, men and women of childbearing potential must agree to use
adequate pregnancy prevention. This includes the use an effective method of contraception
(i.e. condom with spermicide, diaphragm with spermicide, hormone-eluting IUD, hormone-based
contraceptive with condom) for the study duration. Subjects should also agree to use a male
or female condom while off ART. Pregnancy prevention must be practiced continuously for the
duration of study participation. Females of childbearing-age must have a negative pregnancy
test result prior to receiving each infusion of 3BNC117/10-1074. During the course of the
study, if a female subject, or the partner of a male subject suspects or in fact becomes
pregnant, the effected subject should inform the study staff immediately, as well as the
woman s primary care physician.

EXCLUSION CRITERIA:

1. Chronic hepatitis B, as evidenced by a positive test for hepatitis B surface antigen

(HBsAg), or chronic hepatitis C virus (HCV) infection, as evidenced by a positive test
for HCV RNA. Subjects with a positive test for HCV antibody and a negative test for
HCV RNA are eligible.

2. HIV immunotherapy or vaccine(s) received within 1 year prior to screening.

3. Any licensed or experimental non-HIV vaccination (e.g., hepatitis B, influenza,
pneumococcal polysaccharide) received within 2 weeks prior to study enrollment.

4. Receipt of other investigational study agent within 28 days of enrollment.

5. Any active malignancy that may require systemic chemotherapy or radiation therapy.

6. Systemic immunosuppressive medications received within 3 months prior to enrollment
(Not excluded: [1] corticosteroid nasal spray or inhaler; [2] topical corticosteroids
for mild, uncomplicated dermatitis; or [3] oral/parenteral corticosteroids
administered for non-chronic conditions not expected to recur [length of therapy less
than or equal to10 days, with completion in greater than or equal to 30 days prior to
enrollment]).

7. History or other clinical evidence of:

1. Significant or unstable cardiac or cerebrovascular disease (e.g., angina,
congestive heart failure, recent stroke or myocardial infarction).

2. Severe illness, malignancy, immunodeficiency other than HIV, or any other
condition that, in the opinion of the investigator, would make the subject
unsuitable for the study.

8. Active drug or alcohol use or any other pattern of behavior that, in the opinion of
the investigator, would interfere with adherence to study requirements.

9. Pregnancy or breast-feeding at time of screening.

10. Documented multiclass antiretroviral drug resistance that, in the judgment of the
investigator, would pose a risk of virologic failure should additional mutations
develop during the study (Group 1 only).

Co-enrollment Guidelines: Co-enrollment in other trials is restricted to observational
studies or those evaluating the use of a licensed medication and is subject to approval of
the principal investigator (PI).