A Phase 1 Study to Evaluate the Safety, Immunologic and Virologic Responses of MGD014 Therapy in HIV-Infected Individuals on Suppressive Antiretroviral Therapy
Phase: PHASE1
Conditions: HIV-1-infection
Sponsor: MacroGenics

MGD014 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGD014-01 
Amendment 6, 31 March 2021 
CLINICAL TRIAL PROTOCOL: CP-MGD014-01 PROTOCOL 
AMENDMENT 6  
Study Title: 
A Phase 1 Study to Evaluate the Safety, Immunologic 
and Virologic Responses of MGD014 Therapy in 
HIV-Infected Individuals on Suppressive 
Antiretroviral Therapy 
Study Number: 
CP-MGD014-01 
Study Phase: 
Phase 1 
Product Name: 
MGD014 
Product Number: 
MGD014 
IND Number: 
 
UNC IRB Number:  
18-0608 
Contract Site Principal 
Investigator: 
 
Protocol Principal Investigator: 
 
Sponsor: 
MacroGenics, Inc. 
9704 Medical Center Drive 
Rockville, MD 20850 
301.251.5172 
Sponsor’s Medical Monitor: 
  
9704 Medical Center Drive 
Rockville, MD 20850 
301.251.5172 
 
Confidentiality Statement 
This document is confidential. It contains proprietary information of MacroGenics, Inc., that can only be used 
for the purpose of reviewing or performing this study. Any use, viewing, or disclosure of such information that 
is not authorized in writing by the Sponsor is strictly prohibited. 
 
 
 
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MGD014 
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Clinical Trial Protocol: CP-MGD014-01 
Amendment 6, 31 March 2021 
 
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MGD014 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGD014-01 
Amendment 6, 31 March 2021 
TABLE OF CONTENTS 
 
1 
SYNOPSIS ........................................................................................................................ 15 
2 
INTRODUCTION ............................................................................................................ 19 
2.1 
Rationale for Study .................................................................................................. 19 
2.1.1 
Co-targeting human immunodeficiency virus 1 envelope (HIV-1 
env) and CD3 ................................................................................................. 19 
2.2 
Background on MGD014 ......................................................................................... 21 
2.2.1 
MGD014 Nonclinical Pharmacology ............................................................ 22 
2.2.2 
MGD014 Pharmacokinetics and Toxicology ................................................. 29 
2.3 
Summary of Known and Potential Risks and Benefits of MGD014 ....................... 31 
2.4 
Dose Selection ......................................................................................................... 33 
2.4.1 
Selection of Maximum Recommended Starting Dose (MRSD) .................... 33 
2.4.2 
Dose Escalation Strategy ............................................................................... 35 
2.4.3 
Post-Infusion Monitoring ............................................................................... 36 
2.4.4 
Every 2 Week Administration ........................................................................ 37 
3 
STUDY PURPOSE AND OBJECTIVES ......................................................................... 38 
3.1 
Primary Objective .................................................................................................... 38 
3.2 
Secondary Objectives............................................................................................... 38 
3.3 
Exploratory Objectives ............................................................................................ 38 
4 
STUDY DESIGN .............................................................................................................. 39 
4.1 
Overview of Study Design ....................................................................................... 39 
4.2 
Part 1 – Dose Escalation Phase ................................................................................ 39 
4.2.1 
Dose Escalation Rules .................................................................................... 41 
4.3 
Multi-Dose Cohort Expansion Phase (Part 2) .......................................................... 42 
4.4 
Dose Limiting Toxicity ............................................................................................ 43 
4.5 
Study Duration and End of Trial .............................................................................. 44 
4.5.1 
Definition of End of Study ............................................................................. 44 
5 
STUDY PROCEDURES .................................................................................................. 45 
5.1 
Inclusion Criteria ..................................................................................................... 45 
5.2 
Exclusion Criteria .................................................................................................... 48 
5.3 
Guidelines for Discontinuation of Participants from Study Drug 
Administration ......................................................................................................... 50 
5.3.1 
Participant Follow-up after Discontinuation .................................................. 51 
5.3.2 
Guidelines for Discontinuation of Participant from Study ............................ 51 
5.3.3 
Lost to Follow Up Status ............................................................................... 52 
5.4 
Guidelines for Withdrawal of Participant from Study ............................................. 52 
6 
STUDY TREATMENT PROCEDURES .......................................................................... 53 
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Clinical Trial Protocol: CP-MGD014-01 
Amendment 6, 31 March 2021 
6.1 
Regimen ................................................................................................................... 53 
6.2 
Method of Assigning Participants to Treatment Groups .......................................... 53 
6.3 
Blinding.................................................................................................................... 53 
6.4 
Emergency Unblinding ............................................................................................ 53 
6.5 
Study Drug and Supplies ......................................................................................... 53 
6.5.1 
MGD014 ........................................................................................................ 53 
6.5.2 
Vehicle ............................................................................................................ 54 
6.6 
Study Drug Preparation and Administration ............................................................ 54 
6.6.1 
General Guidelines and Precautions .............................................................. 54 
6.6.2 
Study Drug Preparation .................................................................................. 54 
6.6.3 
Monitoring Post-administration ..................................................................... 56 
6.7 
Treatment Compliance ............................................................................................. 57 
6.8 
Packaging and Labeling ........................................................................................... 57 
6.9 
Storage and Accountability ...................................................................................... 57 
6.9.1 
MGD014 Storage ........................................................................................... 57 
6.10 
Return or Destruction of Study Drug ....................................................................... 58 
7 
POTENTIAL ADVERSE EVENTS AND SUPPORTIVE CARE 
MEASURES ..................................................................................................................... 59 
7.1 
Infusion Related Reactions Including Cytokine Release Syndrome ....................... 59 
7.1.1 
Grading of Infusion Reactions ....................................................................... 59 
7.1.1.1 
Premedications and Prophylaxis .......................................................... 59 
7.1.2 
Management of Observed Infusion Reactions ............................................... 60 
7.2 
COVID-19/SARS-CoV-2 Infection ......................................................................... 61 
8 
CONCOMITANT THERAPY AND RESTRICTIONS ................................................... 62 
8.1 
Concomitant Therapy ............................................................................................... 62 
8.1.1 
Prohibited Therapy ......................................................................................... 62 
8.1.2 
Permitted Therapies ....................................................................................... 62 
9 
STUDY PROCEDURES .................................................................................................. 64 
9.1 
Study Visits .............................................................................................................. 64 
9.2 
Informed Consent..................................................................................................... 64 
9.3 
Screening Period ...................................................................................................... 64 
9.4 
Enrollment and Registration .................................................................................... 65 
9.5 
Medical History ....................................................................................................... 65 
9.6 
Prior and Concomitant Medications ........................................................................ 65 
9.7 
ART Adherence ........................................................................................................ 65 
9.8 
Physical Examination............................................................................................... 66 
9.9 
Vital Signs ................................................................................................................ 66 
9.10 
Leukapheresis .......................................................................................................... 66 
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Clinical Trial Protocol: CP-MGD014-01 
Amendment 6, 31 March 2021 
9.11 
Clinical Laboratory Tests ......................................................................................... 67 
9.12 
Central Laboratory Assays ....................................................................................... 67 
9.13 
Pharmacokinetics ..................................................................................................... 67 
9.14 
Immunogenicity ....................................................................................................... 68 
9.15 
Pharmacodynamics .................................................................................................. 68 
9.16 
Sample Collection, Storage, and Shipping .............................................................. 68 
9.17 
Electrocardiography Monitoring .............................................................................. 68 
9.18 
End of Study Visit .................................................................................................... 68 
10 
ASSESSMENT OF PHARMACOKINETICS AND 
PHARMACODYNAMICS............................................................................................... 69 
10.1 
Pharmacokinetics Assessments ................................................................................ 69 
10.2 
Immunogenicity Assessments .................................................................................. 69 
10.3 
Pharmacodynamic Assessments............................................................................... 69 
10.3.1 
Receptor Occupancy and/or T-cell Binding ................................................... 69 
10.3.2 
Serum Cytokine Analysis ............................................................................... 69 
10.3.3 
T cell Phenotype and Function....................................................................... 69 
11 
ASSESSMENT OF EFFICACY ....................................................................................... 70 
11.1 
Efficacy Assessments ............................................................................................... 70 
11.1.1 
Resting CD4 T Cell Infection ........................................................................ 70 
11.1.2 
Plasma for SCA .............................................................................................. 70 
12 
ADVERSE EVENT REPORTING AND ASSESSMENT OF SAFETY ......................... 71 
12.1 
Definitions................................................................................................................ 72 
12.1.1 
Adverse Event ................................................................................................ 72 
12.1.2 
Adverse Drug Reaction .................................................................................. 72 
12.1.3 
Adverse Event of Special Interest .................................................................. 72 
12.1.4 
Attribution/Assessment of Causality ............................................................. 72 
12.1.5 
Serious Adverse Events .................................................................................. 73 
12.1.6 
Severity Criteria ............................................................................................. 73 
12.2 
Adverse Event Collection and Documentation ........................................................ 74 
12.2.1 
All Adverse Events ........................................................................................ 74 
12.2.2 
Immediately Reportable Events ..................................................................... 76 
12.2.3 
Serious Adverse Events .................................................................................. 76 
12.2.4 
Protocol-specific Adverse Events of Special Interest (AESI) ........................ 77 
12.2.5 
Pregnancy ....................................................................................................... 77 
12.2.6 
Reporting of Adverse Events to the Sponsor and DAIDS ............................. 78 
13 
PRODUCT QUALITY COMPLAINT AND HANDLING ............................................. 80 
13.1 
Procedures ................................................................................................................ 80 
13.2 
Contacting Sponsor Regarding the Product Quality ................................................ 80 
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Clinical Trial Protocol: CP-MGD014-01 
Amendment 6, 31 March 2021 
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PLANNED STATISTICAL METHODS .......................................................................... 81 
14.1 
Determination of Sample Size ................................................................................. 81 
14.2 
Analysis Populations ................................................................................................ 81 
14.3 
Demographics and Baseline Characteristics ............................................................ 81 
14.4 
Safety Endpoints ...................................................................................................... 81 
14.4.1 
Adverse Events .............................................................................................. 81 
14.4.2 
Laboratory Values .......................................................................................... 82 
14.4.3 
Other Safety Endpoints .................................................................................. 82 
14.5 
Efficacy Endpoints ................................................................................................... 82 
14.5.1 
Quantitative Viral Outgrowth Assay .............................................................. 82 
14.5.2 
Single Copy Assay ......................................................................................... 83 
14.5.3 
Exploratory Endpoints ................................................................................... 83 
14.6 
Pharmacokinetic Endpoints ..................................................................................... 84 
14.7 
Pharmacodynamic Endpoints ................................................................................... 84 
14.7.1 
Serum Cytokines ............................................................................................ 84 
14.8 
Immunogenicity Endpoints ...................................................................................... 84 
14.9 
Cohort Analyses and Monitoring ............................................................................. 84 
14.10 
Primary Analysis ...................................................................................................... 85 
14.11 
Final Analysis........................................................................................................... 85 
15 
QUALITY CONTROL AND ASSURANCE ................................................................... 86 
15.1 
Monitoring, Auditing and Inspections ..................................................................... 86 
15.2 
Data Entry and Computerized Systems ................................................................... 87 
16 
ADMINISTRATIVE CONSIDERATIONS...................................................................... 88 
16.1 
Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC) Approval......................................................................................................... 88 
16.2 
Ethical Conduct of the Study ................................................................................... 89 
16.3 
Participant Information and Consent ....................................................................... 89 
16.4 
Participant Confidentiality ....................................................................................... 89 
16.5 
Case Report Forms and Study Records ................................................................... 90 
16.6 
Access to Source Documentation ............................................................................ 90 
16.7 
Retention of Data ..................................................................................................... 90 
16.8 
Sample Retention and Further Testing ..................................................................... 90 
16.9 
Financial Disclosure................................................................................................. 91 
16.10 
Publication and Disclosure Policy ........................................................................... 92 
16.11 
Discontinuation of the Study or Study Site.............................................................. 92 
16.11.1 
Discontinuation of Study Site ........................................................................ 92 
16.11.2 
Discontinuation of the Study ......................................................................... 92 
16.12 
Identification of the Principal Investigator .............................................................. 92 
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Clinical Trial Protocol: CP-MGD014-01 
Amendment 6, 31 March 2021 
17 
REFERENCES ................................................................................................................. 93 
 
LIST OF TABLES  
Table 1 
MGD014 Dose Escalation Scheme .................................................................... 36 
Table 2 
Safety Reporting by UNC by Event Type .......................................................... 79 
  
LIST OF FIGURES  
Figure 1 
MGD014 Structure and Mechanism for Redirected T-cell Killing of 
HIV-1 env-expressing Target Cells ..................................................................... 21 
Figure 2 
Impact of Target Cell HIV-1 env Antigen Density on MGD014-
dependent Cytolytic Activity, Cytokine Release and T-cell 
Activation ........................................................................................................... 24 
Figure 3 
HIV-1 env Antigen Expression on Virus-infected CD4 Target Cells 
and MGD014-dependent Cytolytic Activity ...................................................... 26 
Figure 4 
Part 1: Single Ascending Dose Phase Schema ................................................... 40 
Figure 5 
Part 2: Dose Expansion Study Schema .............................................................. 42 
  
LIST OF APPENDICES  
APPENDIX 1 
TIME AND EVENTS SCHEDULE 
APPENDIX 2 
PK, IMMUNOGENICITY, AND PD BIOMARKERS BLOOD     
SAMPLING SCHEDULE: PART 1 AND 2 
APPENDIX 3 
PRINCIPAL INVESTIGATOR’S AGREEMENT 
 
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Clinical Trial Protocol: CP-MGD014-01 
Amendment 6, 31 March 2021 
SIGNATURES  
Study Title: 
A Phase 1 Study to Evaluate the Safety, Immunologic and Virologic 
Responses of MGD014 Therapy in HIV-Infected Individuals on 
Suppressive Antiretroviral Therapy 
Study Number: 
CP-MGD014-01 
 
This clinical study protocol has been approved by:  
Signed: 
See Appended Electronic Signature Page 
Date: 
 
 
 
Medical Monitor 
Executive Clinical Research Director 
MacroGenics, Inc. 
9704 Medical Center Drive 
Rockville, MD 20850 
 
 
Signed: 
See Appended Electronic Signature Page 
Date: 
 
 
 
Executive Director, Biostatistics 
MacroGenics, Inc. 
9704 Medical Center Drive 
Rockville, MD 20850 
 
 
Signed: 
See Appended Electronic Signature Page 
Date: 
 
 
 
University of North Carolina at Chapel Hill 
Division of Infectious Diseases 
120 Mason Farm Rd 
2049G Genetic Medicine Bldg. 
Chapel Hill, NC 27599 
 
 
Signed: 
See Appended Electronic Signature Page 
Date: 
 
 
 
Associate Professor of Medicine 
Division of Infectious Diseases 
 
Medical Director, UNC HIV Cure Center 
University of North Carolina at Chapel Hill 
 
 
Signed: 
See Appended Electronic Signature Page 
Date: 
 
 
 
Professor 
Department of Biostatistics 
University of North Carolina at Chapel Hill 
3107c McGavran-Greenberg Hall 
Chapel Hill, NC 27599 
 
 
 
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Clinical Trial Protocol: CP-MGD014-01 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
ACTG 
AIDS Clinical Trials Group 
ADA 
anti-drug antibody 
ADCC 
antibody dependent cell-mediated cytotoxicity 
AE 
adverse event 
AESI 
adverse event of special interest 
AIDS 
acquired immunodeficiency syndrome 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ART 
antiretroviral therapy 
ARV 
antiretroviral drug 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BBB 
blood-brain-barrier 
BLT mice  
bone marrow, liver, and thymus mice 
BP 
blood pressure 
CD3 
cluster of differentiation 3  
CFAR 
Center for Aids Research 
CHSLC 
CFAR HIV/STD Laboratory Core  
CI 
confidence interval 
CKD 
chronic kidney disease 
CL 
clearance 
CLIA 
clinical laboratory improvement amendments 
Cmax 
maximum serum concentration 
CNS 
central nervous system 
COVID-19 
coronavirus disease 2019 
CRS 
cytokine release syndrome 
CSF  
cerebral spinal fluid 
CSR 
clinical study report 
CTL  
cytotoxic T lymphocytes 
CTRC 
Clinical and Translational Research Center 
DAIDS 
Division of AIDS 
DLT 
dose limiting toxicity 
EAE  
expedited adverse event reporting  
EC50 
half maximal effective concentration   
E/CIA 
enzyme or chemiluminescence immunoassay 
E:T 
effector to target (cell ratio) 
ECG 
electrocardiogram 
ELISA 
enzyme-linked immunosorbent assay 
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env 
envelope; envelope in this document, denotes specifically the HIV-1 env 
glycoprotein 
FcγRs 
Fc-gamma receptors 
FDA 
Food and Drug Administration 
FIH 
first-in-human 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GLP  
Good Laboratory Practice  
gp 41 
glycoprotein 41 
gp 120 
glycoprotein 120 
gp 160  
glycoprotein 160 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus, in this document the virus denotes specifically 
HIV-1 
HIV-1 env 
human immunodeficiency virus 1 envelope 
HLA 
human leukocyte antigen 
IB 
investigational brochure 
IC 
informed consent 
ICFs 
informed consent forms 
ICH 
International Conference on Harmonization 
IDS 
Investigational Drug Services 
IEC 
Independent Ethics Committee 
IFN-γ 
interferon gamma 
IgG 
immunoglobulin G 
IL-2  
interleukin-2 
IL-4 
interleukin-4 
IL-5 
interleukin-5 
IL-6 
interleukin-6 
IL-10  
interleukin-10 
IMC 
infectious molecular clones 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRE 
immediately reportable event 
IRR 
infusion related reaction  
IUPM 
infectious units per million 
IV 
Intravenous(ly) 
kDa 
kilodalton 
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Clinical Trial Protocol: CP-MGD014-01 
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K+ 
potassium 
Kg  
kilogram 
LDH 
lactate dehydrogenase 
LRA 
latency reversing agent 
LTFU 
lost to follow up 
LUM 
luminescence 
mAb 
monoclonal antibody 
MABEL 
minimum anticipated biological effect level 
MAD 
maximum administered dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFI 
mean fluorescence intensity 
MHC 
major histocompatibility complex 
µg 
microgram 
µl 
microliter 
mL 
milliliter 
MRT 
mean residence time 
MTD 
maximum tolerated dose 
NCA 
noncompartmental analysis 
NCI 
National Cancer Institute 
ng 
nanogram 
nM 
nanomolar 
NNRTI 
non-nucleoside reverse transcriptase inhibitors 
NSAID 
non-steroidal anti-inflammatory drug  
NIH 
National Institutes of Health 
NOAEL 
no-observed-adverse-effect level 
OBD 
optimal biologic dose 
PBMC 
peripheral blood mononuclear cell 
pg 
picogram 
PHI 
personal health information  
PID 
participant identifier  
PD 
pharmacodynamics 
PI 
principal investigator 
PK 
pharmacokinetics 
PLWH 
people living with HIV 
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PO 
oral administration 
POCT 
point of care testing 
PQC 
product quality complaint 
PT 
preferred term 
Q2W 
once every 2 weeks 
QVOA 
quantitative viral outgrowth assay 
RBC 
red blood cell 
RNA  
ribonucleic acid  
RPR 
rapid plasma reagin 
RO 
receptor occupancy 
RSV 
respiratory syncytial virus 
SAE 
serious adverse event 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SCA 
single copy assay 
SHIV  
simian human immunodeficiency virus 
SID 
study-specific identifier 
SOC 
system organ class 
SOP 
standard operating procedure 
SPR 
surface plasmon resonance  
SUSAR 
suspected, unexpected serious adverse reactions  
Tmax 
time to maximal concentration 
TCR 
T-cell receptor 
TNF-α 
tumor necrosis factor alpha 
ULN 
upper limit of normal 
UNC-CH 
University of North Carolina at Chapel Hill 
US 
United States 
VOR  
vorinostat 
Vss 
steady-state volume of distribution  
VS 
vital signs 
WOCBP 
women of child-bearing potential 
 
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MGD014 
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Clinical Trial Protocol: CP-MGD014-01 
Amendment 6, 31 March 2021 
1 
SYNOPSIS  
Sponsor: MacroGenics, Inc. 
IND Number: 
 
Name of Product: MGD014 
Study Title: A Phase 1 Study to Evaluate the Safety, Immunologic and Virologic Responses 
of MGD014 Therapy in HIV-Infected Individuals on Suppressive Antiretroviral Therapy 
Study Number: CP-MGD014-01 
UNC IRB Number: 18-0608  
NCT: 03570918 
Study Phase: Phase 1 
Investigator(s)/Centers: 
The study will be carried out at a single institution in the United States (US) experienced in 
the conduct of Phase 1, first-in-human (FIH) studies in participants with human 
immunodeficiency virus (HIV) infection on suppressive antiretroviral therapy (ART). 
Primary Objective(s): 
Characterize the safety and tolerability of MGD014 administered intravenously (IV) to 
persons living with HIV (PLWH) maintained on suppressive ART. 
Secondary Objective(s): 
• Assessment of pharmacokinetics (PK) and immunogenicity (anti-drug antibody 
[ADA]) of MGD014. 
• Assessment of serum cytokine levels following MGD014 administration. 
Exploratory Objective(s): 
• Explore the impact of MGD014 administration on the immunologic response to 
HIV. 
• Explore correlations between virologic and immunologic responses to MGD014. 
• Assess the ability of MGD014 to alter markers of persistent HIV-1 infection.  
Rationale: 
DART® molecules are bispecific, antibody-based molecules that can bind 2 distinct antigens 
simultaneously. T cell redirecting DART® molecules, which have binding arms for a selected 
target antigen and for CD3, are designed to target the antigen-expressing cells for recognition 
and elimination by CD3-expressing T lymphocytes as effector cells. MGD014, a T cell 
redirecting DART® molecule developed for the HIV setting, targets HIV-1 infected, envelope 
(env) glycoprotein-expressing cells for recognition and elimination by T lymphocytes. 
MGD014 is thus being studied to determine if it could be used as an immunotherapeutic 
agent to mediate the clearance of HIV-infected CD4 T cells that express env on their surface. 
In this FIH study, MGD014 will be evaluated as a single agent in PLWH maintained on 
suppressive ART. 
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Clinical Trial Protocol: CP-MGD014-01 
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(a) Screening, eligibility and optional baseline leukapheresis (b) optional leukapheresis post-
treatment for frequency of persistent infection of resting CD4 T cells.   
Abbreviations: ADA = anti-drug antibody; ART = antiretroviral therapy; Leuk = leukapheresis; PK = 
pharmacokinetics; QVOA = quantitative viral outgrowth assay.  
Main Criteria for Inclusion/Exclusion: 
PLWH (18 to 65 years old) on ART with plasma HIV RNA < 50 copies/mL for 24 months 
prior to enrollment. 
Test Product and Mode of Administration: 
MGD014 will be supplied by MacroGenics, and administered via 2-hour infusions, a single 
IV infusion in Part 1, or IV infusion once every 2 weeks for 3 infusions over 4 weeks in 
Part 2. 
Duration of Treatment and Study Duration: 
The overall study duration will be approximately 24 months. For each individual participant, 
study duration will be approximately 10 weeks (Part 1) or 20 weeks (Part 2). 
Treatment Schedule and Procedures: 
See Appendix 1. 
Criteria for Evaluation: 
Safety Assessments 
Safety assessments will be based on medical review of adverse event (AE) reports, the results 
of vital sign (VS) measurements, electrocardiograms (ECGs), physical examinations, and 
clinical laboratory tests. The incidence of AEs will be tabulated and regularly reviewed for 
potential significance and clinical importance. 
PK Assessments 
• Single-dose and multiple-dose PK parameters for MGD014 may be derived from 
MGD014 serum concentration versus time data using non-compartmental analysis. 
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Clinical Trial Protocol: CP-MGD014-01 
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Immunogenicity (ADA) Assessments 
• Immunogenicity determination will be based on the determination of titers of ADA 
in serum over time.  
PD Assessments 
• Examination of RO (and/or T-cell binding). 
• Examination of the ability of MGD014 to impact T cell phenotype (activation 
and/or exhaustion). 
• Characterization of alterations in serum cytokine levels, including but not limited 
to IL-2, IL-5, IL-6, IL-10, IFN-γ, and TNF-α. 
Markers of Persistent HIV-1 Infection (Part 2) 
• The frequency of latent infection in resting CD4 T cells by QVOA, as a direct 
measure of persistent HIV infection. 
• Residual low-level HIV-1 viremia by SCA, as evidence suggests that such HIV-1 
viremia originates in persistently infected cells, and low-level HIV-1 viremia 
might be reduced by an augmented antiviral immune response. 
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Clinical Trial Protocol: CP-MGD014-01 
Amendment 6, 31 March 2021 
2 
INTRODUCTION  
2.1 
Rationale for Study  
Despite successful antiretroviral therapy (ART), human immunodeficiency virus (HIV) persists 
in a latent, transcriptionally quiescent state in rare but persistently infected cells – the latent 
reservoir. This reservoir is the major obstacle to the eradication of infection and a cure for HIV 
[1, 2, 3]. Following reactivation of HIV-1 with a latency reversing agent (LRA), viral antigens 
such as envelope (env) may be presented on the surface of the cell, allowing for recognition and 
clearance of HIV-1. CD8 T cells are the principal effector population responsible for detection 
and clearance of virus-infected cells [4, 5]. However, CD8 T cells in successfully treated (ART 
suppressed) HIV-infected individuals fail to clear persistent infection; the vast majority of HIV-
infected individuals experience rebound of HIV-1 with interruption of ART therapy within a 
matter of days to weeks [6]. 
There are several identified challenges to immune-mediated clearance of the latent HIV-1 
reservoir, including: 1) the likely low levels of env antigen produced on rare latently HIV-1 
infected cells, even following reactivation of HIV-1 with LRAs; 2) the presence of T-cell escape 
variants in the latent reservoir HIV-1; 3) the low frequency of HIV-specific CD8 T cells and 4) 
the dysfunctional HIV-specific CD8 T cell response. 
There is a strong rationale for use of the MGD014 DART® molecule to co-engage HIV-infected 
env-expressing cells and CD3 T cells to induce cytolysis of the infected target cells. In brief, 
MGD014 binds infected target cells through engagement of the cell surface env protein and 
binds effector cells through the T-cell receptor (TCR)/CD3 complex, independently of the 
TCR/major histocompatibility complex (MHC) interaction. The close engagement of the env-
expressing target cells with the effector T cells promotes T-cell activation and potentiates T-cell 
mediated cytolytic killing of target cells. DART® molecules have inter-chain disulfide bonds that 
provide stability and structural compactness; the close positioning of the two binding arms 
facilitates the formation of stable cell-to-cell contacts between target and effector cells, 
contributing to a high level of target cell killing [7, 8, 9]. MGD014 has the potential to overcome 
the challenges described above for immune-mediated clearance of the latent HIV-1 reservoir, 
because it is capable of recognizing low levels of env antigen on target cells and can recruit all 
types of CD3 T cells to serve as effector cells, and thus is not limited by the deficiencies and 
dysfunction associated with HIV-specific CD8 T cells. 
2.1.1 
Co-targeting human immunodeficiency virus 1 envelope (HIV-1 
env) and CD3  
The envelope (env) protein is the only virally-encoded protein expressed on the surface of HIV-1 
infected cells and therefore is the primary target for antibodies or antibody-derived molecules 
capable of redirecting effector cells that mediate cytolytic activity. The env glycoprotein (gp) is 
produced as a gp160 precursor, which is cleaved by furin to form gp120 and gp41 subunits. The 
gp120 and gp41 subunits remain in association with each other and assemble into mature 
‘functional’ trimers, although alternate ‘nonfunctional’ forms of env have also been characterized 
[10]. All env proteins are highly glycosylated. On the cell surface, gp41 subunits are anchored in 
the membrane, while gp120 subunits are noncovalently bound to the gp41 extracellular domains. 
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Mature trimers in ‘closed’ conformations undergo extensive structural rearrangements to form 
‘open’ conformations in response to binding to CD4 [11], one of the receptors for virions. Major 
challenges for utilizing cell surface env antigen as a target are the large diversity of env sequence 
variants among HIV-1 isolates worldwide and the frequent emergence of escape mutants due to 
env sequence changes resulting from error-prone reverse transcription of viral RNA genomes.  
The anti-HIV env component of MGD014 is based on non-neutralizing monoclonal antibody 
(mAb) A32, isolated from an individual with HIV-1, that binds to a discontinuous set of gp120 
residues located in conserved regions C1-C2, which are extremely highly conserved [8, 9, 12]. 
Accordingly, the A32 mAb is broadly reactive with env proteins from diverse HIV-1 isolates, and 
there are no known resistant escape variants; the implication is that viruses lose fitness when 
mutations occur in A32 binding residues [13]. A32 mAb binding is enhanced by the CD4-
inducible conformational changes in the env protein [14, 15, 16, 17]. A32 mAb binds 
inefficiently to env on HIV-1 virions [18], which are comprised of mature env trimers in ‘closed’ 
conformation, but binds to env on surfaces of infected cells and is one of the most potent and 
broadly reactive antibodies to mediate antibody-dependent cell-mediated cytotoxicity (ADCC) 
against env-expressing target cells [12]. The cell surface targets for A32 may consist of env 
trimers in the CD4-induced ‘open’ conformation or nonfunctional forms of env, which may be 
the predominant ones on infected cells [10, 19, 20, 21, 22, 23, 24]. The A32 mAb epitope is the 
earliest epitope known to be expressed on the surface of infected cells during the process of 
syncytia formation [23] or following tier 2 HIV-1 infection [24]. The anti-HIV env arm of 
MGD014 retains the binding properties of the parental A32 mAb. 
CD3 is an invariant complex of proteins required for expression of and signaling through the 
antigen-specific TCR on T cells. CD3 consists of a protein complex and is composed of four 
distinct chains: a CD3γ chain, a CD3δ chain, and two CD3ε chains. These chains associate with 
the TCR and the ζ-chain (zeta-chain). The TCR, ζ-chain, and CD3 molecules together constitute 
the TCR complex, which is responsible for signal transduction in T cells, including activation 
during immune response [25, 26]. CD3 is expressed almost exclusively by T cells and is present 
in all stages of T-cell development [27]. The CD3 arm of MGD014 is derived from hXR32, a 
humanized anti-CD3ε mAb. 
Through co-targeting CD3 and A32, the cytolytic activity of polyclonal CD3 T cells can be 
redirected, in an MHC-independent manner, against the env-expressing infected cells. MGD014 
may thus be able to circumvent or overcome the aforementioned obstacles to clearance of the 
latent reservoir. Studies conducted with the predecessor of MGD014 (HIVA32 x CD3 [basic 
format], a DART® molecule identical to MGD014, except it lacks the Fc region for extended 
serum half-life], demonstrated the ability to mediate potent redirected killing activity (nanomolar 
EC50 values) in vitro against CD4 cells infected by diverse infectious molecular clones (IMC) of 
HIV [8, 9].  The HIVA32 x CD3 molecule targets a highly conserved region of the env antigen 
and does not rely on pre-existing HIV-specificity in the effector cells, but rather recruits from all 
CD3 effector cells. In support of this, in vitro studies demonstrated that HIVA32 x CD3 (basic 
format) was capable of redirecting T cells against both autologous targets infected with diverse 
autologous reservoir HIV-1 as well as against latently infected resting CD4 T cells obtained from 
ART-suppressed PLWH following exposure to the LRA vorinostat (VOR) [8]. As summarized in 
the following sections, MGD014 retains these activities. 
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2.2.1 
MGD014 Nonclinical Pharmacology  
A brief summary of MGD014 nonclinical pharmacology data is provided below; please reference 
the MGD014 Investigator’s Brochure (IB) for a more detailed description. 
Binding of MGD014 to its target antigens, HIV-1 env and human CD3, was characterized in 
vitro by both surface plasmon resonance (SPR) analysis and flow cytometry. SPR analysis using 
recombinant soluble human antigens revealed MGD014 binds with KD values of approximately 
6.9 nM to CD3 and with subnanomolar (<1 naM) KD values to HIV-1 env. Like the parent A32 
antibody, MGD014 binding to HIV-1 env was enhanced in the presence of soluble CD4 protein, 
which is known to trigger conformational changes in HIV-1 env proteins. Flow cytometry 
analyses confirmed the ability of MGD014 to bind natively expressed cell surface CD3 on 
human T cells, as well as to cell surface HIV-1 env on human cell lines engineered to express 
HIV-1 gp140 or gp160 or on human CD4 cells infected by HIV-1 isolates. However, like the 
parental A32 antibody, MGD014 was inefficient at binding HIV-1 virions, indicating that 
MGD014 selectively recognizes the env antigen structures expressed on the surface of HIV-1 
infected cells. 
Consistent with its bispecific binding properties and intended mechanism of action, MGD014 
efficiently mediated the cytolysis of the env-expressing target cell lines in the presence of CD8 T 
cells as effector cells. MGD014 redirected T-cells to mediate the killing of human cell lines 
expressing env antigen at high level (HEK293/D371) or low level (Jurkat-522 F/Y or Jurkat-522 
F/Y GF), respectively (Figure 2 A, B). While maximal cytolysis (Emax) was 22-25% for envhigh 
and envlow target cells by lactate dehydrogenase (LDH) release assay, Emax was >90% for envlow 
target cells by luminescence (LUM) assay. The LDH assay tends to yield low maximal percent 
cytolysis values, because LDH may be released from effector cells as well as target cells and lead 
to higher assay background. By contrast, the LUM assay yields high maximal % cytolysis 
because it is a more sensitive and specific assay but can only be applied when target cells are 
engineered for reporter gene expression (Jurkat-522 F/Y GF cells were engineered to express a 
luciferase reporter gene). The control DART® molecules lacking one of the specificities 
(fluorescein x CD3 or HIVA32 x respiratory syncytial virus (RSV) did not mediate cytolysis, 
confirming that co-engagement of cells expressing the different antigen targets is required for 
cytotoxic T lymphocyte (CTL) activity. When effector cells were from the same donor, the EC50 
values for MGD014-mediated CTL activity against the envhigh and envlow target cell lines were 
6.4-6.6 and 0.7-1.0 ng/mL, respectively. Thus, low levels of cell surface env protein expression 
are sufficient for potent MGD014-mediated killing activity.   
MGD014-dependent killing of the env+ cell lines was associated with concomitant dose-
dependent activation of T cells, as evidenced by upregulation of the activation markers CD25 
and CD137 in both CD4 and CD8 T-cell subsets, and with concomitant induction of cytokine 
production, as evidenced by induction of the release of interferon gamma (IFN-γ) and tumor 
necrosis factor alpha (TNF-α) (Figure 2 C, D, E). However, only low levels of CD8 T-cell 
activation, no CD4 T-cell activation and just trace levels of cytokines and were observed in the 
presence of the Jurkat-522 F/Y (envlow) target cells. The data indicate that MGD014-dependent 
T-cell activation and cytokine release, but not MGD014-dependent cytolytic activity, was highly 
dependent upon on the density of env antigen on the target cells. Moreover, data obtained with a 
fluorescein x CD3 control DART® molecule (which lacks the anti-HIV env specificity) confirm 
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that monovalent DART® molecule binding to CD3 triggered minimal T-cell activation or 
cytokine release. These in vitro findings suggest a low probability for T-cell activation and 
cytokine release when MGD014 is to be administered to HIV participants on ART, because the 
levels of env antigen expressed by CD4 cells infected by a transmitted/founder HIV-1 isolate are 
comparable to those expressed by the envlow cells (Figure 3). 
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Control DART® molecules were fluorescein x CD3 and HIVA32 x RSV. MGD014 EC50 values were 6.4 ng/mL 
and 0.23 ng/mL with the HEK293/D371 and Jurkat522 F/Y target cells, respectively. Also shown is 
MGD014-mediated killing of Jurkat-522 F/Y GF cells (Jurkat-522 F/Y cells engineered to express a luciferase 
reporter gene), thus allowing the viable env-expressing target cells to be specifically and more sensitively 
quantitated by luminescence (LUM) assay. Maximal cytolysis levels measured by the LUM assay are 
substantially higher than those measured by the LDH assay, but the EC50 values from both assay methods are 
comparable. (C) MGD014-mediated release of IFNγ and TNFα under the same conditions as in panel B. (D, 
E) MGD014-mediated induction of activation markers CD25 and CD137, measured by flow cytometry, on 
CD8 T cells (D) or CD4 T cells (E) under the same conditions as in panel B. All experiments, except the one 
conducted with Jurkat-522 F/Y GF cells, were conducted with effector cells from the same HIV-uninfected, 
healthy donor. 
Importantly, MGD014 mediated the redirected killing of CD4 target cells infected by subtype B 
HIV-1 IMCs, including ones derived from transmitted/founder HIV-1 isolates, in the presence of 
autologous CD8 cells as effector cells (Figure 3). Resting CD8 effector cells from both 
uninfected (seronegative) donors and from HIV-1 infected (seropositive) donors on ART were 
similarly effective in mediating MGD014-dependent redirected killing of the autologous HIV-1 
IMC-infected CD4 target cells. With cells from uninfected donors, Emax (maximum cytolysis) and 
EC50 values (mean ± standard deviation) were 72 ± 14% and 1.4 ± 1.7 ng/mL, respectively. 
Similarly, with cells from HIV-infected donors on ART, Emax and EC50 values were 67 ± 24% and 
2.1 ± 4.5 ng/mL, respectively. There were no statistically significant differences in MGD014-
mediated cytolytic activity with cells obtained from uninfected or HIV-infected donors. 
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levels were decreased by more than 27-fold in animals treated with MGD014 compared to those 
treated with the RSV x CD3 control molecule. By 14-days post ART interruption, however, the 
mean viral loads in the MGD014- and RSV x CD3-treated groups were not distinguishable. 
Thus, while treatment with MGD014 inhibited and delayed HIV-1 rebound following ART 
interruption, the effect was transient and did not reduce the eventual magnitude of the HIV-1 
viral load response. The data suggest that the administered MGD014 doses were not sufficient to 
fully clear the HIV-1 infected cells, especially after HIV-1 replication began to increase 
exponentially. It is important to note, however, that the abundance and characteristics of the 
residual infected cell populations harboring active or latent HIV-1 in the HIV-infected humanized 
mouse model following short-term (8-week) ART therapy are likely to be very different from 
those present in HIV-infected individuals maintained on ART for many years. 
The human IgG1 Fc region incorporated into MGD014 has been mutated to greatly reduce or 
eliminate FcR and complement binding and hence Fc-mediated effector functions. SPR analysis 
demonstrated that MGD014 binding to FcγRs, including CD16A (FcγRIIIa), CD32A (FcγRIIa), 
CD32B (FcγRIIb), and CD64 (FcγRI), was greatly reduced compared with a control DART 
protein with a wild-type human IgG Fc. MGD014 binding to complement (C1q) was not 
detected. Importantly, no ADCC or CDC activity was observed for MGD014. These data 
demonstrate that the mutated human IgG1 Fc domain incorporated into MGD014 functionally 
eliminates undesired binding to FcγRs and complement. Furthermore, no hemolysis was 
observed following treatment of either purified red blood cells (RBCs) or whole blood from 
healthy human donors with MGD014 in vitro.  
The potential for MGD014 to mediate the production of cytokines (IFN-γ, IL-2, IL-4, IL-6, 
IL-10, and TNF-α) was evaluated in vitro with peripheral blood mononuclear cells (PBMCs) 
obtained from seronegative donors or PLWH under a variety of conditions, ranging from ones 
that approximate the physiological conditions of PLWH on ART to supra-physiological ones that 
employ target cells at highly elevated frequencies and, in some cases, target cells with highly 
elevated env antigen density, exaggerated to maximize the potential for cytokine induction.  
MGD014 concentrations of 1000 ng/mL or greater did not induce notable cytokine release when 
incubated with PBMCs from HIV-uninfected donors, which lack env+ target cells. When 
presented in immobilized form to PBMCs from HIV-uninfected donors, MGD014 at 
concentrations of 400 ng/mL or greater induced detectable levels of some cytokines (IFN-γ, 
TNF-α, IL-6), as expected, as immobilization of MGD014 results in high localized 
concentrations of the molecule which have an increased potential to interact multivalently with 
CD3 on T cells and induce their activation. This latter condition, however, is not physiologic and 
does not mimic the environment of aviremic PLWH on suppressive ART.  
HEK293/D371 (envhigh) is a cell line that expresses an HIV-1 env protein at levels that greatly 
exceed those observed with HIV-1 infected CD4 cells. When PBMCs from 6 HIV-uninfected 
donors were supplemented with HEK293/D371 (envhigh) target cells at an effector cell to target 
cell (E:T) ratio of 20:1 [which provide a target cell frequency of 5%, which is at least 500-fold 
higher than that (0.0001 – 0.01%) anticipated for PLWH on ART] [29, 30], incubation with 
MGD014 resulted in the induction of IFN-γ, TNF-α, IL-10 and IL-6 at moderate levels (mean 
Emax: 205, 186, 55 and 359 pg/mL, respectively). Under these exaggerated conditions, the mean 
EC50 for MGD014-mediated production of the 4 cytokines was 26.2 ng/mL. In parallel assays to 
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assess MGD014-mediated cytolytic activity against the HEK293/D371 (envhigh) cells, the mean 
EC50 was 1.4 ng/mL. Thus, the potency of MGD014 for redirected T-cell cytolytic activity was 
~20-fold higher than for cytokine release. 
The potential for MGD014-dependent cytokine release was also evaluated with PBMCs obtained 
from aviremic, PLWH maintained on ART or viremic, PLWH naïve to ART. These PBMC 
samples contain physiologically relevant, albeit low, frequencies of env-expressing, HIV-infected 
target cells. The in-vitro incubations with PBMC samples from PLWH on ART represent the best 
approximations of the physiological conditions anticipated to be encountered clinically with 
PLWH maintained on ART, whereas those with PBMC samples from PLWH naïve to ART 
represent more exaggerated conditions. MGD014-dependent cytokine release was absent when 
PBMCs from PLWH on ART or PBMCs from PLWH naïve to ART were incubated with 
MGD014 at concentrations up to 1000 ng/mL. MGD014-dependent cytokine release was also 
absent when PBMCs from both types of PLWH were supplemented with autologous activated, 
HIV-infected CD4 cells at an E:T (PBMC:CD4) ratio of 100:1. Because ~20% of the CD4 cells 
were HIV-infected, the co-mixtures had an overall infected target cell frequency of ~0.2%, which 
exceeds, by 20-fold or more, the target cell frequencies of 0.0001 to 0.01%, or fewer, anticipated 
for PLWH maintained on suppressive ART [29, 30]. 
MGD014-dependent cytokine release was observed when the PBMC samples from the aviremic 
HIV+ donors on ART or viremic HIV+ naïve to ART were supplemented with higher amounts of 
autologous activated, HIV-infected CD4 target cells (E:T ratios of 30:1 or 10:1, which resulted in 
co-mixtures with infected target cell frequencies of ~0.7% or ~2%, exceeding those anticipated 
for PLWH on ART by 70 or 200-fold, respectively). With the co-mixtures derived from PLWH 
HIV+ donors on ART, release of IFN-γ, TNF-α or IL-10 at moderate levels (Emax: 431, 290 and 
187-297 pg/mL, respectively) was observed for 1 of the 4 donors, and the mean EC50 for 
MGD014-mediated release of these cytokines was 24.6 ng/mL. With the co-mixtures derived 
from HIV+ donors naïve to ART, release of IFN-γ or TNF-α at moderate levels (Emax: 285-628 
and 111-210 pg/mL, respectively) was observed for 2 of the 3 donors, and the mean EC50 for 
MGD014-mediated release of these cytokines was 0.42 ng/mL. 
In summary, the most physiologically relevant conditions for assessing the potential for 
MGD014-dependent cytokine release were those conducted with PBMCs from aviremic, HIV+ 
donors on ART, either incubated with MGD014 by themselves or supplemented with autologous 
HIV-infected CD4 cells to achieve a target cell frequency to ~0.2%. Even under the latter 
condition, in which env-expressing HIV-infected target cells were present at frequencies at least 
20-fold higher than anticipated for PLWH on ART, there was no notable cytokine release at 
MGD014 concentrations as high as 1000 ng/mL. Similarly, no cytokine release occurred when 
PBMCs from viremic, PLWH naïve to ART (expected to have higher frequencies of HIV-
infected env-expressing target cells and more highly activated effector T-cell populations due to 
the unsuppressed viral infection) were incubated alone or supplemented with autologous HIV-
infected CD4 cells to achieve a target cell frequency of ~0.2%. Thus, the risk of inducing 
substantial cytokine release following MGD014 administration to PLWH maintained on ART is 
very low. 
However, under the more exaggerated conditions in which PBMCs were supplemented with 
more highly elevated frequencies of target cells, moderate levels of IFN-γ, TNF-α and IL-10 
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were released in response to MGD014 with mean EC50 values of 24.6 ng/mL (PBMCs from 
normal HIV- donors), 26.2 ng/mL (PBMCs from aviremic HIV+ donors on ART) and 0.42 ng/mL 
(PBMCs from viremic HIV+ donors naïve to ART). By comparison, the MGD014-mediated 
cytolytic activity of CD8 T cells directed against autologous HIV-infected CD4 target cells under 
comparably exaggerated conditions yielded EC50 values of 1.4 ng/mL (normal HIV- donors) and 
2.1 ng/mL (aviremic HIV+ donors on ART).  Based on these results, minimum anticipated 
biological effect level (MABEL) values of 1.4-2.1 ng/mL were used to guide selection of the FIH 
starting dose. This represents a highly conservative approach, because MABEL values based on 
assays conducted under the exaggerated, non-physiologic conditions must be considered 
artificially low, and because no cytokine release was detected under the most physiological 
representative conditions with MGD014 concentrations as high as 1000 ng/mL. This 
conservative approach ensures a wide safety margin and acknowledges MGD014 as the first 
T-cell redirecting DART molecule to be administered to PLWH (see Section 2.4). 
2.2.2 
MGD014 Pharmacokinetics and Toxicology  
A brief summary of nonclinical PK and toxicology data with MGD014 are provided below, 
please reference the MGD014 IB for a more detailed description. 
The nonclinical toxicology program for MGD014 was performed exclusively in the cynomolgus 
monkey as MGD014 does not bind to CD3 in rodents or dogs. The cynomolgus monkey was 
selected as the most appropriate animal model for nonclinical safety evaluation of MGD014 
given the homology of cynomolgus monkey and human CD3, the ability of MGD014 to bind 
with similar affinity to monkey and human CD3 and to efficiently mediate redirected T-cell 
killing with effector cells from both species.  
The cynomolgus monkey is a relevant species with regard to the anti-CD3 component of 
MGD014, but not for the anti-HIV env component. The anti-HIV arm of MGD014 does not bind 
to any antigens in humans in the absence of HIV-1 infection and is not known to bind to any 
monkey antigens. Due to the lack of targets for the anti-HIV arm, toxicity assessments related to 
this component of MGD014 are limited to off-target effects in naïve cynomolgus monkeys (i.e., 
ones not infected by an HIV-related virus). However, in PLWH on suppressive ART, env antigen-
expressing infected CD4 target cells are rare – exact frequencies have not been measurable, but 
estimates range from 1 per 104 (0.01 %) to 1 per 106 (0.0001 %) CD4 T cells [29], or even less 
frequent [30]. Due to the extremely low frequencies of target cells in PLWH on ART, the primary 
on-target toxicities of concern would be those related to MGD014 binding to CD3 on T cells, 
which are plentiful. Based on these considerations, the naïve cynomolgus monkey model 
represents an approximation, albeit imperfect, of the conditions anticipated in PLWH on ART. 
The alternative strategy of conducting a toxicology study of MGD014 in monkeys infected by 
virus (simian-human immunodeficiency virus [SHIV]) was not pursued because proof of anti-
HIV activity in animal models is not required per the Food and Drug Administration (FDA) 
Guidance entitled Human Immunodeficiency Virus-1 Infection: Developing Antiretroviral Drugs 
for Treatment (November 2015), and because toxicology evaluation in this model would be 
technically challenging and difficult to interpret. In SHIV-infected monkeys, the analysis for 
toxicological endpoints would be complex because toxicities potentially related to MGD014 
would need to be clearly distinguished from ones related to the SHIV infection. Further, the 
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administration of MGD014 to animals with elevated levels of circulating SHIV and infected 
CD4 T cells would model an unrepresentative physiological condition and potentially reveal 
toxicological findings that are unlikely (or much less likely) to be evident when infected target 
cells are only present at low levels, as is with PLWH on suppressive ART. If a suppressive ART 
regimen were incorporated into the infected animal model to better mimic the status of the 
intended participant population, the analysis would be even more complex, because toxicities 
related to the addition of ARVs (typically comprised of a mixture of 3 drugs administered on a 
daily schedule) would need to be considered. Finally, SHIV infected monkey studies are not 
readily amenable to Good Laboratory Practice (GLP) compliance. Thus, while suitable for 
assessing efficacy and some limited safety parameters associated with MGD014 administration, 
the SHIV infected animal models are not well suited to assess toxicology. 
In the repeat-dose GLP study conducted in cynomolgus monkeys (Study 20093423), 40 animals, 
consisting of 4 groups of 10 animals (5 males, 5 females), received 6 repeated administrations of 
MGD014 at weekly intervals at dose levels of 0 (saline), 0.1, 1 or 10 mg/kg. MGD014, 
administered as a 2-hour IV infusion on a weekly schedule for 6 consecutive weeks, was 
well-tolerated and all animals survived to their scheduled euthanasia. There were no 
MGD014-related effects on any of the following study parameters or end points: clinical signs, 
body weights, food consumption, ophthalmology, electrocardiology, body temperature, blood 
pressure and heart rate, neurologic examination, clinical pathology parameters (hematology, 
coagulation, clinical chemistry, and urinalysis), flow cytometry (percentages of CD4 and CD8 
T-cell subsets and T-cell activation), serum cytokines, gross necropsy findings, organ weights, 
and histopathologic examinations. 
All animals were exposed to the test article after each administration of MGD014. Maximum 
serum concentration (Cmax) and area under the curve (AUC) extrapolated up to infinity (AUCinf ) 
increased proportionally with increasing dose of MGD014. Based on the serum concentration 
profiles at the end of the first weekly dose, there were no significant differences between gender, 
therefore, male and female animals were grouped for subsequent analyses. Based on the 
overlapping dose normalized mean serum concentration profiles of the first week for all 3 doses 
and no significant difference between the total body clearance (CL) and steady-state volume of 
distribution (Vss) among all 3 doses, MGD014 PK was determined to be linear across the dose 
range evaluated (0.1-10 mg/kg). By noncompartmental analysis (NCA), mean Cmax after the first 
dose was 2, 19, and 180 µg/mL for dose levels of 0.1, 1, and 10 mg/kg, respectively, consistent 
with the analysis by two-compartment modeling. By NCA, mean AUCinf after the first dose was 
74, 769, and 7255 hr•µg/mL for dose levels of 0.1, 1, and 10 mg/kg, respectively, consistent with 
the analysis by two-compartment modeling. Mean CL by NCA or two-compartment modeling of 
data after the first dose of MGD014 across all groups were consistent with each other at 1.38 or 
1.4 mL/hr/kg, respectively, substantially lower than the glomerular filtration rate of cynomolgus 
monkeys, as would be expected for a protein of this size (111.8 kDa). Mean VSS by NCA after 
the first dose of MGD014 across all doses was 141 mL/kg and by two-compartment modeling 
was 152 mL/kg, or about 3-fold larger than the plasma space (~45 mL/kg), but less than the 
extracellular space (~200 mL/kg) of cynomolgus monkeys. This indicates some extravasation 
into the extracellular space. Average mean residence time (MRT) after the first dose of MGD014 
was 105 hours (4.4 days) by NCA and 117 hours (4.9 days) by two-compartment modeling. By 
simulation of 6 weekly doses using two-compartment modeling with PK parameters derived 
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from the first cycle of data, accumulation by a factor of 1.29 would be expected assuming PK 
parameters remained constant. 
Anti-drug antibodies (ADA) were confirmed in 10 out of 30 animals that received administration 
of MGD014. Of these, ADA was first detected in 4 animals during the dosing period (between 
Days 29 and 36) and in 6 animals during the recovery period (between Days 50 and 91). 
Although ADA were detected in 10 animals, no obvious changes in the PK profile were observed 
in these animals except for one animal from the 10 mg/kg dose group. 
There were no noteworthy MGD014-related increases in serum concentrations of cytokines 
(IFN-γ, IL-2, IL-4, IL-5, IL-10, or TNF-α). 
There also were no noteworthy MGD014-related changes in the frequencies of circulating CD4 
and CD8 T cells, nor in the frequencies of CD4 and CD8 T cells expressing markers of activation 
or exhaustion (CD25, CD69, PD-1, TIM-3), as determined by flow cytometry. Assessment of 
MGD014 binding to CD4 and CD8 T cells demonstrated that binding to CD3 was 1-2% of 
maximal at 0.1 mg/kg, ~30% of maximal at 1 mg/kg, and maximal at 10 mg/kg, when measured 
at 24-hours post-infusion. Binding to CD3 was transient and nearly completely reversed for the 
low- and mid-dose groups and ~50% reversed for the high-dose group by 7-days post-infusion. 
Based on these results, the no-observed-adverse-effect level (NOAEL) was considered to be 
10 mg/kg/dose, which correlated to Cmax of 180 µg/mL and AUClast of 5604 hr•µg/mL. 
A GLP tissue cross-reactivity study performed on a panel of normal human tissues demonstrated 
that MGD014 staining was observed in the membrane and cytoplasm of lymphocytes in human 
lymphoid and nonlymphoid tissues (MGD014 IB). Nearly identical staining was observed with 
RSV x CD3, a control DART molecule retaining the anti-CD3 specificity of MGD014, but 
lacking the anti-HIV env specificity, indicating that the observed staining with MGD014 solely 
represented reactivity of the CD3 binding domain of MGD014. The staining of these 
lymphocytes was expected based on the known expression of CD3 by T cells [27]. No 
unanticipated cross-reactivity of MGD014 was observed. These findings are consistent with 
those observed in a separate GLP tissue cross-reactivity study in which a panel of HIV-
uninfected human tissues was evaluated with HIVA32 x RSV, a control DART molecule retaining 
the anti-HIV env specificity of MGD014 but lacking the anti-CD3 specificity (Study 20058390). 
There was no staining of human tissues by the HIVA32 x RSV molecule, confirming that the anti-
HIV env specificity of MGD014 is not reactive with antigens expressed by normal (i.e., 
uninfected) human tissues. 
2.3 
Summary of Known and Potential Risks and Benefits of MGD014  
The addition of MGD014 to a person’s ART regimen or the donation of one’s blood cells to this 
research project provide no direct benefit to participants. However, participation makes it 
possible to continue research on HIV, potentially resulting in new treatments for HIV infection. 
Systemic cytokine release is a known potential risk of T-cell redirected therapies. For mAbs, 
most infusion-related events occur within the first 24 hours after dosing. Specifically, with regard 
to cytokine release syndrome (CRS) reactions, these most commonly occur within the first few 
hours of beginning the infusion with licensed therapeutic mAbs, CRS is managed based on the 
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severity of reaction, including temporarily stopping the infusion, administering histamine 
blockers, corticosteroids, and restarting the infusion at a slower rate [31]. Severe reactions such 
as anaphylaxis, angioedema, bronchospasm, hypotension, and hypoxia are infrequent and more 
often associated with mAbs targeted to human proteins or with a non-human mAb, such as a 
murine mAb [32]. 
The probability of inducing substantial cytokine release by a T-cell redirecting DART molecule 
like MGD014 is dependent on the extent of formation of synapses between antigen-expressing 
target cells and CD3-expressing effector T cells. The probability of synapse formation will be 
proportional to the frequency of target cells, the amount (density) of antigen on surfaces of the 
target cells, the number of effector T cells, the binding affinities of the monovalent arms of the 
DART molecule and the amount of DART molecule. In PLWH on suppressive ART, env antigen-
expressing infected CD4 target cells are rare – exact frequencies are not known, but likely to 
range between 1 per 104 (0.01%) and 1 per 106 (0.0001 %) CD4 T cells [29]. The amount of env 
antigen on the surface of HIV-1 infected cells in PLWH on ART is not well characterized, but 
low env antigen densities are observed on human CD4 cells infected with HIV-1 in vitro, 
especially when a transmitted/founder HIV-1 isolate is utilized (MGD014 IB), which is 
consistent with the low number of env antigen spikes (average of only 14) per HIV-1 virion [33, 
34], which are released from the surface of infected cells. While the levels of CD4 and CD8 
T cells in PLWH on ART are close to the normal range, the paucity of env-expressing CD4 target 
cells infers that MGD014-dependent synapses will also be proportionally rare. Thus, the 
likelihood for induction of CRS in PLWH on ART resulting from MGD014-mediated synapse 
formation appears to be extremely low. In PLWH maintained on ART, HIV-1 viral loads are low 
to undetectable (generally <20 or <50 copies/mL depending on which commercial assay is used, 
but typically <5 copies/mL with more highly sensitive research assays). The HIV binding arm of 
MGD014, based on A32 mAb which recognizes a CD4-inducible epitope in the C1-C2 regions 
of gp120, binds to env on the surface of infected CD4 cells, but does not bind to envelope on the 
surface of virions [MGD014 IB]. This unique property will minimize the sequestration of 
MGD014 by circulating virions following its administration and avert any potential toxicities 
that could result from DART:virion complexes. 
The risk for induction of T-cell activation and cytokine release resulting from the binding (in a 
monomeric fashion) of MGD014 to CD3+ T cells in the absence of envelope-antigen expressing 
target cells (no target engagement) also appears to be low, as shown by both in vitro data and the 
absence of detectable cytokine release (or other sign of toxicity) in monkeys treated with up to 
10 mg/kg of MGD014, a condition that led to maximal binding to the CD3 receptors on T cells. 
Finally, the risk of off-target binding by MGD014 is negligible. In a GLP human tissue cross-
reactivity study, MGD014 (HIVA32 x CD3) and a CD3-targeted control DART molecule (RSV x 
CD3) exhibited nearly identical staining of lymphocytes in the periphery and tissues, as 
predicted. In addition, in a second GLP human tissue cross-reactivity study, the HIV-1 
envelope-targeted control DART molecule (HIVA32 x RSV) exhibited no staining, as predicted. 
Thus, there is no evidence of unanticipated off-target cross-reactivity in human tissues. 
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2.4 
Dose Selection  
2.4.1 
Selection of Maximum Recommended Starting Dose (MRSD)  
The initial MGD014 dose proposed for the FIH trial was carefully selected primarily using dose 
selection principles based on estimation of the MABEL in accordance with the Food and Drug 
Administration (FDA) guidance for Estimating the Maximum Safe Starting Dose in Initial 
Clinical Trials for Therapeutics in Adult Healthy Volunteers (July 2005), the recommendations 
for determining a starting dose based on FDA’s Guidance for Industry: S9 Nonclinical 
Evaluation for Anticancer Pharmaceuticals (March 2010), and recent publications by Saber et al. 
‘An FDA oncology analysis of immune activating products and FIH dose selection’ [35] and 
Dudal et al. ‘Application of a MABEL Approach for a T cell-Bispecific mAb: CEA TCB’ [36]. 
A dose of 0.1 µg/kg was selected as the starting dose for the proposed Phase 1 study.  
Because MGD014 has an anti-CD3 arm for engaging T cells, the primary potential concern 
associated with the mechanism of action of MGD014 is CRS.  
For in vitro assays conducted in the absence of HIV-1 env-expressing target cells, there was no 
notable MGD014-dependent cytokine release, such as when PBMCs from normal, uninfected 
donors were incubated with MGD014 at concentrations up to 10 µg/mL. Moreover, neither 
cytokine release nor T-cell activation occurred in cynomolgus monkeys that received MGD014 at 
dose levels as high as 10 mg/kg, which resulted in Cmax concentrations as high as 180 µg/mL and 
achieved maximal binding to CD3 on T cells. Thus, there is no evidence supporting monovalent 
MGD014 engagement of CD3 on T cells as a safety concern. When presented in immobilized 
form to PBMCs from normal donors, MGD014 at concentrations of 400 ng/mL or greater 
induced detectable levels of IFN-γ, TNF-α and IL-6, as expected, since immobilization results in 
high localized concentrations that have an increased potential to interact multivalently with CD3 
on T cells and induce their activation. This latter condition, however, is paraphysiologic and does 
not mimic the environment of nonviremic HIV-infected individuals on ART.  
The most physiologically relevant data on the potential for MGD014-dependent cytokine release 
were obtained from in vitro studies conducted with PBMCs from aviremic donors with HIV-1 on 
ART, which contain immeasurably low, but nonetheless representative, frequencies of circulating 
HIV-infected env-expressing CD4 target cells. No cytokine release was induced when these 
PBMC samples were incubated with MGD014 at concentrations up to 1000 ng/mL. Similarly, no 
MGD014-dependent cytokine release occurred when the PBMCs were supplemented with 
autologous, activated CD4 cells infected in vitro by HIV-1 BaL at an E:T (PBMC:CD4) ratio of 
100:1. Since ~20% of the CD4 cells were infected, the infected target cell frequencies in the co-
mixtures were ~0.2%, which exceeds the anticipated frequencies of target cells in HIV+ PLWH 
on ART (0.0001-0.01%) [29, 30] by 20-fold or more. Thus, there was no MGD014-dependent 
cytokine release under either physiologically relevant or substantially exaggerated in vitro 
conditions. 
With PBMCs from viremic, PLWH naïve to ART (which are expected to contain higher 
frequencies of circulating HIV-infected env-expressing target cells and have a more highly 
activated effector T-cell population due to the unsuppressed HIV-1 viral infection), no cytokine 
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release was induced at MGD014 concentrations up to 1000 ng/mL. Moreover, no 
MGD014-dependent cytokine release occurred when these PBMC samples were supplemented 
with autologous CD4 cells infected in vitro by HIV-1 BaL at the E:T (PBMC:CD4) ratio of 
100:1. Thus, there was no MGD014-dependent cytokine release under substantially exaggerated 
in vitro conditions that could mimic an unintended, worst-case clinical study situation in which 
MGD014-treated, PLWH may have discontinued their ART treatments. 
Under more highly exaggerated in vitro conditions, MGD014-dependent cytokine release was 
observed, which is consistent with its mechanism of action. First, when PBMCs from normal 
HIV- donors were incubated with an envhigh target cell line at an E:T (PBMC:target cell) ratio of 
20:1 (corresponding to a target cell frequency of 5%, which exceeds that anticipated for PLWH 
on ART by 500-fold or more), moderate levels of IFN-γ, TNF-α, IL-10 and IL-6 were released in 
response to MGD014. Mean Emax (maximal cytokine level) values were 55-359 pg/mL and the 
mean EC50 value was 26.2 ng/mL. Under the same conditions, the EC50 for MGD014-mediated 
cytolytic activity against the env-expressing target cells was 1.4 ng/mL. Second, when PBMCs 
from aviremic HIV+ donors on ART were supplemented with autologous activated, HIV-infected 
CD4 cells at E:T (PBMC:CD4) ratios of 30:1 or 10:1 (corresponding to target cell frequencies of 
~0.7 or ~2%, respectively, which exceed those anticipated in PLWH on ART by 70 or 200-fold, 
respectively), moderate levels of IFN-γ, TNF-α and IL-10 were released in response to 
MGD014, but only with 1 of the 4 donors tested. Mean Emax values were 187-359 pg/mL and the 
mean EC50 value was 24.6 ng/mL. Under similar conditions, the EC50 for MGD014-mediated 
cytolytic activity against the infected target cells was 2.1 ng/mL. Third, when PBMCs from 
viremic HIV+ donors naïve to ART were similarly supplemented with autologous activated, HIV-
infected CD4 cells at E:T (PBMC:CD4) ratios of 30:1 or 10:1, moderate levels of IFN-γ, TNF-α 
and IL-10 were released in response to MGD014 for 2 of the 3 donors tested. Mean Emax values 
were 111-628 pg/mL and the mean EC50 value was 0.42 ng/mL. 
Based on the lack of cytokine release at MGD014 concentrations up to 1000 ng/mL under 
conditions that were either most directly relevant to PLWH on ART or were exaggerated by the 
addition of infected CD4 target cells at frequencies exceeding those estimated for PLWH on ART 
by 20-fold or more, the MABEL would be considered to be 1000 ng/mL. Allometric modeling of 
the cynomolgus monkey PK data (Table 1) projects that a first dose Cmax concentration of 1000 
ng/mL in human participants would result from an MGD014 dose of 58 µg/kg. Based on the 
theoretical CD3 RO calculations (Table 1), this Cmax concentration is projected to result in 56% 
RO (and/or T-cell binding). The data from the cynomolgus monkey toxicology study 
demonstrated that maximal binding of MGD014 to CD3 on T cells was not associated with any 
toxicological findings. However, since MGD014 is the first T-cell redirecting DART molecule to 
be administered to PLWH, it is prudent to select a FIH dose projected to yield a lower RO value. 
The in vitro assays for MGD014-mediated cytolytic activity by CD8 T cells directed against 
autologous HIV-infected CD4 target cells yielded EC50 values of 1.4 ng/mL (HIV seronegative- 
donors) and 2.1 ng/mL (aviremic PLWH on ART).  Based on these EC50 values, MABEL values 
of 1.4-2.1 ng/mL were used to guide selection of the FIH starting dose. This represents a highly 
conservative approach, because MABEL values based on assays conducted under non-
physiologic conditions with elevated frequencies of infected target cells must be considered to be 
artificially low. Based on allometric modeling of the cynomolgus monkey PK data, a starting 
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MGD014 dose of 0.1 µg/kg is projected to yield a Cmax concentration of 1.7 ng/mL, which falls 
within the range of the MABEL values, and a theoretical RO of 0.03%. 
By comparison, a conventional toxicology-based approach to selecting the FIH dose level based 
on a NOAEL of 10 mg/kg in the GLP toxicology study in normal cynomolgus monkeys, using a 
body surface area conversion factor of 0.32 for cynomolgus monkeys (see Table 1 of July 2005 
FDA Guidance on estimating Maximum Recommended Starting Dose [MRSD]) would have 
suggested 310 μg/kg as the starting dose if a 10-fold safety factor was applied (projected to yield 
Cmax of 5,323 ng/mL and theoretical RO of 87.3%), or alternatively, 31 μg/kg as the starting dose 
if a more conservative 100-fold safety factor was applied (projected to yield Cmax of 532 ng/mL 
and theoretical RO of 40.8%). 
In summary, the proposed starting dose of 0.1 µg/kg was determined using a highly conservative 
approach to dose selection relying on the determination of MABEL values based on supra-
physiological conditions in which HIV-1 infected CD4 target cells were present at frequencies 
that exceeded those anticipated for PLWH on suppressive ART by 70 to 500-fold or more. At a 
dose of 0.1 µg/kg, human Cmax, AUC, and CD3 RO are projected to be 1.7 ng/mL, 83 ng/mL•h, 
and 0.2%, respectively, which are >105,000-fold, >67,000-fold and ~500-fold lower than the 
Cmax (180 µg/mL), AUClast (5,604 µg/mL•h), and CD3 RO (100%), respectively, observed during 
the first dose cycle at 10 mg/kg in cynomolgus monkeys, the NOAEL dose, thus providing a 
very generous safety margin for first human exposure. 
2.4.2 
Dose Escalation Strategy  
The dose escalation strategy for the single ascending dose phase (Part 1) is summarized in 
Table 1. It depicts dose escalation by half-log increments and shows predicted Cmax and Ctrough(7-
day) serum concentrations and theoretical percentages for CD3 RO. The Ctrough(7-day) serum 
concentrations are shown because MGD014 will be administered at once every 2 weeks (Q2W) 
intervals in the multi-dose expansion cohort (Part 2). 
The top dose of 300 µg/kg is 33-fold lower than the NOAEL dose (10 mg/kg) derived from the 
GLP toxicology study in cynomolgus monkeys, which resulted in Cmax concentrations of 180 
µg/mL and 100% CD3 RO at 24-hours post-infusion. From in vitro studies conducted with CD8 
T cells obtained from HIV+ donors on ART as effector cells and autologous CD4 cells infected 
by subtype B HIV-1 isolates as target cells with an E:T (CD8:CD4) ratio of 33:1, the mean EC90 
value for MGD014-dependent cytolytic activity was 11.6 ng/mL with values ranging from 1.0 to 
119 ng/mL. While these in vitro conditions are exaggerated and not considered to be directly 
representative of the physiological conditions of PLWH on ART, the EC90 values provide a 
useful reference point; MGD014 doses that yield Ctrough(7-day) serum concentrations exceeding the 
upper range of the EC90 values for in vitro cytolytic activity (projected to be achieved at doses 
100 µg/kg and higher) are more likely to exhibit intended levels of biologic activity in vivo.  
Targeting MGD014 doses beyond what is expected to achieve Ctrough(7-day) serum concentrations 
exceeding the EC90 values for in vitro cytolytic activity, however, may be advantageous; env 
antigen-expressing HIV-infected target cells are expected to be very rare and many target cells 
may be situated in localized anatomical sites [B-cell follicular regions of lymph nodes, gut-
associated lymphoid tissue, bone marrow, genital tract, central nervous system (CNS) [1, 37] 
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with potentially reduced penetrance by MGD014 [38, 39]. For example, there is increasing 
evidence that the brain harbors latent HIV-1 infected cells capable of being reactivated [37, 40, 
41, 42], and it may be particularly challenging for MGD014 to gain access to the CNS due to the 
limits imposed by the blood-brain-barrier (BBB). T cells are capable of trafficking to the CNS 
[43, 44] and are known to be present in the cerebral spinal fluid (CSF) of both seronegative 
individuals and PLWH [45, 46]. However, antibody molecules are only able to cross the BBB 
inefficiently; following IV infusion, CSF to serum concentration ratios of 1:200 to 1:800 have 
been reported [38, 39]. MGD014, which bears a mutated IgG1 Fc domain for extended serum 
half-life, would also be expected to cross the BBB inefficiently; thus, the higher serum 
concentrations resulting from the higher doses will favor the attainment of CSF concentrations 
that could enable MGD014-mediated targeted cytolytic activity in the CNS compartment. 
In summary, MGD014 doses as high as 300 µg/kg are expected to be adequately tolerated in 
PLWH on ART and capable of mediating activity against env antigen-expressing HIV-infected 
target cells, possibly even against those residing in ‘sanctuary’ compartments. 
Table 1 
MGD014 Dose Escalation Scheme  
Cohort 
Dose 
(µg/kg) 
Cmax  
(ng/mL) 
Ctrough (7-day)  
(ng/mL) 
Theoretical RO 
at Cmax (%) 
Theoretical RO 
at Ctrough (7-day) (%) 
1 
0.1 
1.7 
0.27 
0.2 
0.03 
2 
0.3 
5.2 
0.8 
0.7 
0.1 
3 
1.0 
17.2 
2.7 
2.2 
0.3 
4 
3.0 
51.5 
8.0 
6.3 
1.0 
5 
10.0 
171.7 
26.8 
18.2 
3.4 
6 
30.0 
515.1 
80.3 
40.0 
9.4 
7 
100.0 
1717.1 
267.5 
69.0 
25.7 
8 
300.0 
5151.4 
802.6 
87.0 
51.0 
Projected Cmax and Ctrough (7-day) values were derived from allometric modeling of cynomolgus monkey PK data, using 
allometric exponents of 0.75 for clearance and 1.0 for volumes of distribution under the assumption of linearity to 
estimate PK in humans. Theoretical CD3 RO values were calculated from the Hill equation (RO = [C] / (KD + [C]) 
using KD = 6.9 nM for human CD3 binding. 
 
2.4.3 
Post-Infusion Monitoring  
Infusion related reactions (IRR) and CRS following infusion of mAb therapy, when they do 
occur, manifest rapidly, with a typical onset within hours of infusion, and generally appear in the 
dose finding phase of studies [47, 48, 49, 50] and have not been observed in participants through 
Cohort 8 in Part 1. Safety profiles of similar MacroGenics-produced DART products currently in 
Phase 1 oncology trials show that all participants who experienced IRR/CRS became 
symptomatic within a 6-hour post-infusion monitoring period. 
The data together suggests that a 12-hour observation period following MGD014 in Part 1 of the 
trial will be sufficient to ensure both the safe administration of the study drug as well as 
management of potential IRR. As an additional conservative measure, the first participant of 
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each dose cohort to receive the specified MGD014 dose level will be monitored for 24 hours 
following MGD014 infusion. Subsequent participants of each dose cohort of Part 1 will be 
monitored for 12 hours. 
In Part 2, each participant will be monitored for 6 hours following the first MGD014 infusion 
and for 4 hours following subsequent infusions. 
2.4.4 
Every 2 Week Administration  
For the multi-dose expansion cohort in Part 2, MGD014 at 300 mcg/kg will be administered IV 
Q2W for a total of three doses over 4 weeks. The Q2W administration of MGD014 is supported 
by the repeat-dose toxicology study in cynomolgus monkeys (Study 20093423) in which 
MGD014 was administered weekly for 6 weeks by 2-hour IV infusions. Simulations based on 
the allometric modeling of the cynomolgus monkey PK data predicts that the concentration 
profiles in human participants will reach steady-state between the third and fourth dosing 
intervals and that the accumulation factor for exposure following the last (sixth) dose will be 
1.84. 
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Clinical Trial Protocol: CP-MGD014-01 
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3 
STUDY PURPOSE AND OBJECTIVES  
3.1 
Primary Objective  
The objective of this study is to characterize the safety and tolerability of MGD014 administered 
IV to PLWH maintained on suppressive ART. 
3.2 
Secondary Objectives  
• Assessment of PK and immunogenicity (ADA) of MGD014. 
• Assessment of serum cytokine levels following MGD014 administration. 
 
3.3 
Exploratory Objectives  
• Explore the impact of MGD014 administration on the immunologic response to HIV. 
• Explore correlations between virologic and immunologic responses to MGD014. 
• Assess the ability of MGD014 to alter markers of persistent HIV-1 infection.  
 
The results of exploratory objectives may not be included in the clinical study report (CSR) or 
database lock unless they represent meaningful findings. 
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4 
STUDY DESIGN  
4.1 
Overview of Study Design  
This is a Phase 1, single-center, open-label study of MGD014 in PLWH infection on stable ART. 
PLWH who began ART during either chronic HIV infection or acute HIV infection with plasma 
HIV RNA < 50 copies/mL for 24 months prior to screening will be consented to the study. The 
screening procedures and initial evaluations that follow the consent determine eligibility for 
study entry. Eligible participants continue their baseline ART regimens throughout the study and 
receive either one infusion (Part 1) or an IV infusion Q2W for a total of three infusions of 300 
mcg/kg of MGD014 for 4 weeks (Part 2).  
4.2 
Part 1 – Dose Escalation Phase  
Single Ascending Dose (Cohort 1 & 2: n= 1 to 4 participants per dose cohort; Cohorts 3- 8: 
n= 3 to 6 participants per dose cohort). Part 1 is a single ascending dose study with a 1+3 
design for cohorts 1 and 2, and a 3+3 design with staggered accrual for cohorts 3-8, with an aim 
of determining the safety, PK, and pharmacodynamics (PD) of ascending doses up to either the 
Optimal Biologic Dose (OBD) or the maximum administered dose. During Part 1, the OBD is 
identified. The OBD is defined as the MGD014 dose that does not exceed the MTD (see 
Section 4.2.1) and achieves either maximum RO of CD3 >95% in all participants within the 
dose cohort, or is at the maximum administered dose (MAD) level of 300 µg/kg. 
Part 1 has 8 unique dose cohorts: 0.1, 0.3, 1.0, 3.0, 10, 30, 100, and 300 (µg/kg). For cohorts 1 
and 2, each dose cohort will consist of 1 participant, unless a dose limiting toxicity (DLT) is 
encountered, which will prompt expansion of the dose cohort to an additional 3 participants (see 
Section 4.2.1). A 2-week DLT period will be observed prior to escalation of the dose to the next 
dose cohort level. For dose cohorts 3-8, each dose cohort will consist of 3 participants, with at 
least 24 hours between the dosing of each participant within the cohort. If a DLT is experienced 
in one of the three participants, the dose cohort will be expanded to 3 additional participants. 
Following infusions, the study will monitor safety parameters as well as the effects of MGD014 
on clinical chemistry, hematology, serum cytokines, T-cell phenotype, CD3 RO, PK, ADA and 
SCA.   
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Clinical Trial Protocol: CP-MGD014-01 
Amendment 6, 31 March 2021 
4.2.1 
Dose Escalation Rules  
Dose escalation from one dose cohort to the next dose cohort level depends upon the clinical 
safety profile (e.g., evaluation of AEs, VS, ECGs, and clinical laboratory parameters) of the dose 
administered up to and including the preceding dose cohort. Participants will not be dosed at the 
next higher dose level until all the safety data collected following each dose through Day 14 is 
reviewed by the principal investigator (PI) (or designee) in conjunction with the medical monitor 
and are determined to demonstrate acceptable safety and tolerability.  
Dose escalation continues until the OBD is achieved, provided MTD is not exceeded. The PI (or 
designee) may also decide to halt dose escalation if, upon review of available RO data, the RO of 
CD3 is >95% in all participants within the dose cohort level, and further dose escalation is not 
expected to provide any additional biologic utility due to saturation of the CD3 receptor. There 
are three possible outcomes after the infusion of MGD014 in each dose cohort: 
Scenario 1: No DLT is encountered, available data on binding to T cells shows CD3 RO 
is ≤ 95%. Dose escalation to next dose cohort occurs. 
Scenario 2: No DLT is encountered, but available data on binding to T cells demonstrates 
CD3 RO is >95% in all participants at this dose level. Further dose escalation will halt, 
and study proceeds to Part 2, using the identified OBD dose. 
Scenario 3: DLT is encountered in at least one participant. Dose cohort is expanded to an 
additional 3 participants. Dosing of the first additional participant will be staggered, 
so that the safety and tolerability of MGD014 is evaluated over the entire 2-week DLT in 
the first additional participant, at the dose in question, prior to dosing any additional 
participants at the same dose level. 
a. If the first additional participant does not experience a DLT during this 2-week 
DLT period, the 2 other additional participants can proceed to receive MGD014 at 
this dose level with a minimum of 24 hours between the dosing of each participant. 
If none of the 3 additional participants experience a DLT, dose escalation to the 
next dose cohort proceeds.  
b. If any of the 3 additional participants experiences a DLT (so in total ≥ 2 of the 
participants experience a DLT within the same dose cohort), no further participants 
will receive a dose at this dose level, as the maximum tolerated dose (MTD) will 
have been exceeded. Part 2 will proceed with the MTD (the dose preceding the 
dose level at which MTD was exceeded). If only 1 participant was enrolled at the 
prior dose level, an additional 3 participants will be enrolled at the prior dose level 
for evaluation of the MTD. 
 
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Clinical Trial Protocol: CP-MGD014-01 
Amendment 6, 31 March 2021 
4.3 
Multi-Dose Cohort Expansion Phase (Part 2) 
Part 2 is a multi-dose expansion cohort with repeat administrations of MGD014 at 300 mcg/kg; 
see Study Part 2 Schema, Figure 5. Up to 6 patients will be enrolled in Part 2.  
Participants previously enrolled in and having completed Part 1 may be considered for 
enrollment in Part 2, provided they continue to meet all eligibility criteria, did not experience any 
DLT in Part 1, and do not have any detectable ADA at the completion of Part 1. 
In Part 2, additional optional assessments on the effects of MGD014 on HIV latent infection 
parameters include measurements of resting cell infection (frequency of persistent infection of 
resting CD4 T cells) by QVOA, SCA, and T-cell phenotype and functional properties. 
Figure 5 
Part 2: Dose Expansion Study Schema  
 
(a) Screening, eligibility and optional baseline leukapheresis (b) optional leukapheresis post-treatment for 
frequency of persistent infection of resting CD4 T cells.   
Abbreviations: ADA = anti-drug antibody; ART = antiretroviral therapy; leuk = leukapheresis; PK = 
pharmacokinetics; QVOA = quantitative viral outgrowth assay.  
Step 1 Optional Baseline Leukapheresis: After obtaining the informed consent and confirmation 
that the participant qualifies for the study, the participant enrolls in the study. If the participant 
gives consent, an optional baseline leukapheresis is completed. The resting CD4 T cells obtained 
in the leukapheresis will determine the baseline frequency of resting CD4 T-cell infection. 
Additionally, baseline measurements at 2 independent, pre-MGD014 time points will determine 
baseline T-cell function and SCA levels. Note: if the frequency of resting CD4 T cell infection is 
≤ 0.3 infected cells per million (IUPM), as measured by QVOA, a further decrease from this low 
frequency of infection cannot be definitively measured given the QVOA assay threshold and 
variance [51]. 
Step 2 Treatment phase: Eligible participants will continue their ART regimen and receive 3 
infusions of MGD014 at the dose of 300 mcg/kg. Participants are monitored for 6 hours on site 
following their first infusion. Participants will be monitored for 4 hours on site following 
subsequent infusions. Clinical and laboratory parameters for safety, including clinical assessment 
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Clinical Trial Protocol: CP-MGD014-01 
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of cytokine release, will be assessed after each MGD014 infusion. PK and PD data will be 
collected, and serial blood draws will be obtained to assess the impact on T cell functional 
properties.  
Step 3 Post-treatment Phase: This phase begins following the Day 28 MGD014 infusion and 
includes the 14 days between Day 28 and Day 42, with the first post-treatment study visit at Day 
42. Step 3 is conducted over a 6-week period. During Step 3, if a baseline leukapheresis was 
performed, a second and final leukapheresis procedure is completed 2 weeks (+/- 2 weeks) 
following the final MGD014 infusion, for assessment of potential reduction in the frequency of 
resting CD4 T cell infection by QVOA. Plasma HIV-1 RNA as measured by SCA may be 
assessed. Serial blood draws will be obtained to determine PK and PD measures, and impact on 
T cell function. 
4.4 
Dose Limiting Toxicity  
DLT will be defined based on drug-related AEs that occur during the DLT period following 
MGD014 administration. For Part 1, the DLT period is 2 weeks following the single MGD014 
infusion. For Part 2, the DLT period is defined as the period from initial infusion of MGD014 
through 2 weeks following the last IV MGD014 infusion. 
The severity of all AEs will be graded according to the Division of AIDS Table for Grading the 
Severity of Adult and Pediatric Adverse Events, corrected Version 2.1, July 2017, which can be 
found on the DAIDS Regulatory Support Center Web site: http://rsc.tech-res.com/clinical-
research-sites/safety-reporting/daids-grading-tables. 
A DLT is any ≥ Grade 2 drug-related AE, with the following exceptions, based on the medical 
judgement of PI (or designee) and medical monitor: 
• Grade 2 laboratory abnormality that lasts <72 hours and is not otherwise associated 
with clinical complications. 
• Grade 2 fatigue that lasts <7 days. 
 
In general, for participants who experience an AE that meets criteria for a DLT, subsequent 
administration of the study drug to that participant should be held pending management and/or 
resolution of the event and assessment of attribution to the study drug.  
In Part 1, if a given dose level is found to exceed the MTD, meaning that ≥ 2 participants 
experience a DLT in a single dose cohort, Part 2 will proceed with the MTD (the dose preceding 
the dose level at which MTD was exceeded). If only 1 participant was enrolled at the prior dose 
level, an additional 3 participants will be enrolled at the prior dose level for evaluation of the 
MTD. 
In Part 2, if ≥ 2 participants experience the same DLT, subsequent administration of the study 
drug to any participant should be held pending review by the PI (or designee), sponsor, and 
independent Safety Monitoring Committee (SMC). If toxicity is unacceptable, the study will be 
discontinued. 
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Clinical Trial Protocol: CP-MGD014-01 
Amendment 6, 31 March 2021 
All participants who discontinue study treatment or follow-up procedures should comply with 
end of study procedures. The sponsor or its designee must be notified about discontinuation 
within 24 hours of such an event. 
4.5 
Study Duration and End of Trial  
For each participant, the study duration will be approximately either 13 weeks (Part 1), or 
19 weeks (Part 2). This includes a post treatment period of 6 weeks following the final MGD014 
infusion through end of study, which is approximately 5 times the anticipated 8-day half-life 
based on preclinical animal studies. As participant accrual will be staggered so that the full 
2-week DLT period will occur prior to dose escalation in Part 1, the overall study duration will 
be approximately 36 months. The end of trial is the date that all participants enrolled have 
completed their end of study visit. The end of trial is when the clinical study database is locked 
after the last participant in the study completes discharge procedures at the last visit and the 
study forms have been entered, monitored, reviewed, and approved by PI. 
4.5.1 
Definition of End of Study  
The end of study will occur after the last patient has met off-study criteria and the data collection 
process is completed (time of study database lock). 
End of study for each patient is defined as follows: The date that the participant meets 
discontinuation criteria or is lost to follow-up. 
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5 
STUDY PROCEDURES  
The eligibility criteria for this study have been carefully considered to ensure the safety of the 
study participants and to ensure that the results of the study can be used. It is imperative that 
participants meet all eligibility criteria and qualifications to participate in the study. No 
exceptions to these criteria will be granted by the sponsor. 
5.1 
Inclusion Criteria  
1. Aged ≥ 18 years and ≤ 65 years of age. 
2. Ability and willingness of participant to provide written informed consent.  
Note: Due to the lack of foreseeable benefit to study participants, no enrollment of 
illiterate or mentally incompetent persons allowed. 
3. HIV-1 infection, documented by any FDA-approved rapid HIV test or HIV enzyme or 
chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and 
confirmed by a licensed Western blot or a second antibody test by a method other than 
the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral 
load. 
Note: The term “licensed” refers to a US FDA-approved kit, which is required for all 
investigational new drug studies.  
The World Health Organization and Centers for Disease Control and Prevention 
guidelines mandate confirmation of the initial test result with a second distinct assay. 
For example, a reactive initial rapid test should be confirmed by either another type of 
rapid assay or an E/CIA that is based on a different antigen preparation and/or 
different test principle (e.g., indirect versus competitive), or a Western blot or a plasma 
HIV-1 RNA assay. 
4. On continuous antiretroviral therapy (ART defined below) for at least 24 months prior 
to screening. 
Note: For study eligibility – participant must not have missed more than 9 total days 
in the 3 months prior to screening. 
5. Permitted ART regimens include: 
a. At least 3 ART agents (not counting ritonavir if less than 200 mg total daily dose 
or cobicistat as one of the agents). 
Note: One of the agents must include an integrase inhibitor, NNRTI (Non-
Nucleoside Reverse Transcriptase Inhibitors), or a protease inhibitor. 
OR 
b. Two (2) ART agents in which one of the agents is either a boosted protease 
inhibitor or an integrase inhibitor, that are FDA approved or are recommended by 
the Department of Health and Human Service Treatment Guidelines. 
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Note: Other potent fully suppressive antiretroviral combinations will be 
considered on a case-by-case basis. 
Note: Changes in drug formulation or dose are allowed (e.g., tenofovir disoproxil 
fumarate (TDF) to tenofovir alafenamide (TAF), ritonavir to cobicistat, or 
separate ART agent dosing to fixed-dose combination), but none within 30 days 
prior to screening. 
Note: Prior changes in, or elimination of, medications for easier dosing schedule, 
intolerance, toxicity, improved side effect profile or within a drug class are 
permitted but none within 30 days prior to screening if an alternative suppressive 
regimen was maintained. 
6. Able and willing to adhere to protocol therapy and treatment schedule. 
7. Agrees not to enroll in another study of an investigational research agent for the 
duration of the participant’s study participation.  
8. Plasma HIV-1 RNA viral load < 50 copies/mL at two time points in the previous 12 
months prior to screening (one time point can be screening) and never ≥ 50 copies/mL 
on 2 consecutive time points in the last 24 months.  
Note: The documented plasma HIV-1 RNA viral load must be performed by any United 
States laboratory that has a Clinical Laboratory Improvement Amendments (CLIA) 
certification or its equivalent certification or accreditation. 
9. Plasma HIV-1 RNA viral load < 50 copies/mL obtained at screening, performed at US 
laboratory that has a CLIA certification or its equivalent certification or accreditation. 
10. CD4 cell count > 350 cells/mm3 obtained at screening, performed at any US 
laboratory that has a CLIA certification or an equivalent certification or accreditation. 
11. Hepatitis C virus (HCV) antibody negative result at study screening or, if the HCV 
antibody result is positive, a negative HCV RNA result at study screening. 
12. Negative Hepatitis B surface antigen result obtained at study screening. 
13. When participating in sexual activity that could lead to pregnancy, male participants 
with partners of childbearing potential must agree to consistently use 2 reliable forms 
of contraception simultaneously from the time of consent through 6 months after their 
last infusion of study drug. Such methods include: condoms (male or female) with or 
without a spermicidal agent; diaphragm or cervical cap with spermicide; intrauterine 
device (IUD); hormone-based contraception. NOTE: For female partners who are 
receiving ritonavir or cobicistat, estrogen-based contraceptives are not reliable and an 
alternative method should be suggested. 
14. Ability and willingness of participant to continue ART throughout the study. 
15. Ability and willingness to provide adequate locator information.  
16. Ability and willingness to communicate effectively with study personnel; considered 
reliable, willing, and cooperative in terms of compliance with the protocol 
requirements. 
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17. Adequate vascular access for MGD014 infusion and leukapheresis.  
Exception: Participants who opt out of the leukapheresis procedure, are not required to 
have adequate vascular access for a leukapheresis procedure. 
18. Participant must have adequate organ function as indicated by the following laboratory 
values, at the screening visit: 
 
Laboratory Values Required for Study Eligibility 
Test Name 
Laboratory Value 
Hematological 
Absolute neutrophil count  
≥ 1,500 /mcL 
Platelets 
≥ 125,000 / mcL 
Hemoglobin 
≥ 12 g/dL (male) and ≥ 11 g/dL (females) 
Coagulation 
Prothrombin Time or INR 
≤ 1.1 x ULN 
Chemistry 
K+ levels 
Within normal limits 
Mg++ levels  
Within normal limits 
Glucose  
Screening serum glucose ≤ Grade 1 (fasting or non- 
fasting) 
Albumin  
≥ 3.5 g/dL 
Renal 
Creatinine clearance determined by the CKD-Epi equation 
found at: 
https://www.qxmd.com/calculate/calculator_251/egfr-
using-ckd-epi 
eGFR > 60 mL/min 
Hepatic 
Serum total bilirubin 
Total bilirubin < 1.5 times the ULN range. If total 
bilirubin is elevated, direct bilirubin must be < 2 times 
the ULN range. 
NOTE: If participant is on an atazanavir-containing 
therapy, then a direct bilirubin should be measured 
instead of the total bilirubin and must be ≤ 1.0 mg/dL. 
AST and ALT 
≤ 1.25 X ULN 
ALK-P 
≤ 1.25 X ULN 
Lipase  
< 1.1 X ULN 
Serum Pregnancy   
Negative 
Abbreviations: ALK-P = Alkaline Phosphatase; ALT = Alanine Transaminase; AST = aspartate aminotransferase; 
CKD-Epi = Chronic Kidney Disease Epidemiology Collaboration; eGFR = estimated glomerular filtration rate; 
INR = international normalized ratio; K+ = potassium; Mg++ = magnesium; ULN = upper limit of normal. 
 
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Labs/procedures completed during a routine clinical care appointment that are the same as the 
study screening labs and/or procedures and completed within the 14 days preceding the 
screening visit can be used to qualify the participant upon approval by the study PI or designee. 
5.2 
Exclusion Criteria  
1. Women of Child-Bearing Potential (WOCBP) are excluded as the in vivo teratogenic 
potential of this compound is unknown. WOCBP include any female who has 
experienced menarche and who has not undergone successful surgical sterilization or 
menopause. 
a. WOCBP must have documentation from a medical record or physician of 
successful surgical sterilization, i.e. hysterectomy, bilateral tubal ligation, 
ESSURE procedure, or bilateral oophorectomy 
b. Post menopause is defined as: amenorrhea ≥ 12 consecutive months without 
another cause or, for women with irregular menstrual periods and on hormone 
replacement therapy, a documented serum follicle stimulating hormone (FSH) 
level > 35 mIU/mL. 
2. Any HIV-1 RNA viral load > 1000 copies/mL within 6 months prior to screening. 
3. History or other evidence of severe illness, immunodeficiency other than HIV, or any 
other condition that would make the potential participant unsuitable for study in the 
opinion of the PI (or designee).  
4. History or other evidence of any condition or process for which signs or symptoms 
could be confused with reactions to MGD014. 
5. History of any HIV immunotherapy or HIV vaccine except for MGD014 within 12 
months prior to screening. 
6. History of clinically significant cardiovascular disease including, but not limited to:  
a. Myocardial infarction or unstable angina within the 6 months prior to the initiation 
of study drug. 
b. Clinically significant cardiac arrhythmias. 
c. Uncontrolled hypertension: systolic blood pressure (SBP) > 180 mmHg, diastolic 
blood pressure (DBP) >100 mmHg that is sustained on repeat measurement 
(without intervention). 
d. Deep vein thrombosis, pulmonary embolism, stroke, or transient ischemic attack 
within the 6 months prior to the initiation of study drug. 
e. QTc prolongation > 480 msec. 
f. Congestive heart failure (New York Heart Association class III-IV). 
g. Pericarditis/clinically significant pericardial effusion. 
h. Myocarditis. 
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7. Evidence of active viral, bacterial, or systemic fungal infection requiring parenteral 
antibiotic, antiviral, or antifungal treatment within 7 days prior to the initiation of 
study drug. Participants requiring any systemic antiviral, antifungal, or antibacterial 
therapy for active infection must have completed treatment no less than one week 
prior to the initiation of study drug 
8. Active COVID-19/SARS-CoV-2 infection. While SARS-CoV-2 testing is not 
mandatory for study entry, testing should follow local clinical practice 
guidelines/standards. Participants with a positive test result for SARS-Cov-2 infection, 
known asymptomatic infection, or suspected infection are excluded. 
9. Active, untreated syphilis (defined as rapid plasma reagin (RPR) positive at screening 
visit, without any documented history of appropriate treatment).  
Note: If positive at screening without history of treatment, participant will be allowed 
one rescreen following documentation of recent, appropriate treatment. 
10. Known allergic hypersensitivity to recombinant proteins, 
 or any 
excipient contained in the drug or vehicle formulation for MGD014. 
11. History of a severe allergic reaction with generalized urticarial, angioedema, or 
anaphylaxis within 2 years of study entry or history of hereditary angioedema, 
acquired angioedema, or idiopathic angioedema. 
12. History of malignancy within the past 5 years or current malignancy that may require 
chemotherapy or radiation therapy. 
Note: a history of non-melanoma skin cancer (e.g. basal cell carcinoma or squamous 
cell skin cancer) with documentation of complete resection or resolution per licensed 
and board-certified dermatology consultant following topical therapy is not 
exclusionary. 
13. Seizure disorder: History of seizure(s) within the past two years.  
Note: history of seizure disorder controlled on anti-epileptic therapy, with no seizure 
within the past two years, does not exclude participant. 
14. History of organ or tissue transplantation. 
15. History of autoimmune disease, including type I diabetes mellitus, with the specific 
exceptions of: 
a. Vitiligo. 
b. Resolved childhood atopic dermatitis. 
c. Psoriasis (with the exception of psoriatic arthritis) not requiring systemic treatment 
(within the past 2 years). 
d. Graves disease with subsequent return to a euthyroid state (clinically and by 
laboratory testing). 
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16. Known psychiatric or substance abuse disorders that preclude compliance with the 
protocol as assessed by the study PI (or designee). Specifically excluded are persons 
with psychoses within the past 3 years, ongoing risk for suicide, or history of suicide 
attempt or gesture within the past 3 years. 
17. Participation in another investigational clinical research study (with the exception of 
an antiretroviral treatment trial that uses FDA approved antiretroviral agents) within 
60 days prior to study screening. 
Note: Co-enrollment in the ACTG 5332 REPRIEVE study (NCT02344290) and using 
FDA approved pitavastatin is permitted provided participant enrolled on ACTG 5332 
and has taken the study provided medication ≥ 4 months. 
Note: Enrollment in investigative trials using FDA approved medications may be 
reviewed on a case-by-case basis. 
18. History of unstable asthma, including sudden acute attacks occurring without an 
obvious trigger or asthma requiring hospitalization. Additional criteria for exclusion 
include:  
In the past year has either of the following: 
a. >1 exacerbation of symptoms treated with oral/parenteral corticosteroids; 
b. Emergency care, urgent care, hospitalization, or intubation for asthma.  
19. Bleeding disorder diagnosed by a doctor (e.g., clotting factor deficiency, coagulopathy, 
or platelet disorder requiring special precautions).  
20. Use of any of the following within 90 days prior to screening: receipt of any blood 
product, immune globulin, immunomodulatory therapy, cytokine therapy, or growth 
stimulating factors such as systemic corticosteroids, cyclosporine, methotrexate, 
azathioprine, anti-CD25 antibody, interferon (IFN), interleukin-2 (IL-2), systemic 
cytotoxic chemotherapy, or investigational therapy. Intent to use immunomodulators 
(e.g., IL-2, IL-12, interferons or TNF modifiers) during the course of the study. 
21. Current use of the following antiretrovirals: maraviroc and/or enfuvirtide. 
22. Positive ADA (anti-MGD014) obtained during screening in Part 2. 
23. Any vaccination with the exception of the flu vaccine, within 30 days prior to 
screening. 
Note: Individuals who require vaccination will delay screening for the study until 30 
days after receiving the last injection.  
5.3 
Guidelines for Discontinuation of Participants from Study Drug 
Administration  
Under certain circumstances, an individual participant’s infusions will be prematurely or 
permanently discontinued. Specific events that will result in stopping a participant’s infusion 
schedule in either Part 1 or Part 2 of the study include: 
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• Failure to meet requirements established for safety assessment 
• Pregnancy  
• Development of a DLT at any time following MGD014 infusion 
• Investigator discretion 
• HIV RNA > 150 copies/mL on 2 consecutive determinations 
 
If the PI (or designee) decides that a participant should be withdrawn from study treatment, the 
sponsor must be alerted within 24 hours. All participants who discontinue treatments should 
comply with protocol specified visits and follow-up as required by the protocol. The only 
exception to this requirement is when a participant withdraws consent for all study procedures or 
loses the ability to consent freely (i.e., is imprisoned or involuntarily incarcerated for the 
treatment of either a psychiatric or physical illness). 
If a participant is withdrawn before completing the study, the reason for withdrawal must be 
documented appropriately in the study documents. 
5.3.1 
Participant Follow-up after Discontinuation  
Participants for whom infusions are discontinued should be counseled on the importance of 
continuing with the study and strongly encouraged to participate in follow-up visits and 
protocol-specified procedures. 
The study will replace all participants who withdraw for reasons unrelated to drug toxicity. If 
participant withdrawal occurs in Part 1 before completion of the DLT period, these participants 
will have inadequate data to support dose escalation, therefore “new” replacement participants 
can enroll at the same dose level as the withdrawn participant. 
The withdrawn participant will continue on study for safety assessments per the end of study 
visit (see Section 9.18). Analysis will be completed on all participant samples, including blood, 
collected at the end of treatment study visit. The data may or may not be included in the final PK, 
PD, or ADA analyses but all clinical safety data will be included in the final CSR. 
5.3.2 
Guidelines for Discontinuation of Participant from Study  
Participants who are no longer on treatment but are still followed on the study (with safety 
evaluations obtained per the Time and Events Schedule in Appendix 1) can be terminated from 
the study for the following reasons: 
• Uncontrolled intercurrent illness that prevents continuing study follow-up or regular 
study visits impossible. 
• Noncompliance with protocol-required evaluations. 
• Participant request for discontinuation from the study, i.e., withdrawal of consent. 
• The sponsor, PI, or regulatory agency terminates the study. 
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5.3.3 
Lost to Follow Up Status  
Participants classified as lost to follow up (LTFU) need to meet both of the following criteria:  
• Failure to respond or reply to 3 documented phone contact attempts.  
• Failure to respond to a certified letter sent to the address provided by the participant. 
 
Only after documentation of these failed attempts to connect with the participant, will the 
participant be determined to be LTFU. 
5.4 
Guidelines for Withdrawal of Participant from Study  
A participant may withdraw or be withdrawn from the study if any of the following occurs: 
• Failure by the participant to attend multiple clinic visits. 
• Failure to receive the first MGD014 infusion.  
• Failure to meet study advancement criteria. 
• Development of an illness that requires treatment with certain medications not allowed 
in this study. 
• Poor adherence to ART as judged by the site PI (or designee). 
• Request by the participant to withdraw from the study and study procedures. 
• Request of the participant’s primary care provider if she/he thinks the study is no 
longer in the best interest of the participant. 
• Participant judged by the PI (or designee) to be at significant risk of failing to comply 
with the provisions of the protocol, as to cause harm to self or seriously interfere with 
the validity of the study results. 
• At the discretion of the Institutional Review Board/Ethics Committee, FDA, National 
Institutes of Health (NIH), Office of Human Research Protection (OHRP), other 
government agencies as part of their duties, Investigator, or industry supporter. 
 
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6 
STUDY TREATMENT PROCEDURES  
Study treatment is MGD014 (also referred to as AEX2028, HIVA32 x CD3, or A32 x hXR32 
MP3) and is the only investigational drug administered in this study. Participants are required to 
continue their baseline ART throughout the study. ART will not be provided by the study. 
Appendix 1 details the schedule of assessments by study day. 
Administration of MGD014 takes place over 2 hours via IV infusion. In Part 1, each participant 
receives a single MGD014 infusion based on his/her assigned dose escalation cohort. In Part 2, 
all participants receive multiple MGD014 doses at the same dose as determined in Part 1. 
6.1 
Regimen  
Part 1: Dose escalation cohort (n= at least 20 participants) is a single ascending dose study with 
an aim of determining the safety, PK, and PD of ascending doses up to either the OBD or the 
MAD. 
Part 2: Dose expansion cohort (n= up to 6) is a multi-dose expansion cohort with repeat Q2W 
IV administrations of MGD014 at the OBD determined in Part 1. This dose was determined to be 
300 mcg/kg.  
6.2 
Method of Assigning Participants to Treatment Groups  
Participants will be assigned sequentially to the dose escalation and multi-dose expansion 
cohorts as specified in Section 4.2 and Section 4.3, respectively. Participants in the cohort 
expansion phase will receive the MGD014 dosage based upon results from the dose escalation 
phase (see Section 4.3). A predetermined number of participants will then be enrolled at the 
selected dose. 
6.3 
Blinding  
This is an open-label study. 
6.4 
Emergency Unblinding  
Not applicable. This is an open-label study. 
6.5 
Study Drug and Supplies  
6.5.1 
MGD014  
 
 
 
 
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MGD014 will be administered by IV infusion after dilution in 
 vehicle. 
6.5.2 
Vehicle  
 
 
6.6 
Study Drug Preparation and Administration  
6.6.1 
General Guidelines and Precautions  
MGD014 is administered to participants at very low doses. All doses employed in this study are 
described in units of micrograms/kilogram: A microgram (μg) is 1 millionth (1/106) of a gram 
(g), 1 thousandth (1/103) of a milligram (mg). 
MGD014 is a CD3-targeting therapy. Therefore, it is possible that MGD014 may induce 
severe/fatal CRS when administered to humans. Errors in dilution could result in 
severe/fatal CRS. 
Every reasonable precaution should be exercised in the preparation, verification, and 
administration of the MGD014 dose. Independent verification of participant weight, the 
calculated dose, and the IV pump setting must be reviewed and documented by a second 
individual trained in these procedures before study drug administration commences. 
6.6.2 
Study Drug Preparation  
Instructions on the preparation of the study drug infusion are detailed in the Pharmacy Manual. 
The University of North Carolina (UNC) Investigational Drug Services (IDS) Pharmacy stores, 
distributes, and maintains accountability for MGD014. The dispensing of each dose will be 
participant specific and by signed prescription. Upon receipt of the MGD014 doses from IDS, 
the study coordinator infuses the MGD014 to the participant in the research clinic according to 
the dose, schedule, and supportive care guidelines. 
 
MGD014 is administered as an open-label IV solution. 
Administer the calculated dose based on the participant’s actual weight at each dosing visit. 
Significant (≥ 10%) change in body weight from Visit 2 should prompt recalculation of dose. 
Study drug administration 
Reference MGD014 SOP entitled ‘MGD014 Product Infusion Guidelines and Emergency 
Management Plan’ for details. 
The following is performed prior to administration of MGD014: 
• Initiate, maintain, and verify IV access.  
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• Pre-dose assessments completed as listed in the Time and Events Schedule (Appendix 
1) and the Blood Sampling Schedule (Appendix 2).  
• Calculate the dose based on the participant’s actual weight at the Enrollment Visit in 
Step 1 (Visit 2). On infusion days, if there is a significant (≥ 10%) change in body 
weight from Visit 2, promptly recalculate the dose for administration. 
• Complete required ECGs in triplicate (approximately 1 minute apart) within 30 
minutes of the infusion. 
• Pre-medicate with the following study provided medications approximately 30 to 60 
minutes prior to infusion: 
o Diphenhydramine 25- 50 mg IV or equivalent H1-antihistamine.  
o Acetaminophen 650 mg oral administration (PO). 
Note: Contact study PI (or designee) for pre-medication doses if participant 
weighs less than 60 kg.   
For administration of MGD014: 
• MGD014 will be administered as an IV infusion over 120 minutes. The infusion rate 
may vary based on the total volume needed to administer the full dose. The total time 
needed to administer the dose may be longer than 120 minutes based on factors such 
as participant tolerance but should be completed no more than 6 hours after the 
product is prepared. Infusion access should be maintained and the participant observed 
for a minimum of 120 minutes following completion of the infusion (see Section 6.6.3 
for details). The MGD014 should be visually inspected for particulate matter and 
discoloration prior to administration. The vial should be returned if solution is cloudy, 
there is pronounced discoloration (solution may have pale-yellow or pale brown 
color), or there is foreign particulate matter. 
• Administer MGD014: Reference MGD014 SOP entitled ‘MGD014 Product Infusion 
Guidelines and Emergency Management Plan’ for details. 
 Do not mix the study drug with, or administer as an infusion with, 
other medicinal products, with the exception of normal saline IV 
solution. 
 All doses of MGD014 will be administered as an IV infusion over 
120 minutes  
Administration of the study drug should begin immediately after preparation but no later than 
4 hours after preparation when stored at room temperature (see Pharmacy Manual). If there is a 
delay in administration of study drug such that it will not be administered on the day of 
preparation, the medical monitor should be notified immediately. Instructions on how to proceed 
will be provided. 
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6.6.3 
Monitoring Post-administration  
Infusion or allergic reactions may occur with the infusion of protein-based therapeutics such as 
MGD014. Precautions for anaphylaxis should be observed during MGD014 administration. 
Supportive measures will follow guidelines established in the MGD014 SOP and may include, 
but are not limited to: epinephrine, antihistamines, corticosteroids, IV fluids, vasopressors, 
oxygen, bronchodilators, diphenhydramine or equivalent H1-antihistamine, and acetaminophen. 
Please refer to Section 7.1.2 for specific guidelines regarding the management of infusion 
reactions. Supportive care measures consistent with optimal patient care will be provided 
throughout the study according to institutional standards. 
The duration of monitoring following MGD014 infusions will vary from 2 to 24 hours post-
infusion depending on participant stage in the protocol and cohort assignment: 
• For Part 1: The first participant within each dose cohort to receive MGD014 will be 
monitored on-site for 24 hours post-infusion. Monitoring will occur in both the 
Clinical and Translational Research Center (CTRC), and in the adjoining main UNC 
hospital in a pre-allocated hospital provided research bed. Subsequent participants 
within the same dose cohort level will be monitored for 12 hours post-infusion in the 
CTRC. 
• For Part 2: Each participant will be monitored in the CTRC for 6 hours on-site 
following receipt of their first MGD014 infusion. The duration of direct monitoring 
may be reduced to 4 hours for subsequent infusions. Participants are required to return 
to the CTRC at designated times for blood collections.  
During the monitoring period, participants are observed for clinical AEs and the following 
procedures are performed: 
• Vital Signs (VS), Part 1: Taken immediately before infusion (approximately 3 minutes 
before the start of the infusion); at 15, 30, and 60 minutes after the start of infusion; at 
end of infusion; and following the infusion, every 15 minutes up to 60 minutes, then at 
2, 4, and 6 hours after the completion of infusion. VS will then be taken every 4 hours 
for the remaining post-infusion monitoring period, unless a clinical event necessitates 
more frequent VS monitoring. Participants admitted to an inpatient bed for completion 
of the 24-hour observation period will have VS completed per hospital unit policy for 
every 4 hour assessments or more frequently as clinically indicated. 
• VS, Part 2: Taken immediately before infusion (approximately 10 minutes prior to 
start of infusion); at 15, 30, and 60 minutes after the start of infusion; at end of 
infusion; and following the infusion, every 15 minutes up to 60 minutes, then every 
60 minutes up to 6 hours after the completion of first infusion and up to 4 hours for 
subsequent infusions.  
• Blood samples for PK, PD, and cytokine release per Appendix 1 and Appendix 2. 
• ECG: Perform 2 ECGs after the infusion is completed; 1) within 30 minutes of end of 
infusion and 2) 60 minutes after infusion. 
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In Part 1, the study coordinator will see participants at 24- and 48-hours post-infusion (± 5 
hours). Contact will be maintained for follow-up of complications and other participant concerns 
that arise during this time. 
In Part 2, the study coordinator will see participants at 24-hours post-infusion (± 5 hours) and on 
Day 3. Telephone or contact participants via their preferred way of communication for study 
visits conducted remotely after infusion to inquire about any reactions or potential treatment 
emergent adverse events (TEAEs). Participants will be instructed to contact the study coordinator 
or Investigator if any signs or symptoms of an AE occur not only after the infusions but at any 
time during the study. 
6.7 
Treatment Compliance  
MGD014 will be administered by trained study site personnel under the supervision of the PI (or 
designee). Records of MGD014 dose calculation, administration, and dosing regimen will be 
accurately maintained by site staff. Study drug accountability will be maintained and monitored 
during the study and at the completion of the study. Accurate accounting of MGD014 must be 
maintained. The PI, in collaboration with IDS Pharmacy, is accountable for study drug. Study 
drug disposition records must be kept in compliance with applicable guidelines and regulations. 
6.8 
Packaging and Labeling  
MGD014 study drug will be labelled according to U.S. requirements. Please see the Study 
Specific Pharmacy Manual for detailed information about the packaging and labeling of the 
study drug. 
6.9 
Storage and Accountability  
6.9.1 
MGD014 Storage  
MGD014 will be stored and dispensed by the UNC Hospitals IDS Pharmacy by prescription on a 
participant specific basis. The clinical supplies storage area at the site will be monitored by the 
IDS staff for temperature consistency. 
Vials containing study drug should be stored upright under refrigeration at 2 - 8°C (36 - 46°F) in 
an appropriate, locked room accessible only to pharmacy personnel, the PI (or designee), or duly 
designated personnel. The IDS staff’s responsibilities include maintaining, monitoring, and 
documenting the temperature in the pharmacy supply storage area per institutional guidelines. 
Vials should be protected from light during storage and should not be shaken or frozen.  
The clean-up and disposal of spilled, wasted, or unused medication and used syringes must be 
documented appropriately (i.e., witnessed) in accordance with applicable federal regulations, 
Good Clinical Practice (GCP) procedures, and the procedures for handling biohazardous 
substances. The IDS Pharmacy follows hospital and standard practices for avoidance of contact 
when preparing the study drug (UNC Hospital Policy (EHA 0024) called “Handling and 
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Disposal of Hazardous Drugs (Antineoplastic, Biologic, Cytotoxic, and Immunosuppressant 
Drugs). 
Accurate accounting of all study drug must be maintained. The IDS will keep an inventory of 
study drugs using the institution’s drug accountability logs. Study drug disposition records are 
kept in compliance with applicable guidelines and regulations. 
When the study is completed, copies of all study drug accountability records must be provided to 
the sponsor. Original study drug accountability records must be maintained with the rest of the 
documentation for inspection by the study monitors. 
6.10 
Return or Destruction of Study Drug  
Upon completion or termination of the study, all unopened vials of MGD014 study drug and 
 vehicle must be returned to MacroGenics or its representative, unless the site has 
received written authorization from MacroGenics to destroy study drug and/or vehicle at the site. 
All study drug returns to MacroGenics or its representative must be accompanied by the 
appropriate documentation and be clearly identified by protocol number on the outermost 
shipping container. 
Additional details regarding storage, handling, and accountability can be found in the Pharmacy 
Manual. 
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7 
POTENTIAL ADVERSE EVENTS AND SUPPORTIVE CARE 
MEASURES  
7.1 
Infusion Related Reactions Including Cytokine Release Syndrome  
MGD014 is an immune-modulation agent that may lead to T cell activation and killing of HIV-
infected cells. Activation of T cells can be associated with the production of various cytokines. 
IRR (including CRS) may occur with MGD014. These reactions may manifest with signs and 
symptoms that may include, but are not limited to, fever, chills, headache, rash, pruritus, 
arthralgia, hypo- or hypertension, bronchospasm, or other symptoms. 
IRR (including CRS) associated with MGD014 administration should be managed according to 
the standard practice of medicine. General guidelines for the management of such reactions are 
provided in the SOP. However, severe reactions may require more intensive interventions (e.g., 
steroids, anti-TNFα antibodies, and/or IL-6 inhibitors). 
Participants will be monitored closely for the development of IRR during infusions. The infusion 
room/area will have immediate access to medications and supportive measures for the treatment 
of severe hypersensitivity reactions, inclusive of resuscitation equipment and other supplies for 
the emergency management of an allergic/toxic reaction. All supportive measures consistent with 
optimal patient care will be provided throughout the study according to institutional standards.  
Symptoms of fever or chills will be carefully assessed and treated based on the assessment of the 
PI (or designee). An evaluation for infection including COVID-19 should be performed. Please 
refer to Section 7.1.2 for guidance regarding the management of infusion reactions. 
7.1.1 
Grading of Infusion Reactions  
Infusion reactions should be graded according to the criteria for acute systemic allergic reaction 
located in the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse Events, corrected Version 2.1, July 2017, which can be found on the DAIDS Regulatory 
Support Center Web site: http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids-
grading-tables. 
7.1.1.1 
Premedications and Prophylaxis  
In clinical testing of other CD3-based bispecific molecules, including BITE (blinatumomab) and 
DART® molecules used for oncology indications, administration of pre-medications has proven 
to be helpful in ameliorating symptoms associated with cytokine release. Although the risk of 
induction of cytokine release should be low in participants treated with MGD014, as a 
precaution, participants will be premedicated with antipyretics and/or antihistamines prior to 
dosing with MGD014 (see Section 6.6.2). The use of corticosteroids will be reserved for those 
circumstances where cytokine release symptoms develop despite the administration of 
premedication prior to dosing with MGD014 (Section 7.1.2). 
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7.1.2 
Management of Observed Infusion Reactions  
All changes in the infusion of MGD014, including interruption of the infusion and its duration, 
as well as reductions in infusion rate and duration must be recorded. 
The treatment guidelines (which may be modified as needed by the responsible PI (or designee) 
according to the best practices of medicine) for MGD014 infusion reactions will be in the study 
SOP. 
Grade 1: 
• Slow the infusion rate by 50%. 
• Monitor the participant for worsening of condition. 
• If the infusion reaction recurs and/or persists at the decreased rate of infusion, the rate 
of the infusion may be further reduced by 50% one additional time only. 
• Continue rate at 50% reduction and increase dose rate to the original rate by doubling 
the infusion rate after 30 minutes, as tolerated. 
• If symptoms persist but do not worsen, completion of the infusion will be at the 
discretion of the site PI (or designee) with careful monitoring. 
 
Grade 2: 
• STOP THE INFUSION AND DISCONNECT THE INFUSION TUBING FROM THE 
PARTICIPANT. NO FURTHER MGD014 SHOULD BE ADMINISTERED. 
• TO AVOID EXACERBATION OF INFUSION REACTION OR CRS: DO NOT 
FLUSH THE TUBING – ASPIRATE RESIDUAL DRUG FROM THE CATHETER. 
• Administer antihistamines and corticosteroids per SOP, and other 
medications/treatment as medically indicated. 
• IV fluids, supplemental oxygen, and bronchodilators should be considered as 
appropriate. 
 
Grade 3: 
• STOP THE INFUSION AND DISCONNECT THE INFUSION TUBING FROM THE 
PARTICIPANT. NO FURTHER MGD014 SHOULD BE ADMINISTERED. 
• TO AVOID EXACERBATION OF INFUSION REACTION OR CRS: DO NOT 
FLUSH THE TUBING – ASPIRATE RESIDUAL DRUG FROM THE CATHETER. 
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• Administer antihistamines and corticosteroids per SOP and other 
medications/treatment as medically indicated. 
• IV fluids, supplemental oxygen, and bronchodilators should be considered as 
appropriate. 
 
Grade 4: 
• STOP THE INFUSION AND DISCONNECT THE INFUSION TUBING FROM THE 
PARTICIPANT. NO FURTHER MGD014 SHOULD BE ADMINISTERED. 
• TO AVOID EXACERBATION OF INFUSION REACTION OR CRS: DO NOT 
FLUSH THE TUBING – ASPIRATE RESIDUAL DRUG FROM THE 
CATHETER. 
• Administer antihistamines and corticosteroids per SOP and other 
medications/treatment as medically indicated. Consider additional medications as per 
SOP (e.g., an IL-6 receptor inhibitor or IL-6 inhibitor, an IL-2 receptor inhibitor, 
and/or an anti-TNF antibody). 
• Give epinephrine or bronchodilators as indicated. 
• Support ventilation and blood pressure as indicated. 
 
7.2 
COVID-19/SARS-CoV-2 Infection  
The following guidelines apply to participants with confirmed (positive by regulatory authority 
approved/authorized test) or presumed (test pending/clinical suspicion) coronavirus disease 2019 
(COVID-19)/severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: 
For participants with active SARS-CoV-2 infection, study drug should be delayed for at least 
14 days from the start of symptoms.  
Prior to restarting study drug, participants should be afebrile for 72 hours and SARS-CoV-2–
related symptoms should have recovered to ≤ Grade 1 for a minimum of 72 hours. The sponsor 
should be informed when resuming study drug. 
The sponsor must be informed within 24 hours of awareness of a participant with COVID-19/ 
SARS-CoV-2 infection. 
 
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8 
CONCOMITANT THERAPY AND RESTRICTIONS  
8.1 
Concomitant Therapy  
All concomitant medications, including ART and prophylactic pre-infusion medications 
administered during the participant’s participation in the study until the end of treatment visit 
must be recorded in the source document. All changes in infusions of study drug, including 
interruptions and their duration, as well as reductions in rate and duration, must be recorded. 
Medications taken within 4 weeks prior to administration of each infusion must also be recorded 
on the source documentation. 
8.1.1 
Prohibited Therapy  
The following rules concerning concurrent treatment(s) will apply in this study: 
• Participants may not receive other investigational drugs during the period of study 
participation. 
• Participants may not be switched to an ART regimen containing maraviroc and/or 
enfuvirtide. 
• The use of other immune-suppressive agents is prohibited, unless they are being used 
to treat an AE. 
• Restrictions on medications taken prior to enrollment in the study are described in 
Section 5.2. 
• Vaccinations, inclusive of flu vaccines, prohibited within 4 days prior to Day 0 
through 5 days after last infusion of study drug. 
• Participants requiring any systemic antiviral, antifungal, or antibacterial therapy for 
active infection must have completed treatment no less than one week prior to 
initiation of study drug.  
 
8.1.2 
Permitted Therapies  
Participants may receive the following concurrent therapy: 
• Regularly prescribed medications such as antipyretics, analgesics, antidepressants, 
sleep medications, megestrol acetate, testosterone, and other medications for chronic 
conditions that do not interact with MGD014; 
• Oral and topical antibiotics for bacterial infections;  
• Intermittent use of inhaled corticosteroids (e.g., for chronic obstructive pulmonary 
disease [COPD], asthma) is only permitted for participants not receiving ritonavir or 
cobicistat as part of their current ART regimen and after consultation with the study PI 
or designee). 
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• Sporadic topical use of corticosteroids (e.g., creams) to small areas of the skin 
(15 cm2) after consultation with the PI (or designee) is only permitted for participants 
who are not receiving ritonavir or cobicistat as part of their current ART regimen; and 
• For treatment of IRR (Grade 1 and Grade 2) flu-like symptoms, non-steroidal anti-
inflammatory drugs (NSAIDs) may be used to alleviate symptoms under a physician’s 
guidance and for a limited period of time. 
 
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9 
STUDY PROCEDURES  
This section provides a general description of the procedures and assessments associated with 
this study. The timing of the study procedures is presented in Appendix 1. 
9.1 
Study Visits  
During the COVID-19 pandemic, alternative methods for conducting study assessments should 
be considered when compliance, feasibility, and safety can be assured. These methods may 
include: 
• Remote visits, e.g., via telephone/video (using compliant video-conference tools as 
permitted by HIPAA regulations) 
• Use of primary care centers and local laboratories for blood draws and 
imaging/radiographs 
If alternative methods are used, local laboratory reference ranges will be documented and 
submitted to the sponsor. If local laboratory testing other than McLendon or LabCorp are used, 
their results and laboratory accreditation should be retrieved and documented in the participant’s 
study records. 
9.2 
Informed Consent  
Prior to performing any study-related procedure or assessments, the study coordinator discusses 
the study with the potential participant and obtains signed informed consent. This 
communication will be documented. Labs/procedures completed during a routine clinical care 
appointment that are the same as the study screening labs and/or procedures and completed 
within the 14 days preceding the screening visit can be used to qualify the participant upon 
approval by the study PI or designee. 
9.3 
Screening Period  
Screening evaluations will be performed within 8 weeks (56 days) prior to study drug 
administration on Day 0 unless otherwise specified. At the 1st screening visit, participants will 
screen for the study. Only those participants who meet all eligibility criteria specified in 
Section 5.1 Inclusion Criteria and Section 5.2 Exclusion Criteria will be enrolled. A unique PID 
will be assigned during the screening visit. Participants who had previously completed Part 1 and 
are being considered for Part 2 will maintain the same PID and will be assigned a new study-
specific identifier (SID). 
Participants who are unable to meet protocol defined eligibility criteria at the Screening Visit 
(Step 1, Visit 1) may be eligible to re-screen again at the PI (or designee)’s discretion. In such 
cases, the same PID will be used. If a screen failure or the failure to enroll is due to the inability 
to meet one of the laboratory parameters (hematology, chemistry, HIV RNA, or CD4 T cell 
count), a laboratory retest of the failed criteria may be performed one time only. If the repeat 
value is within eligibility requirements, the participant can enroll on the study. 
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9.4 
Enrollment and Registration  
Step 1 Visit 1 determines eligibility and enrollment at Visit 2. Once the potential participant has 
been determined to be eligible for enrollment into the study, the participant must be registered 
with MacroGenics. The following information should be provided during registration:  
• Year of birth  
• Date of signed informed consent  
• Planned date of first administration  
 
Instructions for the registration process are provided in the Study SOP. 
9.5 
Medical History  
Significant medical history should be obtained during the screening visit. All concurrent medical 
conditions in the last 60 days and any significant medical conditions (e.g., hospitalizations, 
surgeries, prior medical history) should be collected. Medical history obtained at Screening will 
include demographic information (e.g., date of birth, gender, race, and ethnicity, etc.), 
participant’s medical history, HIV testing history (CD4 and VL) and HIV medication history, 
inclusive of prior genotypes (if available). Safety updates will occur at all clinical visits, 
according to Appendix 1. 
During the Step 1 screening period (prior to MGD014 administration), any untoward event that 
occurs should be collected as a concurrent medical history and not as an AE, unless it is due to a 
protocol-related procedure. Thereafter (i.e., after the time of study drug administration), any 
untoward event should be collected as an AE. 
9.6 
Prior and Concomitant Medications  
All concomitant medications administered during screening and the participant’s participation in 
the study until the end of study visit must be recorded in the source. Concomitant medications 
will be reviewed at every study visit. 
Prescription and non-prescription medications taken within 4 weeks prior to screening must be 
recorded on the source document. 
9.7 
ART Adherence  
ART adherence will be reviewed at every visit. Non-adherence will be defined as having missed 
more than 9 total days in the 3 months prior to screening. Assess any missed doses while on 
study and discuss with PI (or designee). Continuance on study will be contingent on ART 
adherence. 
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9.8 
Physical Examination  
Complete physical examination will include examination of skin, head, eyes, ears, nose, throat, 
lymph nodes, heart, chest, lungs, abdomen, extremities, and neurologic system according to 
schedule specified in Appendix 1. A directed physical exam will be performed at the visits 
indicated in the SOE, according to Appendix 1, and includes VS. The targeted or directed 
physical exam addresses any previously identified or new event that the participant experiences 
since the last study visit or any unresolved signs or symptoms previously experienced. In 
addition to the VS, this assessment includes updates to signs and symptoms, and clinical 
assessment of HIV disease. 
9.9 
Vital Signs  
At each study visit, the VS (body temperature (T), pulse (P), respiratory rate (RR), seated blood 
pressure (BP)) and weight will be recorded according to the schedule specified in Appendix 1. 
Height is only required at Step 1, Visit 1. 
Repeat VS (T, P, RR, BP) may also be captured as necessary to elucidate the course of any 
untoward event or AE and may be inclusive of all or individual VS components as required to 
address monitoring of the AE. 
9.10 
Leukapheresis  
Part 1: 
The leukapheresis is optional in Part 1. Participants consenting to this optional procedure will 
have the procedure at Visit 2 or at any time point between Visit 2 and the day of the infusion. 
Part 2: 
The leukapheresis is optional in Part 2. Participants consenting to this optional procedure will 
undergo 2 leukapheresis procedures in Part 2. The first leukapheresis occurs at baseline 
completed at Visit 2. The second leukapheresis procedure will occur in Step 3, the post treatment 
phase, approximately 2 weeks post-completion of MGD014 therapy (± 2 weeks). 
All leukapheresis products will be transported on the day of collection to the 
 
Laboratory on the UNC campus. 
NOTE: Refer to the Apheresis SOP and Study Specific Lab Manual for procedures specific to 
this study. 
Participants who experience a Grade 3 or higher toxicity during the leukapheresis will be 
evaluated on a case by case basis to understand the cause of the Grade 3 event. If the clinical 
situations (i.e., vaso-vagal response) that lead to the discontinuation of the leukapheresis 
procedure is determined by the study PI in collaboration with the apheresis medical director to be 
situational and poses no apparent harm to the participant, the leukapheresis procedure may be 
repeated. However, if determined by the study PI, apheresis medical director, or the medical 
monitor that repeated leukapheresis would be harmful to the participant, then he/she will be 
terminated from the study. 
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The only exception to this discontinuation policy will be related to elevations in BP. Elevated BP 
observed during the leukapheresis procedure will be monitored via apheresis Lab policies. These 
will be noted and documented but will not be used to discontinue study participation.  
9.11 
Clinical Laboratory Tests  
Blood and urine specimens will be collected according to the schedule specified in Appendix 1. 
Safety laboratory tests can be performed up to 7 days prior to the infusion and must be reviewed 
before study drug administration. 
Monitoring HIV RNA levels 
In the event of HIV-1 viral load of ≥ 50 copies/mL after the infusion of MGD014, the following 
should occur per standard of care: 
• Adherence to ART should be carefully assessed and documented. 
• A standard HIV RNA assay should be repeated within 1-4 weeks. 
• HIV resistance testing will be performed at the time of drawing a confirmatory 
sample. 
• In the event of HIV-1 viremia ≥ 150 copies/mL, the participant may continue with 
study treatment if repeat testing is < 100 copies/mL within 4 weeks and < 50 
copies/mL within 12 weeks. 
• HIV RNA will be repeated every 2 weeks, or sooner as clinically indicated, until <50 
copies/mL. 
• In the event of confirmed HIV-1 viremia and documented adherence to ART, ART 
should be managed by the primary care provider in discussion with the study team. 
The results of the HIV resistance tests will be shared with the participants and their 
care providers. 
 
9.12 
Central Laboratory Assays  
Study specific safety and research samples will be collected at the research visit. Safety and 
clinically relevant assays will be performed at UNC McLendon Laboratories or LabCorp. 
Research assays will be processed and stored in associated research laboratories. Additional 
details on collection, processing, storage, and shipping of samples will be provided in the Study 
Specific Laboratory Manual. 
9.13 
Pharmacokinetics  
Blood samples for MGD014 PK and ADA will be collected at the time points shown in 
Appendix 1 and Appendix 2. Further details of blood collection and processing will be provided 
in the Study Specific Laboratory Manual. Actual collection date and time must be recorded in the 
source documents. 
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9.14 
Immunogenicity  
Blood samples will be collected from the participant’s arm contralateral to the site of IV 
infusion. If an indwelling catheter is used, the fluid in the indwelling catheter will be removed 
and discarded prior to the collection of blood sample for ADA assessment. 
9.15 
Pharmacodynamics  
Appendix 1 and Appendix 2 lists the sampling schedule to be followed for the assessment of the 
PD activity of MGD014. Further details of blood collection and processing will be provided in 
the Study Specific Laboratory Manual. Actual collection times must be recorded in the source 
documents. 
9.16 
Sample Collection, Storage, and Shipping  
All blood samples acquired for PK and ADA described in Section 10 will be processed at the 
UNC CFAR HIV/STD Laboratory Core (CHSLC) and shipped to MacroGenics for analysis. 
All blood samples acquired for serum cytokine assays described in Section 10.3.2 will be 
processed at CHSLC and shipped to Duke University for analysis. 
Samples for RO, T cell phenotype, resting CD4 T Cell infection, and exploratory research assays 
(Sections 10.3.1, 10.3.3, and 11.1.1, respectively) will remain at UNC for processing and 
storage. 
Samples for Plasma HIV-1 RNA SCA assays described in Section 11.1.2 will be processed at 
UNC CHSLC, stored, and shipped in batch to National Cancer Institute (NCI) for analysis. 
Details on laboratory specimen processing, storage, and shipping will be provided in the Study 
Specific Laboratory Manual. 
9.17 
Electrocardiography Monitoring  
Twelve-lead ECGs will be obtained according to Appendix 1 in order to evaluate the potential 
cardiac effects of MGD014, including QT interval. There are no requirements for fasting and no 
restrictions for fluid and food intake by the participants during this study. ECGs will be obtained 
as per Appendix 1. 
9.18 
End of Study Visit  
End of study visit occurs after the last dose of study drug. See  Appendix 1, Time and Events 
Schedule.  
 
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10 
ASSESSMENT OF PHARMACOKINETICS AND 
PHARMACODYNAMICS  
10.1 
Pharmacokinetics Assessments  
Serum concentrations of MGD014 will be monitored. Single and multiple dose PK parameters of 
Cmax, time to maximal concentration (Tmax), area under the concentration-time curve for a dosing 
interval (AUCtau), trough concentration (Ctrough), CL, Vss, and terminal half-life (t1/2) will be 
derived from serum concentration versus time data. Population PK analyses may be conducted 
using data from this study alone or combined with data from other studies. 
10.2 
Immunogenicity Assessments  
Blood samples for immunogenicity assessments (ADA) will be collected at the time points 
shown in Appendix 2. 
10.3 
Pharmacodynamic Assessments  
10.3.1 
Receptor Occupancy and/or T-cell Binding  
The receptor occupancy of MGD014 binding sites on CD3-expressing T cells in peripheral blood 
will be estimated. The percentages of T cells in peripheral blood with MGD014 bound will be 
measured. 
% RO = (MFI of anti-MGD014 events with saline)/(MFI of anti-MGD014 events with excess 
MGD014) ×100. An event is defined as either a CD4-expressing or CD8-expressing T cell that 
has MGD014 binding to the T cell as detected by an anti-MGD014 antibody.  
10.3.2 
Serum Cytokine Analysis  
Serum samples will be analyzed for concentrations of serum cytokines, which will include, but 
not be limited to, IFN-γ, IL-2, IL-5, IL-6, IL-10, and TNF-α. 
10.3.3 
T cell Phenotype and Function  
Flow cytometry panels for T cell phenotyping will include: T cell subsets, surface expression 
levels of activation of T cells, and exhaustion of T cells. Functional changes to circulating CD8 
T cells by flow cytometry may be assessed. 
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ASSESSMENT OF EFFICACY  
11.1 
Efficacy Assessments  
Efficacy will be assessed by examination of the ability of MGD014 administration to alter 
markers of persistent HIV-1 infection in individuals on ART if the participant consents to the 
optional leukapheresis through evaluation of: a) the frequency of resting CD4 T cell infection by 
QVOA and b) levels of plasma HIV-1 RNA, as measured by SCA. 
11.1.1 
Resting CD4 T Cell Infection  
Lymphocytes by continuous-flow leukapheresis (samples obtained as per Appendix 1) and 
resting CD4 T cells are isolated as previously described [52]. 
Quantitative viral outgrowth assay measurements determine the frequency of CD4 resting cell 
infection, expressed as infectious units per million (IUPM). The resting cell infection frequency 
is a measure of the lowest detectable HIV reservoir. A statistically significant decline in the HIV 
reservoir would be considered evidence of a reduction in the HIV reservoir. 
11.1.2 
Plasma for SCA  
Residual low-level HIV-1 viremia by SCA, as evidence suggests that such HIV-1 viremia 
originates in persistently infected cells, and low-level HIV-1 viremia might be reduced by an 
augmented antiviral immune response.  
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ADVERSE EVENT REPORTING AND ASSESSMENT OF SAFETY  
The safety assessment will be based on the evaluation of all AEs that occur from the time of 
initiation of administration of study drug through the End of Treatment Visit or 30 days after the 
last dose of study drug (whichever is later) and will be determined based on signs, symptoms, 
physical examination findings, and/or laboratory test results from enrolled participants, as 
appropriate. 
If an AE occurs, the study coordinator, in collaboration with the PI, will evaluate the severity and 
seriousness of the AE and the relationship to the study drug, and will document the findings.  
All adverse events will be graded according to the Division of AIDS Table for Grading the 
Severity of Adult and Pediatric Adverse Events, corrected Version 2.1, July 2017, which can be 
found on the DAIDS Regulatory Support Center Web site: http://rsc.tech-res.com/clinical-
research-sites/safety-reporting/daids-grading-tables. 
AEs reported between the time the potential participant signs the informed consent form (ICF) 
and the administration of the first dose of study drug will be captured as medical history unless 
the AEs are attributed to protocol-specified procedures that are not part of standard of care that 
occur during this time period, in which case the AEs will be collected on the Source Document 
Adverse Event Form. Protocol-related AEs and SAEs will be collected from the time the 
participant has consented to study participation. 
SAEs considered related to study drug may be reported at any time, even after the participant’s 
final treatment visit. 
The reporting of laboratory abnormalities as both laboratory findings and AEs should be avoided. 
Laboratory abnormalities should not be reported as AEs unless any one of the following are met: 
• Any criterion for an SAE is fulfilled 
• The laboratory abnormality causes the participant to discontinue from the study 
treatment 
• The laboratory abnormality causes the participant to interrupt the study treatment 
• The laboratory abnormality causes the participant to modify the dose of study 
treatment 
• The laboratory abnormality requires intervention 
• The PI (or designee) determines the laboratory value as an abnormal change from 
baseline and is of clinical significance for that participant 
• Laboratory values consistent with the DAIDS designation of Grade 3 (events as severe 
or medically significant) and Grade 4 (events as life-threatening), should be reported 
as AEs or SAEs, as appropriate. 
 
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12.1 
Definitions  
12.1.1 
Adverse Event  
AE means any untoward medical occurrence in a participant or clinical trial participant 
associated with the use of a drug in humans, whether or not considered drug related. An adverse 
event can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example, see Section 12.2.1), symptom or disease temporally associated with the use 
of a medicinal product, whether or not considered related to the medicinal product. 
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities. 
12.1.2 
Adverse Drug Reaction  
Adverse drug reaction (ADR) is a noxious and unintended response to the medicinal product 
related to any dose. As used herein, the phrase "response to a medicinal product" means that a 
causal relationship between a medicinal product and an AE is at least a reasonable possibility. 
12.1.3 
Adverse Event of Special Interest  
An AE of special interest (AESI) is an event of scientific and medical interest or concern to the 
sponsor, for which ongoing monitoring and rapid communication to the sponsor could be 
appropriate. It may be a serious or non-serious AE, which may require further investigation in 
order to characterize and understand it. 
12.1.4 
Attribution/Assessment of Causality  
Attribution/Assessment of Causality is a determination that describes the relationship or 
association of the study drug with an adverse event.  
This assessment of causality or relationship of AEs to the study drug is provided by the PI and is 
determined by 1) temporal relationship of the event to the administration of study drug; 2) 
whether an alternative etiology has been identified, and 3) biological plausibility.  
The causality assessment categories that will be used for this study are described below.  
Causality assessments that are considered not related to study drug: 
Not related: 
The event is related to an etiology other than the study drug (the 
alternative etiology must be documented in the participant’s medical record). 
Unlikely: 
The event is unlikely to be related to the study drug and likely to be 
related to factors other than study drug. An alternate explanation is more likely (e.g., 
concomitant drugs, concomitant disease), or the relationship in time suggests that a causal 
relationship is unlikely. 
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If an AE or SAE is considered "unlikely" or "unrelated" to study drug, the PI should offer his/her 
clinical opinion as to what factor(s), agent(s), or process(s) were the likely causative mechanism 
for the event. 
Causality assessments that are considered related to study drug: 
Possible: 
There is an association between the event and the administration of the 
study drug and there is a plausible mechanism for the event to be related to study drug; 
but there may also be alternative etiology, such as characteristics of the participant’s 
clinical status or underlying disease. 
Probable: 
There is an association between the event and the administration of study 
drug, a plausible mechanism for the event to be related to the study drug and the event 
could not be reasonably explained by known characteristics of the participant’s clinical 
status or an alternative etiology is not apparent. 
Definite: 
There is an association between the event and the administration of study 
drug; a plausible mechanism for the event to be related to the study drug, causes other 
than the study drug have been ruled out, and/or the event re-appeared on re-exposure to 
the study drug. 
 
12.1.5 
Serious Adverse Events  
An SAE is any AE that results in any of the following outcomes: 
• Death 
• Life-threatening (immediate risk of death) 
• Inpatient hospitalization for longer than 24 hours or prolongation of existing 
hospitalization (even if the event is Grade 1) 
• Persistent or significant disability or incapacity 
• Congenital anomaly/birth defect 
• Important medical events  
 
12.1.6 
Severity Criteria  
Event severity will be assigned according to the assessment of the PI using Division of AIDS 
(DAIDS) grading table Version 2.1. 
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Severity Grade for Parameters Not Identified in the Grading Table:  
The functional table below should be used to grade the severity of an AE that is not specifically 
identified in the grading table. In addition, all deaths related to an AE are to be classified as 
Grade 5. 
 
PARAMETER  
GRADE 1  
MILD  
GRADE 2 
MODERATE  
GRADE 3 
SEVERE  
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING  
Clinical adverse 
event NOT 
identified elsewhere 
in the grading table  
Mild symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional activities 
with intervention 
not indicated  
Moderate symptoms 
causing greater than 
minimal 
interference with 
usual social & 
functional activities 
with intervention 
indicated  
Severe symptoms 
causing inability to 
perform usual social 
& functional 
activities with 
intervention or 
hospitalization 
indicated  
Potentially life-
threatening 
symptoms causing 
inability to perform 
basic self-care 
functions with 
intervention 
indicated to prevent 
permanent 
impairment, 
persistent disability, 
or death  
 
12.2 
Adverse Event Collection and Documentation  
12.2.1 
All Adverse Events  
Adverse Events (AEs) leading to discontinuation, potential autoimmune events, AEs of ≥ Grade 
3 severity, related adverse events, and lab abnormalities as well as safety concerns, will be 
communicated in a timely manner to the UNC IRB, MacroGenics, National Institute of Allergy 
and Infectious Diseases (NIAID), and FDA per the reporting requirements of each 
body/authority. The sponsor of this study is MacroGenics. The PI at UNC-CH will be 
responsible for reporting to MacroGenics, who in turn, will be responsible for reporting to 
NIAIDs, and FDA per the reporting requirements of each body/authority. AEs occurring after the 
participant undergoes early termination or completes the trial need not be reported unless the 
event is serious, and the PI believes that the event may have been caused by the study drug or a 
protocol procedure. 
All participants who receive at least one dose of study drug will be considered evaluable for 
safety. AEs will be determined based on signs, symptoms, physical examination findings, and/or 
laboratory test results from enrolled participants as appropriate. 
All AEs whether serious or non-serious, will be evaluated from the time a signed and dated ICF 
is obtained until 30 days following the last dose of study drug. AEs and SAEs reported between 
the time the participant signs the ICF and the administration of the first dose of study drug will 
be captured as concurrent medical history unless the events are attributed to protocol-specified 
procedures. AEs attributed to protocol-specified procedures will be recorded in the database and 
provided to the sponsor. Additionally, the IRE form will be completed and provided, as 
appropriate. 
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All AEs must be reported, regardless of seriousness, severity, or presumed relationship to study 
drug, must be recorded using medical terminology in the AE source document. AEs will be 
coded to the Preferred Term using the current version of MedDRA available at study initiation. 
All records will need to capture: 
• The details of the duration, severity, and seriousness of each AE, 
• The action taken with respect to the study drug(s), 
• The PI attribution/causality assessment concerning the relationship of the AE to study 
therapy, 
• The outcome of the event. 
 
Whenever possible, diagnoses should be given when signs and symptoms are due to a common 
etiology (e.g. cough, runny nose, sneezing, sore throat, and head congestion should be reported 
as "upper respiratory infection"). All treatment measures that are required for AE management 
must be recorded in the source document. The intensity (severity) of AEs will be assessed and 
serious events will be determined by the definition provided in Section 12.1.5 above. 
Clinical Laboratory Changes: Safety laboratory assessments will be carried out locally at UNC 
and evaluated by the PI to ensure participant safety. The PI is responsible for reviewing the 
results of all laboratory tests as they become available. 
• Laboratory values that fall outside of a clinically accepted reference range or values 
that differ significantly from previous values must be evaluated by the Investigator (or 
designee) for clinical significance. The Investigator (or designee) may repeat the 
laboratory test or request additional tests to verify the results of the original laboratory 
tests. 
• If the Investigator determines the laboratory value is an abnormal change from 
baseline and is of clinical significance for that participant, it is considered an AE. 
• Generally, Grade 1 and Grade 2 laboratory findings need not be reported as AEs unless 
deemed clinically significant by the Investigator. 
• Consistent with the DAIDS designation of Grade 3 events as severe or medically 
significant and Grade 4 events as life-threatening, Grade 3 and Grade 4 laboratory 
findings should be reported as AEs or SAEs, as appropriate. 
• The test result or finding should be reported as the AE. Such laboratory values should 
generally be recorded as “increased” or “decreased” (e.g., change from baseline 
potassium of 5.0 to 3.5 mEq/L =potassium decreased). 
 
The sponsor has responsibility for appropriate reporting of AEs to the regulatory authorities. The 
sponsor will also report to the Investigator (or designee) all suspected unexpected serious 
adverse reactions (SUSARs). The Investigator (or designee) must report SUSARs to the UNC 
IRB, unless otherwise required and documented by the IRB. 
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12.2.2 
Immediately Reportable Events  
IREs are AEs that must be reported immediately to MacroGenics within 24 hours of the study 
site’s awareness of the event: 
• All SAEs  
• Pregnancy in a study participant or partner of a study participant. 
• The following AESI: ≥ Grade 2 CRS /IRR 
• Administration of a dose significantly greater (specifically, + 20 % or higher) than the 
planned dose, and results in an event of clinical consequence. 
• AEs leading to permanent discontinuation of study drug in an individual participant. 
• Withdrawal of the participant from study drug administration for any reason 
• Product quality issues with an associated clinical consequence. 
• Participant diagnosed with COVID-19/SARS-CoV-2 infection.  
 
In those cases, in which the IRE is considered related to study drug, the study drug may be 
discontinued, and the participant will continue participation in the study for observational safety 
and analysis (except for cases where the participant is withdrawn from the study by the PI (or 
designee) or withdrew the consent). At any time after completion of the study, if an PI (or 
designee) becomes aware of a SAE that s/he suspects is related to study drug, the PI (or 
designee) should report the event to MacroGenics Product Safety. 
12.2.3 
Serious Adverse Events  
All SAEs occurring during the study must be reported to MacroGenics and the UNC IRB per the 
MacroGenics and UNC IRB reporting requirements. A written report (IRE Form) will be faxed 
or emailed to MacroGenics within 24 hours. Additional information will be supplied as 
requested. All SAEs occurring during the study will be reported by MacroGenics to DAIDS 
following guidelines for expedited AE (EAE) reporting and to the FDA according to those 
regulatory bodies’ guidelines. 
After 30 days following the last dose of study drug administration only SAEs the PI (or 
designee) considers related to study drug or a protocol procedure, should be reported to the 
sponsor.  
Information regarding SAEs will be transmitted to the sponsor using the IRE Form, which must 
be completed and signed by the PI from the study site and transmitted to the sponsor within 24 
hours of the site becoming aware of the serious adverse event.  
All Grade 3 or Grade 4 SAEs considered related to study drug must be followed until recovery to 
baseline or Grade 1 with the date of resolution recorded in the source documents. In addition, the 
investigator should report all reportable Grade 3 or Grade 4 SAEs to the IRB. Resolution of an 
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event is defined as the return to pre-treatment status or stabilization of the condition with the 
expectation that it will remain chronic. 
All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the participant's participation in the study, must be followed until any of the 
following occurs: 
• The event resolves. 
• The event stabilizes. 
• The event returns to baseline, if a baseline value/status is available. 
• The event can be attributed to etiology other than the study drug or to factors unrelated 
to study conduct.  
• It becomes unlikely that any additional information can be obtained (participant or 
health care practitioner refusal to provide additional information, lost to follow-up 
after demonstration of due diligence with follow-up efforts). 
 
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the 
course of a participant 's participation in a study must be reported as a SAE, except 
hospitalizations for the following: 
• Hospitalizations not intended to treat an acute illness or adverse event (e.g., social 
reasons such as pending placement in long-term facility). 
• Surgery or procedure planned before entry into the study (must be documented in the 
source document). 
 
12.2.4 
Protocol-specific Adverse Events of Special Interest (AESI)  
Specific adverse events or groups of adverse events will be followed as part of standard safety 
monitoring activities by the sponsor. All AEs will be reported in the database. The sponsor will 
be notified of these events within 24 hours of awareness by the site, if grade 2 or greater, 
regardless of seriousness (i.e., serious and non-serious adverse events). 
• CRS 
• IRR   
 
12.2.5 
Pregnancy  
All initial reports of pregnancy in female participants or partners of male participants must be 
reported to the sponsor by the study-site personnel within 24 hours of their knowledge of the 
event using the Immediately Reportable Event form. Additionally, the Pregnancy Notification 
Form should be completed. Abnormal pregnancy outcomes (e.g. spontaneous abortion, fetal 
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death, stillbirth, congenital anomalies, ectopic pregnancy) are considered serious adverse events 
and must be reported using the IRE Form. Any participant who becomes pregnant during the 
study must discontinue further study drug administration. 
Because the effect of the study drug on sperm is unknown, pregnancies in partners of male 
participants included in the study will be reported by the study-site personnel within 24 hours of 
their knowledge of the event. If the female partner of a male participant becomes pregnant within 
24 weeks after the last MGD014 infusion, a request to the partner will be made to complete a 
Pregnant Partner Consent Form so that the pregnant partner, fetal and/or newborn information 
can be collected. 
Upon confirmation of the pregnancy with a serum pregnancy test, the participant will be 
followed for the outcome of pregnancy. All live newborns will be followed at six months after 
the birth, and all necessary information will be collected to assess the effects of study drug on the 
newborn. If necessary, the follow-up period will be extended for the newborn. 
12.2.6 
Reporting of Adverse Events to the Sponsor and DAIDS  
Throughout the study, the Investigator must document all AEs in the source documents (and 
database) in a timely manner. IREs, as defined in Section 12.2.2 are events that must be reported 
immediately to MacroGenics Product Safety or designee within 24 hours of being identified and 
be entered into the database within 5 calendar days. The sponsor, MacroGenics, is responsible 
for reporting to DAIDS. 
All reportable AEs must have their severity graded along with attribution to study drug recorded. 
AEs leading to discontinuation, potential autoimmune events, AEs of ≥Grade 3 severity related 
to MGD014, as well as safety concerns will be communicated within 24 hours to MacroGenics 
and the UNC IRB, as required. MacroGenics will report to the DAIDS and FDA per their 
reporting requirements. 
All AEs and SAEs must be followed until resolution, or they become chronic, or stable. The 
resolution status of such an event must be documented. In addition, the PI should report all 
follow-up for reportable AEs and SAEs to the UNC IRB and MacroGenics. MacroGenics will 
report all follow up to DAIDS and FDA. 
The PI (or designee) will immediately complete and transmit the Immediately Reportable Event 
(IRE) Report Form, within 24 hours of identifying the event, to MacroGenics Product Safety or 
designee. The IRE Report Form and Completion Guidelines, and Contact Information for 
Reporting IREs, are found in the Study Procedures Manual. 
For reports of pregnancy, the IRE Report Form AND the MacroGenics Pregnancy Exposure 
Form must be completed and transmitted. The Investigator must attempt to follow the pregnancy 
to term or termination in order to report the outcome and health status of the mother and child. 
The Pregnancy Exposure Form is found in the Study Procedures Manual. 
Please refer to the Table 2 for reporting timeframes by event type: 
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Table 2 
Safety Reporting by UNC by Event Type  
Event Type 
Report to MG via 
Immediately 
Reportable Event 
Form within 24 hours 
of awareness 
Pregnancy 
Exposure Form 
(within 24 hours 
of awareness)  
to MG 
Adverse 
Event Form  
(UNC 
database) 
Report to 
UNC IRB  
 All SAEs 
X 
 
X 
X 
Pregnancy in a study 
participant or partner of a 
study participant 
X 
X 
X 
X 
AESIs: ≥ Grade 2 Cytokine 
Release Syndrome/Infusion-
Related Reaction 
X 
 
X 
X 
Administration of a dose 
significantly greater 
(specifically, + 20% or 
higher) than the planned 
dose, and results in an event 
of clinical consequence. 
X 
 
X 
X 
AEs leading to permanent 
discontinuation of study drug 
in an individual participant. 
X 
 
X 
X 
Withdrawal of the 
participant from study drug 
administration for any reason 
X 
 
X 
X 
Product quality issues with 
an associated clinical 
consequence. 
X 
 
X 
X 
COVID-19/SARS-CoV-2 
Infection 
X 
 
X 
X 
Non-serious AEs 
 
 
X 
 
 
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13 
PRODUCT QUALITY COMPLAINT AND HANDLING  
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, i.e., any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of participants, 
investigators, and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor 
has established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates 
will be conducted in accordance with those procedures. 
13.1 
Procedures  
All initial PQCs must be reported to the sponsor by the study-site personnel, after being made 
aware of the event, and those that are associated with clinical consequences must be reported 
within 24 hours.  
If the defect is combined with a SAE, the study-site personnel must report the PQC to the 
sponsor according to the SAE reporting timelines (refer to Section 12.2.3). A sample of the 
suspected product should be maintained for further investigation if requested by the sponsor. 
13.2 
Contacting Sponsor Regarding the Product Quality  
The name(s) (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed in the Study Specific Procedure Manual.  
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14 
PLANNED STATISTICAL METHODS  
The majority of the statistical summaries for this Phase 1 trial will be descriptive. Summary 
statistics will consist of absolute and relative frequencies of each category of discrete variables of 
means, standard deviations, coefficient of variations, medians, and minimum and maximum 
values of continuous variables. 
14.1 
Determination of Sample Size  
The number of participants is not based on statistical power calculations. A 1+3 design is utilized 
in the first two dose levels of Part 1 because the starting dose is considered biologically 
conservative and the anticipated risk of DLT is low. A 3+3 design is used for dose cohorts 3-8. 
The total sample size of Part 1 is at least 20, but will depend upon the occurrence of DLTs and 
potential need for expanded dose level cohorts (see Section 4.2.1). Part 2 of the study will have 
six (n=6) participants. This study overall plans to have approximately 26 HIV-1 infected, ART 
suppressed participants in total (Part 1 + Part 2). No inferential statistics will be calculated in 
Part 1. This sample size is considered biologically sufficient to evaluate the primary objective of 
this study (first in human evaluation of safety and tolerability of MGD014). 
14.2 
Analysis Populations  
All participants who receive any MGD014 infusion will be included in the safety data sets. 
Participants enrolled in the Part 1 single-dose cohort will contribute to analysis of the OBD and 
MTD. Participants enrolled in the Part 2 multi-dose cohort will contribute to multi-dose safety, 
PK, and PD analyses. 
14.3 
Demographics and Baseline Characteristics  
Participant disposition, demographics, baseline characteristics, disease history, medical history, 
concomitant medications, and study drug exposure data will be summarized using descriptive 
statistics. Key demographic and baseline characteristics include biological sex, race/ethnicity, 
age, baseline ART regimen, years on ART, and nadir CD4. 
14.4 
Safety Endpoints  
14.4.1 
Adverse Events  
Adverse events will be coded to the Medical Dictionary for Regulatory Activities (MedDRA). 
Events prior to treatment (e.g., due to study-related procedure) will be listed separately in an 
appendix to the final CSR.  
The following tables of AE data will be created to summarize the number and percent of 
participants who experience at least one event of each of the following types: 
• All AEs 
• Drug related AEs by severity grade 
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• AEs by severity grade 
• All SAEs (this may be a listing if there are few events) 
• Drug-related SAEs 
• Fatal AEs (this may be a listing if there are few events) 
• AEs that result in study discontinuation 
• AEs that lead to withdrawal of study drug 
• AEs categorized as AESI and/or IREs 
• AEs with severity grade 3 or greater 
• Drug-related AEs with severity grade 3 or greater 
 
All of these tables will display the number and percent of participants that experience the given 
event and will display events by System Organ Class (SOC) and Preferred Term (PT). Events 
will be displayed alphabetically for SOC and in descending order of overall PT incidence within 
each SOC. 
14.4.2 
Laboratory Values  
Summaries of abnormal laboratory values will display descriptive statistics for numerically 
quantified labs. Summaries will be grouped by lab panel (e.g., hematology, blood chemistry, and 
urinalysis) and will be displayed by visit for each lab parameter. Graphs of mean values over 
time or individual values at each time point may be used. Mean change from baseline may also 
be graphed. Graphs of individual values are preferred when feasible due to the small sample size 
of this study. 
In cases where an abnormality resulted in a repeat lab test, the repeat value will be used for the 
summaries. A list of repeated labs including original values and repeat values will be included. 
Shift tables will be used to display the number and percent of participants who have a shift in 
their lab values from normal at baseline to each post-baseline visit by severity grade. 
14.4.3 
Other Safety Endpoints  
Electrocardiograms will be collected and analyzed for evidence of cardiac toxicity, especially 
prolongation of QT interval. Vital signs will be summarized with descriptive statistics at each 
visit and time point where they are collected. 
14.5 
Efficacy Endpoints  
14.5.1 
Quantitative Viral Outgrowth Assay  
For participants who completed the optional leukapheresis, a comparison of pre-MGD014 and 
post-MGD014 frequency of HIV infection per million resting CD4T cells will be performed 
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using a non-parametric 2-sided exact sign test to assess whether or not a significant decrease of 
IUPM is observed. The primary comparison will be between the leukapheresis taken at baseline 
and approximately 2 weeks following the last MGD014 infusion in Part 2 (at Day 42 ± 2 weeks). 
The sign test used for this analysis makes minimal statistical assumptions and is based solely 
upon whether each participant is observed to have a decrease in HIV infection within resting 
CD4 cells following MGD014 treatment. Results will be presented as the proportion with 
decreased IUPM and the corresponding confidence interval (CI). If the observed proportion with 
decreased IUPM is 100% (6/6 participants) the corresponding 95% CI will span from [0.541, 
1.000]; this CI would exclude a null hypothesis of no change (H0: probability of decrease=0.50). 
Precision calculations for QVOA analysis 
Number of participants with decrease in IUPM 
Binomial 95% CI (Clopper-Pearson) 
6 of 6 (100%) 
[0.541, 1.000] 
5 of 6 (83%) 
[0.359, 0.996] 
IUPM=infectious units per million CI=confidence interval 
 
14.5.2 
Single Copy Assay  
For participants who completed the optional leukapheresis, a comparison of pre-MGD014 and 
post-MGD014 measurements of residual low-level HIV-1 viremia quantified by SCA using a 
nonparametric 2-sided exact sign test will be performed to assess whether or not a significant 
decrease in plasma HIV-1 viremia is observed. Left-censored observations (SCA < 1 copy) are 
anticipated and the sample size is six (6) participants. Based on background data from the AIDS 
Clinical Trials Group (ACTG) trial A5244, we assume a 10% probability that participants (with 
plasma HIV-1 RNA <50 copies/mL at screening, per eligibility) will have a SCA measurement 
below the limit of detection (<1 copy) at the pre-MGD014 measurement [54]; it is unknown how 
large of an effect MGD014 will have upon SCA levels post-therapy. The precision calculations 
provided above in the QVOA analysis section apply here, i.e., if the observed proportion with 
decreased low-level HIV-1 viremia as measured by SCA is 100% (6/6 participants) the 
corresponding 95% CI will span from [0.541, 1.000] and the null hypothesis can be rejected. 
14.5.3 
Exploratory Endpoints  
Additional exploratory endpoints are defined as change in a quantitative measure from baseline 
to post-MGD014 administration. Using a two-sided 0.05 significance level, 10,000 empirical 
simulations from a normal distribution with mean change equal to 2 standard deviations (SD) 
with n=6 evaluable participants achieved 86 % power to detect a statistically significant change 
from baseline to post-infusion using an exact Wilcoxon signed-rank test (for paired data). 
Observed virologic and immunologic measurements may not be normally distributed or may be 
partially censored due to assay limits of quantification. A Wilcoxon signed-rank test will be used 
for continuous outcome measures when appropriate; otherwise, an exact sign test will be utilized. 
Potential immune correlates of antiviral impact will be assessed graphically (e.g., scatter plots, 
correlate heat map) and estimated with a non-parametric rank based correlation method. 
Additionally, association between antiviral impact of MGD014 and baseline participant clinical 
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characteristics, such as stage of HIV infection (acute vs. chronic) at initiation of ART, will also 
be described and examined. Correlation including one or more measures from the same 
participant may be assessed using Kendall’s tau for clustered data [53]. Exploratory analyses will 
be conducted using a two-sided 0.05 significance level with no adjustment for multiplicity. 
14.6 
Pharmacokinetic Endpoints  
Geometric means and percent coefficients of variation may be reported for Cmax, AUC, and 
Ctrough; arithmetic means and standard deviations may be reported for t1/2, CL, and Vss; and 
medians, minimum, and maximum will be reported for Tmax. 
14.7 
Pharmacodynamic Endpoints  
Summary statistics for biomarkers, such as but not limited to those listed under Section 10.3 and 
corresponding changes from baseline, will be summarized and may also be presented graphically 
as will possible associations between changes in PD measures of interest and MGD014 dose and 
exposure. 
14.7.1 
Serum Cytokines  
Data will be tabulated and summarized by dose panel and time. Plots of serum cytokine levels 
versus time may be provided. Additional analyses may be conducted in order to characterize the 
relationship between the MGD014 serum concentrations and serum cytokines (e.g., an exposure-
response analysis), if deemed appropriate. 
14.8 
Immunogenicity Endpoints  
The proportion of participants who are negative for MGD014 ADA at baseline and become 
positive in this assay, the proportion of participants who are negative at baseline and remain 
negative, and those who have positive ADA at baseline that increases or decreases in titer over 
the course of treatment will be summarized. Positive samples will be evaluated for neutralizing 
capacity and the incidence of neutralizing antibodies will also be summarized. The impact of 
immunogenicity on safety, PK, and PD will be summarized and explored graphically. 
14.9 
Cohort Analyses and Monitoring  
As described in Section 4.2.1, the decision to escalate doses from cohort to cohort will only 
occur based on consensus supporting escalation by PI (or designee) and the medical monitor. The 
medical monitor and the PI (or designee) will review aggregate safety data up through Day 14 
from all dosed participants from the prior dose cohort. 
An independent Safety Monitoring Committee (SMC) will receive monthly study progress and 
safety monitoring reports. Study feasibility and the achievement of study milestones will be 
assessed in these reports. Additionally, accrual, baseline characteristics, conduct of the study 
(including premature study discontinuations), any interruptions of ART, virologic failures, and all 
reported toxicities and events will be monitored during the study on a monthly basis. The 
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individual safety data will be reviewed monthly to assess relation of all reported toxicities and 
AEs to the study treatment. The monthly data will be shared with the SMC for review. 
If at any time during the study, two or more participants experience a toxicity that is Grade 3 or 
higher and definitely, probably, or possibly related to study treatment (as judged by the protocol 
team), or two or more participants experience the same DLT that is Grade 2 or higher, then 
enrollment into the study will be temporarily suspended and the independent SMC will be asked 
to review all safety data; review the relation to study treatment of the event(s); and recommend 
how the study should proceed with respect to resuming enrollment and continuing study 
treatment. 
14.10 
Primary Analysis  
Not applicable. 
14.11 
Final Analysis  
Final analysis of all data will be carried out at the End of the Study. 
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15 
QUALITY CONTROL AND ASSURANCE  
Quality review activities will be undertaken to ensure accurate, complete, and reliable data. 
MacroGenics Inc. or designees will do the following: 
• Provide instructional material to the study site, as appropriate. 
• Sponsor a start-up training session (Investigator Meeting or Study Initiation Visit) to 
instruct the Investigator and study coordinators. This session will give instruction on 
the protocol, and study procedures. 
• Make periodic visits to the study site to monitor protocol compliance and general 
Good Clinical Practice (GCP) compliance. 
• Be available for consultation and stay in contact with the study site personnel by mail, 
e-mail, telephone, and/or fax. 
• Conduct a quality review of the database. 
 
15.1 
Monitoring, Auditing and Inspections  
To ensure the safety of participants in the study, compliance with applicable regulations, and to 
ensure accurate, complete, and reliable data, the Investigator will keep records of laboratory 
tests, clinical notes, and participant medical records in the participant files as source documents 
for the study. 
An independent study monitor will monitor the study on a regular basis throughout the study 
period according to the study monitoring plan. The Investigator will allocate adequate time for 
such monitoring activities. The study monitor periodically will conduct a review of a sample of 
the participant data recorded on source documents at the study site. The Investigator will also 
ensure that the monitor is given access to all the above noted study-related documents, source 
documents (regardless of media) and study-related facilities (e.g., investigational pharmacy, etc.), 
and has adequate space to conduct the monitoring visit. Queries may be raised if any datum is 
unclear or contradictory. The Investigator and site personnel must address all queries in a timely 
manner. 
Participation as an Investigator in this study implies acceptance of the potential for inspection by 
the study sponsor/representatives, US or non-US government regulatory authorities, IRB/IEC 
and applicable compliance and quality assurance offices. The Investigator will permit study-
related audits and inspections and will provide access to all study-related documents (e.g., source 
documents, regulatory documents, data collection instruments, study data, etc.). The Investigator 
will ensure the capability for inspections of applicable study-related facilities (e.g., 
investigational pharmacy, CTRC, etc.). 
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15.2 
Data Entry and Computerized Systems  
An electronic data capture system will be used in this trial. Other data assessments, such as 
central laboratory assessments, will be managed by MacroGenics or central vendors for transfer 
to MacroGenics Inc. or representative for use in the study analysis. 
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16 
ADMINISTRATIVE CONSIDERATIONS  
16.1 
Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC) Approval  
The Investigator should provide the sponsor with a statement of compliance from the IRB/IEC 
indicating compliance with the applicable regulations in the region and International Conference 
on Harmonization (ICH). Any documents that the IRB/IEC may need to fulfill its 
responsibilities, such as the protocol and any amendments, Investigator’s Brochure (IB), and 
information concerning participant recruitment, payment or compensation procedures, or 
information from the sponsor will be submitted to the UNC IRB. The IRB’s written approval of 
the study protocol and the ICFs will be in the possession of the Investigator and the sponsor 
before the study drug is initiated at the Investigator’s site. The Investigator will transmit the 
IRB’s approval statement to the sponsor. This approval must include the date of review and refer 
to the study by protocol title and/or study number and version number and refer to the ICFs by 
version number or date. If the IRB or institution uses its own unique number for the protocol 
instead of the sponsor’s number, that unique number should be noted on the approval statement. 
The date of approval and/or expiration must be included. 
Protocol modifications or changes may not be initiated without approval from the sponsor, 
except when necessary to eliminate immediate hazards to the participants. Such modifications 
will be submitted to DAIDS; written verification that the modification was submitted and 
approved should be obtained. Modifications should then be submitted to the IRB and PRO prior 
to implementation. 
The Investigator must, where required by local regulations, submit to the IRB: 
• The protocol and the IB and any amendments or updates. 
• The informed consent form(s) and any amendments or changes. 
• Any documents given to participants or potential participants (e.g., recruitment 
materials, diary cards) and the plan for distribution/use. 
• Revisions of other documents originally submitted for review or for notification. 
• Serious and/or unexpected AEs occurring during the study. 
• New information that may adversely affect the safety of participants or conduct of the 
study. 
• At minimum, an annual update and/or request for re-approval of study, unless 
otherwise specified by IRB. 
• Protocol deviations. 
• Notification when the study has been completed. 
• Proof of indemnity/liability insurance. 
• Other documents required by the IRB. 
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16.2 
Ethical Conduct of the Study  
The investigational study will be conducted according to the Protection of Human Subjects (21 
CFR 50), IRBs (21 CFR 56), Obligations of Clinical Investigators (21 CFR 312.60 − 312.69), the 
current ICH Guideline for Good Clinical Practice (ICH E6), and all other applicable regulations. 
16.3 
Participant Information and Consent  
It is the responsibility of the Investigator to obtain and document written informed consent (IC) 
from the participant. IC in compliance with the principles of informed consent in ICH E6 and all 
applicable local regulations should be obtained before any protocol-specified procedures or 
interventions are conducted. The sponsor reserves the right to delay initiation of the study at a 
site where informed consent forms (ICFs) do not meet the standards of applicable local 
regulations or ICH E6. 
Information should be given to the participant in both oral and written form, and participants 
must be given ample opportunity to inquire about details of the study. 
The ICF generated by the Investigator must be approved by the IRB. The Investigator will 
provide the sponsor with a copy of the IRB-approved ICF and a copy of the IRB’s written 
approval before the start of the study. 
Informed consent forms must be written (and appropriately translated in the participant’s native 
language or language in which the participant has fluency) so as to be understood by the 
prospective participant. Informed consent will be documented by the use of a written consent 
form approved by the IRB. The ICF must be signed and dated by the participant and by the 
person who conducted the discussion of the informed consent. 
All versions of each participant’s signed ICF must be kept on file by the Investigator for possible 
inspection by regulatory authorities and/or authorized MacroGenics monitoring and regulatory 
compliance persons. The participant should receive a copy of the signed and dated written ICF 
and any other written information provided to the participants. 
16.4 
Participant Confidentiality  
To maintain confidentiality of participants, all research laboratory specimens, evaluation forms, 
reports, and other records will be identified by a coded number. Clinical information will not be 
released without written permission of the participant, or an individual with legal decision-
making authority for the participant or the participant’s interests, except as necessary for 
monitoring by the relevant regulatory authorities, the sponsor of the clinical study, or the 
sponsor’s representative. The Investigator must also comply with all local applicable privacy 
regulations [e.g., US Health Insurance Portability and Accountability Act of 1996 (HIPAA)], on 
protection of individuals with regard to personal data. 
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16.5 
Case Report Forms and Study Records  
Source data in a clinical study are the original records or certified copies where clinical 
observations are first recorded, which may include, but are not limited to, the participant’s 
medical file, original laboratory reports, histology, and pathology reports (as applicable). The 
Investigator is responsible for maintaining adequate and accurate medical records from which 
accurate information will be entered onto source documents designed to capture data pertinent to 
the clinical investigation. Data should be recorded on paper source documents or electronic 
medical records system. The electronic database should be completed in their entirety by the 
Investigator or his/her designee. Prior to database lock, the Investigator will verify the 
completeness and accuracy of the data and indicate that he/she has done so by providing an 
electronic signature on the appropriate document. The Investigator will retain a copy of all 
source documents. 
16.6 
Access to Source Documentation  
The Investigator and study center will permit the sponsor, its representatives, IRB and all 
relevant regulatory agencies access to all original source data and documents regardless of 
media, for study monitoring audits and inspections. 
16.7 
Retention of Data  
Per ICH guidelines, all essential documents, including source documents (regardless of media), 
signed ICFs, and laboratory test results, should be retained by the Investigator for at least 2 years 
after last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed since 
formal discontinuation of clinical development of the investigational product. There may be 
other circumstances for which MacroGenics Inc. is required to maintain study records for longer 
periods; therefore, MacroGenics Inc. should be contacted before study records are removed from 
the control of the investigational site for any reason. The Investigator must obtain written 
permission from MacroGenics Inc. prior to destruction of study documents. 
16.8 
Sample Retention and Further Testing  
Samples acquired for protocol-specified assays will be retained for at least 1 year following the 
end of the study and may be retained up to 2 years after last approval of a marketing application 
in an ICH region and until there are no pending or contemplated marketing applications in an 
ICH region or until at least 2 years have elapsed since formal discontinuation of clinical 
development of the investigational product. If potential participants consent, or an individual 
with legal decision-making authority for the participant or the participant’s interests consent, to 
the use of their study samples for non-study research purposes, these samples may also be used 
for exploratory testing (including assay development/ optimization). 
A separate IRB application will be submitted for future analysis involving these blood samples. 
These stored samples will only be used for research including genetic studies of the stored samples, 
after specific further review and approval by the UNC IRB. 
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Any remaining specimens that will be stored for future research will be stored safely and 
securely in a research specimen storage laboratory at the University of North Carolina at Chapel 
Hill (UNC-CH). No protected health information (PHI) will be included with the samples. The 
samples will be identified by coded number to maintain participant confidentiality. The link 
between Participant Identifier Code on the samples and PHI is maintained in a secured file on a 
secured server in the control of the principal Investigator at UNC-CH. Future researchers would 
not have access to this link. Only study personnel, people who work at the research specimen 
storage laboratory at UNC-CH and IRB approved researchers will have access to the 
participants’ samples. Since all the stored specimens are de-identified, the people who work at 
the research specimen storage laboratory will not have any personally identifying information 
that would link to a participant. The IRB approved researchers who receive the specimens may 
receive information pertaining to lab assay values, age, and sex of the specimen donor, but will 
not be given the name or any other information that identifies the donor/participant. These 
samples will be stored up to 15 years. 
16.9 
Financial Disclosure  
The Investigator and Sub-Investigators will be required to disclose any applicable financial 
arrangement as defined in US regulation (i.e., 21 CFR 54). 
The following information will be collected about the Investigators, their spouse and each 
dependent child: any significant payments of other sorts from MacroGenics, Inc., or any alliance 
partner, such as a grant to fund ongoing research, compensation in the form of equipment, 
retainer for ongoing consultation or honoraria; any proprietary interest in the study drug; and any 
significant equity interest in MacroGenics, Inc., as defined in 21 CFR 54. Investigators are 
obliged to update the sponsor with any changes in reported information up to 1 year following 
the end of the study. 
In addition, Investigators and Sub-Investigators will be required to disclose if they are an 
employee of MacroGenics, or an immediate family member of a MacroGenics employee, officer, 
or director. This is in order to assist MacroGenics with its compliance with Securities and 
Exchange Commission rules requiring disclosure of certain transactions with related persons as 
defined in 17 CFR 229.404. “Immediate family member of a MacroGenics employee” means a 
child, stepchild, parent, stepparent, spouse, sibling, mother-in-law, father-in-law, son-in-law, 
brother-in-law, or sister-in-law of any MacroGenics employee, officer, or director or any person 
sharing the household of such MacroGenics employee, officer, or director. 
In consideration of participation in the study, MacroGenics, Inc., will pay the Investigator or 
nominated payee the sums set out in the payment schedule attached to the Investigator 
agreement. 
Financial disclosure information will be documented in writing and signed and dated by the 
Investigator. This information will be collected prior to that Investigator taking part in the 
research. 
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16.10 
Publication and Disclosure Policy  
This policy will be codified in the agreement between the site and the sponsor. This includes 
authorship issues, scheduling analyses, prioritizing analyses for reports, publications, 
presentations, and developing a review and approval process. 
16.11 
Discontinuation of the Study or Study Site  
16.11.1 
Discontinuation of Study Site  
Site participation may be discontinued if MacroGenics, Inc., the Investigator, a regulatory 
authority, or the IRB/IEC of the study site deems it necessary for any reason. 
16.11.2 
Discontinuation of the Study  
The study may be discontinued by a regulatory authority or at the discretion of the sponsor. 
The Investigator maintains the right to discontinue his/her participation in the study should 
his/her clinical judgment so dictate. The Investigator will notify the IRB of any study 
discontinuation. Study records must be retained as noted above. 
16.12 
Identification of the Principal Investigator  
 will be the Principal Investigator for this study. As part of her responsibilities, 
the Principal Investigator will review the final CSR. Agreement with the final CSR will be 
documented by the dated signature of the Principal Investigator. 
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17 
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41. Marban C, Forouzanfar F, Ait-Ammar A, et al. Targeting the Brain Reservoirs: Toward 
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Composition of Cerebrospinal Fluid in HIV-1 Infected and Uninfected Subjects. PloS one 
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cerebrospinal fluid of patients with neurological diseases. Journal of neurology 2014; 
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47. Winkler U, Jensen M, Manzke O, Schulz H, Diehl V., Engert A. Cytokine-release 
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48. Baldo BA. Adverse events to monoclonal antibodies used for cancer therapy: Focus on 
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Guidelines. Annals of oncology: official journal of the European Society for Medical 
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50. Lenz HJ. Management and preparedness for infusion and hypersensitivity reactions. The 
Oncologist 2007; 12:601-609. 
51. Crooks AM, Bateson R, Cope AB, et al. Precise Quantitation of the Latent HIV-1 
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54. Gandhi RT, Zheng L, Bosch RJ, Chan ES, Margolis DM, Read S, et al. The effect of 
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4 
MGD014 Infusion: MGD014 will be administered by staff competent in antibody infusion; the PI (or designee) or a licensed physician assistant (PA), nurse 
practitioner (NP) or Research Nurse. A research assistant (RA) may obtain and record vital signs and provide other participant care necessary during the 
MGD014 infusion. 
Part 1: The first participants of each dose cohort are monitored for 24 hours on site following infusion; subsequent participants at the same dose level will be 
monitored for 12 hours on site following infusion. 
Part 2: Participants are monitored for 6 hours on site following their first infusion. Participants will be monitored for 4 hours on site following subsequent 
infusions. 
5 
Participant identifier (PID) assignment: This is a computer generated 5-digit number assigned to each participant after the informed consent is signed.  
6 
Study-specific identifier (SID) assignment: This is a sequential study specific number assigned to each participant at enrollment.  
7 
Dose Cohort Assignment: Part 1 only: This assignment occurs at the time of infusion and determined by the prior participant’s safety data collected during 
their 2-week DLT period following the dose.  
8 
Medical History: Medical history obtained at screening will include demographic information (date of birth, gender, race, ethnicity), participant’s medical 
history, and HIV medication history, and (CD4 nadir and peak HIV-1 viral load, if available).  
9 
Physical Exam:  Includes a complete review of systems, and vital signs. Obtain the weight at screening, and prior to the dose of MGD014 at each infusion.  
10 Vital Signs:  
a. Screening visit: T, P, BP, and RR and includes height and weight measurements.  
b. Infusion Visits: vital signs include T, P, BP, and RR. The weight is only taken upon arrival at the clinic. Vital signs are taken before infusion 
(approximately 10 minutes before the infusion); at 15, 30, and 60 minutes after the start of infusion; at end of infusion; then every 15 minutes up 
to and including 60 minutes, then every 60 minutes up to 6 hours after the completion of first infusion and up to 4 hours for subsequent 
infusions after the completion of infusion. Vital signs have a +/- 5-minute window. 
c. Repeat VS (T, BP, P and RR) with a +/- 5-minute window, may also be captured as necessary to elucidate the course of any untoward event or 
AE and may be inclusive of all or individual VS components as required to address AE monitoring. 
d. Part 1 participants staying in the hospital as an inpatient will have VS assess Q 4 hours with a +/- 5-minute window per hospital unit policy or 
more frequently as clinically indicated. 
e. All other visits: vital signs include T, P, BP, and RR. 
11 PI Review of ART History: if available the most recent HIV-1 genotype should be obtained and presented to PI for review at this time. 
12 Directed Physical Assessment: Guided by review of systems and participant history and addresses any previously identified or new event that the participant 
experiences since the last study visit or any unresolved signs or symptoms previously experienced.  
13 ART and ART adherence: Non-adherence will be defined as having missed more than 9 total days in the 3 months prior to screening. Assess any missed 
doses while on study and discussed with Study PI (or designee). Continuance on study will be contingent on adherence. 
14 Concomitant medications: Include all current medications and any as needed (PRN) medications used.  
a. All medications taken within 4 weeks of study screening.  
b. After study entry, record only new over-the-counter, herbal, dietary and vitamin supplements, and prescription medications. Mark any 
discontinued medications. 
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c. Document all doses of MGD014 treatments and permanent discontinuation.  
15 ECG: Perform in triplicate (approximately 1 minute apart). 
a. Screening Visit:  
a. Part 1; Performed within 28 days of the first dose of MGD014. 
b. Part 2: Performed within 56 days of the first dose of MGD014. 
b. Infusion Visits: pre-infusion (within 30 min), end of infusion (within 30 min of the End of Infusion (EOI), 1 hour after the EOI (+/- 5 minutes 
after EOI). 
c. End of Study Visit 
16 Signs and Symptoms and Diagnosis:  
a. Screening: record all diagnosis and disease, record all graded baseline labs, signs and symptoms that occurred within 28 days of screening. 
Untoward events due to protocol-related procedures should be recorded as AEs. 
b. After study entry: Record all AEs related to study drug product regardless of grade.  
17 Pre-MGD014 Infusion Medications (Diphenhydramine or equivalent H1-antihistamine and Acetaminophen) and other medications administered for 
hypersensitivity Anaphylactic Reaction:  
a. Diphenhydramine (IV) or equivalent H1-antihistamine and the Acetaminophen (oral) administered by licensed study staff. 
b. Administration of medications for treatment of adverse reactions to the MGD014 will follow hospital policy and the UNC HIV Cure Center 
SOP entitled “DART Infusion Guidelines and Emergency Management Plan”. 
18 Post-Infusion Assessment: Participants provided with instructions to contact study staff about any reactions that occur after receipt of MGD014. Part 1 
participants will return to the clinic on Days 1 and 2. Part 2 participants will return for Day 3 assessment and for post-infusion Day 14 and Day 28 to be 
contacted approximately 2 to 3 days after the study drug administration to inquire about reactions or any potential treatment emergent adverse events (TEAEs). 
Infusion reactions graded per the DAIDS Toxicity Table. 
19 Chemistries: Na, K, Cl, bicarbonate, BUN, creatinine, glucose, Ca, total protein, AST, ALT, alkaline phosphatase, total bilirubin, and Mg. Indirect bilirubin 
required if participant on atazanavir. Clinical labs scheduled for the day of infusion (this is inclusive of CBC) can be obtained within 7 days of infusion.  
20 Pregnancy test: Serum pregnancy test done on all women at screening. Urine pregnancy test/POCT done on all women at or within 72 hours of each infusion. 
Test results must be negative, documented and reviewed by study PI or designee prior to each infusion.  
21 For ADA, PK, PD, RO, Serum Cytokine, and T Cell Phenotype measurements, please refer to Appendix 2 for detailed schedule. 
22 CBC done for leukapheresis procedure only. 
23 Optional Leukapheresis procedure. The QVOA samples will be collected as part of the leukapheresis product for participants having the optional procedure. 
Abbreviations: ART= antiretroviral therapy; BMI = body mass index; CBC = complete blood count; DAIDS = Division of AIDS; ECG = electrocardiogram; 
FSH = follicle stimulating hormone; HLA = human leukocyte antigen; INR = international normalized ratio; IUPM = infectious units per million; IV = 
intravenous; PI = principal investigator; PD = pharmacodynamics; PID = Participant identifier; POCT = point of care testing; PRN = as needed; PT/aPTT = 
prothrombin time/activated partial thromboplastin time; QVOA = quantitative viral outgrowth assay; RNA = ribonucleic acid; RPR = Rapid Plasma Reagin; 
SID = Study-specific identifier; SOP = standard operating procedure; VL = viral load; VL = vital signs.  
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MGD014 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGD014-01 
Amendment 6, 31 March 2021 
 
 
 
Appendix 2  
PK, Immunogenicity, and PD Biomarkers Blood  
 
 
 
Sampling Schedule: Part 1 and 2  
PART 1 
Pharmacokinetics, Immunogenicity, and Pharmacodynamic Biomarkers  
Blood Sampling Schedule for MGD014 
MGD014  
Dosing 
Treatment 
Day 
PK 
Sampling Time 
(Hours) a 
ADA 
Sampling Time 
(Hours) 
Receptor 
Occupancy 
(Hours) 
Serum 
Cytokines b 
(Hours) 
T cell 
Phenotype 
(Hours) 
X 
0 
0 c 
(Pre-infusion) 
0 c 
(Pre-infusion) 
0 c 
(Pre-infusion) 
0 c 
(Pre-infusion) 
0 c 
(Pre-infusion) 
 
0 
EOI  
(within 5 min. 
before EOI) 
 
 
 
 
 
0 
1 
(post EOI) 
 
1 
(post EOI) 
  
1 
(post EOI) 
 
0 
4 
(post EOI) 
 
4 
(post EOI) 
4 
(post EOI) 
4 
(post EOI) 
 
1 
24 
+/- 5 hour 
(post EOI) 
 
X 
 (post EOI) 
X 
(post EOI) 
X 
(post EOI) 
 
2 
48 
+/- 5 hour 
 (post EOI) 
 
X 
X 
 
 
7 
166 
+/- 2 day 
 (post EOI) 
 
X 
X 
X 
 
14 
334 
+/- 2 day 
 (post EOI) 
X 
 
 
 
 
21 
502 
+/- 2 day 
 (post EOI) 
 
 
 
 
 
28 
670 
+/-2 days  
 (post EOI) 
X 
 
 
 
 
42 
(EOT 
visit) 
1006  
+/- 5 days 
 (post EOI) 
X 
 
 
 
a 
Do not collect PK samples from infusion port. Obtain PK samples as follows: Pre-infusion: Before start of infusion on 
visit day (dosing day) or day before. When collecting multiple samples, collect the PK sample first.  
b 
Additional samples may be obtained selectively at additional time points in participants who experience signs and 
symptoms of cytokine release. 
c 
All pre-dose PK, ADA, Receptor Occupancy including T-cell binding, cytokines, and T-cell Phenotype samples will be 
collected prior to start of MGD014 infusion; the start of MGD014 infusion is designated as time = 0 hour. 
Note: Actual start and end of infusion times, PK, and ADA sample collection times will be recorded on the source 
documents. All sample time points are hours after EOI, unless otherwise specified. Samples required at EOI can be drawn 
up to 5 minutes before the infusion is complete, post EOI samples can be drawn +/- 5 minutes; duration of infusion = 120 
minutes. 24 - and 48-hour samples will be drawn on Day 1 and 2 respectively.  
Abbreviations: ADA = Anti-drug antibody; EOI = end of infusion; PK = Pharmacokinetic. 
 
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MGD014 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGD014-01 
Amendment 6, 31 March 2021 
 
 
 
PART 2 
Pharmacokinetics, Immunogenicity, and Pharmacodynamic Biomarkers  
Blood Sampling Schedule for MGD014 
MGD014  
Dosing 
Treatment 
Day 
PK a 
Sampling 
Time (Hours)  
ADA 
Sampling 
Time 
(Hours) 
Receptor 
Occupancy b 
(Hours) 
Serum 
Cytokines c 
(Hours) 
T cell 
Phenotype 
(Hours) 
X 
0 
0 d 
(Pre-infusion) 
 
0 d 
(Pre-infusion) 
0 d 
(Pre-infusion) 
0 d 
(Pre-infusion) 
 
0 
EOI 
 
 
 
 
 
 
0 
1 
(post EOI) 
 
 
 
 
 
0 
4 
(post EOI) 
 
4 
(post EOI) 
4 
(post EOI) 
4 
(post EOI) 
 
1 
24 
+/- 5 hours 
(post EOI) 
 
24 
+/- 5 hours 
(post EOI) 
24 
+/- 5 hours 
(post EOI) 
24 
+/- 5 hours 
(post EOI) 
 
3 
72 
+/- 5 hours 
(post EOI) 
 
 
72 
+/- 5 hours 
(post EOI) 
 
X 
14 
0 
(Pre-infusion) 
0 
(Pre-infusion) 
0 
(Pre-infusion) 
 
0 
(Pre-infusion) 
 
14 
EOI 
 
4 
(post EOI) 
4 
(post EOI) 
4 
(post EOI) 
X 
28 
0 
(Pre-infusion) 
0 
(Pre-infusion) 
0 
(Pre-infusion) 
 
0 
(Pre-infusion) 
 
28 
EOI 
 
4 
(post EOI) 
4 
(post EOI) 
4 
(post EOI) 
 
42 
1008 hours 
+/- 1 day 
 
 
 
 
 
 
77 
(EOS 
visit) 
1848 hours 
+/- 3 days 
X 
X 
 
X 
a 
Do not collect PK samples from infusion port. Obtain PK samples as follows: Pre-infusion: Before start of infusion on 
visit day (dosing day) or day before. When collecting multiple samples, collect the PK sample first.  
b 
If at any time in Step 3 RO reaches below the limit of detection, at the discretion of the PI or designee, further 
measurement of RO may be deemed unnecessary. 
c 
Additional samples may be obtained selectively at additional time points in participants who experience signs and 
symptoms of cytokine release. 
d 
All pre-dose PK, ADA, Receptor Occupancy including T-cell binding, cytokines, and T-cell Phenotype samples will be 
collected prior to start of MGD014 infusion; the start of MGD014 infusion is designated as time = 0 hour. 
Abbreviations: ADA = Anti-drug antibody; EOI = end of infusion; PK = Pharmacokinetic. 
Note: Actual start and end of infusion times, PK, and ADA sample collection times will be recorded on the source 
documentation. All sample time points are hours after EOI, unless otherwise specified. Samples required at EOI can be 
drawn up to 5 minutes before the infusion is complete, post EOI and 4 hr post EOI samples can be collected +/- 5 minutes; 
duration of infusion = 120 minutes. 24- and 72-hour samples will be drawn on Day 2 and 4, respectively. 
 
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MGD014 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGD014-01 
Amendment 6, 31 March 2021 
 
 
 
Appendix 3  
Principal Investigator’s Agreement  
Study Title: 
A Phase 1 Study to Evaluate the Safety, Immunologic and Virologic 
Responses of MGD014 Therapy in HIV-Infected Individuals on 
Suppressive Antiretroviral Therapy 
Study Number: 
CP-MGD014-01  
 
I have read the protocol described above. 
I have fully discussed the objectives of this trial and the contents of this protocol with the 
sponsor’s representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution of the ethical review of the study, 
without written authorization from MacroGenics, Inc. It is, however, permissible to provide 
information to a participant in order to obtain consent. 
I agree to conduct this trial according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the trial in 
accordance with ICH guidelines on GCP and with the applicable regulatory requirements. 
I understand that the sponsor may decide to suspend or prematurely terminate the trial at any 
time for whatever reason; such a decision will be communicated to me in writing. 
Conversely, should I decide to withdraw from execution of the trial, I will communicate my 
intention immediately in writing to the sponsor. 
Signed: 
 
Date: 
 
Name (printed): 
 
Title: 
 
Affiliation: 
 
Address: 
 
Phone Number: 
 
 
 
 
 
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CP-MGD014-01 Protocol Amendment 6 (31-Mar-2021)
This is the electronic signature page for the above referenced document.
User Task: eSignatories Approval
Data Management/Statistics Approval
(Intended or Designee)
31-Mar-2021 18:13:56 GMT+0000
User Task: eSignatories Approval
arch Approval (Intended or Designee)
02-Apr-2021 06:28:38 GMT+0000
User Task: eSignatories Approval
Management/Statistics Approval
(Intended or Designee)
06-Apr-2021 10:18:04 GMT+0000
User Task: eSignatories Approval
esearch Approval (Intended or Designee)
06-Apr-2021 13:25:55 GMT+0000
User Task: eSignatories Approval
Research Approval (Intended or Designee)
06-Apr-2021 15:38:34 GMT+0000
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