Conditions: Human Immunodeficiency Virus
Keywords: 3BNC117-LS 10-1074-LS Broadly Neutralizing Antibody
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 6
Healthy volunteers: no

Brief summary:
The proposed study is a phase 1, open label, single arm study to evaluate the safety, pharmacokinetics and antiviral activity of single intravenous infusions of 3BNC117-LS and 10-1074-LS, each monoclonal antibody (mAb) dosed at 30 mg/kg in viremic human immunodeficiency virus (HIV)-infected individuals.

Detailed description:
The proposed study is a phase 1, open label, single arm study to evaluate the safety, pharmacokinetics and antiviral activity of single intravenous infusions of 3BNC117-LS and 10-1074-LS in viremic HIV-infected individuals.

Ten eligible participants will be enrolled sequentially in the study and will receive each mAb, dosed at 30 mg/kg intravenously and in sequence on study day 0. Following mAb administration, study participants will return for safety assessments on days 1 and 3, and weeks 1, 2, 3 and 4 following dosing, then bi-weekly or monthly until the end of study follow up. All participants will be followed for 24 weeks after 3BNC117-LS and 10-1074-LS administration.

Safety assessments will be performed at multiple time points following 3BNC117-LS and 10-1074-LS infusions. Serum samples for pharmacokinetic (PK) measurements will be collected before and at the end each mAb infusion administration and at multiple subsequent time points during study follow up. Samples will also be collected for measurement of HIV-1 plasma RNA levels before 3BNC117-LS and 10-1074-LS infusions (screen and day 0) and at every follow up visit. T cell subsets will also be monitored during study follow up. Assessments will also include measurement of anti-drug antibody responses and sequencing of plasma envelope before infusions and after viral rebound (first time point after viremia nadir is reached and viral load (VL) is \> 1,000 copies/ml).

Participants will be advised and encouraged to start antiretroviral therapy (ART) within 4 weeks of receiving 3BNC117-LS and 10-1074-LS infusions or sooner if: VL fails to decrease by \> 0.5 log10 copies/ml within 2 weeks of antibody infusions, VL increases \> 0.5 log10 copies/ml between weekly measurements or significant T-cell decline (confirmed CD4+ T cells \< 200 cells/μl) is noted.

Arms:
arm 1: HIV-infected individuals, off ART, and with plasma HIV-1 RNA levels between 500 and 100,000 copies/ml by standard assays. Study participants will receive a single intravenous infusion of 3BNC117-LS and a single infusion of 10-1074-LS. The antibodies will be administered sequentially and dosed at 30 mg/kg.

Interventions: intervention 1: 3BNC117-LS intervention 2: 10-1074-LS
Intervention descriptions: intervention 1: Intravenous infusion of 3BNC117-LS at 30mg/kg intervention 2: Intravenous infusion of 10-1074-LS at 30mg/kg

Protocol document:
Prot_SAP_000.pdf: 
 
        Rockefeller University 
Original IND 131872
June 3, 2021 
Protocol: MCA-0994 
 
Confidential 
Page 1 
 
 
An open label, single arm study of the safety, 
pharmacokinetics and antiretroviral activity of the 
combination of 3BNC117-LS and 10-1074-LS in viremic HIV-
infected individuals. 
 
 
Clinical Trial Phase: 1 
 
 
Local Protocol Number: MCA-0994 
 
 
DAIDS-ES Number: 38670 
 
 
NIAID Funding Mechanism:  
National Institute of Allergy and Infectious Diseases (NIAID) 
1U01AI145921  
 
Pharmaceutical and other Study Product Support Provided by: 
Celldex Therapeutics, Inc. 
 
 
PI: Marina Caskey, MD 
 
 
IND Sponsor: The Rockefeller University  
 
IND # 131872 
 
Principal Investigator/Protocol Chair: Marina Caskey, MD 
 
DAIDS Medical Officer/Medical Monitor: Randall Tressler, MD 
 
 
Version Number: Version 2.0 
 
Version Day Month Year: 3 June 2021 
 
 
 
Rockefeller University Institutional Review Board
IRB NUMBER: MCA-0994
IRB APPROVAL DATE: 08/03/2021
IRB EXPIRATION DATE: 05/27/2022


 
        Rockefeller University 
Original IND 131872
June 3, 2021 
Protocol: MCA-0994 
 
Confidential 
Page 2 
Confidentiality Statement 
This document is confidential and is to be distributed for review only to investigators, potential 
investigators, consultants, study staff, and applicable independent ethics committees or 
institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from The Rockefeller University, unless it is necessary to obtain informed 
consent from potential study participants. 
 
Statement of Compliance 
The clinical trial will be conducted in compliance with the protocol, with the International 
Conference on Harmonization Good Clinical Practice E6 (ICH-GCP), and with 45 CFR 46 and 21 
CFR 50, 56 and 312. All protocol investigators have completed Protection of Human Subjects 
Training. 
 
Rockefeller University Institutional Review Board
IRB NUMBER: MCA-0994
IRB APPROVAL DATE: 08/03/2021
IRB EXPIRATION DATE: 05/27/2022


 
        Rockefeller University 
Original IND 131872
June 3, 2021 
Protocol: MCA-0994 
 
Confidential 
Page 3 
Signature Page 1 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable U.S. federal 
regulations and ICH guidelines. 
The Lead Principal Investigator (Protocol Chair) should sign Signature Page 1. A copy of 
this Signature Page 1 should be filed with the holder of the Regulatory documents and a 
copy should be maintained at the site. 
 
 
Principal Investigator: _______________________________________________ 
Print/Type 
 
Signed: ______________________________      Date:  ____________________ 
Name/Title  
 
 
 
 
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IRB NUMBER: MCA-0994
IRB APPROVAL DATE: 08/03/2021
IRB EXPIRATION DATE: 05/27/2022


 
        Rockefeller University 
Original IND 131872
June 3, 2021 
Protocol: MCA-0994 
 
Confidential 
Page 4 
TABLE OF CONTENTS 
PROTOCOL SUMMARY .......................................................................................................... 10 
1 
KEY ROLES ....................................................................................................................... 14 
 
Study Sites and associated Institutions ............................................................ 14 
 
Individuals .................................................................................................................. 16 
2 
LAY SUMMARY ................................................................................................................. 18 
3 
OBJECTIVES AND RATIONALE ................................................................................... 18 
 
Background ............................................................................................................... 18 
 
Preclinical Characterization of 3BNC117-LS and 10-1074-LS ...................... 19 
3.2.1 
Fc Modification to Extend Half-life ................................................................... 19 
3.2.2 
In Vitro Characterization of 10-1074-LS and 3BNC117-LS ......................... 20 
3.2.3 
3BNC117-LS and 10-1074-LS In Vivo Activity in Non-human Primates ... 22 
3.2.4 
10-1074-LS Tissue Cross Reactivity Study ................................................... 23 
3.2.5 
3BNC117-LS Tissue Cross Reactivity Study ................................................. 23 
3.2.6 
10-1074 In Vivo Toxicology Study in Rats ..................................................... 24 
3.2.7 
3BNC117 In Vivo Toxicology Study in Rats ................................................... 24 
 
Clinical Safety of Monoclonal Antibodies to Treat or Prevent Infection ... 25 
 
Clinical Experience with Fc-modified Antibodies to Enhance Binding to 
the FcRN Receptor .............................................................................................................. 25 
 
Clinical Experience with 10-1074 (IND 123713) ................................................ 26 
 
Clinical Experience with 3BNC117 (IND 118225) ............................................. 26 
 
Clinical Experience with 3BNC117 and 10-1074 in Combination ................ 27 
 
Clinical Data with 3BNC117-LS and 10-1074-LS .............................................. 29 
 
10-1074-LS and 3BNC117-LS Drug Product Manufacture............................. 31 
 
Hypotheses ................................................................................................................ 32 
 
Aims ............................................................................................................................. 32 
 
Outcomes ................................................................................................................... 33 
4 
STUDY DESIGN ................................................................................................................. 33 
5 
STUDY POPULATION ...................................................................................................... 35 
 
Inclusion Criteria ...................................................................................................... 35 
 
Exclusion Criteria..................................................................................................... 35 
6 
METHODS AND PROCEDURES ................................................................................... 36 
 
Screening Procedure and Study Visits .............................................................. 36 
6.1.1 
Pre-Screening Questionnaire ........................................................................... 36 
6.1.2 
Screening Visit .................................................................................................... 36 
6.1.3 
Study Drug Administration Visit ....................................................................... 37 
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IRB NUMBER: MCA-0994
IRB APPROVAL DATE: 08/03/2021
IRB EXPIRATION DATE: 05/27/2022


 
        Rockefeller University 
Original IND 131872
June 3, 2021 
Protocol: MCA-0994 
 
Confidential 
Page 5 
6.1.4 
Post-Study Drug Administration Visit .............................................................. 38 
6.1.5 
Final Visit/Early Termination Visit .................................................................... 38 
6.1.6 
Discontinuation of Study Drug Infusions and/or Participant Withdrawal 
from Study ........................................................................................................................... 38 
6.1.6.1 
Discontinuation of Study Drug Infusion .................................................. 38 
6.1.6.2 
Withdrawal from the Study (Early Termination) .................................... 39 
6.1.6.3 
Follow Up after Withdrawal from Study (Early Termination) ............... 39 
 
Study Procedures .................................................................................................... 39 
6.2.1 
Consent Procedure ............................................................................................ 39 
6.2.2 
Study Assignment and Randomization ........................................................... 40 
6.2.3 
Study Drug Administration Procedure ............................................................ 40 
6.2.4 
Medical History and Physical Examination .................................................... 40 
6.2.5 
Ophthalmologic Evaluations ............................................................................. 41 
6.2.6 
Diagnostic Work Up in the Event of Grade 3 or 4 Elevations in Total 
Bilirubin 41 
6.2.7 
Monitoring for Cytokine Release Associated Adverse Events and 
Treatment of Cytokine Release Syndrome .................................................................... 41 
6.2.8 
Family Planning Counseling ............................................................................. 42 
6.2.9 
Safety Assessments .......................................................................................... 42 
6.2.9.1 
Solicited Adverse Events .......................................................................... 42 
6.2.9.2 
Unsolicited Adverse Events ...................................................................... 43 
6.2.10 
Blood Collection, Storage and Shipment ........................................................ 43 
6.2.11 
Routine Laboratory Parameters ....................................................................... 43 
6.2.12 
Antiretroviral and Immunogenicity Assessments .......................................... 43 
6.2.13 
Pharmacokinetic Evaluations ........................................................................... 44 
6.2.14 
Specimen Shipment Preparation, Handling and Storage ............................ 45 
6.2.15 
Biohazard Containment ..................................................................................... 46 
6.2.16 
Compensation ..................................................................................................... 46 
7 
INVESTIGATIONAL PRODUCTS ................................................................................... 47 
 
Regimen ...................................................................................................................... 47 
 
Study Product Formulation and Preparation ................................................... 47 
 
Dispensing and Handling of Investigational Product .................................... 48 
 
Accountability and Disposal of Used and Unused Investigational Product
 
48 
 
Assessment of Participant Adherence with Study Product ......................... 48 
 
Concomitant Medications and Procedures....................................................... 48 
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IRB NUMBER: MCA-0994
IRB APPROVAL DATE: 08/03/2021
IRB EXPIRATION DATE: 05/27/2022


 
        Rockefeller University 
Original IND 131872
June 3, 2021 
Protocol: MCA-0994 
 
Confidential 
Page 6 
 
Permitted Medications and Procedures............................................................. 48 
 
Prohibited Medications and Procedures ........................................................... 48 
 
Precautionary Medications and Procedures .................................................... 49 
 
Required Medications ............................................................................................. 49 
 
Rescue Medications ................................................................................................ 49 
8 
DATA ANALYSIS .............................................................................................................. 49 
 
Analysis of Safety, PK and Antiretroviral Effects ........................................... 49 
 
Sample Size Considerations ................................................................................. 50 
 
Enrollment/Stratification/Randomization/Blinded Procedures ................... 52 
 
Participant Enrollment and Follow-Up ............................................................... 52 
9 
DATA AND SAMPLE STORAGE ................................................................................... 52 
 
Data Collection ......................................................................................................... 52 
 
Quality Control and Quality Assurance ............................................................. 53 
10 
RECRUITMENT AND ADVERTISING ....................................................................... 53 
 
Participant Retention .............................................................................................. 54 
11 
POTENTIAL BENEFITS TO PARTICIPANTS .......................................................... 54 
12 
POTENTIAL RISKS TO THE PARTICIPANT INCLUDING TO THE FETUS ..... 54 
13 
PROCEDURES TO MINIMIZE RISK .......................................................................... 55 
14 
ALTERNATIVE METHODS OR TREATMENTS ...................................................... 57 
15 
DATA AND SAFETY MONITORING PLAN .............................................................. 57 
 
Safety Monitoring Committee ............................................................................... 57 
 
Safety Review ............................................................................................................ 59 
 
Clinical Site Monitoring .......................................................................................... 59 
 
Adverse Event Classification ................................................................................ 60 
 
Reporting Adverse Events..................................................................................... 60 
 
Reporting Unanticipated AEs ............................................................................... 60 
 
Clinical Laboratory Improvement Amendment/Clinical Laboratory 
Evaluation Program (CLIA/CLEP) .................................................................................... 60 
 
Toxicity Management and Stopping Rules ....................................................... 60 
 
Other Disease Events ............................................................................................. 60 
 
Critical Event Reporting ..................................................................................... 61 
16 
CLINICAL TRIAL REGISTRATION ............................................................................ 61 
17 
STUDY DISCONTINUATION....................................................................................... 61 
18 
BIBLIOGRAPHY ............................................................................................................ 62 
 
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IRB NUMBER: MCA-0994
IRB APPROVAL DATE: 08/03/2021
IRB EXPIRATION DATE: 05/27/2022


 
        Rockefeller University 
Original IND 131872
June 3, 2021 
Protocol: MCA-0994 
 
Confidential 
Page 7 
TABLE OF TABLES 
Table 1:  
3BNC117 and 3BNC117-LS In Vitro Neutralizing Activity of Against Selected HIV-1 
Pseudoviruses ............................................................................................................................ 21 
Table 2: 
10-1074-LS and 10-1074 In Vitro Neutralization Activity Against a Selected Panel of 
Pseudoviruses ............................................................................................................................ 21 
Table 3. Margin of Error at 95% Confidence Level for Estimating the Mean Elimination Half-life 
of 3BNC117-LS and 10-1074-LS ................................................................................................ 51 
Table 4. Minimum average decline in plasma viremia that can be detected for varying sample 
sizes 
52 
 
TABLE OF FIGURES 
Figure 1: Protective effects of 3BNC117-LS and 10-1074-LS monoclonal antibodies against 
virus acquisition in rhesus macaques. ........................................................................................ 22 
Figure 2: Viral load after 3BNC17/10-1074 infusions in viremic HIV-1-infected participants. ..... 29 
Figure 3: Serum levels of 3BNC117 and 10-1074 parental and LS variants. ............................. 31 
Figure 4: Study Design ............................................................................................................... 34 
 
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IRB NUMBER: MCA-0994
IRB APPROVAL DATE: 08/03/2021
IRB EXPIRATION DATE: 05/27/2022


 
        Rockefeller University 
Original IND 131872
June 3, 2021 
Protocol: MCA-0994 
 
Confidential 
Page 8 
LIST OF ABBREVIATIONS 
10-1074 
Anti-HIV-1 bNAb targeting the V3 loop of gp120 
10-1074-LS 
10-1074 with mutations in the Fc domain to extend half-life 
3BNC117 
Anti-HIV-1 bNAb targeting the CD4 binding site of gp120  
3BNC117-LS 
3BNC117 with mutations in the Fc domain to extend half-life 
Ab 
Antibody 
AE 
Adverse Event/Adverse Experience 
ART 
Antiretroviral Therapy 
ATI 
Analytic Treatment Interruption 
bNAbs 
Broadly Neutralizing Antibodies 
CD4 
T-cell Surface Glycoprotein CD4 
CFR 
Code of Federal Regulations 
cGMP 
Current Good Manufacturing Practices 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF  
Case Report Form 
CRSO  
Clinical Research Support Office 
CTSA  
Clinical and Translational Science Award 
CCTS  
Center for Clinical and Translational Science 
DNA 
Deoxyribonucleic Acid 
DSMB  
Data and Safety Monitoring Board 
FDA  
Food and Drug Administration 
FWA  
Federal-Wide Assurance 
GCP  
Good Clinical Practice 
gp120 
HIV-1 Envelope Glycoprotein 120 
HIPAA  
Health Insurance Portability and Accountability Act 
HIV-1  
Human immunodeficiency virus 
hu-mice 
Humanized Mice 
ICF  
Informed Consent Form 
ICH  
International Conference on Harmonization 
I.M.  
Intramuscularly 
IND  
Investigational New Drug 
IRB  
Institutional Review Board 
I.V.  
Intravenously 
mAb 
Monoclonal antibody 
MTD 
Maximum tolerated dose 
N  
Number (typically refers to participants) 
NHP 
Non-human primate 
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IRB NUMBER: MCA-0994
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        Rockefeller University 
Original IND 131872
June 3, 2021 
Protocol: MCA-0994 
 
Confidential 
Page 9 
NIAID  
National Institute of Allergy and Infectious Diseases, NIH 
NIH  
National Institutes of Health 
OHRP  
Office for Human Research Protections 
OHSR  
Office for Human Subjects Research 
PBMC 
Peripheral Blood Mononuclear Cell 
PI  
Principal Investigator 
RU  
The Rockefeller University 
RUH  
The Rockefeller University Hospital 
QA  
Quality Assurance 
QC  
Quality Control 
RNA 
Ribonucleic Acid 
SAE  
Serious Adverse Event/Serious Adverse Experience 
S.C.  
Subcutaneously 
SHIV 
Chimeric Simian/Human Immunodeficiency Virus 
SMC 
Safety Monitoring Committee 
SOP  
Standard Operating Procedure 
T cell 
T lymphocyte 
V3 loop 
Third Variable Loop of HIV-1 Envelope gp 120 
WCMC  
UPENN 
Weill Cornell Medical College 
University of Pennsylvania 
 
 
 
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IRB NUMBER: MCA-0994
IRB APPROVAL DATE: 08/03/2021
IRB EXPIRATION DATE: 05/27/2022


 
        Rockefeller University 
Original IND 131872
June 3, 2021 
Protocol: MCA-0994 
 
Confidential 
Page 10 
PROTOCOL SUMMARY 
Title 
An open label, single arm study of the safety, pharmacokinetics and antiretroviral 
activity of the combination of 3BNC117-LS and 10-1074-LS in viremic HIV-infected 
individuals. 
Short Title 
3BNC117-LS and 10-1074-LS in Viremic HIV-infected Individuals 
 
Protocol 
Number 
MCA-0994 
Phase 
Phase 1 
 
Study Design 
The proposed study is a phase 1, open label, single arm study to evaluate the safety, 
pharmacokinetics and antiviral activity of single intravenous infusions of 3BNC117-LS 
and 10-1074-LS, each mAb dosed at 30 mg/kg in viremic HIV-infected individuals.  
 
Study participants will receive a single intravenous infusion of 3BNC117-LS and a 
single infusion of 10-1074-LS. The antibodies will be administered sequentially and 
dosed at 30 mg/kg. Following mAb administration, study participants will return for 
safety assessments on days 1 and 3, and weeks 1, 2, 3 and 4 following dosing, then 
bi-weekly or monthly until the end of study follow up as indicated in the Time of Events 
Schedule (Appendix A). All participants will be followed for 24 weeks after 3BNC117-
LS and 10-1074-LS administration (see Study design).   
 
Study Design 
 
 
Safety assessments will be performed at multiple time points following 3BNC117-LS 
and 10-1074-LS infusions. Serum samples for PK measurements will be collected 
before and at the end each mAb infusion administration and at multiple subsequent 
time points during study follow up, as indicated in the Time of Events Schedule 
(Appendix A). Samples will also be collected for measurement of HIV-1 plasma RNA 
levels before 10-1074-LS and 3BNC117-LS infusions (screen and day 0) and at every 
follow up visit. T cell subsets will be monitored during study follow up. Assessments will 
also include measurement of anti-drug antibody (ADA) responses and sequencing of 
plasma envelope before infusions and after viral rebound, if it occurs prior to 
antiretroviral therapy (ART) initiation (first time point after viremia nadir is reached and 
viral load (VL) is > 1,000 copies/ml). 
 
Participants will be advised and encouraged to start ART within 4 weeks of receiving 
3BNC117-LS and 10-1074-LS infusions, or sooner if:  
1) VL fails to decrease by >0.5 log10 copies/ml within 2 weeks of antibody 
infusions,  
2) VL increases > 0.5 log10 copies/ml between weekly measurements or 
3) Significant T-cell decline (confirmed CD4+ T cell count < 200 cells/μl) is noted.  
Rockefeller University Institutional Review Board
IRB NUMBER: MCA-0994
IRB APPROVAL DATE: 08/03/2021
IRB EXPIRATION DATE: 05/27/2022


 
        Rockefeller University 
Original IND 131872
June 3, 2021 
Protocol: MCA-0994 
 
Confidential 
Page 11 
Study 
Duration 
24 months 
 
Study 
Center(s) 
 
RU site (The Rockefeller University) 
Cornell site (Weill Cornell Medicine Clinical Trials Unit) 
UPENN site (Perelman School of Medicine University of Pennsylvania)  
 
Objectives 
Primary objectives  
- 
To evaluate the safety and tolerability profile of single intravenous infusions of 
3BNC117-LS in combination with 10-1074-LS at a single dose level (30 mg/kg, 
each mAb) in HIV-infected individuals off ART. 
- 
To determine the pharmacokinetic profile of single intravenous infusions of 
3BNC117-LS in combination with 10-1074-LS at a single dose level (30 mg/kg, 
each mAb) in HIV-infected individuals off ART. 
- 
To determine the effect of single intravenous infusions of 3BNC117-LS in 
combination with 10-1074-LS at a single dose level (30 mg/kg, each mAb) on 
plasma HIV-1 RNA levels in viremic HIV-infected individuals. 
 
Secondary objective  
- 
To assess the frequency and magnitude of treatment-induced anti-drug antibody 
responses (anti-3BNC117-LS and anti-10-1074-LS antibodies) after a single 
intravenous infusion. 
 
Exploratory objectives 
- 
To evaluate the association between reduction in plasma viremia and predicted 
sensitivity to both 3BNC117-LS and 10-1074-LS by the Monogram PhenoSense 
assay (defined as IC50s < 0.25 µg/ml) and other non-CLIA-certified assays. 
- 
To genotype viral escape variants that may arise after administration of 
3BNC117-LS in combination with 10-1074-LS in viremic HIV-infected individuals. 
- 
To characterize the impact of treatment-induced anti-drug antibody (ADA) 
responses on the safety, pharmacokinetics and antiviral activity of 3BNC117-LS 
and 10-1074-LS. 
- 
To evaluate HIV-1 specific T and B cell immune responses following 3BNC117-
LS and 10-1074-LS infusions.  
- 
To analyze gene expression profiles in HIV-1 infected CD4+ T cells. 
 
Endpoints 
Primary Outcomes 
- 
The occurrence of treatment-related solicited and unsolicited grade 3 and serious 
adverse events (including confirmed laboratory abnormalities). 
- 
The pharmacokinetic profile (including: peak concentrations, half-life, area under 
curve and clearance rate) of 3BNC117-LS and 10-1074-LS, when administered 
intravenously and in combination to viremic HIV-infected individuals. 
- 
The decline in plasma HIV-1 RNA levels after 3BNC117-LS plus 10-1074-LS 
intravenous infusions in viremic HIV-infected individuals through week 4 after 
infusions. 
 
Secondary Outcome 
- 
Proportion of individuals with treatment-induced ADA against each mAb and 
magnitude of the response.  
- 
The rate of adverse events and confirmed laboratory abnormalities that occur 
during the study follow up period after 3BNC117-LS and 10-1074-LS 
administration. 
 
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IRB NUMBER: MCA-0994
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IRB EXPIRATION DATE: 05/27/2022


 
        Rockefeller University 
Original IND 131872
June 3, 2021 
Protocol: MCA-0994 
 
Confidential 
Page 12 
Exploratory Outcomes 
- 
Time until return of viremia to baseline levels in participants who elect to remain off 
ART after 4 weeks. 
- 
Decline in plasma viremia after antibody infusions across 3BNC117-LS and 10-
1074-LS IC50 and IC80 cut points determined by PhenoSense assay or other assays 
(e.g. bulk PBMC cultures or Q2VOA followed by TZM/bl assay).  
- 
Phenotypic and genotypic analysis of baseline and escape viruses that might arise 
after single infusions of 3BNC117-LS and 10-1074-LS in viremic HIV-infected 
individuals. 
- 
Proportion of participants with reduction in half-life or antiviral activity concomitant 
with ADA. 
- 
Relationship of adverse events to ADA. 
- 
Frequency and magnitude of HIV-1 specific T cell responses and serum 
neutralizing activity against a multi-clade panel of HIV-1 pseudoviruses, following 
3BNC117-LS and 10-1074-LS infusions.  
- 
Gene expression profiles by single RNA sequencing of HIV-1 infected CD4+ T 
cells. 
Number 
of 
Participants 
5 to 10 
Study 
Population 
HIV-infected individuals, off ART, and with plasma HIV-1 RNA levels between 500 and 
125,000 copies/ml by standard assays.  
 
Inclusion 
Criteria 
Inclusion Criteria: 
- 
Males and females, >18 years of age.  
- 
Confirmed HIV-1 infection. 
- 
Off ART for at least 4 weeks with HIV-1 plasma RNA levels between 500 and 
125,000 copies/mL (ART-naïve or off ART due to intolerance or by choice). 
- 
Current CD4+ T cell count > 300 cells/μl. 
- 
Participants who can become pregnant and are engaging in sexual activity that 
could lead to pregnancy agree to use two effective methods of contraception (i.e. 
condom with spermicide, diaphragm with spermicide, hormone-eluting IUD, 
hormone-based contraceptive with condom) from 10 days prior to and six months 
after 3BNC117-LS and 10-1074-LS administration.  
- 
Participants who can impregnate a partner and are engaging in sexual activity that 
could lead to pregnancy agree to use barrier protection from 10 days prior to and 
six months after 3BNC117-LS and 10-1074-LS administration to avoid 
impregnating a partner who can get pregnant.  
- 
Willingness to use barrier protection during sexual activity while not on ART to 
decrease the risk of HIV transmission to a partner at risk for HIV infection.  
 
Exclusion 
Criteria 
Exclusion Criteria  
- 
Have a history of AIDS-defining illness within 3 years prior to enrollment. 
- 
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 (such as autoimmune 
diseases), other than HIV infection, that in the opinion of the investigator would 
preclude participation. 
- 
Hepatitis B or C infection as indicated by the presence of Hepatitis B surface 
antigen (HBsAg) or hepatitis C virus RNA (HCV-RNA) in blood. 
- 
Laboratory abnormalities in the parameters listed below:  
- 
Absolute neutrophil count ≤ 1,000 cells/μl; 
- 
Hemoglobin ≤ 10 gm/dL; 
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IRB NUMBER: MCA-0994
IRB APPROVAL DATE: 08/03/2021
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        Rockefeller University 
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Protocol: MCA-0994 
 
Confidential 
Page 13 
- 
Platelet count ≤ 100,000 cells/μl; 
- 
ALT ≥ 1.5 x ULN; 
- 
AST ≥ 1.5 x ULN; 
- 
Alkaline phosphatase ≥ 1.5 x ULN; 
- 
Total bilirubin > 1.25 x ULN;  
- 
eGFR < 60 mL/min/1.73m2. 
- 
Pregnancy or lactation. 
- 
Any vaccination within 14 days prior to mAb infusions, except influenza vaccine. 
- 
Receipt of another investigational product currently or within the past 12 weeks, or 
expected concurrent participation in another study in which investigational products 
will be administered. 
- 
Receipt of any experimental HIV vaccine or anti-HIV monoclonal antibody therapy 
in the past. 
- 
History of severe reaction to a vaccine or drug infusion or history of severe allergic 
reactions. 
- 
Individuals with known hypersensitivity to any constituent of the investigational 
products. 
 
Study 
Product, 
Dose, Route, 
Regimen 
 
Study Products: 
- 
3BNC117-LS is a recombinant, fully human monoclonal antibody (mAb) of the 
IgG1κ isotype that specifically binds to the CD4 binding site (CD4bs) within HIV-1 
envelope gp-120. It contains two one-amino acid modifications in the Fc region to 
extend its biological half-life. 
 
- 
10-1074-LS is a recombinant, fully human monoclonal antibody (mAb) of the IgG1λ 
isotype that specifically binds to the V3 loop within HIV-1 envelope gp-120. It 
contains two one-amino acid modifications in the Fc region to extend its biological 
half-life. 
 
Dose, Route Regimen: 
Single intravenous infusion of 3BNC117-LS and single intravenous infusion of 10-1074-
LS, each dosed at 30 mg/kg. 
 
Statistical 
Methodology 
 
For safety, the number and percentage of participants experiencing one or more AEs 
will be summarized by relationship to study drug and severity. Pharmacokinetic 
parameters will be calculated using standard non-compartmental analysis methods.  
 
Plasma HIV-1 RNA levels will be evaluated at multiple time points following 3BNC117-
LS and 10-1074-LS infusions and the log reduction in HIV-1 RNA levels from baseline 
(day 0) will be calculated. 
 
Continuous data will be summarized by descriptive statistics, including sample size, 
mean, standard deviation, median and range.  Categorical data will be summarized by 
the number and percentage of participants with an outcome. 
 
 
 
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1 
KEY ROLES 
 
Study Sites and associated Institutions 
Study Sites:  
1) Rockefeller Site:  
The Rockefeller University Hospital, New York, NY 
1230 York Ave. 
New York, NY 10065 
Contact Person: Marina Caskey, MD 
Phone Number: (212) 327-7396 
Fax Number: (212) 327-7234 
E-mail: mcaskey@mail.rockefeller.edu 
 
2) Cornell Site 
Weill Cornell Medical Center Clinical Trials Unit, New York, NY 
525 East 68th Street 
New York, NY 10021 
Contact Person: Timothy Wilkin, MD 
T: (212) 746-4177 
F: (212) 746-8852 
Email: tiw2001@med.cornell.edu 
 
3) University Of Pennsylvania (UPENN) Site:  
 
- 
Perelman School of Medicine University of Pennsylvania, Philadelphia, PA 
502 Johnson Pavilion, 3610 Hamilton Walk 6073 
Philadelphia, PA 19104 
Contact Person: Pablo Tebas, MD 
T: (215) 349-8091 
F: (215) 349-8011 
Email: pablo.tebas@uphs.upenn.edu 
Clinical Laboratories: 
- 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
NY, NY 10065 
 
- 
New York Presbyterian – Weill Cornell Medical Center 
525 East 68th Street 
New York, NY 10021 
 
- 
University of Pennsylvania Processing CTU Laboratory 
3610 Hamilton Walk 
319 Johnson Pavilion 
Philadelphia PA 19104-6073 
United States of America 
Telephone - Primary: 215-746-8516; Secondary: 215-898-3296; Mobile: 126-7319-6584 
Fax: 215-573-4235 
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Alan Wanicur (alan.wanicur@uphs.upenn.edu) 
- LabCorp 
330 W 58th St 
New York, NY, 10019 
Funder:  
National Institute of Allergy and Infectious Diseases (NIAID) 
Data Management:  
Emmes Corporation 
401 N. Washington St. Suite 700 
Rockville, MD 20850 
Independent Safety Monitoring:  
International AIDS Vaccine Initiative (IAVI) 
125 Broad Street, 9th Floor 
New York, NY 10004  
 
DAIDS Program Officer:  
Tia Morton, RN, MS 
 
DAIDS Medical Officer:  
Randall Tressler, MD 
 
 
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Individuals 
Rockefeller Sub-Site 
Cornell Sub-Site  
UPENN Site  
Principal Investigator: 
Marina Caskey, MD 
Associate Professor of Clinical 
Investigation 
The Rockefeller University 
1230 York Avenue Box 95 
New York, NY 10065 
Phone Number: 212 327-7396 
Fax Number: 212 327-7234 
E-mail: 
mcaskey@rockefeller.edu 
Principal Investigator: 
Timothy Wilkin, MD MPH 
Associate Professor of Medicine  
Weill Cornell Medical College 
525 East 68th Street 
New York, NY 10021 
Phone Number: (212) 746-4177 
Fax Number: (212) 746-8852 
Email: tiw2001@med.cornell.edu 
 
Principal Investigator: 
Pablo Tebas, MD  
Professor of Medicine 
Perelman School of Medicine  
3400 Civic Center Blvd 
Philadelphia, PA 19104 
Phone Number: (215) 349-8091 
Fax Number: (215) 349-8011 
Email: 
pablo.tebas@uphs.upenn.edu 
Co-Investigators: 
Michel Nussenzweig, MD, PhD 
Christian Gaebler, MD 
Irina Shimeliovich, MD, PhD  
Thiago Oliveira, PhD 
Katrina Millard, ANP 
Arlene Hurley, ANP 
Melissa La Mar 
 
Co-Investigators: 
Brad Jones, PhD 
Douglas Nixon, MD, PhD 
Roy (Trip) Gulick, MD MPH 
Kristen Marks, MD 
Marshall Glesby, MD 
Co-Investigator: 
Katherine Bar, MD 
 
Statistician: 
Caroline Jiang, MS 
The Rockefeller University 
1230 York Avenue 
HOS 237, New York, NY 10065 
Email:  cjiang@rockefeller.edu  
 
Collaborators/Consultants: 
- 
Georgia Tomaras, PhD 
Duke University 
Rm 4079 MSRB II, 106 Research Drive 
Durham, NC 27710 
 
- 
Margaret Ackerman, PhD 
Dartmouth College 
14 Engineering Dr |  
Hanover, NH 03755 
 
- 
Daniel Kaufmann, PhD 
University of Montreal, Canada 
900 St-Denis Street, Viger Tower, Room R09-456 
Montreal, PQ H2X 0A9 - Canada 
 
 
- 
Michael Seaman, PhD 
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Beth Israel Deaconess Medical Center 
330 Brookline Ave 
E/CLS-1001 
Boston, MA 02215 
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2 
LAY SUMMARY 
Broadly neutralizing antibodies against HIV arise in a small fraction of HIV-infected individuals. 
These antibodies might be able to play an important role in protection from acquisition of HIV 
infection, and also have the potential to alter the course of HIV infection. 3BNC117 and 10-1074 
are anti-HIV neutralizing antibodies identified and cloned from two people living with HIV. They 
were chosen for clinical development for their neutralizing breadth and potency against diverse 
viral strains. Both antibodies have shown favorable safety, pharmacokinetics and antiviral activity 
in clinical trials. 3BNC117-LS and 10-1074-LS-LS are modified versions of the original antibodies 
and are expected to have extended duration of activity. The safety and pharmacokinetics profiles 
of 3BNC117-LS and 10-1074-LS are currently being evaluated in first-in-human studies in healthy 
volunteers and in people living with HIV. In this study, we aim to evaluate the safety, 
pharmacokinetics and the virologic effects of the combination of 3BNC117-LS and 10-1074-LS 
on HIV viral loads in people living with HIV who are not on antiretroviral therapy.   
 
3 
OBJECTIVES AND RATIONALE 
 
Background 
Despite the success of combination antiretroviral therapy (ART) in suppressing viral replication 
and preventing disease progression, HIV-1 persists in latent reservoirs (Chun, Carruth et al. 
1997). In addition, worldwide HIV incidence rates have declined slowly, with 1.8 million new 
infections reported in 2017 (UNAIDS 2018). The use of antiretroviral agents by HIV-uninfected 
individuals before potential sexual exposure to HIV-infected partners, known as pre-exposure 
prophylaxis (PrEP), is a new effective preventive approach against HIV-1. However, an important 
challenge to the success of such strategy is that its efficacy is highly dependent on adherence to 
a daily oral drug regimen (Hanscom, Janes et al. 2016). Therefore, the search for novel preventive 
and therapeutic interventions is of high priority.  
Passive administration of anti-HIV-1 bNAbs has been evaluated in humans. Earlier antibodies 
(such as 2G12, 4E10, 2F5) were administered intravenously at doses ranging from 0.5 to 2 gm 
and were generally found to be safe and well tolerated. However, these early studies showed that 
the selected HIV-1 bNAbs passively transferred to HIV-infected individuals had rather limited 
effects on delaying viral rebound during interruption of antiretroviral treatment (Trkola, Kuster et 
al. 2005, Mehandru, Vcelar et al. 2007).  
A new generation of highly potent broadly neutralizing antibodies (bNAbs) may represent a novel 
strategy to combat HIV-1 infection. The advent of single-cell cloning techniques allowed the 
identification of potent bNAbs that target multiple epitopes on the HIV-1 envelope. Some of the 
new bNAbs demonstrate in vitro neutralizing activity against over 90% of HIV-1 pseudoviruses 
derived from diverse clades, even at low concentrations (Klein, Mouquet et al. 2013, West, Scharf 
et al. 2014). Broadly neutralizing antibodies are potential alternatives to standard antiretroviral 
drugs as they are likely to be safe and well tolerated, and to persist at neutralizing levels for longer 
periods of time. 
Passive transfer of bNAbs can prevent simian-human immunodeficiency virus (SHIV) infection 
after high-dose intravenous challenge in non-human primates (Mascola, Lewis et al. 1999, 
Shibata, Igarashi et al. 1999, Shingai, Nishimura et al. 2013, Shingai, Donau et al. 2014). 
Neutralizing antibodies can also protect from multiple low dose mucosal challenges (Hessell, 
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Poignard et al. 2009, Moldt, Rakasz et al. 2012, Gautam, Nishimura et al. 2016, Gautam, 
Nishimura et al. 2018). 
3BNC117 and 10-1074 are two of the most potent broadly neutralizing antibodies available 
(Scheid, Mouquet et al. 2011, Mouquet, Scharf et al. 2012). They were chosen for clinical 
development for their neutralizing breadth and potency, and their antiretroviral activity when 
tested in humanized mice (hu-mice) and non-human primates (NHP) models (Klein, Halper-
Stromberg et al. 2012, Pietzsch, Gruell et al. 2012, Horwitz, Halper-Stromberg et al. 2013, 
Shingai, Nishimura et al. 2013, Shingai, Donau et al. 2014, Gautam, Nishimura et al. 2016). Both 
antibodies have been evaluated in clinical studies, either alone or in combination. 3BNC117 and 
10-1074 have shown favorable safety profiles in both HIV-infected and HIV-uninfected 
participants, and half-lives of approximately 2 and 3 weeks, respectively. A single infusion of 
3BNC117 and 10-1074 at 30 mg/kg led to decline in plasma viremia of approximately 1.5 log10 
copies/ml in viremic individuals (Caskey, Klein et al. 2015, Caskey, Schoofs et al. 2017). The 
modified LS versions of these two antibodies contain two one-amino acid substitutions of 
methionine to leucine at Fc position 428 (M428L), and asparagine to serine at Fc position 434 
(N434S). These substitutions enhance the antibody binding affinity to the neonatal Fc receptor 
(FcRn), prolonging its half-life in vivo.  
The safety and pharmacokinetics profiles of 3BNC117-LS and 10-1074-LS are currently being 
evaluated in two first-in-human studies in healthy volunteers and HIV-infected individuals 
(NCT03254277, NCT03554408).  
In this proposed study, we aim to evaluate the safety, pharmacokinetics and the virologic effects 
of the combination of 3BNC117-LS and 10-1074-LS on plasma viremia in HIV-infected individual 
who are not on ART.   
 
Preclinical Characterization of 3BNC117-LS and 10-1074-LS 
3.2.1 
Fc Modification to Extend Half-life 
FcRn is an MHC class I like molecule associated with beta-2-microglobulin (β2m), known to play 
a role in IgG transport and homeostasis. It functions to protect IgG and albumin from catabolism, 
which explains the prolonged half-life of these two proteins compared with other classes of 
immunoglobulins and liver synthesized proteins. FcRn binds to the Fc portion of IgG with high 
affinity at an acidic pH (6.0 – 6.5) and protects the bound Ig from degradation in lysosomes. FcRn 
is a recycling receptor and it releases bound IgG into the extracellular space when it returns to 
the cell surface, thus prolonging the half-life of IgG (Roopenian and Akilesh 2007, Ward and Ober 
2009). 
Mutations in the CH2-CH3 domain of the IgG Fc region can enhance binding affinity to FcRn at 
low pH, and in turn extend antibody serum half-life. Two sets of mutations in the Fc domain, YTE 
(M252Y, S254T, T256E) and LS (M428L/N434S), are being evaluated in antibodies currently 
undergoing clinical testing (i.e. MEDI-557, VRC01-LS, VRC07-523LS). 
The LS mutations were identified through rational design methods and high-throughput protein 
screening. The M428L/N434S variant of an anti-vascular endothelial growth factor IgG (Xtend-
VEGF) provided 11-fold improvement in human and non-human primate FcRn binding affinity at 
pH 6.0 and prolonged antibody half-life by approximately 3-fold (Zalevsky, Chamberlain et al. 
2010).  
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Ko et al. evaluated if modulation of FcRn binding affinity can enhance the protective efficacy of 
the anti-HIV-1 antibody, VRC01. Similar to 3BNC117, VRC01 targets the CD4 binding site of HIV-
1 gp-120. The VRC01LS-mutant bound to HIV-1 gp 120, similarly to the unmutated VRC01 
antibody, and showed enhanced binding to FcRn at pH 6.0. VRC01LS exhibited a 12-fold higher 
human FcRn binding affinity than VRC01, whereas both displayed similar binding to human 
FcγRIIIa, FcγRIIa and FcγRIIb. These data suggest that VRC01LS does not differ from VRC01 
with respect to ADCC effector function or immune suppression through FcγRIIa or FcγRIIb. 
Moreover, VRC01LS showed comparable ADCC activity to VRC01 in an in vitro ADCC assay 
using human PBMCs as effector cells and HIV-infected CEM-NKR cells (a NK-cell-resistant 
human T leukemia cell line) as targets. In addition, VRC01LS showed similar in vitro neutralization 
potency and breadth against HIV-1 strains than the unmutated antibody (Ko, Pegu et al. 2014). 
In vivo, the VRC01LS mutant had a 2.5-fold longer half-life in rhesus macaques (VRC01, 4.65 
days; VRC01LS, 11.80 days) and a slower clearance rate. Low dose VRC01LS (0.3 mg kg) 
protected rhesus macaques from intrarectal challenge with SHIVBaLP4 (Ko, Pegu et al. 2014). 
Another study evaluated the protective efficacy of a single intravenous infusion of VRC01 or 
VRC01LS (20 mg/kg) against weekly low dose (10 TCID50) SHIVAD8-EO intrarectal challenges 
(Gautam, Nishimura et al. 2016). VRC01LS showed median protection time of 14.5 weeks, while 
VRC01 protected animals for a median of 8 weeks. In HIV-uninfected individuals, VRC01-LS 
showed an elimination half-life of 71 +/- 18 days, which is more than 4-fold longer than VRC01’s 
half-life (Gaudinski, Coates et al. 2018). 
3.2.2 
In Vitro Characterization of 10-1074-LS and 3BNC117-LS 
Binding affinities of 10-1074-LS and 10-1074, 3BNC117-LS and 3BNC117 for all human FcγRs 
were analyzed by surface plasmon resonance (SPR) analysis. As expected, the presence of the 
LS mutations had no impact on FcγR binding when comparing the unmodified 10-1074 and 
3BNC117 mAbs and their respective LS versions.  
 
The in vitro neutralizing activities of the unmutated 3BNC117, 3BNC117-LS, 10-1074, and 10-
1074-LS drug products were measured by a GLP TZM.bl luciferase-based neutralization assay 
performed in the laboratory of Dr. Michael Seaman (Beth Israel Deaconess Medical Center, 
Boston). In this assay, virus neutralization is detected as reduction in luciferase reporter gene 
expression after single round infection in TZM.bl cells. MuLV (murine leukemia virus) is used as 
a negative control. 
 
The antibodies were tested at a primary concentration of 25 µg/ml and titrated 5-fold to a 
concentration of < 0.001 µg/ml. A panel of twelve tier 2 HIV-1 pseudoviruses from different HIV 
clades was used to compare 3BCN117 to 3BNC117-LS. The median and 80% inhibitory 
concentrations (IC50 and IC80) were calculated and are displayed in Table 1. As expected, 
3BNC117-LS titers were highly concordant with the unmutated 3BNC117 reference standard (< 
2-fold difference for all IC50/IC80 measurements). 
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Table 1:  3BNC117 and 3BNC117-LS In Vitro Neutralizing Activity of Against Selected 
HIV-1 Pseudoviruses  
 
A panel of 10 tier HIV-1 pseudoviruses with known sensitivity to 10-1074 but resistant to 3BNC117 
was used to compare the neutralizing activities of 10-1074 and 10-1074-LS. These pseudoviruses 
were selected to characterize the current clinical lot of 10-1074-LS, but also to allow measurement 
of 10-1074 neutralizing activity in future 10-1074-LS plus 3BNC117-LS co-formulated products. 
The median and 80% inhibitory concentrations (IC50 and IC80) were calculated and are displayed 
in Table 2. As expected, 10-1074-LS titers were highly concordant with both the reference 
standard and the 10-1074 clinical lot (< 3-fold difference for all IC50 and IC80 measurements). 
Table 2: 
10-1074-LS and 10-1074 In Vitro Neutralization Activity Against a Selected 
Panel of Pseudoviruses  
 
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3.2.3 
3BNC117-LS and 10-1074-LS In Vivo Activity in Non-human Primates 
The in vivo activity of 10-1074-LS and 10-1074-LS in combination with 3BNC117-LS was 
evaluated in a non-GLP study in rhesus macaques conducted at NIH/NCI. Animals were 
administered a single intravenous infusion of 10-1074-LS (20 mg/kg) or 3BNC117-LS (20 mg/kg); 
or a single subcutaneous injection containing both 3BNC117-LS and 10-1074-LS in combination 
(7.5 mg/kg, each mAb) (Figure 1). In addition, animals that received no mAbs served as controls. 
All animals were challenged weekly with low doses of SHIVAD8-EO (10 TCID50 intrarectally, starting 
1 week after mAb administration. The median time to infection after 10-1074-LS was 27 weeks 
(range 18-37 weeks), as compared to the previously reported 12.5 weeks with the unmodified 10-
1074; and the median time to infection after 3BNC117-LS was 16.5 weeks (range 11-23 weeks), 
as compared to the previously reported 13 weeks with the unmodified 3BNC117. Control animals 
were infected after a median of 3 weeks. The combination of 3BNC117-LS plus 10-1074-LS, at a 
lower dose (7.5 mg/kg of each mAb), protected animals for a median of 20 weeks (Gautam, 
Nishimura et al. 2018). These results demonstrate that the introduction of the LS mutations 
significantly extends the antiviral effects of bNAbs.  
 
The estimated average half-life of 10-1074-LS was approximately 29 days, as compared to 9 days 
for 10-1074, and the estimated average half-life of 3BNC117-LS was 18 days as compared to 9 
days for 3BNC117. The median mAb serum concentrations at breakthrough of infection were 
calculated to be 0.13 and 1.07 μg/ml for the unmodified 10-1074 and 10-1074-LS, respectively; 
0.20 and 0.28 μg/ml for the unmodified 3BNC117 and 3BNC117-LS, respectively; and 0.67 μg/ml 
for the mAb combination group. The slightly higher breakthrough plasma bNAb concentration 
observed for the 10-1074-LS mAb (1.07 μg/ml) compared to the other three individual mAbs 
analyzed cannot be presently explained despite their similar potencies when measured in vitro 
(Gautam, Nishimura et al. 2018). 
 
Of note, one of the six recipients of 3BNC117-LS and 10-1074-LS s.c. (DFM6) experienced rapid 
decay of serum antibody levels, which fell to background levels between weeks 4 and 6 after 
administration. This rapid clearance of 10-1074-LS correlated with the emergence of anti-10-
1074-LS antibody responses and infection following 6 weekly viral challenges.  
 
Non-GLP safety assessments were performed during this study. No clinical adverse events were 
observed in these rhesus macaques following intravenous administration of 10-1074-LS alone or 
subcutaneous administration of 3BNC117-LS plus 10-1074-LS over a 40-week observation 
period. In addition, no clear changes in hematologies were observed during follow up after 
administration.   
Figure 1: Protective effects of 3BNC117-LS and 10-
1074-LS monoclonal antibodies against virus acquisition 
in rhesus macaques.  
Kaplan–Meier showing the infection rates for controls (no 
mAb), recipients of 3BNC117-LS plus 10-1074-LS in 
combination (7.5 mg/kg ea. mAb, s.c., once).  
Weeks 
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3.2.4 
10-1074-LS Tissue Cross Reactivity Study 
A tissue cross-reactivity study was performed on a full panel of human tissues. The objective of 
this study was to determine the potential cross reactivity of 10-1074 and 10-1074-LS with 
cryosections of human tissues. In order to detect binding, the test articles were applied to 
cryosections of normal human tissues (at least 3 donors per tissue) at two concentrations (25 and 
5 µg/mL).  
10-1074 and 10-1074-LS moderately to strongly stained cytoplasmic granules/globules of rare or 
rare to occasional epithelium in the pituitary adenohypophysis at the higher concentration of both 
test articles.  Similar staining was observed at the lower concentration except in one donor where 
staining was reduced in intensity and frequency with 10-1074 only. 
In the thyroid, 10-1074 and 10-1074-LS stained the cytoplasm and cytoplasmic granules of 
follicular epithelium in the thyroid.  This staining was weak or weak to moderate and rare or 
occasional to frequent at the higher concentration of 10-1074 with a reduction or absence of 
staining at the lower concentration, while this staining was weak to moderate or moderate to 
strong and occasional to frequent at the higher concentration of 10-1074-LS with variably present 
staining at the lower concentration.   
As the HIV-1 envelope glycoprotein is a viral protein not expected to be expressed in any normal 
human tissues, the epithelial staining observed in the pituitary and thyroid with 10-1074 and 
10-1074-LS in the current study represented unexpected tissue cross-reactivity.  However, this 
staining was cytoplasmic in nature, and monoclonal antibody binding to cytoplasmic sites 
generally is considered of little to no toxicologic significance due to the inability of antibody 
therapeutics to access the cytoplasmic compartment in vivo.  No plasma membrane staining was 
observed with 10-1074 and 10-1074-LS in the human tissues. 
3.2.5 
3BNC117-LS Tissue Cross Reactivity Study 
A tissue cross-reactivity study was performed on a full panel of human tissues. The objective of 
this study was to determine the potential cross reactivity of 3BNC117 and 3BNC117-LS with 
cryosections of human tissues. In order to detect binding, the test articles were applied to 
cryosections of normal human tissues (3 donors per tissue) at two concentrations (10 and 2 
µg/mL). Staining with 3BNC117 and 3BNC117-LS was observed in the human tissue panel as 
summarized below: 
• Plasma membrane only: 
- squamous epithelium in the esophageal mucosa 
• Plasma membrane and cytoplasm: 
- Kupffer cells (specialized macrophages) in the liver 
- macrophages in the lymph node 
• Cytoplasm only: 
- acinar epithelium of the pancreas, endocrine epithelium in the pituitary, squamous epithelium 
in the epidermis of the skin, germinal epithelium in the testis, and glandular epithelium in the 
uterus (endometrium) 
- extracellular material in the placenta and spinal cord. 
As the HIV-1 envelope glycoprotein is a viral protein not expressed in any normal human tissue, 
all staining observed with 3BNC117 and 3BNC117-LS represented unexpected tissue cross 
reactivity. Membrane staining with 3BNC117 and 3BNC117-LS was present in Kupffer cells of the 
liver, macrophages of the lymph node, and mucosal epithelium of the esophagus. All other cellular 
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staining with 3BNC117 and 3BNC117-LS in the current study was cytoplasmic in nature and was 
considered of little to no toxicologic significance, as it is unlikely that the cytoplasm and 
cytoplasmic structures would be accessible to the test articles in vivo. The toxicologic relevance 
of the binding of 3BNC117 and 3BNC117-LS to extracellular material in the placenta and spinal 
cord is unknown.  
In general, the observed staining was more intense and/or frequent with 3BNC117-LS compared 
to 3BNC117, however the staining pattern was similar between the two test articles. 
3.2.6 
10-1074 In Vivo Toxicology Study in Rats 
Since 10-1074-LS has the same antigen binding characteristics and showed comparable binding 
as 10-1074 in the GLP-compliant human tissue crossreactivity study (Section 3.2.5), the 
previously performed toxicology study of 10-1074, supports the proposed phase 1 clinical study.  
 
10-1074 was evaluated for safety in a multidose study in rats. Twice weekly intravenous 
administration of 10-1074 at doses of 4, 15, and 60 mg/kg/injection, as well as the combination 
intravenous dose of 10-1074 and 3BNC117 (each 60 mg/kg once weekly), and twice weekly 
doses of 10-1074 at 60 mg/kg/injection via the subcutaneous route, for a 25-day dosing period 
were considered well-tolerated in male and female Sprague Dawley rats.  Main animals were 
euthanized on Day 27; following the end of the 45-day recovery period, recovery animals (control 
and high dose groups) were euthanized on Day 71. 
 
Test item-related findings were consistent with an immune response to repeated administration 
of a foreign protein primarily in subcutaneously-dosed animals, as would be expected when 
evaluating a human protein in rats.  These consisted of slight increases in white blood cells counts 
(primarily neutrophils), slight decrease in platelets, mononuclear cell infiltrate, sinusoid 
histiocytosis, and/or sinusoid dilatation in the liver, and lymphoid hypercellularity, sinusoid 
histiocytosis, and/or extramedullary hematopoiesis in the spleen. The changes reversed 
completely following a 45-day Recovery period in the Recovery rats receiving 60 mg/kg 
intravenously. 
 
Based on the results of this study, and absence of apparent direct toxicity of 10-1074 in the 
presence of apparent immunogenicity, the No-Observed-Adverse-Effect-Level (NOAEL) of 10-
1074 in the rat was considered to be 60 mg/kg/injection when administered either by the 
intravenous or subcutaneous route twice weekly and the combination intravenous dose of 10-
1074 and 3BNC117 (each 60 mg/kg/injection once weekly), for up to 25 days. 
3.2.7 3BNC117 In Vivo Toxicology Study in Rats 
Since 3BNC117-LS has the same antigen binding characteristics and showed comparable 
binding as 3BNC117 in the GLP-compliant human tissue crossreactivity study (Section 3.2.5), the 
previously performed toxicology study of 3BNC117, supports the proposed phase 1 clinical study.  
 
3BNC117 was evaluated for safety in a multidose study in rats to determine its toxicity and 
toxicokinetic profiles, following twice weekly intravenous/subcutaneous administrations to 
Sprague-Dawley rats over 25 days and to assess the reversibility of any changes following a 47-
day recovery period. Main animals were euthanized on Day 27; following the end of the 47-day 
recovery period, recovery animals were euthanized on Day 72. 
 
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Protocol: MCA-0994 
 
Confidential 
Page 25 
Despite some animals producing anti-drug antibodies, the rats appeared to have maintained 
adequate drug exposure in the study, with twice per week dosing for four weeks. Aside from 
injection site findings, there were no 3BNC117 related effects, in the Main and Recovery group 
animals, on clinical observations, body weight, food consumption, body temperature, clinical 
pathology parameters, organ weights or macroscopic and microscopic observations, and the 
NOAEL (no-observed-adverse-effect level) was determined to be the high dose of 60 mg/kg twice 
a week for four weeks.  
 
Clinical Safety of Monoclonal Antibodies to Treat or Prevent Infection 
Several monoclonal antibodies that target HIV-1 gp120 have been evaluated in clinical studies. 
2F5 and 4E10 are IgG1 (kappa) monoclonal antibodies that target the membrane-proximal 
ectodomain of gp41, while 2G12 binds to a carbohydrate moiety on the silent face of gp41. These 
neutralizing antibodies were evaluated in combination in HIV-infected individuals. The first two 
studies included ART-naïve individuals. The antibodies were administered intravenously at 0.5 to 
1 gm doses; 4 to 8 weekly infusions were given (Armbruster, Stiegler et al. 2004). Two other 
studies with 2F5, 4E10 and 2G12 included HIV-infected individuals on suppressive ART. The 
antibodies were administered intravenously at doses ranging from 1 to 2 g for each antibody; 13-
16 weekly antibody infusions were given. ART was interrupted following 1 or 4 antibody infusions 
(Trkola, Kuster et al. 2005, Mehandru, Vcelar et al. 2007). Antibody infusions were well tolerated 
in most participants; mild and transient adverse events were reported only occasionally. No 
serious adverse events (SAEs) were recorded. Adverse events included body aches, fatigue, 
flushed sensation, joint soreness and redness at infusion site. A low-level antibody response 
against 2G12 was found in two participants. Anti-4E10 and anti-2F5 IgM and IgG immune 
responses were not detected, even after repeated infusions of high doses of the mAbs. This 
antibody combination did not significantly delay viral rebound or decreased plasma viremia. 
 
VRC01 is another human anti-HIV-1 broadly neutralizing antibody, targeting the CD4 biding site 
of HIV-1 gp120. It has been evaluated in both HIV-infected and HIV-uninfected individuals at 
doses ranging from 5 to 40 mg/kg. (Ledgerwood, Coates et al. 2015, Lynch, Boritz et al. 2015, 
Bar, Sneller et al. 2016). Reported adverse events assessed as possibly related to VRC01 were 
mild in severity and resolved with no residual effects. No related serious adverse events or dose-
limiting toxicities have been reported. The half-life of VRC01 in HIV-uninfected individuals was 15 
days and no anti-VRC01 antibody responses were detected (Ledgerwood, Coates et al. 2015). 
The half-life of VRC01 in HIV-infected individuals was 12 days for intravenous infusion and 11 
days for subcutaneous injection. No anti-VRC01 antibodies were detected. In viremic individuals 
with virus sensitive to VRC01, a reduction in viremia of 1.1 to 1.8 log10 copies/ml was observed.  
 
VRC01 is currently being tested in two multi-center phase 2b studies to evaluate its safety and 
efficacy to reduce acquisition of HIV-1 infection in women (NCT02568215), MSM or transgender 
persons who have sex with men (NCT02716675). Participants are administered up to 10 
intravenous VRC01 infusions of 10 or 30 mg/kg every 8 weeks. Over 4,000 participants enrolled 
in the study in the Americas and in several African countries. 
 
Clinical Experience with Fc-modified Antibodies to Enhance Binding to the FcRN 
Receptor 
VRC01LS is another human anti-HIV-1 CD4 binding site antibody that has been modified in the 
Fc region to include the LS substitutions (M428L/N434S). Like 3BNC117-LS, it is being evaluated 
for HIV-1 therapy and prevention. VRC01LS is being evaluated in four ongoing clinical studies in 
HIV-infected (NCT02840474) and HIV-uninfected adults (NCT02599896, NCT02797171), and in 
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Protocol: MCA-0994 
 
Confidential 
Page 26 
infants (NCT02256631). VRC01LS showed good safety profile in a first-in-human study in HIV-
uninfected participants. A total of 37 participants were administered VRC01LS, and received one 
or three intravenous infusions or subcutaneous injections at 5, 20 or 40 mk/kg dose levels. There 
were no SAEs or DLTs. Mild malaise and myalgia were the most common adverse events (AEs). 
There were six AEs assessed as possibly related to VRC01LS administration, and all were mild 
in severity and resolved during the study. The mean (±SD) serum concentration 12 weeks after 
one IV administration of 20 mg/kg or 40 mg/kg were 180 ± 43 μg/mL (n = 7) and 326 ± 35 μg/mL 
(n = 5), respectively. The mean (±SD) serum concentration 12 weeks after one IV and SC 
administration of 5 mg/kg were 40 ± 3 μg/mL (n = 2) and 25 ± 5 μg/mL (n = 9), respectively. 
VRC01LS clearance rate was 36 ± 8 mL/d with an elimination half-life of 71 ± 18 days. VRC01LS 
retained its expected neutralizing activity in serum, and anti-VRC01 antibody responses were not 
detected (Gaudinski, Coates et al. 2018). 
 
Clinical Experience with 10-1074 (IND 123713) 
10-1074 was evaluated in a phase 1 study in both HIV-uninfected and HIV-infected individuals 
(NCT02511990). Study participants were administered one intravenous infusion of 10-1074 at 
increasing dose levels (3 mg/kg, 10 mg/kg or 30 mg/kg), and were followed for 24 weeks after 
infusion. A total of 33 study participants enrolled in the study (14 HIV-uninfected, 16 viremic HIV-
infected, and 3 ART-HIV-infected individuals received 10-1074 was generally safe and well 
tolerated. A total of 57 adverse events were reported during a follow-up period of 6 months, 88% 
of these were of grade 1 severity. The most commonly reported adverse event deemed possibly 
related to the study drug was transient, mild headache. There were no serious adverse events, 
or grade 3 related adverse events. A safety data summary is included in the 10-1074 Investigator’s 
Brochure (IB). 
 
10-1074 was eliminated more rapidly in HIV-1-infected individuals than in uninfected participants, 
resulting in a t1/2 of 24 and 12.8 days in uninfected and HIV-1-infected individuals, respectively. 
Thirteen viremic participants received 10-1074 at 30 mg/kg. Eleven of these participants were 10-
1074-sensitive and showed a rapid decline in viremia by a mean of 1.52 log10 copies/ml (range, 
0.9–2.06 log10 copies/ml). The nadir was reached after an average of 10 days (range 7–25 days).  
Virologic analysis revealed the emergence of 10-1074-resistant viruses within 28 days after 
infusion. Emerging escape variants carried mutations in known contact sites (N332, N334 and 
D/N425), were generally resistant to the related V3-specific antibody PGT121, but remained 
sensitive to antibodies targeting non-overlapping epitopes, such as the anti-CD4-binding-site 
antibodies 3BNC117 and VRC01 (Caskey, Schoofs et al. 2017). 
 
Clinical Experience with 3BNC117 (IND 118225) 
A phase 1 study tested a single infusion of 3BNC117 at increasing dose levels in both HIV-
infected and HIV-uninfected individuals (n= 55, 22 HIV-uninfected and 33 HIV-infected). 
3BNC117 was generally safe and well-tolerated, and mild transient myalgia, fatigue and 
headache were the most commonly reported AEs. There were no serious adverse events, or 
grade 3 related adverse events. A safety data summary is included in the 3BNC117 Investigator’s 
Brochure (IB). 
 
3BNC117’s half-life was found to be approximately 17.6 days in HIV-uninfected and 9.6 days in 
viremic HIV-infected individuals. When administered at 30 mg/kg, 3BNC117 induced rapid 
decreases in plasma HIV-1 RNA levels that varied between individuals from 0.8 to 2.5 log10 
copies/ml, and the mean drop in viral load (VL) was 1.48 log10 at nadir. The median time to reach 
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Protocol: MCA-0994 
 
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the lowest level in viremia was 7 days (range 7-21 days). Viral strains carrying different env 
mutations emerged after treatment, and some of them were associated with different levels of 
3BNC117 resistance (Caskey, Klein et al. 2015, Schoofs, Klein et al. 2016). A mathematical 
model of HIV-1 dynamics suggested that 3BNC117 effects were not simply limited to free viral 
clearance and blocking new infection, but also included potentially significant acceleration of 
infected cell clearance (Lu, Murakowski et al. 2016). Experiments using infected human cells in 
mice confirmed the idea that 3BNC117 infusion clears infected cells in vivo (Lu, Murakowski et 
al. 2016). In addition to lowering plasma viremia, 3BNC117 enhanced serum neutralizing activity 
against autologous and heterologous viruses in HIV-infected individuals (Schoofs, Klein et al. 
2016). 
3BNC117 has also been studied in the setting of analytical treatment interruption (ATI, 
(NCT02446847)). Thirteen ART-treated participants with 3BNC117-sensitive viruses isolated 
from PBMC cultures underwent ATI and received two to four 3BNC117 infusions at 30 mg/kg. 
The infusions delayed viral rebound for an average of 8.4 weeks, in contrast to an average of 2-
3 weeks in studies that simply stopped ART. In 4 of 13 treated individuals, viral suppression was 
maintained until antibody levels fell below 20 μg/ml. In contrast to non-interventional ATI studies 
where rebound viremia is typically polyclonal, rebound viremia arose predominantly from a single 
provirus and emerging viruses showed decreased sensitivity to 3BNC117 compared to pre-
treatment viruses isolated from PBMC cultures, indicating that 3BNC117 restricted viral 
emergence from the reservoir and selected resistant strains. Re-initiation of ART rapidly 
suppressed viremia (Scheid, Horwitz et al. 2016). An additional study (NCT02588586) in which 
individuals that remained on ART were given 2 infusions of 3BNC117 3 months apart showed no 
measurable reduction in the number of latently-infected cells in viral outgrowth assays (Cohen, 
Lorenzi et al. 2018). 
 
Overall, 3BNC117 was given to 88 individuals in these 3 studies and was found to be generally 
safe and well-tolerated. The most common related AEs reported were headache (18%), 
malaise/fatigue (16%) and upper respiratory infection (12.5%). 
 
Clinical Experience with 3BNC117 and 10-1074 in Combination 
The combination of 3BNC117 plus 10-1074, administered intravenously, was tested in two 
phase 1 studies. In one study (NCT02824536) HIV-uninfected individuals received 1-3 doses of 
the antibody combination at 3 or 10 mg/kg or placebo. A total 24 of participants enrolled in the 
study, and 18 received the 3BNC117 and 10-1074 combination. In the second study 
(NCT02825797), HIV-infected individuals on or off ART received 1 to 3 doses of 3BNC117 at 10 
or 30 mg/kg each or placebo. Fifteen study participants discontinued ART and received up to 3 
infusions of the mAbs at weeks 0, 3 and 6. A total of 34 individuals enrolled (30 received the 
antibody combination and 4 received placebo). Of those, 12 received 3 infusions of 30 mg/kg, 
administered 3 weeks apart, and 3 received 3 infusions of 30 mg/kg, 2 weeks apart.  
 
There were no SAEs in these two studies of the combined parental antibodies, and the safety 
profile of the 3BNC117 plus 10-1074 combination was similar to what was observed with either 
antibody alone. Most reported AE’s were graded as mild (77%), and the most commonly reported 
AEs were upper respiratory infection, headache and malaise/fatigue. The estimated half-lives of 
3BNC117 and 10-1074 in HIV-uninfected individuals when given in combination were similar to 
what was observed when the antibodies were administered alone: 3BNC117’s half-life when in 
combination with 10-1074 was 18.4 ± 2.5 days versus 17.6 ± 5.7 days when administered alone; 
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Protocol: MCA-0994 
 
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Page 28 
10-1074’s half-life when in combination with 3BNC117 was 22.3 ± 1.5 days versus 24 ± 6.6 days 
when administered alone.  
 
The combination of 3BNC117 and 10-1074 significantly delayed viral rebound in the absence of 
ART. In this study group, participants with baseline sensitivity to 3BNC117 and 10-1074, defined 
as IC50 < 2 µg/ml against viruses outgrown from PBMC, discontinued ART two days after the first 
infusions of 3BNC117 and 10-1074 (week 0) and received two additional combination antibody 
infusions at weeks 3 and 6. Of the 15 participants enrolled, 6 participants experienced viral 
rebound (VL > 200 copies/ml) prior to or at week 12 (or 6 weeks after last mAb infusions). Four 
of these participants had viral blips (VL < 100 copies/ml) prior to first mAb infusions and decreased 
baseline sensitivity to at least one of the antibodies, and the two other participants had pre-existing 
resistance to either 3BNC117 or 10-1074. The median time to rebound for 7 of the 9 antibody-
sensitive participants who experienced viral rebound during the study period was 21 weeks, or 15 
weeks after last mAb infusions. The average 3BNC117 serum concentration at the time of 
rebound in these sensitive participants was 1.9 µg/ml. In contrast, the average serum 
concentration of 10-1074 at rebound was 14.8 µg/ml. The difference in the antibody 
concentrations at the time of rebound is consistent with the longer half-life of 10-1074 which 
resulted in a period of 10-1074 monotherapy and selection or development of resistance. 
Remarkably, 2 of the 9 individuals have now maintained viral control for 10 to 11 months. These 
results show that the combination of 3BNC117 and 10-1074 successfully maintained viral 
suppression in participants harboring sensitive viruses until serum levels of at least one of the 
antibodies declined below 10 µg/ml. Moreover, development of resistance to both antibodies did 
not occur (Mendoza P 2018). 
 
Seven HIV-1 infected participants, who were pre-screened for baseline sensitivity to 3BNC117 
and 10-1074 (defined as IC50 < 2 µg/ml against viruses outgrown from PBMC) enrolled in two 
additional study groups and were administered one or three doses of 3BNC117 plus 10-1074 at 
30 mg/kg of each mAb, at week 0 or weeks 0, 2 and 4. The average decline in viral load for all 7 
viremic participants was 1.65 log10 copies/ml and viremia remained significantly reduced until day 
86. The median time to reach the lowest viremia level was 24 days (range 7-56 days), whereas  
a decline in viremia of > 1.0 log10 copies/ml was reached within 14 days after the first antibody 
infusions.  Analysis of circulating plasma viruses by single genome amplification (SGA) showed 
that 3 of the 7 enrolled participants carried pre-existing resistance to one or both antibodies. These 
participants showed either no response or short-lived decline in viremia after antibody infusions. 
The 4 individuals with sensitive viruses showed a more pronounced drop in viremia compared 
with the other individuals (average of 2.05 log10 copies/ml) and viremia was significantly reduced 
until day 94. The participant with the highest initial viral load (97,800 copies/ml; 9343) was the 
first to rebound at 8 weeks (Figure 2). The 2 individuals with the lowest initial viral loads, 91C22 
and 9342 (750 and 2,550 copies/ml, respectively), demonstrated suppression to near or below 
the limit of detection for 12 and 16 weeks, respectively. Finally, viremia in participant 91C34 was 
reduced for a period of 12 weeks but never dropped below 810 copies/ml. Despite persistent 
viremia, resistance against both antibodies did not develop in this participant for as long as bNAb 
serum levels were above 10 µg/ml.  
 
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Original IND 131872
June 3, 2021 
Protocol: MCA-0994 
 
Confidential 
Page 29 
 In comparison to a single 
infusion of either 3BNC117 or 
10-1074, viremic individuals 
receiving 
one 
or 
three 
infusions of the combination 
of both antibodies showed 
significantly prolonged viral 
suppression. 
Rebound 
viremia was associated with 
the appearance of viruses 
that were resistant to 10-1074 
in 3 of the 4 antibody-
sensitive 
participants, 
but 
remained 
sensitive 
to 
3BNC117. 
This 
is 
again 
consistent with the relatively 
shorter half-life of 3BNC117, 
which led to a period of 10-
1074 monotherapy at the end 
of the observation period. The 
participant with the lowest 
initial viral load only returned 
to baseline viremia after both 
antibodies were below the 
limit of detection, and rebound 
viruses remained sensitive to 
both antibodies. Overall none 
of the 4 participants that were 
initially sensitive to the two 
antibodies developed de novo 
resistance 
to 
3BNC117, 
despite the residual viremia 
observed in three of these 
participants 
and 
frequent 
recombination events between circulating viruses (Bar-On, Gruell et al. 2018). 
 
These results highlight some of the limitations of immunotherapy with the combination of 
3BNC117 and 10-1074 in viremic individuals. Whereas 2 antibodies may be sufficient to achieve 
and/or maintain suppression in individuals harboring sensitive viruses with very low levels of 
viremia or ART-suppressed individuals undergoing ATI, additional antibodies or combinations of 
small molecule drugs and antibodies would be required if this type of therapy is to be considered 
for viremic individuals. In this protocol, we will evaluate the safety, pharmacokinetics and in vivo 
antiviral activity of the long-acting variants of 3BNC117 and 10-1074 in viremic individuals. 
Participants will be encouraged and advised to initiate ART within 4 weeks after antibody infusions 
to achieve sustained viral suppression. 
 
 
Clinical Data with 3BNC117-LS and 10-1074-LS 
Safety summary: 
Figure 2: Viral load after 3BNC17/10-1074 infusions in viremic 
HIV-1-infected participants.  
(a-c) Changes in viremia and bNAb serum concentrations in HIV-1-
infected participants showing (a) late rebound, (b) early rebound or 
(c) no response after 3BNC117 and 10-1074 combination therapy. 
Upper graphs show HIV-1 RNA in copies/ml (black, left y-axis), and 
3BNC117 (red) and 10-1074 (blue) serum levels (right y-axis, as 
determined by TZM-bl). X-axis shows weeks after the first antibody 
infusion. Dashed line indicates the lower limit of detection of HIV-1 
RNA (20 copies/ml). Arrows indicate antibody infusions. Lower 
graphs show log10 changes of HIV-1 RNA copies compared to day 
0. Green shading depicts viral suppression compared to day 0. 
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3BNC117-LS and 10-1074-LS are being evaluated in two ongoing first-in-human (FIH) phase 1 
studies (NCT03254277, NCT03554408). Twenty-seven participants (6 HIV-infected individuals 
on suppressive ART) received 10-1074-LS at doses ranging from 150 mg or 300 mg SC up to 30 
mg/kg IV, and 39 (15 HIV-infected individuals on suppressive ART) received 3BNC117-LS at the 
same dose levels. The admixture of the two antibodies has also been administered 
subcutaneously to 18 HIV-uninfected participants so far. Both intravenous infusions and 
subcutaneous injections have been well tolerated without Grade 3 adverse events or serious 
adverse events deemed possibly related to the antibodies reported to date. The safety profiles of 
the LS-variants so far are similar to the parental antibodies.  
 
10-1074-LS: Twenty-seven participants received a single dose of 10-1074-LS at doses ranging 
from 3 to 30 mg/kg (IV) or 140 or 280 mg (SC). Sixteen additional participants received a single 
SC injection of the combination of 10-1074-LS and 3BNC117-LS. Of the enrolled participants, 37 
were HIV-uninfected. Study follow up is ongoing. As of June 2019, 8 solicited AEs were reported, 
all of Grade 1 severity: erythema/skin discoloration (n=2) and pain at administration site (n=1), 
headache (n=2), feverishness (n=2), malaise/fatigue (n=2), and myalgia (n=1). In addition, 43 
non-solicited AEs were reported. Of these, 8 were graded as moderate: localized musculoskeletal 
pain (n=3), rash (n=1), elevated systolic blood pressure (n=1), abdominal pain (n=1), upper 
respiratory infection (URI) (n=1) and sciatica (n=1). Two reported events were of Grade 3 severity: 
nephrolithiasis and elevated diastolic blood pressure. Two participants experienced a Grade 3 
decline in hemoglobin from baseline. All other adverse events (n=32) were of Grade 1 severity, 
and of these, 5 were considered possibly, probably or definitely related to IP administration. The 
most common adverse events were those related to upper respiratory infections, localized 
musculoskeletal pain and symptoms of gastroenteritis.   
 
3BNC117-LS: Thirty-nine participants received a single dose of 3BNC117-LS at doses ranging 
from 3 to 30 mg/kg (IV) or 150 or 300 mg (SC). Of the enrolled participants, twenty-seven were 
HIV-uninfected. As of June 2019, 5 solicited AEs were reported, all of Grade 1 severity. These 
included tenderness at administration site (n=1), headache (n=1), malaise/fatigue (n=1), and 
nausea (n=2). In addition, 39 non-solicited AEs reported by 23 enrolled participants. Of these, 6 
were of Grade 2 severity: worsening hypertension (n=2), hyperbilirubinemia (n=1), URI symptoms 
(n=1), excessive alcohol intake (n=1), and elevated creatinine (n=1). One reported event was of 
Grade 3 hyperalbuminuria measured prior to 3BNC117-LS administration, which did not recur. 
An instance of Grade 4 hypokalemia was also reported in a participant without associated 
complaints, which resolved upon repeat testing. 
 
Pharmacokinetics: 
The parental 3BNC117 showed an average half-life of 17 days in HIV-uninfected individuals, and 
10-1074 showed an average half-life of 24 days in the same study population. Preliminary 
analysis of pharmacokinetics in the ongoing first-in-human study of 3BNC117-LS suggests that 
its half-life is > 60 days in HIV-uninfected individuals, or 3.9-fold longer than 3BNC117 (Figure 
3a-b). Whereas the half-life of 10-1074-LS appears to be > 90 days (Figure 3c-d). Additional 
safety and pharmacokinetics data continues to be generated under the two ongoing FIH studies 
of 3BNC117-LS and 10-1074-LS. 
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Figure 3: Serum levels of 3BNC117 and 10-1074 parental and LS variants.  
Graphs show mean and s.e.m serum concentrations (y-axis) following a single administration of 3BNC117, 
3BNC117-LS, 10-1074 or 10-1074-LS. (A) 10-1074-LS, administered SC alone (140 mg, n=6; 280 mg, 
n=6), or admixed with 3BNC117-LS (140 mg combo, n=6). (B) 10-1074 or 10-1074-LS, administered SC 
alone (each group, n=3). (C) 3BNC117-LS, administered IV alone (150 mg, n=6; 300 mg, n=6), or admixed 
with 10-1074-LS (150 mg combo, n=6). (D) 3BNC117 or 3BNC117-LS, administered IV alone (each group, 
n=3). 
 
 
10-1074-LS and 3BNC117-LS Drug Product Manufacture  
The manufacture of the recombinant human monoclonal antibodies 10-1074-LS and 3BNC117-
LS were carried out by in vitro serum-free CHO cell culture. 10-1074-LS and 3BNC117-LS were 
manufactured by Celldex therapeutics as sterile solutions intended for parenteral use, in 
compliance with Good Manufacturing Practices (GMP). No animal-derived raw materials were 
used during the cell culture, purification, and formulation of the drug substance. The drug 
substance was manufactured in a dedicated suite utilizing single-use equipment (e.g., WAVE 
bioreactor) to minimize potential for product cross contamination. A low pH step and a 
nanofiltration step were used for virus inactivation and reduction.  In addition, two chromatography 
column steps contribute to viral clearance: MabSelect SuRe (Protein A Chromatography) and 
Sartobind Q (Anion Exchange Chromatography).  Testing for adventitious agents was performed 
in accordance to FDA Points to Consider in the Manufacture and Testing of Monoclonal Antibody 
Products for Human Use (1997). The clinical trial products were formulated as a single-use sterile 
solution intended for parenteral use. Drug product stability-testing programs are established to 
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monitor the quality of 10-1074-LS and 3BNC117-LS over the duration of the clinical dosing period 
as well as to gain predictive information regarding the product’s stability characteristics, and are 
based on 21 CFR 211.166 and ICH Q1A (R2) and ICH Q5C.  
- 
10-1074-LS stability will be evaluated in real time at the recommended storage conditions of 5 
± 3°C as well as at accelerated temperature conditions of 25 ± 2°C / 60 ± 5% RH.  
- 
3BNC117-LS stability will be evaluated in real time at the recommended storage conditions 
of 5 ± 3°C as well as at accelerated temperature conditions of 25 ± 2°C / 60 ± 5% RH.  
 
 
Hypotheses 
The administration of single infusions of the combination of 3BNC117-LS and 10-1074-LS to 
viremic HIV-infected participants (30 mg/kg of each mAb) will be generally safe and well tolerated 
and will lead to significant decline in plasma viremia. Both LS-variant antibodies will demonstrate 
longer half-lives and lower clearance rates when compared to data available from the two parental 
antibodies. 
 
Aims  
Primary objectives  
- 
To evaluate the safety and tolerability profile of single intravenous infusions of 3BNC117-LS 
in combination with 10-1074-LS at a single dose level (30 mg/kg, each mAb) in HIV-infected 
individuals off ART. 
- 
To determine the pharmacokinetic profile of single intravenous infusions of 3BNC117-LS in 
combination with 10-1074-LS at a single dose level (30 mg/kg, each mAb) in HIV-infected 
individuals off ART. 
- 
To determine the effect of single intravenous infusions of 3BNC117-LS in combination with 
10-1074-LS at a single dose level (30 mg/kg, each mAb) on plasma HIV-1 RNA levels in 
viremic HIV-infected individuals. 
Secondary objective 
- 
To assess the frequency and magnitude of treatment-induced anti-drug antibody responses 
(anti-3BNC117-LS and anti-10-1074-LS antibodies) after a single intravenous infusion.  
Exploratory objectives 
- 
To evaluate the association between reduction in plasma viremia and predicted sensitivity to 
both 3BNC117-LS and 10-1074-LS by the Monogram PhenoSense assay (defined as IC50s < 
0.25 µg/ml) and other non-CLIA-certified assays. 
 
- 
To genotype viral escape variants that may arise after administration of 3BNC117-LS in 
combination with 10-1074-LS in viremic HIV-infected individuals. 
 
- 
To characterize the impact of treatment-induced anti-drug antibody (ADA) responses on the 
safety, pharmacokinetics and antiviral activity of 3BNC117-LS and 10-1074-LS. 
 
- 
To evaluate HIV-1 specific T and B cell immune responses following 3BNC117-LS and 10-
1074-LS infusions.  
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- 
To analyze gene expression profiles in HIV-1 infected CD4+ T cells. 
 
Outcomes 
Primary Outcomes:  
- 
The occurrence of treatment-related solicited and unsolicited grade 3 and serious adverse 
events (including confirmed laboratory abnormalities). 
 
- 
The pharmacokinetic profile (including: peak concentrations, half-life, area under curve and 
clearance rate) of 3BNC117-LS and 10-1074-LS, when administered intravenously and in 
combination to viremic HIV-infected individuals. 
- 
The decline in plasma HIV-1 RNA level after 3BNC117-LS plus 10-1074-LS intravenous 
infusions in viremic HIV-infected individuals through week 4 after infusions. 
 
Secondary Outcomes: 
- 
Proportion of individuals with treatment-induced ADA against each mAb and magnitude of the 
response.  
 
- 
The rate of adverse events and confirmed laboratory abnormalities that occur during the study 
follow up period after 3BNC117-LS and 10-1074-LS administration. 
Exploratory Outcomes: 
- 
Time until return of viremia to baseline levels in participants, who elect to remain off ART after 
4 weeks. 
 
- 
Decline in plasma viremia after antibody infusions across 3BNC117-LS and 10-1074-LS IC50 
and IC80 cut points determined by PhenoSense assay or other assays (e.g. bulk PBMC 
cultures or Q2VOA followed by TZM/bl assay).  
 
- 
Phenotypic and genotypic analysis of baseline and escape viruses that might arise after single 
infusions of 3BNC117-LS and 10-1074-LS in viremic HIV-infected individuals. 
 
- 
Proportion of participants with reduction in half-life or antiviral activity concomitant with ADA. 
 
- 
Relationship of adverse events to ADA. 
 
- 
Frequency and magnitude of HIV-1 specific T cell responses and serum neutralizing activity 
against a multi-clade panel of HIV-1 pseudoviruses, following 3BNC117-LS and 10-1074-LS 
infusions.  
 
- 
Gene expression profiles by single RNA sequencing of HIV-1 infected CD4+ T cells. 
 
4 
STUDY DESIGN 
The proposed study is a phase 1, open label, single arm study to evaluate the safety, 
pharmacokinetics and antiviral activity of single intravenous infusions of 3BNC117-LS and 10-
1074-LS in viremic HIV-infected individuals. (Figure 4, Study Design). 
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Figure 4: Study Design 
 
 
Ten eligible participants will be enrolled sequentially in the study and will receive each mAb, dosed 
at 30 mg/kg intravenously and in sequence on study day 0. Following mAb administration, study 
participants will return for safety assessments on days 1 and 3, and weeks 1, 2, 3 and 4 following 
dosing, then bi-weekly or monthly until the end of study follow up as indicated in the Time of 
Events Schedule (Appendix A). All participants will be followed for 24 weeks after 3BNC117-LS 
and 10-1074-LS administration.   
 
Safety assessments will be performed at multiple time points following 3BNC117-LS and 10-1074-
LS infusions. Serum samples for PK measurements will be collected before and at the end each 
mAb infusion administration and at multiple subsequent time points during study follow up, as 
indicated in the Time of Events Schedule (Appendix A). Samples will also be collected for 
measurement of HIV-1 plasma RNA levels before 3BNC117-LS and 10-1074-LS infusions 
(screen and day 0) and at every follow up visit. T cell subsets will also be monitored during study 
follow up. Assessments will also include measurement of ADA responses and sequencing of 
plasma envelope before infusions and after viral rebound (first time point after viremia nadir is 
reached and VL is > 1,000 copies/ml). 
 
Participants will be advised and encouraged to start ART within 4 weeks of receiving 3BNC117-
LS and 10-1074-LS infusions or sooner if: VL fails to decrease by >0.5 log10 copies/ml within 2 
weeks of antibody infusions, VL increases > 0.5 log10 copies/ml between weekly measurements 
or significant T-cell decline (confirmed CD4+ T cells < 200 cells/μl) is noted. Participants with 
current CD4 counts > 300 cells/μl will be eligible to enroll in the study. Studies with the unmodified 
3BNC117 and 10-1074 in the same study population used the same criterion for entry and showed 
that CD4 counts remained stable during follow up prior to ART initiation (Caskey, Klein et al. 2015, 
Caskey, Schoofs et al. 2017) (Bar-On et al. 2018). We have maintained the same criterion in this 
study to facilitate enrollment, given the overall favorable safety profile seen in the previous studies 
using similar cutoff. To account for the possibility of transient CD4 count fluctuations in 
participants who have starting CD4 counts of about 300 cells/mm3, we selected 200 cells/mm3 as 
the cutoff to re-initiate ART sooner than 4 weeks. The selected CD4 count levels might delay 
initiation of ART by 1 or 2 weeks, compared to using a slightly higher cutoff. It is also unlikely that 
participants will experience an accelerated decline in CD4 counts in the course of 4 weeks from 
antibody infusions that would pose significant additional risk of poor outcomes, such as 
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development of opportunistic infections. However participants will be closely monitored during this 
period. 
  
5 
STUDY POPULATION 
 
Inclusion Criteria 
1. Males and females, >18 years of age.  
2. Confirmed HIV-1 infection. 
3. Off ART for at least 4 weeks with a HIV-1 plasma RNA level between 500 and 125,000 
copies/mL (ART-naïve or off ART due to intolerance or by choice). 
4. Current CD4+ T cell count > 300 cells/μl. 
5. Participants who can become pregnant and are engaging in sexual activity that could lead 
to pregnancy agree to use two effective methods of contraception (i.e. condom with 
spermicide, diaphragm with spermicide, hormone-eluting IUD, hormone-based 
contraceptive with condom) from 10 days prior to and six months after 3BNC117-LS and 
10-1074-LS administration.  
6. Participants who can impregnate a partner and are engaging in sexual activity that could 
lead to pregnancy agree to use barrier protection from 10 days prior to and six months 
after 3BNC117-LS and 10-1074-LS administration to avoid impregnating a partner who 
can get pregnant.  
7. Willingness to use barrier protection during sexual activity while not on ART to decrease 
the risk of HIV transmission to a partner at risk for HIV infection.  
 
Exclusion Criteria  
1. Have a history of AIDS-defining illness within 3 years prior to enrollment. 
2. History of systemic corticosteroids, immunosuppressive anti-cancer, or other medications 
considered significant by the trial physician within the last 6 months. 
3. Any clinically significant acute or chronic medical condition (such as autoimmune 
diseases), other than HIV infection, that in the opinion of the investigator would preclude 
participation. 
4. Hepatitis B or C infection as indicated by the presence of Hepatitis B surface antigen 
(HBsAg) or hepatitis C virus RNA (HCV-RNA) in blood. 
5. Laboratory abnormalities in the parameters listed below:  
- 
Absolute neutrophil count ≤ 1,000 cells/μl; 
- 
Hemoglobin ≤ 10 gm/dL; 
- 
Platelet count ≤ 100,000 cells/μl; 
- 
ALT ≥ 1.5 x ULN; 
- 
AST ≥ 1.5 x ULN; 
- 
Alkaline phosphatase ≥ 1.5 x ULN; 
- 
Total bilirubin > 1.25 x ULN;  
- 
eGFR < 60 mL/min/1.73m2. 
6. Pregnancy or lactation. 
7. Any vaccination within 14 days prior to mAb infusions, except for influenza vaccine. 
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8. Receipt of another investigational product currently or within the past 12 weeks, or 
expected concurrent participation in another study in which investigational products will 
be administered. 
9. Receipt of any experimental HIV vaccine or anti-HIV monoclonal antibody therapy in the 
past. 
10. History of severe reaction to a vaccine or drug infusion or history of severe allergic 
reactions. 
11. Individuals with known hypersensitivity to any constituent of the investigational products.  
 
6 
METHODS AND PROCEDURES 
 
Screening Procedure and Study Visits 
The Time of Events Schedule summarizes the frequency and timing of various study 
assessments. See Appendix A. At the Cornell site, recruitment, screening, and follow up visits 
during the study period will be performed either at the Weill Cornell Medical Center (WCMC), and 
antibody infusions will occur at the Rockefeller University Hospital (RUH). At the RU and UPENN 
sites, all study procedures will occur at the RUH or at the Center for Human Phenomic Science 
(CHPS) at the Perelman Center for Advanced Medicine (PCAM) of the Perelman School of 
Medicine University, respectively. 
6.1.1 
Pre-Screening Questionnaire 
Potential participants will first undergo pre-screening by telephone to assess medical history and 
qualification for the study. Potential participants will have the opportunity to discuss the study and 
ask questions of the study recruiter at this time. Those who are eligible and interested in 
participation will attend a screening visit at the RUH, WCMC, or UPENN McGregor Outpatient 
Clinics. 
6.1.2 
Screening Visit 
Initial Screening Visit: 
Study personnel will answer any questions about the study. Written informed consent will be 
obtained prior to conducting any study procedures. To ensure informed consent, the principal 
investigator or designee will discuss the following processes individually with each potential 
participant: 
1. Risk-reduction counseling including safer sex (including discussion of sexual activity that 
could lead to HIV transmission) and pregnancy avoidance counseling; 
2. One must assume that no improvement in control of HIV infection will occur given the 
experimental nature of the monoclonal antibodies; 
3. That sexually active males and females, participating in sexual activity that could lead to 
pregnancy, should use two reliable forms of contraception for 10 days prior to and six months 
following 3BNC117-LS and 10-1074-LS administration. 
If the potential participant consents to participate, site personnel will: 
• 
Perform complete medical history (including review of concomitant medications); 
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• 
Perform a general physical examination including height, weight, vital signs (pulse, 
respiratory rate, blood pressure and temperature), examination of skin, respiratory, 
cardiovascular and abdominal systems; 
• 
Collect blood and urine specimens for all tests as indicated in the Time of Events Schedule 
(Appendix A); 
• 
Perform a pregnancy test for all female volunteers of child-bearing potential. 
If the initial screening visit occurs more than 49 days prior to the date of 3BNC117-LS and 10-
1074-LS administration, only laboratory tests (blood and urine specimens) will be repeated and a 
review of the medical history will be performed.  
HIV-1 infected participants that do not meet eligibility criteria due to HIV viral load levels outside 
of the range specified in the protocol will be independently counseled regarding their HIV care. 
Participants will be counseled and encouraged to initiate therapy and referrals to HIV providers 
will be provided, if needed. 
6.1.3 
Study Drug Administration Visit 
Prior to administration of the investigational product(s), site personnel will: 
• 
Review the informed consent form administered at the screening visit with the participant; 
• 
Answer any questions about the study; 
• 
Review interim medical history (including concomitant medications); 
• 
Review safety laboratory data; 
• 
Perform a directed physical examination including weight, vital signs (pulse, respiratory 
rate, blood pressure and temperature) and any further examination indicated by history or 
observation; 
• 
Collect blood and urine specimens for all tests as indicated in the Time of Events Schedule 
(Appendix A); 
• 
Perform pregnancy and safer sex counseling; 
• 
Perform a serum pregnancy test for all female volunteers of child-bearing potential and 
obtain results prior to drug infusion.  
• 
Perform baseline assessment and record any systemic symptoms; 
• 
3BNC117-LS and 10-1074-LS will be prepared for administration according to 
Appendix C; 
Antibody Administration: 
• 
3BNC117-LS will be administered via a peripheral vein over 30 minutes. The IV line will 
be flushed with normal saline after all the contents of the infusion bag are administered. 
• 
10-1074-LS will be administered after 3BNC117-LS infusion is completed and the line is 
flushed with normal saline. It will also be administered via a peripheral vein over 30 
minutes. The IV line will be flushed with normal saline after all the contents of the infusion 
bag are administered. 
• 
If participants develop grade 3 acute infusion reaction, an immediate hypersensitivity 
reaction or a life-threatening event during study drug administration, the infusion will be 
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discontinued and will not be reinitiated (see Section 6.1.7.1). If the acute infusion reaction 
occurs during 3BNC117-LS infusion, 10-1074-LS infusion will not be infused. 
• 
Participants will be observed for adverse reactions at the study site for 1 hour after the 
end of the 10-1074-LS infusion. Presence or absence of adverse events will be recorded 
at 1 hour post infusion.  
• 
Vital signs (pulse, respiratory rate, blood pressure and temperature) will be monitored 
before administration, at the end of each infusion, 30 minutes (+/- 10min) post final 
infusion, and at 1 hour (+/- 10 min) post final infusion;  
• 
Rescue medications, including acetaminophen, diphenhydramine (or an alternative 
antihistaminic) and glucocorticoids will be available in the RUH or at the Center for 
Human Phenomic Science (CHPS) at the Perelman center for advanced Medicine 
(PCAM) of the Perelman School of Medicine University for use if clinically indicated.  
6.1.4 
Post-Study Drug Administration Visit 
Participants will be followed through study week 24.  
At these follow up visits the following will be conducted: 
• 
Review of interim medical history and use of concomitant medications; 
• 
Perform a symptom-directed physical examination if symptoms are present; 
• 
Local and systemic solicited and unsolicited adverse events will be assessed; 
• 
Pregnancy and safer sex counseling; 
• 
Vital Signs; 
• 
Collect blood and urine specimens for all tests as indicated in the Time of Events Schedule 
(Appendix A); 
• 
In case of adverse event(s), the participant will be assessed and followed up by the clinical 
team. Supplemental visit(s) for further investigation can be planned at the discretion of the 
principal investigator or designee. Supplemental visit(s) may be recommended if clinically 
indicated or to clarify observations. 
Specific procedures to be performed at each follow up visit for all study groups are illustrated in 
the Time of Events Schedules (Appendix A).  
Any abnormalities (adverse events) including laboratory abnormalities, should be subsequently 
followed until the event or its sequelae resolve or stabilize.  
6.1.5 
Final Visit/Early Termination Visit 
Assessments will be undertaken according to the Time of Events Schedule (Appendix A). 
6.1.6 
Discontinuation of Study Drug Infusions and/or Participant Withdrawal from 
Study 
6.1.6.1 
Discontinuation of Study Drug Infusion 
Antibody intravenous infusion will be discontinued for any of the following reasons: 
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1. Grade 3 acute infusion reactions that occur during infusion. 
2. Any immediate hypersensitivity reaction (such as urticarial rash; bronchospasm; laryngeal 
edema; anaphylaxis; syncope). 
3. Life threatening medical event during 3BNC117-LS or 10-1074-LS infusion. 
6.1.6.2 
Withdrawal from the Study (Early Termination) 
Participants may be withdrawn from the study permanently for the following reasons: 
1. Participants may withdraw from the study at any time if they wish to do so, for any reason. 
2. Following an adverse event at the discretion of the investigator (or designee). 
3. Request of the primary care provider if s/he thinks the study is no longer in the best interest 
of the participant. 
4. Participant judged by the investigator to be at significant risk of failing to comply with the 
protocol in a manner that might lead to harm to self or seriously interfere with the validity of 
the study results. 
5. At the discretion of the FDA or investigator. 
6.1.6.3 
Follow Up after Withdrawal from Study (Early Termination) 
Any adverse event resulting in withdrawal of a participant will be followed up until resolution or 
until the adverse event is judged by the principal investigator or designee to have stabilized where 
possible. 
At the time of withdrawal, provided the participant is willing, all the requested termination visit 
procedures will be performed according to the Time of Events Schedule (Appendix A). 
The date and reason for withdrawal (early termination) from the study should be collected and 
reported to the Sponsor at the RU, the SMC, and the local IRBs.  
A pregnant participant will not receive the study drugs. If pregnancy occurs after 3BNC117-LS 
and 10-1074-LS administration, the participant will be followed until the end of the study and until 
delivery, if delivery occurs after the study has ended. Approximately 2-4 weeks after delivery, the 
baby will be examined by a pediatrician to assess his/her health status. The outcome of the 
pregnancy and the health status of the baby will be reported to the Sponsor at the RU, the SMC, 
and the local IRBs. 
 
Study Procedures  
6.2.1 
Consent Procedure 
Prior to the initiation of any study related procedures, the potential participants will be given a 
copy of the most recent IRB stamped and approved informed consent to read. Additionally, the 
PI or study staff member who has been designated to consent will discuss the specifics of the 
study including but not limited to the purpose of the research, procedures, time commitment, 
required tasks, test article, alternative treatments, benefits, risks, confidentiality, etc. in a 
comprehensible (non-scientific) manner, using language readily understandable by the 
participant. Participants will be told that participation is voluntary and that, if they do not consent, 
they will not be penalized. The person consenting will assure the voluntariness of the participant. 
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A private, confidential setting will be provided for the potential participant to read and discuss the 
informed consent free from coercion, undue influence or constraints of time. All participants will 
be given a chance to ask questions and express concerns. They will be given the option to take 
the consent home and discuss it with family, friends, and /or health care providers. After a 
participant and the person conducting the consenting process sign and date the consent, the 
participant will be given a copy of the signed informed consent form.  
An enrollment note will be written in the source document as to who obtained consent, how, when, 
were questions asked and answered, and that a copy of the informed consent was given to the 
participant. 
The "Teach Back" method will be used to ask research participants to repeat or “Teach Back” the 
information, concepts and directions that the staff member has attempted to convey to the 
participant. This method is used to assess comprehension and retention of protocol requirements, 
adverse event information, risks and benefits, and the participant's rights described in the 
Informed Consent process. 
6.2.2 
Study Assignment and Randomization 
Enrollment will be open-label, and participants will be enrolled sequentially as they meet 
enrollment criteria. Study ID numbers will be assigned by the Emmes Corporation, to prevent 
over-enrollment. Over-enrollment will only be permitted to replace participants lost to follow up 
prior to week 4, as discussed in Section 8.2 Sample Size Considerations.  
6.2.3 
Study Drug Administration Procedure 
3BNC117-LS will be provided in single-use vials containing 1 mL of the product at a concentration 
of 150 mg/mL. 10-1074-LS will be provided in single-use vials containing 1 mL of the product at 
a concentration of 140 mg/mL. 
The volume of 3BNC117-LS to be administered will be calculated by the site research pharmacist. 
Weight measurements collected at the day 0 visit will be used to calculate the dose of 3BNC117-
LS. The appropriate volume of 3BNC117-LS will be diluted in sterile normal saline to a total 
volume of 100 mL, and will be administered as an intravenous infusion over 30 minutes.   
The volume of 10-1074-LS to be administered will be calculated by the site research pharmacist. 
Weight measurements collected at the day 0 visits will be used to calculate the dose of 10-1074-
LS. The appropriate volume of 10-1074-LS will be diluted in sterile normal saline to a total volume 
of 100 mL, and will be administered as an intravenous infusion over 30 minutes, after the infusion 
of 3BNC117-LS is completed. 
The study drugs will be administered via a peripheral vein in one of the upper extremities. The 
administration site should be free of potentially complicating dermatologic conditions. The entire 
contents of the infusion bags must be administered. At the end of each infusion, the IV line will be 
flushed with Normal Saline to ensure all the study drug has been delivered. 
6.2.4 
Medical History and Physical Examination 
At the time of screening, participant’s past medical history will be collected and will include details 
of any previous reaction to vaccination, and contraceptive practices. Interim medical histories will 
be collected at time-points according to the Time of Events Schedule (Appendix A).  
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A general physical examination will be conducted at screen including weight, height, vital signs, 
and examination of skin, respiratory, cardiovascular and abdominal systems. At the study drug 
administration and follow up visits, directed physical examinations will be performed according to 
the Time of Events Schedule (Appendix A). A directed physical examination will include vital 
signs, examination of infusion site, and any further examination indicated by history or 
observation. 
6.2.5 
Ophthalmologic Evaluations 
In the tissue cross-reactivity study (TCR) in human tissues, 3BNC117 stained rare cells in the 
conjunctival recesses, and 10-1074 stained the cytoplasm of nerve cells in the optic nerve of the 
eye. In vivo GLP toxicology studies performed in rats with 3BNC117 and 10-1074, alone and in 
combination, did not show toxicity in ocular tissues. Moreover, these tissue binding findings were 
not reproduced in repeat TCR studies comparing the unmodified with the LS variants.  
 
In humans, approximately 6% of participants enrolled in 3BNC117 trials reported mild ocular 
complaints (such as pruritus, conjunctival erythema, increased lacrimation, blurry vision) during 
study follow up of 6 to 12 months. In all instances, symptoms resolved without specific treatment, 
and evaluations by an ophthalmologist at 1 or 5 months after 3BNC117 administration did not 
reveal changes from baseline. It remains unclear if these symptoms were related to 3BNC117 
infusions. Two ocular symptoms were reported during 10-1074 studies (grade 1, dry eyes and 
diplopia), and follow up ophthalmologic exams did not reveal abnormalities or changes from the 
baseline exams. A temporal relationship between time of 3BNC117 and/or 10-1074 
administrations and the occurrence of ocular complaints is not clear at this time To date, only 1 
out of 39 participants reported an ocular AE in the studies of 3BNC117-LS alone or in combination 
with 10-1074-LS. This was grade 1 ocular pruritus, which occurred 3 days post-infusion and 
resolved 1 day later.  
 
The occurrence of ocular AEs will be monitored as solicited AEs. Participants will be evaluated 
by an ophthalmologist (including slit lamp exam) prior to 3BNC117-LS and 10-1074-LS 
administration. In addition, participants will be monitored for the occurrence of ocular symptoms. 
If symptoms of ocular disease develop after study infusions and persist for > 48 hrs, participants 
will be promptly referred to an ophthalmologist for diagnosis and management. 
6.2.6 
Diagnostic Work Up in the Event of Grade 3 or 4 Elevations in Total Bilirubin 
Transient elevations in total bilirubin have been observed following 3BNC117 dosing and in 1 
participant who received 3BNC117-LS. Typically, these are isolated laboratory abnormalities of 
grade 1 severity that resolve within a few weeks without need for specific treatment. A causal 
relationship has not been determined but bilirubin levels will be followed during study follow up. 
Any participant with a grade 3 or 4 elevation in total bilirubin will undergo a diagnostic work up 
that includes right upper quadrant ultrasound, testing for gamma glutamyl transferase (GGT) HAV 
(IgM and IgG), HBV (hepatitis B surface antigen and IgM anti-hepatitis B core antigen), HCV (anti-
hepatitis C antibody and HCV PCR), EBV (IgM and IgG VCA and EBNA antibodies), CMV (IgM 
and IgG), VZV (IgM and IgG) and HSV (IgM and IgG), and any other relevant laboratory tests as 
determined by the investigators. These evaluations will be of no cost to the participant. 
6.2.7 
Monitoring for Cytokine Release Associated Adverse Events and Treatment of 
Cytokine Release Syndrome, Immediate Hypersensitivity Reactions or Other 
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Life-Threatening Adverse Events 
Based on previous clinical experience with similar monoclonal antibodies, it is unlikely that 
administration of 3BNC117-LS and 10-1074-LS would lead to cytokine release syndrome. 
However, a potential side effect of a monoclonal antibody can be the stimulation of a massive 
release of cellular cytokines, which can have profound effects on blood pressure, vascular 
integrity, and myocardial, lung, liver, and kidney functions. If cytokine release syndrome occurs, 
the participant may need to be treated with intravenous fluids, vasopressors, and high-dose 
corticosteroids and may require ventilator support. 
Study participants will be observed at the site infusion unit on the day of study drug administration. 
3BNC117-LS and 10-1074-LS will each be administered over 30 minutes. Participants will remain 
in the unit for at least 60 minutes after last infusion. Access to a twenty-four hour on-call physician 
is available at all sites. The study sites are equipped with crash carts for immediate medical care, 
should the need arise. In case of an emergency, after stabilization of the volunteer, he/she will be 
transferred to a tertiary care center for specialized medical care.  
6.2.8 
Family Planning Counseling 
During screening and subsequent study visits, study personnel will counsel participants about the 
importance of prevention of pregnancies and the use of condoms, as well as other effective family 
planning methods. Condoms will be provided. 
Female study participants of reproductive potential are defined as pre-menopausal women who 
have not had a sterilization procedure (e.g. hysterectomy, bilateral oophorectomy, tubal ligation 
or salpingectomy). Women are considered menopausal if they have not had a menses for at least 
12 months and have a FSH of greater than 40 IU/L or if FSH testing is not available, they have 
had amenorrhea for 24 consecutive months. 
Should pregnancy occur, a pregnant participant will not receive the study drug(s). If pregnancy 
occurs after study drug administration, the participant will be followed until the end of the study 
and until delivery, if it occurs after the study has ended. Approximately 2-4 weeks after delivery, 
a pediatrician will examine and assess the health status of the baby. The baby’s health status will 
be reported to the Sponsor at the RU, the local IRBs, and the SMC.  
6.2.9 
Safety Assessments 
6.2.9.1 
Solicited Adverse Events 
Solicited adverse events in this study include presence of feverishness, chills, headache, nausea, 
vomiting, malaise, myalgia and arthralgia occurring in the two weeks following 3BNC117-LS and 
10-1074-LS administration, as well as infusion site reaction or extravasation changes. 
Solicited adverse events will be collected prospectively by structured interviews on infusion and 
post-infusion follow up visits; recorded and graded according to pre-established criteria (see 
Appendix B). The DAIDS AE Grading Table, corrected v2.1 (July 2017) will be used to grade 
adverse events in HIV-infected participants. In addition, the Common Terminology Criteria for 
Adverse Events (CTCAE) v5.0 (27Nov2017) grading scale will be used for reporting and grading 
adverse events in all groups occurring within 24 hours of the start of 3BNC117-LS and 10-1074-
LS infusions that are considered infusion reactions or cytokine release syndromes. Symptoms 
that 
may 
constitute 
an 
infusion 
reaction 
or 
cytokine 
release 
syndrome 
include: 
fever and/or shaking chills, flushing and/or pruritus, alterations in heart rate and blood pressure, 
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dyspnea or chest discomfort, back or abdominal pain, nausea, vomiting, and/or diarrhea, skin 
rash. 
Vital signs (pulse, respiratory rate, blood pressure and temperature) will be measured prior to 
each antibody infusion, at the end, and 1-hour post-infusion, and will be graded according to the 
CTCAE v5.0 toxicity table and recorded. All medications required for treatment of adverse events 
will be recorded. 
6.2.9.2 
Unsolicited Adverse Events 
During all follow up visits, the occurrence of unsolicited adverse events will be assessed following 
an open question to participants, with the dates of commencement and resolution and any 
medication required. Adverse events will be followed to resolution or stabilization. They will be 
graded as indicated in the appropriate toxicity table (Appendix B). 
Laboratory abnormalities that are considered clinically significant and are grade 3 or higher will 
be reported as adverse events. 
6.2.10 
Blood Collection, Storage and Shipment 
Venous blood will be collected at every study visit according to the Time of Events Schedule 
(Appendix A). Up to 120 mL will be collected at day 0. Up to 100 mL will be collected at other 
visits. At no time will the total volume of blood collected exceed 550 ml over an 8-week period. All 
specimens will be handled according to Processing Laboratory SOPs. Frozen PBMCs, plasma, 
and serum will be processed and stored at the study sites.  
6.2.11 
Routine Laboratory Parameters 
Laboratory 
parameters 
will 
routinely 
include 
hematology 
(WBC 
and 
differential, 
hemoglobin/hematocrit, platelets), clinical chemistry (creatinine, total and direct bilirubin, AST and 
ALT, alkaline phosphatase), and urinalysis (dipstick). TSH, T3, and free T4 will be measured at 
week 0 and week 4. Female participants will have serum beta-HCG measured on the day of study 
drug administration, and urine beta-HCG checked at screening and follow up visits. The laboratory 
samples for these tests will be collected at the time points indicated in the Time of Events 
Schedule (Appendix A).  
In the event of an abnormal laboratory value, participants may be asked to have additional 
sample(s) collected at the discretion of the principal investigator or designee.  
HIV-1 viral load and CD4+ T cell counts will be closely monitored as outlined in the Time of Events 
Schedule (Appendix A).  
Participants will be screened for syphilis (RPR), gonorrhea and chlamydia (urine GC/Chlamydia 
nucleic acid amplification test), and viral hepatitis (HBsAg and HCV viral load) at the Screening 
Visit.  
6.2.12 
Antiretroviral and Immunogenicity Assessments 
1. Standard HIV-1 viral load assay (CLIA-certified). The detection range of the assay is 20-
10x106 copies/ml. HIV-1 viral load will be determined at multiple time points before and after 
3BNC117-LS and 10-1074-LS administration. 
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2. Levels of circulating CD4+ and CD8+ T cell counts will be determined by a CLIA-certified 
assay. 
3. Measurement of 3BNC117-LS and 10-1074-LS levels by sandwich ELISA will be performed 
in the laboratory of Dr. Georgia Tomaras at Duke University by qualified assays. mAb levels 
will be measured in serum at multiple time points during the study, according to the Time of 
Events Schedule (Appendix A).  
4. Anti-drug (3BNC117-LS or 10-1074-LS) antibody responses in serum. Assays will be 
performed in the Laboratory of Dr. Margaret Ackerman at Dartmouth College by qualified 
assays, according to the Time of Events Schedule (Appendix A). 
5. 3BNC117-LS and 10-1074-LS sensitivity (CLIA-certified). Baseline (day 0) sensitivity to 
3BNC117-LS and 10-1074-LS will be evaluated by a PhenoSense assay developed by 
Monogram. In this assay, a library of pseudoviruses expressing envelope sequences isolated 
from PBMC proviral DNA is tested for neutralization sensitivity to a given bNAb in TZM.bl cells. 
Sensitivity will be defined as IC50s < 0.25 µg/ml. This assay will be performed at Monogram. 
6. Genotyping – Sequencing of HIV-1 env viral isolates will be performed in plasma samples 
collected before and after 3BNC117-LS and 10-1074-LS infusions. Genotyping will be 
performed in the RU Laboratory of Molecular Immunology. 
7. Phenotyping of viral escape variants in viremic participants - HIV-1 pseudoviruses expressing 
selected envelope sequences will be generated for subsequent characterization by in vitro 
neutralization assays. Representative sequences, including sequences with substitutions not 
known to confer reduced susceptibility to 3BNC117 or 10-1074, will be selected for phenotypic 
analysis. Pseudoviruses will be generated in the RU Laboratory of Molecular Immunology and 
neutralization assays will be performed in the Laboratory of Dr. Michael Seaman at Beth Israel 
Deaconess Medical Center. 
8. HLA-typing will be performed on PBMC samples at a contract laboratory.  
9. Functional properties of cytotoxic T cells analysed by flow cytometry at baseline and following 
3BNC117-LS and 10-1074-LS infusions. These assays will be performed in the RU Laboratory 
of Molecular Immunology.  
10. TZM-bl neutralization assay will be performed in the laboratory of Dr. Michael Seaman of the 
Beth Israel Deaconess Hospital in Boston. This assay will be performed to determine serum 
neutralizing activity against a panel of pseudoviruses representative of multiple clades at 
baseline and following 3BNC117-LS and 10-1074-LS infusions.  
11. Gene expression profile of isolated HIV-1 infected cells by single cell RNA sequencing will be 
performed in the RU Laboratory of Molecular Immunology.    
Optimal sample collection, processing, cryopreservation, archiving and storage will be 
maintained. Additional studies will be performed as warranted at the discretion of the 
investigators. 
6.2.13 
Pharmacokinetic Evaluations 
3BNC117-LS and 10-1074-LS serum levels will be measured by validated sandwich ELISA 
methods performed at Duke University. Serum samples will be collected before 3BNC117-LS and 
10-1074-LS administration, at the end of the 3BNC117-LS and 10-1074-LS intravenous infusions 
and at all follow up visits.  
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Pharmacokinetic parameters, including AUC, Cmax, T1/2, Tmax, clearance rate and others will be 
estimated by performing a non-compartmental analysis (NCA). Pharmacokinetic parameters will 
be examined to correlate exposure with safety and pharmacodynamic parameters (decline in 
plasma HIV-1 RNA), and variance, based on population intrinsic factors such as weight and 
gender, will be explored.  
6.2.14 
Specimen Shipment Preparation, Handling and Storage 
• 
Safety labs:  
Specimens collected for safety labs at RUH will be transported to Memorial Sloan Kettering 
Cancer Center laboratory (MSKCC) via a courier. Specimens for LabCorp will be picked up by 
LabCorp staff at RUH.  
 
Safety labs will be collected and tested at the WCMC and the UPENN sites.  
 
• 
Research labs: 
Specimens collected at RUH will be transported to the Clinical Processing lab in the Laboratory 
of Molecular Immunology by laboratory staff. The buildings are adjacent to each other and are 
connected by an underground tunnel.  
 
Specimens collected at WCMC will be transported to the Processing Lab on site at the local 
Clinical Trials Unit.  
 
Specimens collected at UPENN will be transported to the Processing Lab on site at the local 
Clinical Trials Unit.  
 
1. Peripheral Blood Mononucleated Cells (PBMC) (isolated from ACD tubes or from 
leukapheresis): PBMCs are isolated using density gradient centrifugation with Histopaque.  
 
PBMC sample aliquots will be stored in liquid nitrogen freezers located at the local sites. PBMCs 
will also be used for future phenotypic and functional assays to characterize B, T and NK cells, 
as well future assessments to proviral HIV-1 DNA. 
 
2. Plasma: Samples will be collected from ACD tubes after an initial centrifugation step, prior to 
PBMC isolation. The collected plasma sample goes through a second centrifugation step and is 
aliquoted in 1 or 10 ml volumes and stored at -80 degrees Celsius.  
 
Plasma samples will be stored at the local sites. Plasma samples will be used to isolate circulating 
viral sequences. 
 
3. Serum: Samples will be collected in Serum Separation Tubes (SST). Following centrifugation, 
serum from multiple tubes, from the same participant, will be pooled, divided in 200 or 500 μl 
aliquots and stored at -80 degrees Celsius.  
 
Serum samples will be shipped to the laboratory of Drs. Georgia Tomaras and Margaret 
Ackerman. Serum samples will be used for measurement of 3BNC117-LS and 10-1074-LS levels, 
anti-3BNC117-LS and anti-10-107-LS antibodies and for in vitro neutralization assays. The 
remaining aliquots will be stored at the local sites. 
 
All infectious specimens will be transported using packaging mandated in the Code of Federal 
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Regulations, 42 CFR Part 72.  Member carriers such as FedEx will accept or reject packages of 
dangerous goods on strict adherence to the International Air Transportation Association (IATA) 
Dangerous Goods Regulations (DGR).  Shipments will be compliant with IATA DGR 
requirements.  
6.2.15 
Biohazard Containment 
As the transmission of HIV-1 and other blood-borne pathogens can occur through contact with 
contaminated needles, blood, and blood products, appropriate blood and secretion precautions 
will be employed by all personnel in the drawing of blood and shipping and handling of all 
specimens for this study, as currently recommended by the Centers for Disease Control and 
Prevention and the National Institutes of Health. 
6.2.16 
Compensation 
Participants will be compensated according to standards at each study site.  
 
 
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7 
INVESTIGATIONAL PRODUCTS 
Investigational Drug Name: 
10-1074-LS 
Manufacturer Name of Drug: 
Celldex Therapeutics, Inc. 
IND Number: 
136387 
IND Sponsor:  
Rockefeller University 
 
Investigational Drug Name: 
3BNC117-LS 
Manufacturer Name of Drug: 
Celldex Therapeutics, Inc. 
IND Number: 
131872 
IND Sponsor:  
Rockefeller University 
 
 
Regimen 
- 
3BNC117-LS and 10-1074-LS will be administered intravenously, in sequence, at 30 mg/kg 
(each mAb) once.  
 
Study Product Formulation and Preparation 
Study Drugs Formulation: 
- 
3BNC117-LS will be provided by Celldex Therapeutics in single-use vials containing 1 mL of 
3BNC117-LS protein at a concentration of 150 mg/mL in a 1.0 mL buffered solution composed 
of 10 mM Histidine, 245 mM Trehalose, 10 mM Methionine, 0.05% Polysorbate 20, pH 5.2. 
The drug product is brownish yellow in appearance and slightly opalescent at storage 
conditions. 
- 
10-1074-LS will be provided by Celldex Therapeutics in single-use vials containing 1 mL of 
10-1074-LS protein at a concentration of 140 mg/mL in buffered solution composed of 5 mM 
Histidine, 250 mM Trehalose, 10 mM Methionine, 5 mM Sodium Acetate, 0.05% Polysorbate 
20, pH 5.5. The drug product is brownish yellow in appearance and slightly opalescent at 
storage conditions. 
Preparation: 
- 
Each mAb will be diluted in normal saline (NaCl 0.9%) to a volume of 100 mL for intravenous 
infusion. Normal saline will be obtained by the local site pharmacies. 
- 
3BNC117-LS and 10-1074-LS are stored at 5 ± 3°C. The appropriate dose of each mAb 
should be drawn soon after vials are removed from the refrigerator. Vials should be checked 
for particulates before drawing doses, but no other swirling or inversion are needed.  
- 
The appropriate dose will be calculated by the site research pharmacist according to 
participant’s weight (measured at the day 0 visit). 3BNC117-LS and 10-1074-LS will be 
dispensed in a small volume parenteral infusion, diluted in normal saline (NaCl 0.9%) ready 
for administration by the study investigators. Standard 18G needles are recommended to 
draw the required dose of each mAb to decrease the preparation time. Prior to injection of the 
mAb solution into the IV bag, remove air from the syringe and inject slowly, to avoid foaming.  
After preparation, infusion bags should be handled gently to avoid foaming (do not shake). 
Infusion bags should also be checked for particulates.  
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- 
3BNC117-LS and 10-1074-LS should be administered through a 0.2 or 0.22 micron in-line 
filter. 
- 
Finished infusion preparations with IV lines attached and primed may be stored at either room 
temperature or refrigerated. Infusion beyond use dating depends upon the IV product 
preparation method and local pharmacy SOPs.  A recommendation is to begin the infusion 
within 4 hours of preparation, if stored at room temperature, and 6 hours, if stored refrigerated 
(2-8 C). 
 
Dispensing and Handling of Investigational Product: 
3BNC117-LS and 10-1074-LS will be shipped from Celldex Therapeutics and will be stored in the 
site research Pharmacy at 5 ± 3°C.  
Trial personnel will ensure that the study ID number on the infusion bag matches the study ID 
assigned to the participant prior to administration.  
 
Accountability and Disposal of Used and Unused Investigational Product 
The date, allocation number and location of storage of the vials will be recorded in a log.  During 
the trial, the product accountability form, and the dispensing log will be monitored. At the end of 
the trial, unused vials will be returned to Celldex Therapeutics, transferred to the Laboratory of 
Molecular Immunology at RU for research purposes only, or destroyed. 
 
 
Assessment of Participant Adherence with Study Product 
Not applicable. Participants will be administered 3BNC117-LS and 10-1074-LS at the study sites 
on study day 0.   
 
 
Concomitant Medications and Procedures 
Use of concomitant medications will be reviewed at each study visit.  Each participant will have a 
medication reconciliation record, which will be updated if schedule or dose level changes, and if 
new medications are initiated.    
 
Participants will be advised and encouraged to initiated ART 12 weeks after 3BNC117-LS and 
10-1074-LS infusions. The initiated ART regimen will be recorded.  
 
 
Permitted Medications and Procedures 
We do not anticipate significant drug interactions with the study products at this time, therefore, if 
clinically necessary, participants can be initiated on other medications for intercurrent illnesses 
that might occur during their study participation. 
 
 
Prohibited Medications and Procedures 
We do not anticipate significant drug interactions with the study products at this time. Participants 
that enroll in the study agree to not participate in other studies of investigational drugs. In addition, 
they should not participate in studies that require frequent blood sample collection. 
 
Use of systemic corticosteroids (long term use), immunosuppressive anti-cancer, interleukins, 
systemic interferons, systemic chemotherapy within 6 months of study enrollment is not permitted. 
Short term use of systemic steroids (e.g. steroid taper for allergic or infusion reactions or asthma 
exacerbation) is permitted. 
 
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Precautionary Medications and Procedures 
We do not anticipate significant drug interactions with the study products at this time. Participants 
that enroll in the study agree to not participate in other studies of investigational drugs. In addition, 
they should not participate in studies that require frequent blood sample collection. 
 
 
 Required Medications 
Not applicable. Participants will be advised and encouraged to initiated ART within 4 weeks after 
3BNC117-LS and 10-1074-LS infusions within 4 weeks of receiving 3BNC117-LS and 10-1074-
LS infusions, or sooner if: VL fails to decrease by >0.5 log10 copies/ml within 2 weeks of antibody 
infusions, VL increases > 0.5 log10 copies/ml between weekly measurements or significant T-cell 
decline (confirmed CD4+ T cell count < 200 cells/μl) is noted.    
 
  Rescue Medications 
If volunteers develop grade 3 acute infusion reaction, an immediate hypersensitivity reaction or a 
life-threatening event during study drug administration, the infusion will be discontinued and will 
not be reinitiated (see Section 6.1.7.1). Rescue medications, including acetaminophen, 
diphenhydramine and glucocorticoids will be available at the clinical sites for use if clinically 
indicated. 
8 
DATA ANALYSIS 
 
Analysis of Safety, PK and Antiretroviral Effects 
Primary Outcomes 
- 
Safety: The safety population will include all participants who receive a dose of 3BNC117-LS 
and 10-1074-LS. A baseline measurement and at least one laboratory, vital sign, or other 
safety-related measurement obtained after 3BNC117-LS and 10-1074-LS dosing may be 
required for inclusion in the analysis of a specific safety parameter.  
The number and percentage of participants experiencing one or more AEs will be summarized 
by relationship to study drug, and severity. AEs will be summarized by the number and 
percentage of participants who experienced the event, according to system organ class (SOC) 
and preferred term. AEs will also be summarized by severity grade and by relationship to 
study drug according to the DAIDS AE Grading Table, corrected v2.1 (July 2017). The CTCAE 
v5.0 grading scale will be used for reporting and grading adverse events occurring within 24 
hours of the start of 3BNC117-LS and/or 10-1074-LS infusions that are considered infusion 
reactions or cytokine release syndromes. Changes in hematology, chemistry, and other 
laboratory values will be summarized descriptively. Changes will be calculated relative to the 
values collected at baseline.  
- 
Pharmacokinetic parameters: will be calculated using standard non-compartmental analysis 
methods. Pharmacokinetic parameters, including AUC, Cmax, T1/2, Tmax, clearance and 
others will be summarized. Pharmacokinetic parameters will be examined to correlate 
exposure with safety and pharmacokinetics parameters, and variance based on population 
intrinsic factors such as weight and gender will be explored.  
- 
Antiretroviral activity: The magnitude of change in plasma HIV-1 RNA levels from baseline will 
be evaluated. Plasma HIV-1 RNA levels will be evaluated prior to and at multiple time points 
following 3BNC117-LS and 10-1074-LS infusions and the log copies/ml reduction in HIV-1 
RNA level from baseline will be calculated.  
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Secondary Outcomes 
- 
Anti-3BNC117-LS and anti-10-1074-LS antibodies: The frequency of induced anti-3BNC117-
LS or anti-10-1074-LS antibodies will be reported. Occurrence of ADA will be evaluated by a 
three-tiered approach using validated screening and confirmatory assays, followed by tittering 
of responses to determine if responses were treatment-induced or treatment-boosted. 
Other Exploratory Measurements 
- 
Genotyping and phenotyping of HIV isolates will be performed to analyze the induction of 
escape mutations following 3BNC117-LS and 10-1074-LS infusions in viremic individuals 
enrolled in the study. Specifically, we will perform single genome amplification (SGA) of 
plasma viruses to define the relationship between individual responses to antibody therapy 
and circulating virus sensitivity to the antibodies. CMV-promoter-based pseudoviruses will be 
constructed from selected SGA sequences and tested for bNAb sensitivity in a TZM-bl assay. 
Results will be descriptive.  
Continuous data will be summarized by descriptive statistics, including the sample size, mean, 
standard deviation, median and range. Categorical data will be summarized by the number and 
percentage of participants. 
The analysis of study data will be primarily descriptive, with emphasis on tabular and graphical 
displays. Summary statistics will be calculated, along with point and interval estimates of solicited 
and unsolicited adverse events. The pharmacokinetic profiles of a single administration of 
3BNC117-LS in combination with 10-1074-LS will also be determined. This study is exploratory, 
and any statistical inferences will be hypothesis generating and not confirmatory. 
 
Sample Size Considerations 
Five to 10 evaluable participants are sought. The total number of screened participants to achieve 
5 to 10 evaluable participants is estimated to be 15 to 30. Replacement for 2 participants lost to 
follow up prior to week 4 will be allowed.  
 
Safety: 
We expect that the administration of a single infusion of 3BNC117-LS in combination with 10-
1074-LS will be generally safe and well tolerated.  
 
The sample size of 5 to 10 participants receiving 3BNC117-LS and 10-1074-LS in combination 
will provide 95% probability of observing a treatment-related AE that would occur in 26% to 45% 
or more of treated participants. If none of the participants experiences a grade 3 AE related to 
3BNC117-LS and/or 10-1074-LS, the one-sided 95% upper confidence bound for the rate of AEs 
in the population is 25.9% to 45.1%. 
 
Pharmacokinetics:  
Based on the pharmacokinetic profile of VRC01LS in humans, another anti-HIV-1 antibody 
targeting the same gp120 site as 3BNC117-LS, 3BNC117-LS and 10-1074-LS data in NHP, and 
preliminary 3BNC117-LS and 10-1074-LS data in humans, it is expected that the half-lives of 
3BNC117-LS and 10-1074-LS will be approximately 3-fold higher than the unmodified antibodies. 
Therefore, we expect that 3BNC117-LS will have a t1/2 in humans of approximately 70 days. 
Similarly, we expect that 10-1074-LS will have a t1/2 in humans of approximately 90 days. 
 
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In a previous study with 10-1074, the mean elimination half-life of approximately 24 days (SD 6.6 
days) in HIV-uninfected and 12.8 days (SD 4.9 days) in viremic HIV-infected individuals (Caskey 
et al 2017). 3BNC117 has a mean elimination half-life of approximately 17.6 days (SD 5.7 days) 
in HIV-uninfected and 9.6 days in viremic HIV-infected individuals (SD 2.9 days) (Caskey et al., 
2015). PK parameters were maintained when the two antibodies were administered in 
combination.  
  
The margins of error at 95% confidence level for estimating the mean elimination half-life of either 
mAb, based on standard deviations in the range of 4.5 to 6.5 days using the available 
pharmacokinetics data of 3BNC117 and 10-1074, and 5 or 10 participants are included in Table 
3. 
Table 3. Margin of Error at 95% Confidence Level for Estimating the Mean Elimination Half-
life of 3BNC117-LS and 10-1074-LS 
Standard 
Deviation 
(days) 
95% margin of error 
(+/- days) 
n = 5 
95% margin of error 
(+/- days) for n = 10 
4.5 
3.9 
2.8 
5 
4.4 
3.1 
5.5 
4.8 
3.4 
6 
5.3 
3.7 
6.5 
5.7 
4.0 
Antiviral activity: 
Single infusions of 3BNC117 and 10-1074, dosed at 30 mg/kg, led to an average decline in 
viremia of 1.48 log10 copies/ml (range = 0.8-2.5 and SD = 0.6 log10 copies/ml) (Caskey, Klein et 
al. 2015) and 1.52 log10 copies/ml (range = 0.9-2.06 and SD = 0.4 log10 copies/ml) (Caskey, 
Schoofs et al. 2017). The average decline in viral load for 4 viremic participants who received one 
or three infusions of the 3BNC117 and 10-1074 combination was 2.05 log10 copies/ml (range = 
1.58-2.57 and SD = 0.7 log10 copies/ml) (Bar-On et al. 2018).  
A recent study, ACTG NWCS 413, utilized the Monogram PhenoSense assay to estimate 
baseline 3BNC117 and 10-1074 sensitivity of  HIV pseudovirions that express envelope proteins 
representative of the quasispecies of proviral HIV-1 DNA in PBMCs. For 3BNC117, the median 
IC50 was 0.087 µg/mL (Q1, Q3 of 0.061, 0.183) and median IC80 was 0.301 µg/mL (Q1, Q3 of 
0.206, 0.680); whereas for 10-1074, the median IC50 was 0.044 µg/mL (Q1, Q3 of 0.020, 0.222) 
and median IC80 was 0.184 µg/mL (Q1, Q3 of 0.066, 1.578). 61% (37/61) of the participants’ virus 
swarms fell under the predicted sensitivity threshold of IC80 < 1 µg/mL to both 3BNC117 and 10-
1074, with 77% and 74% falling under this level for 3BNC117 only and 10-1074 only, respectively, 
and 89% for either antibody. 
Table 4 shows the minimum average decline in plasma HIV-1 RNA levels (log10 copies/ml) that 
can be detected with 80% power and a two-sided 0.05 test, assuming a standard deviation of 0.7 
(log10 copies/ml) from the 3BNC117 plus 10-1074 data. If 4 out of 10 participants harbor viruses 
sensitive to both antibodies, the minimum average decline in plasma HIV-1 RNA levels that can 
be detected with 80% power and a two-sided 0.05 test is 1.49 log10 copies/ml. If we assume 60% 
of the participants will be sensitive to either antibody, the probability of observing at least 4 
responders (HIV-1 RNA ≥ 0.5 log10 copies/ml) out of up to 10 enrolled participants who receive 
3BNC117-LS and 10-1074-LS is 0.95.  
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Table 4. Minimum average decline in plasma viremia that can be detected for varying 
sample sizes 
N 
SD 
(log10 
copies/ml) 
two-sided test alpha =0.05 
Minimum average decline in plasma 
HIV-1 RNA (log10 copies/ml) 
Effect size 
3 
0.7 
2.29 
3.26 
4 
0.7 
1.49 
2.13 
5 
0.7 
1.18 
1.68 
6 
0.7 
1.00 
1.43 
7 
0.7 
0.89 
1.27 
8 
0.7 
0.81 
1.16 
9 
0.7 
0.75 
1.07 
10 
0.7 
0.70 
1.00 
 
 
Enrollment/Stratification/Randomization/Blinded Procedures 
This will be an open-label, single arm study. Participants will be enrolled sequentially, as they 
meet enrollment criteria for study participation. Enrollment will be competitive between the RU, 
WCMC and UPENN sites.  Study ID numbers will be assigned by the Emmes Corporation. 
 
 
Participant Enrollment and Follow-Up 
The total number of evaluable participants in the study will be 5 to 10.  
 
An over-enrollment of 2 participants will be allowed if participants drop-out prior to week 4. 
Participants who are discontinued from the study due to AEs will not be replaced. Additional 
participants will be enrolled after study withdrawal is confirmed. If a participant drops out after 
receiving 1 or both study drugs, he/she will be invited to return every 4 weeks, for at least 3 months 
after antibody infusion, for safety monitoring only.   
9 
DATA AND SAMPLE STORAGE 
 
Data Collection 
The Principal Investigator(s) will oversee how the data are collected, entered, and protected. All 
study data will be collected by the clinical study staff using designated source documents and 
entered onto the appropriate electronic case report forms (eCRFs).  All study data must be 
verifiable to the source documentation. All source documents will be kept in a locked facility at 
the clinical sites and remain separate from participant identification information (name, address, 
etc.) to ensure confidentiality. All data with participant identifiers will be kept in a locked facility 
and/or encrypted files. Source documentation will be available for review to ensure that the 
collected data are consistent with the eCRFs.  
All eCRFs and laboratory reports will be reviewed by the site’s clinical team, who will ensure that 
they are accurate and complete. 
All research samples will have a unique identifier.  The PIs will be responsible for ensuring project 
compliance, data analysis and entry, regulatory monitoring, and coordination of the activities of 
the entire study team.  Standard GCP practices will be followed to ensure accurate, reliable and 
consistent data collection. 
Source documents include, but are not limited to: 
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- 
Signed Informed Consent Documents 
- 
Dates of visits including date of 3BNC117-LS and 10-1074-LS administration 
- 
Documentation of any existing conditions or past conditions relevant to eligibility  
- 
Reported laboratory results 
- 
All adverse events  
- 
Concomitant medications  
- 
Reported unsolicited and solicited adverse events 
 
 
Quality Control and Quality Assurance  
Quality control checks (manually and automated) will be run on the Emmes Corporation 
generated database. Any missing data or data anomalies will be communicated to the sites for 
clarification/resolution. 
10 RECRUITMENT AND ADVERTISING 
Both men and women, > 18 years of age will be recruited for the study from the community at 
large and will be referred by physicians in the community.   We will make every effort to recruit 
minorities and women. 
- 
RU Site: 
Rockefeller University Hospital: The Clinical Research Support Office at the Rockefeller University 
Hospital (CRSO) will utilize the Volunteer Repository. Advertisements will also be placed: online 
(e.g. Craigslist, Centerwatch, etc), in newspapers (Metro, AMNY) and at the Rockefeller campus.  
 
The CRSO will conduct telephone screenings of selected Volunteer Repository members, and of 
volunteers who call 1-800-RUCARES, to facilitate screening efficiently. Based on IRB approved 
eligibility criteria, potentially eligible candidates pre-screened by CRSO staff will be referred to the 
study coordinator/investigator for further evaluation.  
 
In addition, referrals are expected through existing collaboration between Rockefeller and the 
Montefiore Medical Center AIDS Center and the Clinical Core of the Einstein-Rockefeller-CUNY 
CFAR. 
 
- 
Cornell (WCMC) Site: 
Recruitment fliers will be placed in the Weill Cornell Clinical Trials Unit, and interested participants 
will contact study investigators. Approximately 2,500 patients are followed at the two clinic sites. 
Providers will refer newly diagnosed individuals who choose not to initiate ART or people who 
have fallen out of care or have had lapses in ART coverage. The site will also engage with a large 
network of providers who refer patients for clinical trials, and pursue direct to advertising to 
potential participants through social media, online and print media.  
 
- UPENN Site:  
At the University of Pennsylvania Health system approximately 2,000 patients receive HIV care, 
and 150 new HIV-infected patients are seen each year. The site has an extensive network of 
referrals from the community (Philadelphia FIGTH, the Partnership and the Health Centers of the 
city) as well as a dedicated group that does outreach for research projects in collaboration with 
the Penn CFAR. 
 
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IRB NUMBER: MCA-0994
IRB APPROVAL DATE: 08/03/2021
IRB EXPIRATION DATE: 05/27/2022


 
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 Participant Retention  
This study requires frequent follow up visits, which can be challenging to participants. The study 
staff will review the study schedule in detail with potential participants in advance of enrollment 
and attempt to facilitate transportation to the clinical site, if needed. Frequent visits allow ongoing 
communication between study investigators and participants and can decrease the risk of 
participants being lost to follow up. Participants will be contacted by phone or email (whichever is 
preferred to the participant) prior to their next appointment, not more than 3-5 days in advance. 
Study investigators will consult participant’s primary care physician on any changes in treatment, 
which can also improve participant retention.  
11 POTENTIAL BENEFITS TO PARTICIPANTS 
There is no direct benefit to participants participating in this study. 
12 POTENTIAL RISKS TO THE PARTICIPANT INCLUDING TO THE FETUS 
This study entails moderate risk to study participants since 3BNC117-LS and 10-1074-LS are 
investigational new drugs with limited human safety data. 
 
While each mAb product has unique safety issues related to its mechanism of action, the major 
safety concern related to mAbs in general is an infusion/hypersensitivity reaction. These types of 
reactions are more common for mAbs that contain murine elements, compared to human mAbs, 
such as 3BNC117-LS and 10-1074-LS. Passive administration of anti-HIV-1 antibodies has been 
evaluated in humans in the past, including the parental 3BNC117 and 10-1074 antibodies. Both 
3BNC117-LS and 10-1074-LS are undergoing first-in-human testing. As observed with other 
monoclonal antibodies, anti-HIV-1 antibodies were generally safe and well-tolerated and most 
adverse events observed were transient malaise/fatigue and headache.  
• 
Immunologic symptoms such as listed below are possible with administration of a mAb and 
will be considered adverse events of interest. Potential allergic-type reactions during and 
immediately following the administration of 3BNC117-LS and 10-1074-LS will be carefully 
monitored.  
o Constitutional symptoms, such as fever, rigors/chills; 
o Infusion 
site 
reaction/extravasation 
changes, 
pruritus, 
urticaria, 
erythema, 
desquamation, ulceration; 
o Serum sickness like syndromes as evidenced by fever, rash, arthralgia, arthritis, 
nephritis; 
o Deposition of immune complexes in the kidneys leading to renal insufficiency;  
o Anaphylaxis; Adult Respiratory Distress Syndrome, bronchospasm/wheezing; 
o Cytokine release syndrome/ acute infusion reaction.  
• 
3BNC117-LS and/or 10-1074-LS-resistant viral strains might be selected following 
administration of 3BNC117-LS with 10-1074-LS. Development of antibody resistance might 
limit the future use of these mAbs and other mAbs targeting the same HIV-1 envelope 
epitopes by the study participant, if they are licensed for clinical use. 
 
• 
In a tissue cross-reactivity (TCR) study performed in human tissues, 3BNC117 stained rare 
cells in the conjunctival recesses, and 10-1074 stained the cytoplasm of nerve cells in the 
optic nerve of the eye. In vivo GLP toxicology studies performed in rats with 3BNC117 and 
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IRB APPROVAL DATE: 08/03/2021
IRB EXPIRATION DATE: 05/27/2022


 
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Original IND 131872
June 3, 2021 
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10-1074, alone and in combination, did not show toxicity in ocular tissues. Moreover, these 
tissue binding findings were not reproduced in repeat TCR studies comparing the unmodified 
with the LS variants.  
 
In humans, approximately 6% of participants enrolled in 3BNC117 trials reported mild ocular 
complaints (such as pruritus, conjunctival erythema, increased lacrimation, blurry vision) 
during study follow up of 6 to 12 months. In all instances, symptoms resolved without specific 
treatment, and evaluations by an ophthalmologist at 1 or 5 months after 3BNC117 
administration did not reveal changes from baseline. It remains unclear if these symptoms 
were related to 3BNC117 infusions. Two ocular symptoms were reported during 10-1074 
studies (grade 1, dry eyes and diplopia), and follow up ophthalmologic exams did not reveal 
abnormalities or changes from the baseline exams. A temporal relationship between time of 
3BNC117 and/or 10-1074 administrations and the occurrence of ocular complaints is not clear 
at this time To date, only 1 out of 39 participants reported an ocular AE in the studies of 
3BNC117-LS alone or in combination with 10-1074-LS. This was grade 1 ocular pruritus, 
which occurred 3 days post-infusion and resolved 1 day later.  
 
Although binding to ocular tissues was not observed in TCR studies with the LS variants of 
3BNC117 and 10-1074, participants will undergo a baseline ophthalmologic evaluation and 
will be monitored closely and evaluated by an ophthalmologist after mAb administration if 
ocular complaints occur.  
 
• 
Transient elevations in total bilirubin have been observed following 3BNC117 dosing. 
Typically, these are isolated laboratory abnormalities of grade 1 severity that resolve within a 
few weeks without need for specific treatment. A causal relationship has not been determined 
but bilirubin levels will be followed closely during study follow up. 
 
• 
In the cross-reactivity study in human tissues with 10-1074 and 10-1074- LS staining in the 
epithelium of the pituitary adenohypophysis and follicular epithelium in the thyroid were 
observed.  Staining was cytoplasmic in nature, and therefore considered of low toxicologic 
concern. However, TSH, T3, and free T4 will be measured at study week 0 and week 4, and 
additional work up pursed if indicated.  
 
• 
Blood drawing and phlebotomy can be associated with pain, bruising, anemia or infection at 
the site of venipuncture. Rarely, fainting may follow phlebotomy. 
 
• 
The adverse effects the administration of 3BNC117-LS with 10-1074-LS would have in a fetus 
or unborn child are unknown. 
• 
Participants may engage in increased risk taking after receiving anti-HIV-1 mAbs. One to one 
counseling will be routinely performed. 
13 PROCEDURES TO MINIMIZE RISK 
• 
With any new investigational drug, there is a possibility of totally unexpected side effects. On 
the day of 3BNC117-LS and 10-1074-LS administration, participants will be observed for one 
hour after administration. The clinical sites are equipped for providing emergency medical 
interventions in the unlikely event of acute allergic or other reactions. In case of an emergency, 
after stabilization of the participant, he/she will be transferred to a tertiary care center for 
specialized medical care. 
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IRB APPROVAL DATE: 08/03/2021
IRB EXPIRATION DATE: 05/27/2022


 
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• 
Participants will have regularly scheduled visits to the outpatient clinic and routine safety 
laboratories. 
 
• 
Participants will be closely monitored for the development of symptoms of ocular disease 
(such as blurry vision, increased lacrimation, redness, dryness, pain) and the study 
investigators will perform a directed exam of the eyes. If participants develop symptoms or 
signs of ocular disease, they will be referred to an ophthalmologist for diagnosis and 
management. These evaluations will be performed at no cost to the participant. 
• 
HIV-1 RNA levels and CD4+ T cell counts will be monitored during the study. Participants will 
be advised and encouraged to start ART within 4 weeks of receiving 3BNC117-LS and 10-
1074-LS infusions. ART may be initiated sooner if: VL fails to decrease by >0.5 log10 copies/ml 
within 2 weeks of antibody infusions, VL increases > 0.5 log10 copies/ml between weekly 
measurements or significant T-cell decline (confirmed CD4+ T cell count < 200 cells/μl) is 
noted. ART will be initiated in collaboration with the participant’s HIV primary care physician. 
ART will not be provided by the study.  
• 
Females of childbearing potential and who participate in sexual activity that might lead to 
pregnancy will be advised to use two reliable forms of contraception from 10 days prior to and 
six months after 3BNC117-LS and 10-1074-LS administration. In addition, a pregnancy test 
will be performed at screening, on the day of mAb administration, and throughout the course 
of the study. Males who are not anatomically sterile and who participate in sexual activity that 
might lead to pregnancy will be advised to use condoms from 10 days prior to and six months 
after 3BNC117-LS and 10-1074-LS administration. Condoms will be provided. Safer sex 
counseling will be provided for the entire duration of the study. 
• 
To minimize risks associated with phlebotomy, blood drawing will be performed by 
experienced phlebotomists under aseptic conditions. Subjects will be closely monitored for 
signs and symptoms of anemia. 
• 
Participants will have regularly scheduled visits to the site outpatient clinics and routine safety 
laboratories will be checked according to the Time of Events Schedule (Appendix A).  
• 
Adverse events will be monitored and graded using the DAIDS AE Grading Table, corrected 
v2.1. The CTCAE v5.0 grading scale will be used for reporting and grading adverse events 
related to infusion reactions and cytokine release syndromes in all groups. All toxicity tables 
are included in Appendix B. 
• 
Adverse events will be managed by the site clinical trial teams who will assess and treat the 
event as appropriate, including referral to an independent physician and/or department.  
• 
Safety monitoring at each site will be conducted by the study investigators, by an external 
Study Monitoring Committee (SMC), and by the International AIDS Vaccine Initiative (IAVI). 
The proposed study will be reviewed by a centralized IRB. The Rockefeller University will 
perform the initial review and will follow progress through annual reports and by immediate 
notification of serious adverse events. The local IRBs at WCMC and UPENN will follow 
progress through annual reports and by immediate notification of serious adverse events.   
Any serious and unanticipated adverse events will be immediately reviewed by the study 
investigators. Site investigators will notify the local IRB and the sponsor at the RU within 2 
working days from the investigators being made aware of the event. The RU sponsor will 
notify the FDA, per 21 CFR 312, for serious adverse events deemed at least possibly related 
Rockefeller University Institutional Review Board
IRB NUMBER: MCA-0994
IRB APPROVAL DATE: 08/03/2021
IRB EXPIRATION DATE: 05/27/2022


 
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Original IND 131872
June 3, 2021 
Protocol: MCA-0994 
 
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to the study products. The SMC will be available to the investigators for consultation and 
review of severe adverse events if needed.  
14 ALTERNATIVE METHODS OR TREATMENTS 
HIV-infected individuals who are off ART at the time of screening may choose to start ART 
immediately, instead of participating in the study. 
15 DATA AND SAFETY MONITORING PLAN 
This is a phase 1 study of two investigational products, which exposes study participants to 
“moderate risk”. A Study Monitoring Committee (SMC) will be established to monitor the study. 
 
Safety Monitoring Committee 
The purpose of the Safety Monitoring Committee (SMC) is to provide an ongoing assessment of 
participant safety during the conduct of the study.  The SMC will consist of three independent 
individuals who have no relationship to the Principal Investigator and Co-Investigators involved in 
the trial, and one non-voting member from DAIDS. No member of the SMC will have any direct 
responsibility for the clinical care of study participants.  No representative of Celldex Therapeutics, 
the Rockefeller University, or their designees may be a member of the SMC. However, the SMC 
may invite the principal investigator (PI) or designee and a Celldex Therapeutics, and/or 
Rockefeller University representative to an open session of a SMC meeting to provide information 
on study conduct, present data, or to respond to the members’ questions. Dr. Pat Fast, from the 
International AIDS Vaccine Initiative (IAVI) can be invited to participate in SMC meetings and to 
comment on study occurrences, as the medical monitor for the study. 
The names, university affiliation and title, area of expertise, and contact information of each of the 
SMC are provided below:  
 
Magdalena Sobieszczyk, MD, MPH 
Associate Professor of Medicine 
Columbia University College of Physicians and Surgeons 
622 W 168th St  
New York, NY 10032 
Email: mes52@cumc.columbia.edu 
Areas of expertise: HIV vaccine clinical trials 
 
Michael Keefer, MD 
Professor of Medicine 
University of Rochester Medical Center 
601 Elmwood Ave, Box 689 
Rochester, NY 14642 
Email: Michael_keefer@urmc.rochester.edu 
Areas of expertise: HIV vaccine clinical trials 
 
Eric Daar, MD 
Chief, Division of HIV Medicine Harbor-UCLA Medical Center 
Professor of Medicine 
David Geffen School of Medicine at UCLA  
1124 W. Carson St., CDCRC 205 Torrance, CA 90502 
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IRB EXPIRATION DATE: 05/27/2022


 
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Original IND 131872
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Email: edaar@labiomed.org  
Areas of expertise: clinical management of HIV infection  
 
Randall L. Tressler, MD (non-voting member) 
Medical Officer  
Division of AIDS/NIAID/NIH 
5601 Fishers Lane, Rm 9E49 
Rockville, MD 20852 
Email: randall.tressler@nih.gov 
Areas of expertise: clinical evaluation of antiretrovirals  
 
At least two members of the SMC must be in attendance (phone, video, or in-person meetings) 
to constitute a quorum for an SMC meeting. SMC members may also review and comment by 
email, if scheduling cannot be worked out in a timely manner.  One member of the SMC will be 
appointed as chair of the committee.  The SMC chair (or his/her alternate) will be responsible for 
summarizing and communicating in writing SMC acknowledgments and recommendations to the 
PI within 5 business days following each SMC meeting and/or review.   
The SMC will be asked to review study safety data on an interim basis and in the following 
scenarios: 
1. Grade 3 solicited and unsolicited adverse events judged by the principal investigator or 
designee to be possibly, probably or definitely related to 3BNC117-LS and/or 10-1074-LS. 
2. Grade 3 laboratory adverse events confirmed on retest and judged by the principal 
investigator or designee to be possibly, probably or definitely related to 3BNC117-LS and/or 
10-1074-LS. 
3. The investigator will report any “late occurring” DLT (i.e., a DLT occurring after 12 weeks of 
dosing) to the SMC. The investigators and SMC will mutually assess this information, along 
with safety from other participants, to determine whether a change to study conduct is 
warranted.  
4. If two or more grade 3 adverse events, deemed probably or definitely related to the study 
drugs occur, no additional administration of the investigational products will take place 
pending a Safety Monitoring Committee (SMC) review.  The SMC will provide a 
recommendation regarding subsequent enrollment in the study. 
5. If a grade 2 ophthalmic AE, judged to be at least possibly related to 3BNC117-LS and/or 10-
1074-LS occurs, or any grade 3 or 4 ophthalmic AE occur, regardless of causality assessment, 
no additional administration of the investigational product will take place pending a Safety 
Monitoring Committee (SMC) review. The SMC will provide a recommendation regarding 
subsequent enrollment in the study. 
6. SAEs, which are deemed possibly, probably or definitely related to 3BNC117-LS and/or 10-
1074-LS. by the principal investigator or designee, and unanticipated adverse events will be 
reported to the SMC within 2 working days of the site becoming aware of the event. 
If there is one SAE, grade 3 or higher, and judged as possibly, probably or definitely related 
to the administration of 3BNC117-LS and/or 10-1074-LS by the principal investigator or 
designee, no additional administration of the investigational product(s) will take place pending 
a review by at least two members of the SMC. Following this review, the SMC will make a 
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IRB NUMBER: MCA-0994
IRB APPROVAL DATE: 08/03/2021
IRB EXPIRATION DATE: 05/27/2022


 
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Original IND 131872
June 3, 2021 
Protocol: MCA-0994 
 
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recommendation to the principal investigator regarding the continuation of investigational 
product administration. 
The occurrence of such adverse events will not result in a study pause, unless it is judged by 
the principal investigator or designee that the risk/benefit ratio of the study has changed such 
that risk of currently enrolled or future participants has increased; or unless recommended by 
the IRB, SMC, or FDA. 
7. If, at any time, a fatal, life-threatening or permanently disabling SAE with a suspected causal 
relationship to 3BNC117-LS and/or 10-1074-LS occurs, no further administration of the 
investigational product(s) will occur until a consensus plan forward has been approved by 
investigators, SMC, the IRB and the FDA.  
All updated versions of the protocol, investigator’s brochure, and related documents will be 
provided to the SMC members and the DAIDS Medical Officer (MO) and DAIDS Program Officer 
(PO). The review of trial data by the SMC will take place at least annually. Prior to data review, 
the study team will provide the SMC with updated records of all adverse events (AEs) of a grade 
2 or higher. 
 
The SMC will acknowledge receipt of annual reports and will indicate if there are concerns with 
the continuation of the study. The SMC will provide a written report to the sponsor at the RU and 
the site PIs after each evaluation. The PIs in turn will distribute these reports to the study team 
and the local IRBs and the DAIDS MO and DAIDS PO. 
 
 Safety Review  
Participants will be closely monitored for 1 hour after the 10-1074-LS infusion at the study sites. 
The study sites are equipped for providing emergency medical interventions in the unlikely event 
of acute allergic or other reactions. The clinical trial units at all sites are equipped with crash carts 
for immediate medical care, should the need arise.  
 
In case of an emergency at RUH, after stabilization of the volunteer, he/she will be transferred to 
the neighboring tertiary care center, New York Presbyterian Hospital (Cornell) for specialized 
medical care.  
 
The study site investigators will review and grade AE’s on an ongoing basis for the duration of the 
study. Safety monitoring will be conducted by IAVI, which will review clinical records and adverse 
events.  
 
Clinical Site Monitoring 
Safety monitoring will be conducted by the study investigators, by the external Study Monitoring 
Committee (SMC) and by the International AIDS Vaccine Initiative (IAVI).  
The proposed study will be reviewed by a centralized IRB. The Rockefeller University will perform 
the initial review and will follow progress through annual reports and by immediate notification of 
serious adverse events. The local IRBs at WCMC and UPENN will follow progress through annual 
reports and by immediate notification of serious adverse events. External monitoring will occur at 
least quarterly and will be conducted by IAVI.  
Rockefeller University Institutional Review Board
IRB NUMBER: MCA-0994
IRB APPROVAL DATE: 08/03/2021
IRB EXPIRATION DATE: 05/27/2022


 
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Original IND 131872
June 3, 2021 
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Adverse Event Classification 
The DAIDS AE Grading Table, corrected v2.1 (July 2017) will be used for reporting and grading 
adverse events. The CTCAE v5.0grading scale will be used for reporting and grading adverse 
events related to infusion reactions and cytokine release syndromes. All toxicity tables are 
included in Appendix B. 
 
Reporting Adverse Events 
All adverse events will be reported to the local IRBs at and the SMC at least annually.  Serious 
Adverse Events, (SAEs) will be reported to the local IRBs, SMC, and to the sponsor at The 
Rockefeller University within two working days of identification of the SAE. The RU sponsor will 
report SAEs considered at least possibly related to the study products will be reported directly to 
the FDA, per 21 CFR 312. 
 
Reporting Unanticipated AEs 
Unanticipated Adverse Events (UAEs) will be reported to the local IRBs and SMC.  UAEs that are 
related and greater than moderate severity must be reported to the local IRBs, SMC, and to the 
sponsor at The Rockefeller University within two working days of identification of the UAE.  UAEs 
considered at least possibly related to the study products will be reported by the RU sponsor to 
the FDA, per 21 CRF 312.  
 
 
Clinical Laboratory Improvement Amendment/Clinical Laboratory Evaluation 
Program (CLIA/CLEP) 
 
This study includes tests that are not CLIA/CLEP certified. The results of such tests will not be 
used in clinical decision-making or shared with participants or their health care providers. 
 
 
Toxicity Management and Stopping Rules 
 
A dose limiting toxicity (DLT) will be defined as any adverse event of Grade 3 or greater toxicity, 
if the study investigators recognize a probable or definite attribution to 3BNC117-LS and/or 10-
1074-LS mAb. Clinically significant grade 3 laboratory abnormalities must be confirmed by a 
repeat test, obtained as soon as possible following the initial result. 
 
Investigators will promptly notify the PI and Sponsor at The Rockefeller University in the event of 
any DLT.  
 
In the case of two or more DLTs, further enrollment or infusions of 3BNC117-LS and/or 10-1074-
LS will not occur until investigators and SMC review the events and all available safety data. 
Enrollment will stop but participants will continue to be monitored by the study investigators. The 
SMC members will make a recommendation to the principal investigators regarding the 
continuation of the trial.  
 
 Other Disease Events  
 
Adverse events will be followed until resolved or considered stable during each scheduled study 
visit or during unscheduled study visits if warranted.  If adverse events deemed related to the 
study drugs are not resolved at the time of final study visit, participants will be referred for 
appropriate medical care until the symptoms resolve or the participant’s condition becomes 
Rockefeller University Institutional Review Board
IRB NUMBER: MCA-0994
IRB APPROVAL DATE: 08/03/2021
IRB EXPIRATION DATE: 05/27/2022


 
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Original IND 131872
June 3, 2021 
Protocol: MCA-0994 
 
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stable. 
 
 Critical Event Reporting 
 
All critical events, as defined by the DAIDS Critical Events Manual, will be reported to DAIDS as 
per the Critical Events Manual. 
16 CLINICAL TRIAL REGISTRATION 
The proposed study involves testing of FDA regulated drugs or biologics and will be registered at 
www.ClinicalTrials.gov. 
 
17 STUDY DISCONTINUATION 
The study may be discontinued at any time by the local IRBs, NIAID, the FDA or other government 
entities as part of their duties to ensure that research participants are protected. In the event that 
the study is discontinued, 3BNC117-LS and 10-1074-LS infusions will be halted and participants 
will be followed to ensure resolution of all adverse events. It is not applicable in this study to have 
participants continue therapy elsewhere as the investigational products do not provide the 
participants any direct benefit. In addition, the study does not have placebo recipients. 
Rockefeller University Institutional Review Board
IRB NUMBER: MCA-0994
IRB APPROVAL DATE: 08/03/2021
IRB EXPIRATION DATE: 05/27/2022


 
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Original IND 131872
June 3, 2021 
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18 BIBLIOGRAPHY 
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IRB NUMBER: MCA-0994
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IRB EXPIRATION DATE: 05/27/2022


 
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Carlton, C. Laurencot, R. T. Bailer, S. Narpala, A. B. McDermott, A. M. Namboodiri, J. P. Pandey, 
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