A Phase 1, Randomized Double-Blind, Placebo-Controlled, Single Ascending Dose Safety, Tolerability, and Pharmacokinetics Study of SAB-176 in Healthy Adults
Phase: PHASE1
Conditions: Influenza Type A, Influenza Type B, Influenza
Sponsor: SAb Biotherapeutics, Inc.

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A Phase 1, Randomized Double-Blind, Placebo-Controlled, Single Ascending Dose Safety, 
Tolerability, and Pharmacokinetics Study of SAB-176 in Healthy Adults
 
 
 
 
 
 
 
 
 
 
 
 
Contract Research Organization: 
PPD 
Phase 1 Clinic 
7551 Metro Center Drive, Suite 200 
Austin, TX 78744 
 
 
 
 
 
 
 
IND Sponsor: 
SAB Biotherapeutics, Inc. 
2301 E. 60th St. North 
Sioux Falls, SD 57104 
 
IND# 19714 
 
 

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CLINICAL LABORATORIES 
PPD 
Phase 1 Clinic 
7551 Metro Center Drive, Suite 200 
Austin, TX 78744 
 
PPD  
2246 Dabney Road  
Richmond, VA 23230  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RESEARCH LABORATORIES 
SAB Biotherapeutics, Inc. 
2301 E. 60th St. North 
Sioux Falls, SD 57104 
 
 
 
 
 

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TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................................ 3 
LIST OF TABLES .......................................................................................................................... 6 
LIST OF FIGURES ........................................................................................................................ 6 
LIST OF ABBREVIATIONS ......................................................................................................... 7 
PROTOCOL SUMMARY .............................................................................................................. 8 
PRÉCIS ........................................................................................................................................... 9 
1 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ............................. 10 
1.1 
Background ................................................................................................................... 10 
1.2 
Rationale ....................................................................................................................... 11 
2 
STUDY OBJECTIVES ......................................................................................................... 11 
2.1 
Primary Objective ......................................................................................................... 11 
2.2 
Secondary Objectives.................................................................................................... 11 
3 
INVESTIGATIONAL PLAN ............................................................................................... 12 
3.1 
General .......................................................................................................................... 12 
3.2 
Study Design ................................................................................................................. 12 
3.3 
Definitions for the Purpose of this Study ...................................................................... 13 
4 
STUDY POPULATION ....................................................................................................... 14 
4.1 
Research Subject Selection ........................................................................................... 14 
4.2 
Recruitment ................................................................................................................... 14 
4.3 
Inclusion Criteria  ......................................................................................................... 14 
4.4 
Exclusion Criteria ......................................................................................................... 15 
4.5 
Justification of Exclusions of Pregnant Women and Children ..................................... 16 
4.5.1 
Exclusion of Pregnant and Breastfeeding Women ............................................... 16 
4.5.2 
Exclusion of Children ........................................................................................... 16 
4.6 
Subject Withdrawal ....................................................................................................... 16 
4.7 
Discontinuation of Subject by Investigator................................................................... 16 
4.8 
Discontinuation of Study .............................................................................................. 17 
4.9 
Emergency Unblinding ................................................................................................. 17 
5 
TREATMENT ...................................................................................................................... 17 
5.1 
Randomization and Blinding ........................................................................................ 17 
5.2 
Formulation, Packaging and Labeling .......................................................................... 18 
5.2.1 
SAB-176 ............................................................................................................... 18 
5.2.1.1 
Label ................................................................................................................. 18 
5.2.1.2 
Storage .............................................................................................................. 18 
5.2.2 
Saline Control ....................................................................................................... 18 
5.3 
Dosing and Administration ........................................................................................... 18 
5.4 
Justification of Dose ..................................................................................................... 20 
5.5 
Study Drug Accountability ........................................................................................... 20 

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5.6 
Concomitant Medications ............................................................................................. 20 
5.7 
Prohibited Medications ................................................................................................. 20 
6 
STUDY PROCEDURES ...................................................................................................... 20 
6.1 
Personnel for Study Procedures .................................................................................... 20 
6.2 
Screening....................................................................................................................... 20 
6.2.1 
Informed Consent.................................................................................................. 20 
6.2.2 
Demographics ....................................................................................................... 20 
6.2.3 
Medical History .................................................................................................... 21 
6.2.4 
Clinical Data ......................................................................................................... 21 
6.2.5 
Physical Exam ....................................................................................................... 21 
6.2.6 
Laboratory Testing ................................................................................................ 21 
6.2.7 
Determination of Eligibility .................................................................................. 21 
6.3 
Detailed Description of Assessments............................................................................ 22 
6.3.1 
Schedule of Assessments ...................................................................................... 22 
6.3.2 
Location of Study Drug Administration ............................................................... 22 
6.3.3 
Randomization ...................................................................................................... 23 
6.3.4 
Study Day -1 to Day 0 - Baseline Evaluation ....................................................... 23 
6.3.4.1 
Interval History and Exam ................................................................................ 23 
6.3.4.2 
Assessment of Baseline Symptoms .................................................................. 23 
6.3.4.3 
Laboratory Testing ............................................................................................ 23 
6.3.5 
Study Day 0: Study Drug Administration ............................................................. 23 
6.3.6 
Study Day 0: Peri-Administration Assessments ................................................... 24 
6.3.7 
Study Day 1........................................................................................................... 24 
6.3.7.1 
Interval History and Exam ................................................................................ 24 
6.3.7.2 
Assessment of Symptoms ................................................................................. 24 
6.3.7.3 
Laboratory Testing ............................................................................................ 24 
6.3.8 
Study Day 3 (+1) ................................................................................................... 24 
6.3.8.1 
Interval History and Exam ................................................................................ 25 
6.3.8.2 
Assessment of Symptoms ................................................................................. 25 
6.3.8.3 
Laboratory Testing ............................................................................................ 25 
6.3.9 
Study Day 7 (+/-1) ................................................................................................ 26 
6.3.9.1 
Interval History and Exam ................................................................................ 26 
6.3.9.2 
Assessment of Symptoms ................................................................................. 26 
6.3.9.3 
Laboratory Testing ............................................................................................ 26 
6.3.10 
Study Day 21 (+/- 1) ............................................................................................. 26 
6.3.10.1 
Interval History and Exam ............................................................................ 26 
6.3.10.2 
Assessment of Symptoms ............................................................................. 26 
6.3.10.3 
Laboratory Testing ........................................................................................ 26 
6.3.11 
Study Day 42 (+/- 2) ............................................................................................. 27 
6.3.11.1 
Interval History and Exam ............................................................................ 27 
6.3.11.2 
Assessment of Symptoms ............................................................................. 27 
6.3.11.3 
Laboratory Testing ........................................................................................ 27 
6.3.12 
Study Day 90 (+/- 7) ............................................................................................. 27 
6.3.12.1 
Interval History and Exam ............................................................................ 27 
6.3.12.2 
Assessment of Symptoms ............................................................................. 27 

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6.3.12.3 
Laboratory Testing ........................................................................................ 27 
7 
MEASURES OF SAFETY, EFFICACY, AND COMPLIANCE ........................................ 28 
7.1 
Safety Evaluations ........................................................................................................ 28 
7.1.1 
Laboratory Evaluations ......................................................................................... 28 
7.1.2 
Physical Examinations .......................................................................................... 28 
7.1.3 
Vital Signs, Including SaO2 .................................................................................. 28 
7.2 
Measures of Pharmacokinetics and Immunogenicity ................................................... 28 
8 
RISKS AND BENEFITS ...................................................................................................... 29 
8.1 
Potential Risks .............................................................................................................. 29 
8.1.1 
Risks of SAB-176 ................................................................................................. 29 
8.1.2 
Risk of Intravenous Catheter ................................................................................ 32 
8.1.3 
Risks of Phlebotomy ............................................................................................. 32 
8.2 
Potential Benefits .......................................................................................................... 32 
8.3 
Alternatives ................................................................................................................... 32 
9 
RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS, AND DATA ........ 32 
9.1 
Intended Use of the Samples/Specimens/Data ............................................................. 32 
9.2 
Storage of Samples/Specimens/Data ............................................................................ 32 
9.3 
Storage of Genetic Samples .......................................................................................... 32 
9.4 
Tracking Samples.......................................................................................................... 32 
9.5 
Use of Samples/Specimens/Data at the Completion of the Protocol ............................ 32 
9.6 
Reporting Loss or Destruction of Samples/Specimens/Data ........................................ 32 
10 ASSESSMENT OF SAFETY ............................................................................................... 33 
10.1 
Toxicity Scale ............................................................................................................... 33 
10.1.1 
Causality ............................................................................................................... 33 
10.2 
Recording/Documentation ............................................................................................ 34 
10.3 
Definitions..................................................................................................................... 34 
10.4 
Adverse Event Reporting .............................................................................................. 35 
10.4.1 
Expedited Reporting to the site IRB ..................................................................... 35 
10.4.2 
Annual Reporting to the site IRB.......................................................................... 36 
10.4.3 
Investigator Reporting Responsibilities to the Sponsor ........................................ 36 
10.5 
FOLLOW-UP OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ...... 37 
10.6 
Sponsor’s Reporting Responsibilities ........................................................................... 37 
11 CLINICAL MONITORING STRUCTURE ......................................................................... 37 
11.1 
Site Monitoring Plan ..................................................................................................... 37 
11.2 
Data and Safety Monitoring .......................................................................................... 38 
11.2.1 
Investigator Safety Monitoring ............................................................................. 38 
11.3 
Safety Review and Communications Plan (SRCP) ...................................................... 38 
11.4 
Safety Monitoring Plan ................................................................................................. 38 
11.5 
Sponsor Medical Monitor ............................................................................................. 38 
11.6 
Treatment Interruption or Discontinuation ................................................................... 38 
11.7 
Pausing Rules ................................................................................................................ 39 
11.8 
Dose Escalation Rules................................................................................................... 39 

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11.9 
Study Endpoints ............................................................................................................ 40 
11.9.1 
Primary Endpoint .................................................................................................. 40 
11.9.2 
Secondary Endpoints ............................................................................................ 40 
12 ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................................ 40 
12.1 
Informed Consent Process ............................................................................................ 40 
12.2 
Subject Confidentiality ................................................................................................. 40 
13 DATA MANAGEMENT AND MONITORING ................................................................. 41 
13.1 
Data Management Responsibilities............................................................................... 41 
13.2 
Data Capture Methods .................................................................................................. 41 
13.3 
Types of Data ................................................................................................................ 41 
13.4 
Source Documents and Access to Source Data/Documents ......................................... 41 
13.5 
Record Retention .......................................................................................................... 41 
14 References ............................................................................................................................. 43 
 
LIST OF TABLES 
 
Table 1: Cohorts and Dose Levels ................................................................................................ 12 
Table 2. Example of dosing timeline ............................................................................................ 12 
Table 3: Dosing and Administration ............................................................................................. 19 
Table 4: Schedule of Assessments ................................................................................................ 22 
 
 
LIST OF FIGURES 
Figure 1: SAB-176 Vial Label ...................................................................................................... 18 
 
 

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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CKD-EPI  
Chronic Kidney Disease Epidemiology Collaboration 
CLIA 
Clinical Laboratory Improvement Amendment of 1988 
CRF 
Case Report Form 
CRIS 
Clinical Research Information System 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
HA 
Hemagglutinin 
HAC 
Human Artificial Chromosome 
HAI 
Hemagglutination Inhibition 
hIgG 
Human Polyclonal IgG  
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IgG 
 
Immunoglobulin 
IVIg 
Immunoglobulin for Intravenous Use 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
Intravenous 
K 
Potassium 
LDH 
Lactate Dehydrogenase 
MN 
Microneutralization 
 
Na 
Sodium 
NIH 
National Institutes of Health 
OTC 
Over-the-Counter 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PT 
Prothrombin Time  
PTT 
Partial Thromboplastin Time  
SAE 
Serious Adverse Event/Serious Adverse Experience 
SRCP 
Safety Review and Communication Plan 
SUSAR 
Serious and Unexpected Suspected Adverse Reaction 
TBD 
To Be Determined 
Tc 
Transchromosomic 
TKO 
Triple Knockout 
UDS 
Urine Drug Screen 
UP 
Unanticipated Problem 
UPnonAE 
Unanticipated Problem that is not an Adverse Event 
 
 
 

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PROTOCOL SUMMARY 
 
Full Title:   
A Phase 1, Randomized Double-Blind, Placebo-Controlled, Single 
Ascending Dose Safety, Tolerability, and Pharmacokinetics Study of 
SAB-176 in Healthy Adults 
Short Title:   
SAB-176 
Clinical Phase:   
1 
IND Sponsor:  
SAB Biotherapeutics, Inc. 
Conducted by:   
PPD 
Principal Investigator: 
Rebecca N. Wood-Horrall, M.D.  
Sample Size: 
27 subjects  
Accrual Ceiling:   
150 (up to 150 subjects screened to randomize a total of 27 subjects) 
Study Population:   
Healthy Volunteers aged 18 to 60 years 
Accrual Period: 
Start Date:  TBD 
End Date:  TBD 
Study Duration: 
Start Date:  TBD 
End Date:  TBD 
Study Design:  
Randomized, Double-Blind, Placebo-Controlled, Dose-escalating 
Study Agent: 
Active: SAB-176 
Control: Normal (0.9%) saline  
Primary Objective: 
To evaluate the safety and tolerability of SAB-176 in healthy adults, 
following single intravenous administration at escalating dose-levels 
 
Secondary Objectives: 
• 
To evaluate the pharmacokinetics of intravenously administered SAB-
176 in healthy adults, following single intravenous administration at 
escalating dose-levels 
• 
To determine the ability of serum levels of SAB-176 to neutralize 
Type A and Type B influenza viruses 
• 
To evaluate the immunogenicity of SAB-176 
 
Primary Endpoint: 
Type and frequency of adverse events experienced by subjects receiving 
SAB-176 at escalating dose-levels, as compared to control saline 
Secondary Endpoints: 
 
• 
Pharmacokinetic profile of intravenously administered SAB-176 in 
healthy adults 
• 
Serum Type A and B Hemagglutination Inhibition (HAI) Assays 
• 
Serum Type A and B Microneutralization (MN) Assays 
• 
Frequency and concentrations of antibodies caused by SAB-176, as 
measured by: 
o Anti-IgG antibodies using rheumatoid factor  
o Anti-SAB-176 

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PRÉCIS 
 
The administration of convalescent plasma or hyperimmune immunoglobulin G (IgG) is often 
used for treatment of infectious diseases. However, production of large quantities of anti-
pathogen human plasma and/or immunoglobulin with high affinity and avidity antibodies 
currently requires donations by convalescent humans, a process that can limit availability for a 
number of reasons. One novel alternative source is transchromosomic (Tc) bovine that produce 
fully human polyclonal IgG (hIgG) de novo and mount a robust antibody immune response after 
vaccination. 
 
This study will evaluate the safety, tolerability, and immunogenicity of SAB-176, a fully human 
polyclonal anti-Influenza IgG produced from transchromosomic bovine. Beginning with a low 
single-dose, subjects are randomized to receive either SAB-176 or a normal saline control, and 
evaluated on Study Days 1, 3, 7, 21, 42, and 90.  The safety and tolerability is evaluated using 
symptoms, clinical laboratory tests, pharmacokinetics, and immunogenicity assays. Utilizing a 
series of stopping rules and a medical monitor, the dose will be escalated as safety and 
tolerability are established.  
 

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1 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
1.1 
Background 
Influenza causes substantial morbidity and mortality worldwide despite available antivirals and 
vaccines. Influenza is responsible for 226,000 excess hospitalizations and 30,000 to 50,000 
deaths each year in the United States alone (1). Effective therapeutics are needed to prevent 
mortality or morbidity in those afflicted with severe influenza. Human plasma (delivered as 
Fresh Frozen Plasma units) or human intravenous immunoglobulin (hIVIg) with anti-influenza 
antibodies have been proposed as treatments for severe influenza (2). A limitation with plasma or 
hIVIg is that large numbers of human plasma donors/units must be screened to identify those few 
with a higher-than-average hemagglutination inhibition (HAI) titers to multiple strains of 
influenza. However, recent clinical trials have not shown benefit to hospitalized patients with 
severe Type A influenza infections treated with human-derived anti-influenza plasma or hIVIg 
(3, 4).  
SAB Biotherapeutics, Inc., has developed SAB-176 to address the production limitations and 
lack-of-clinical efficacy of human-derived plasma or hIVIg. SAB-176 is a unique anti-influenza 
hIgG containing fully human polyclonal IgG antibodies with extremely high HAI and 
microneutralization (MN) titers against past, current, and potentially future strains of Type A 
influenza (H1N1/H3N2) and both lineages of Type B influenza (Yamagata/Victoria). SAB-176 
is purified from the plasma of immunized transchromosomic (Tc) bovines that were immunized 
with a quadrivalent recombinant hemagglutinin (HA) protein vaccine produced in insect cells. 
The HA antigens match the four influenza strains recommended yearly for the Northern 
hemisphere by the Center for Disease Control and Prevention (CDC). 
Furthermore, Tc bovine hIgGs have an IgG1 subclass content of approximately 80-90% versus 
approximately 60% for human-derived IVIg. IgG1 strongly activates complement and effector 
cells (NK cells, neutrophils, monocytes, etc.) of the innate immune system. SAB-176 is therefore 
much different than human-derived anti-influenza hIVIgs. SAB Biotherapeutics believes that 
SAB-176’s distinct attributes, in combination with early treatment of severe influenza disease, 
could demonstrate that the product reduces morbidity and mortality in patients with Type A 
and/or B influenza.  
The genome of Tc bovines contains a human artificial chromosome (HAC) comprising the entire 
human Ig gene repertoire (human Ig heavy chain [IgH] and human kappa light chain) that reside 
on 2 different human chromosomes (hChr), specifically the IgH locus from hChr14 and the 
Immunoglobulin kappa (Igk) locus from hChr2. The system maintains the ability to use the 
genetic information provided by the immunoglobulin gene repertoires for generating the 
seemingly unlimited diversity of human polyclonal antibodies (pAbs).  
Fully hIgG (hIgG/hIgκ) can then be produced in these Tc bovines after vaccination with suitable 
antigens, and these animals produce up to 15 g/L of IgG antibodies in their plasma (similar to 
humans which have 7-16 g/L IgG). SAB-176 is an anti-influenza hIgG prepared in this system. 

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Tc bovines receive repeated doses of a quadrivalent recombinant HA protein vaccine produced 
in insect cells. Just prior to immunization of the Tc bovine, the HA proteins are mixed with 
adjuvants.  
Plasma is collected using an automated plasmapheresis system. After collection of sufficient 
volume, plasma undergoes Quality Control testing, is frozen and stored. Once it is ready to be 
processed, qualified frozen plasma is thawed, pooled, fractionated by caprylic acid (CA) and 
clarified by depth filtration in the presence of filter aid. The clarified sample containing hIgG is 
further purified by affinity chromatography, first using an anti-human IgG kappa affinity column 
to capture hIgG pAbs and remove residual non-hIgG and bovine plasma proteins (BPP). The 
sample is subsequently passed through an anti-bovine IgG (bIgG) heavy chain specific affinity 
column to further remove residual IgG molecules that contain a bovine heavy chain. The hIgG 
fraction is then subjected to a Q Sepharose chromatography polishing step to further reduce 
impurities, nanofiltration, final buffer exchange, concentration and sterile filtration. Finally, the 
product is terminally filtered and filled into vials.  
The drug product will be administered intravenously and will be diluted in saline per the clinical 
protocol.  
1.2 
Rationale 
This study will evaluate the safety and pharmacokinetics of SAB-176. This will both advance 
treatments for Type A and Type B influenza viruses, as well as establish the safety of the 
platform that could be used to quickly develop therapeutics for other emerging infectious 
diseases.  
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
• 
To evaluate the safety and tolerability of SAB-176 in healthy adults, following single 
intravenous administration at escalating dose-levels 
2.2 
Secondary Objectives 
• 
To evaluate the pharmacokinetics of intravenously administered SAB-176 in healthy 
adults, following a single intravenous administration at escalating dose-levels 
• 
To determine the ability of serum levels of SAB-176 to neutralize Type A and Type B 
influenza viruses 
• 
To evaluate the immunogenicity of SAB-176, as measured by: 
Anti-IgG antibodies using rheumatoid factor  
Anti-SAB-176 

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3 
INVESTIGATIONAL PLAN 
3.1 
General 
Study size:  27 subjects (up to 150 subjects screened to randomize a total of 27 subjects) 
Study duration: 1 year 
Study duration of individual subjects (not including screening): 90 days 
Sex distribution: males and females 
Age range: 18 to 60 years 
3.2 
Study Design 
This safety and tolerability study of intravenous (IV) SAB-176 consists of up to 4 single dose-
levels or cohorts (cohort 1–4) in a double-blind, randomized, placebo-controlled dose-escalating 
cohort design. Four cohorts of 2-10 subjects each will be administered a single IV dose of SAB-
176 or saline placebo.  At very low doses, the concern is primarily allergic or T-cell 
activation/cytokine storm, so small cohort sizes should be utilized.  As the target dose is 
approached, the sample size will increase to increase the likelihood of detecting toxicity events.   
The cohorts and dose levels are outlined in Table 1. 
 
Table 1: Cohorts and Dose Levels 
Cohort 
Number of Subjects  
Receiving SAB-176 
Number of Subjects  
Receiving Saline 
Control 
1 mg/kg 
10 mg/kg 
25 mg/kg 
50 mg/kg 
1 
2 
 
 
 
1 
2 
 
4 
 
 
2 
3 
 
 
6 
 
2 
4 
 
 
 
8 
2 
 
The number of subjects dosed will follow the limitations below: 
• The first three subjects of each cohort will be dosed every other day (48-hour interval).  
• For Cohorts 2-4, 48 hours after the third subject is dosed, up to 3 subjects may be dosed 
per day, until the cohort is completed, and no more than 8 subjects will be dosed per 
week.    
• For cohorts 2, 3, and 4, additional dosing in the cohort may continue only after the safety 
committee recommends continuation after reviewing the safety data from the 3 initial 
subjects of the cohort. 
•  After the first three in each cohort, subsequent subjects will be observed for at least 4 
hours before beginning the next infusion in the next subject.   
 
Table 2. Example of dosing timeline 
 
Infusion Day 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Subject 1 
X 
 
 
 
 
 
 
 
 
Subject 2 
 
 
X 
 
 
 
 
 
 
Subject 3 
 
 
 
 
X 
 
 
 
 
Subject 4 
 
 
 
 
 
 
X* 
 
 

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Table 2. Example of dosing timeline (con’t) 
 
Infusion Day 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Subject 5 
 
 
 
 
 
 
X 
(>4 hrs post 
Subject 4) 
 
 
Subject 6 
 
 
 
 
 
 
X 
(>4 hrs post 
Subject 5) 
 
 
Subject 7 
 
 
 
 
 
 
 
X 
 
Subject 8 
 
 
 
 
 
 
 
X 
(>4 hrs post 
Subject 7) 
 
Subject 9 
 
 
 
 
 
 
 
X 
(>4 hrs post 
Subject 8) 
 
Subject 10 
 
 
 
 
 
 
 
 
X 
* Additional enrollment in the cohort may continue only after the safety committee recommends continuation after 
reviewing the safety data from the three initial subjects of the cohort. 
 
NOTE: Only 1 subject should be infused at any given time. An infused subject should be 
observed for at least four hours prior to beginning the next infusion. 
 
Beginning with a low single-dose, subjects are randomized to receive either SAB-176 or placebo 
on Day 0. Subjects are then evaluated on Study Days 1, 3, 7, 21, 42, and 90. 
 
3.3 
Definitions for the Purpose of this Study  
Definitions for the Purpose of this Study:  
Enrolled 
For the purpose of collecting data and samples and reporting adverse events (AEs), a subject 
will be considered enrolled beginning from when the informed consent form is signed until 
the subject is considered “screen failure”, “discontinued”, or “completed”. 
 
Randomized 
Subjects are considered randomized when they meet all of the following criteria: 
◦ 
Enrolled (as defined above) 
◦ 
Confirmation that the inclusion and exclusion criteria are met 
◦ 
Randomization number is assigned 
 
Screen Failures 
Subjects are considered screen failures when they meet one or more of the following criteria 
after signing consent: 
◦ 
Screening tests reveal that the subject is ineligible 
◦ 
Subject withdraws consent before being randomized 
 

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Discontinued 
Subjects are considered discontinued when they meet one or more of the following criteria: 
◦ 
Subject withdraws consent after being randomized and prior to the completion of Day 
90 (see Section 4.6) 
◦ 
Subject is withdrawn after enrollment by Investigator (see Section 4.7) including lost 
to follow-up 
 
Completed 
Subjects are considered completed when they are followed through Study Day 90 and 
complete the final study follow-up visit (Study Day 90). 
 
4 
STUDY POPULATION 
4.1 
Research Subject Selection 
Healthy volunteers will be recruited for this study. 
4.2 
Recruitment 
Volunteers will be recruited through the posting of advertisements or via a pre-existing registry 
of potential subjects. All flyers and advertisements will be submitted to the Institutional Review 
Board (IRB) for approval. 
4.3 
Inclusion Criteria  
1. 
Age ≥18 years and ≤60 years 
2. 
Body mass index (BMI) of 19-32 kg/m2 
3. 
Subjects must have values in normal ranges for basic labs (i.e., CBC, PT/INR, 
Chem-7, and LFTs), unless deemed not clinically significant by the PI. 
4. 
Estimated glomerular filtration rate ≥85 mL/min at screening, calculated using the 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula 
5. 
Subjects must agree to: 
• Not take any prescription or over-the-counter (OTC) medications with the 
exception of acetaminophen, ibuprofen, vitamins, seasonal allergy 
medications, and/or contraceptive medications, or others unless approved by 
the study investigator, for a period 7 days prior to study drug administration 
(i.e., Day 0) 
1) 
Use one of the following in order to avoid pregnancy: 
• Females who are able to become pregnant (i.e., are not 
postmenopausal, have not undergone surgical sterilization, and are 
sexually active with men) must agree to use at least 2 effective 
forms of contraception from the date of the subject’s signing of the 
informed consent form through 60 days after the last dose of study 
drug. At least one of the methods of contraception should be a 
barrier method.   

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• Males who have not undergone surgical sterilization and are 
sexually active with women must agree to use condoms plus have 
a partner use at least one additional effective form of contraception 
from the date of the subject’s signing of the informed consent form 
through 60 days after the last dose of study drug. 
• Neither females or males should donate oocysts or sperm for use in 
artificial insemination through 60 days after the last dose of study 
drug. 
4.4 
Exclusion Criteria 
1. 
Any history of allergy, anaphylaxis, or severe reaction to beef products (including 
milk and gelatin) 
2. 
Any history of allergy, anaphylaxis, or severe reaction to IVIg or human blood 
products 
3. 
Any chronic medical problem/condition that require medications needed to maintain 
the subject’s health.  Exceptions to this restriction can be allowed for minor health 
conditions that are treated with Tylenol, over-the-counter non-steroidal anti-
inflammatories, vitamins, seasonal allergy medications, or oral/transdermal/IUD 
contraceptives, etc. The study investigator will make a determination to exclude a 
subject based upon their medical history and the type and frequency of the drug 
substance. 
4. 
History of cardiovascular disease, cardiomyopathy, heart failure, or unexplained 
syncope 
5. 
Abnormal clinically significant 12-lead electrocardiogram (ECG), per PI discretion 
6. 
Subjects who have been laboratory confirmed or clinically diagnosed with influenza 
within seven days prior to infusion (by subject history) will be deferred from 
infusion. Any subject with signs and symptoms of an active respiratory infection on 
the day of infusion will be deferred until the infection is cleared in the opinion of the 
investigator. Subjects that present with an active upper respiratory infection on the 
day of infusion will be tested with an FDA licensed Influenza A/B Antigen Test. 
Signs and symptoms constituting an upper respiratory infection include cough, sore 
throat, or rhinorrhea with or without fever. 
7. 
Enrollment will be delayed for all patients who have other intercurrent infections 
(e.g., gastroenteritis, abscess, etc.). 
8. 
Women who are breast-feeding 
9. 
Positive urine or serum pregnancy test 
10. 
Positive urine drug screen (UDS) 
11. 
Clinically significant results, including laboratory results, as determined by study 
investigator 
12. 
Positive rheumatoid factor 
13. 
IgA deficiency (defined as IgA < 7 mg/dL) 

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14. 
Participation in another research study with receipt of any investigational drug 
within 5 half-lives or 30 days, whichever is longer, prior to study drug 
administration (i.e., Day 0) and until completion of the study 
15. 
Participation in any other research study until the completion of the study 
16. 
Receipt of blood products within 2 months prior to study drug administration (i.e. 
Day 0) 
17. 
Receipt of any vaccination within 30 days prior to study drug administration (i.e. 
Day 0) 
18. 
Any acute or chronic condition that, in the opinion of the Investigator, would limit 
the subject’s ability to complete and/or participate in this clinical study 
4.5 
Justification of Exclusions of Pregnant Women and Children 
4.5.1 
Exclusion of Pregnant and Breastfeeding Women 
Pregnant women are excluded from this study because the effects of SAB-176 on the developing 
human fetus are unknown with the potential for teratogenic or abortifacient effects.  Because 
there is an unknown but potential risk for adverse events (AEs) in nursing infants secondary to 
treatment of the mother with SAB-176, women that are breastfeeding will also be excluded from 
the study. 
4.5.2 
Exclusion of Children 
Because there are insufficient data regarding dosing or AEs events available in adults to judge 
the potential risk in children, children are excluded from this study. 
4.6 
Subject Withdrawal 
Subjects (or their legal surrogates if subjects become unable to make informed decisions) can 
terminate study participation at any time without prejudice.  If a subject terminates participation 
before completing the study, the reason for this decision will be recorded in the study record. 
 
Best efforts will be made to follow withdrawn subjects who have received study drug 
administration for safety.  Subjects who withdraw from the study after study drug administration 
will not be replaced. 
4.7 
Discontinuation of Subject by Investigator 
The Investigator has the right to withdraw subjects from the study. Subjects may be withdrawn 
from the study for any of the following reasons: 
◦ 
The subject is lost to follow-up. 
◦ 
The Investigator believes that continuation in the study would be detrimental to the 
subject.  In general, subjects withdrawn for AEs will still be followed for safety 
follow-up if possible. 
◦ 
If, in the Investigator’s best judgment, discontinuation is in the subject’s best interest. 
 
The reason for withdrawal from the study is to be recorded in the study record.  All subjects 
should be followed for safety assessments.   If a non-serious AE is unresolved at the time of 
discontinuation, efforts should be made to follow up until the event resolves or stabilizes, the 
subject is lost to follow-up, or there is some other resolution of the event.  The Investigator 
should make every attempt to follow all serious adverse events (SAEs) to resolution. 

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Subjects withdrawn from the study after study drug administration will not be replaced. 
4.8 
Discontinuation of Study 
SAB Biotherapeutics as the study sponsor, the study site IRB, and the Food and Drug 
Administration (FDA) may terminate this study at any time.  Reasons for terminating the study 
may include, but are not limited to, the following: 
◦ 
The incidence or severity of an AE in this or other studies indicates a potential health 
hazard to subjects. 
◦ 
If there is one death, irrespective of attribution by the investigator/medical monitor. 
Subject enrollment is unsatisfactory. 
◦ 
Data recording is inaccurate or incomplete. 
◦ 
Investigators do not adhere to the protocol or applicable regulatory guidelines in 
conducting the study. 
4.9 
Emergency Unblinding 
If a subject experiences a SAE, and the treating clinician requests unblinding of the study 
treatment, the Principal Investigator (PI) or designee will be contacted.  If the PI or designee is in 
agreement that unblinding is necessary, the PI or designee will contact the PPD Phase 1 Clinic 
Pharmacy for release of the randomization code for the subject to the treating clinician.  For 
individual subject unblinding, the site will follow their unblinding procedures per SOP-
AUSCLN-506. The sponsor and Medical Monitor will be informed within one business day that 
unblinding was necessary.  In this case, the subject is still considered enrolled in the study, and 
the data is still used for analysis. 
5 
TREATMENT 
5.1 
Randomization and Blinding 
 
The randomization schedule will be generated using SAS Version 9.4 or later (SAS Institute Inc, 
Cary, North Carolina), which will link sequential volunteer randomization numbers to treatment 
codes. The randomization schedule and the volunteer-specific emergency unblinding 
documentation will be provided to the unblinded pharmacist(s) at the clinic site. 
 
Study participants and study team (PI and associate Investigators and study staff) will be blinded 
throughout the entire study.  The study team will be unblinded after the Study Day 90 visit, all 
laboratory (and immunogenicity) results are available, and the final monitoring visits has 
occurred.   
 
The infusion will be provided in an opaque bag to obscure the bag, since SAB-176 may develop 
bubbles similar to what is seen with IVIg, if the product is agitated.  This process has been used 
in other studies (INSIGHT influenza IVIG) and was successful in maintaining blinding of the 
study team. 

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5.2 
Formulation, Packaging and Labeling  
5.2.1 
SAB-176 
SAB-176 is a purified human immunoglobulin G (hIgG) designed to specifically bind to Type A 
and Type B influenza viruses. The product is in development for use as a therapeutic agent to 
treat patients who are infected with Type A and Type B influenza viruses. The hIgG is purified 
from the plasma of immunized transchromosomic (Tc) bovines that were immunized with a 
quadrivalent recombinant hemagglutinin (HA) protein vaccine produced in insect cells.  
 
The product is in a sterile liquid form formulated in 10 mM glutamic acid monosodium salt, 262 
mM D-sorbitol, 0.05 mg/mL Tween 80, pH 5.5.  The drug product will be administered 
intravenously and will be diluted in saline per the clinical protocol. 
5.2.1.1 Label 
 
Figure 1: SAB-176 Vial Label 
5.2.1.2 Storage  
Store SAB-176 at 2-8° C 
5.2.2 
Saline Control 
Subjects randomized to the control infusion will receive normal (0.9%) saline in approximately 
the same volume as they would have received if randomized to the active arm.  
5.3 
Dosing and Administration 
The NIH clinical center guidelines for administration of a standard human 10% IVIg 
(10g/100mL) are for the initial rate to be 0.6 mL/kg/hr, and the rate can be increased gradually to 
a maximum of 4.8 mL/kg/hr, if tolerated.   
 
SAB-176 will be prepared in the following dilutions: 
• Cohort 1 will be prepared as a solution 1mg/1ml (0.1% solution by weight), which is 
1/100th the concentration of standard human IVIg (e.g. Gammunex). 
• Cohort 2 will be prepared as a solution 4mg/1ml (0.4% solution by weight), which is 
1/25th the concentration of standard human IVIg.   
• Cohorts 3&4 will be prepared as a solution 20mg/1ml (2% solution by weight), which is 
1/5th the concentration of standard human IVIg.   
 
The dose of study drug will be calculated based on the subject’s dose cohort and weight (up to a 
maximum weight of 100 kg).  The pharmacy will prepare a bag containing the dose of SAB-176 
plus as much normal (0.9%) saline as is needed to reach the above listed concentrations.  The 
infusion will be provided in an opaque bag to obscure the bag (as the SAB-176 may develop 

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bubbles like IVIg if agitated).  The drip chamber will also be covered, but accessible if needed 
by nursing staff for verification of flow rate, etc. 
 
Table 3: Dosing and Administration 
Cohort 
Dose 
(mg/kg) 
Concentration 
Start Rate 
(mL/kg/hr) 
End Rate 
(mL/kg/hr) 
Start Rate 
(mg/kg/hr) 
End Rate 
(mg/kg/hr) 
Proportion of 
Human IVIG 
Rate 
Duration 
(mins) 
(approx.) 
1 
1 
1 mg/mL (0.1%) 
0.5 
2 
0.5 
2 
1/120th – 1/240th  
53 
2 
10 
4 mg/mL (0.4 %) 
0.5 
3 
2 
12 
1/30th - 1/40th 
85 
3 
25 
20 mg/mL (2 %) 
0.5 
1 
10 
20 
1/6th - 1/12th 
83 
4 
50 
20 mg/mL (2 %) 
0.5 
2 
10 
40 
1/6th - 1/10th 
97 
 
The infusion will be started at of 0.5 mL/kg/hr, escalating by 0.5 mL/kg/hr increments every 15 
minutes to a maximum specified above (end rate). 
 
It is anticipated that the infusion is prepared the morning of the infusion.  Since the study drug 
has been shown stable for 24 hours when mixed in saline, the infusion should be started within 6 
hours of preparation in order to assure completion within normal working hours.   
 
The dosing of an individual subject will be slowed and or stopped (depending on clinical 
assessment) for the following: 
• hypotension (systolic or mean blood pressure decreases by 20 mmHg) 
• shortness of breath, wheezing, or desaturation 
• pain, tenderness, erythema, or swelling around the infusion site 
• fevers, chills 
• Other adverse reactions not specified, that are concerning for infusion related adverse 
events 
After clinical assessment, and resolution or improvement of the event of concern, the infusion 
may be resumed.  If the event is not resolving in a reasonable amount of time, the infusion will 
not be resumed.  
 
However, in order to establish absolute criteria for stopping an infusion – the treatment should be 
immediately stopped should any of the following occur: 
• Profound hypotension (systolic blood pressure < 85 mmHg) 
• Shortness of breath, wheezing, or sustained (i.e., ≥ 10 seconds) oxygen saturation < 92% on 
room air 
• Severe (Grade ≥ 3) local infusion site reactions, including pain, tenderness, erythema, or 
swelling as defined in the protocol-specified toxicity grading scale 
• Body core temperature exceeding 38.5°C 
• Suspected sepsis 
• Severe chest pain 
• Suspected anaphylaxis 
 
The subject’s actual time of drug administration will be recorded in the source documents. 

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5.4 
Justification of Dose 
The proposed starting dose for this Phase 1 study is 1 mg/kg administered as a single IV 
infusion. Based on the non-clinical toxicology results in New Zealand white rabbits, the no 
observed adverse effect level was considered to be 725.30 mg/kg/day or higher.  The 725.30 
mg/kg dose was the maximum dose available to test due to dose volume limitations for the 
species. Using body surface area calculations (5) and 5X safety factor, a 50 mg/kg dose (The 
maximum therapeutic target dose for SAB-176) is equivalent to 770.8 mg/kg in rabbits. The 
planned 1 mg/kg starting dose for humans is approximately 47X lower than the maximum 
recommended starting dose. 
5.5 
Study Drug Accountability 
The study pharmacist is unblinded, and will maintain accurate drug accountability records. This 
log will not be shown to the study Investigators.  When the study is completed, copies of the 
study drug accountability records will be returned to the sponsor, and the originals will be 
maintained at the study site.  Copies of the drug accountability records must be maintained with 
the rest of the documentation for the study.  All unused study drug must be disposed of upon 
authorization by SAB or its designee. All records regarding the disposition of study drug must be 
available for inspection by the study monitors and regulatory authorities. 
5.6 
Concomitant Medications 
Subjects will be monitored throughout the study for use of concomitant medications.  Any 
prescription medications, OTC preparations, herbal remedies, and/or nutritional supplements 
taken during the study period must be recorded in the research record. 
5.7 
Prohibited Medications 
Subjects will refrain from receipt of any investigational drug within 5 half-lives or 30 days, 
whichever is longer, prior to Day 0 and during the entire study.  
6 
STUDY PROCEDURES 
6.1 
Personnel for Study Procedures 
The physical examination (excluding vital signs) will be performed by a physician, nurse 
practitioner, or physician’s assistant.  All other assessments may be performed by other 
appropriately trained members of the investigative team as noted on the Delegation of 
Responsibilities form. 
6.2 
Screening  
Screening evaluations may be done up to 28 days before Day 0.  
6.2.1 
Informed Consent 
The Investigator or designated staff will review informed consent with the subject.  One 
informed consent form will be used for both screening and enrollment into this protocol. 
6.2.2 
Demographics 
The following information should be recorded: 
• 
Age 

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• 
Sex 
• 
Ethnicity  
• 
Race 
6.2.3 
Medical History 
The following information should be recorded: 
• 
Medical history including any chronic medical conditions 
• 
Current use of prescription and OTC medications within the last 7 days 
• 
History of allergies 
• 
Current or recent participation in any other research protocols 
6.2.4 
Clinical Data  
• Vital signs (See Section 7.1.3) 
• 12-lead ECG (See Section 7.3) 
 
6.2.5 
Physical Exam 
A brief physical exam to ensure there are not medical conditions that would increase a subject’s 
risk for participation in this study (Section 7.1.2) 
 
6.2.6 
Laboratory Testing 
The following tests will be performed the day of screening: 
• CBC with differential 
• Reticulocyte count  
• Prothrombin Time (PT) and Partial Thromboplastin Time (PTT) 
• Chemistry panel  
• Quantitative Immunoglobulins  
• Routine urinalysis  
• Urine biomarkers  
• Serum or urine pregnancy test (females of childbearing potential only) 
• Rheumatoid factor 
(Elements of each panel are listed in Section 7.1.1) 
 
6.2.7 
Determination of Eligibility 
Once the screening evaluation is complete, eligibility will be determined based on the inclusion 
and exclusion criteria.  Eligible subjects will be contacted, and if still interested in participating, 
will be scheduled to return to the Clinical Center for randomization and study drug 
administration.  The period of time between screening evaluation visit and administration of 
study drug should not exceed 28 days. 
 
Subjects that are found to be ineligible will be contacted (or told directly if found ineligible 
during screening evaluation), and the reason for ineligibility will be discussed.  If desired by the 
subject, and if applicable for the reason for ineligibility, the results will be shared with their 

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health care provider and/or the subject will be assisted in finding definitive medical care for said 
condition. 
6.3 
Detailed Description of Assessments 
6.3.1 
Schedule of Assessments  
The schedule of assessments is described in Table 3. The day when the subject is randomized is 
denoted as Study Day 0, the first day after enrollment is Study Day 1, etc.  
 
Table 4: Schedule of Assessments 
  
Screen 
Baseline 
  
Day +/- Window 
−28 to -
1 
-1 to 0 
1 
2 
3 (+1) 
7 ± 1 
21 ± 2 
42 ± 3 
90 ± 7 
Evaluation/Procedure 
  
Prior to 
infusion 
  
 
  
  
  
  
  
ELIGIBILTY 
  
  
  
 
  
  
  
  
  
Informed consent 
X 
  
  
 
  
  
  
  
  
Demographics 
X 
  
  
 
  
  
  
  
  
Medical history 
X 
  
  
 
  
  
  
  
  
RANDOMIZATION/ STUDY 
DRUG  
  
  
  
 
  
  
  
  
  
Randomize subject 
  
X 
  
 
  
  
  
  
  
Study drug administration 
  
X 
  
 
  
  
  
  
  
STUDY PROCEDURES 
  
  
  
 
  
  
  
  
  
Assess Symptoms 
 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs                 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review of concomitant medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam                                      
X 
 
if needed to assess AEs 
ECG 
X 
 
 
 
 
 
 
 
 
Adverse events 
  
X 
X 
X 
X 
X 
X 
X 
X 
SAFETY LABORATORY a 
  
  
  
 
  
  
  
  
  
CBC                                  
X 
X 
  
X 
X 
X 
  
X 
X  
PT/PTT 
X 
X 
 
X 
X 
X 
 
X 
X 
Reticulocyte Count 
X 
X 
 
X 
X 
X 
 
X 
X 
Chemistry Panel                                   
X 
X 
  
X 
X 
X 
  
X 
  
Urinalysis 
X 
X 
  
X 
X 
X 
  
X 
  
Quantitative Immunoglobulin  
 X 
X 
  
X 
X 
X 
X 
X 
X 
Rheumatoid factor 
X 
X 
  
X 
X 
X 
X 
X 
X 
Urine biomarkers 
 X 
X 
  
X 
X 
X 
  
X 
 
Pregnancy test (urine or serum) 
X 
X 
  
 
  
  
  
  
  
UDS 
X 
X 
 
 
 
 
 
 
 
REFERENCE PROCEDURE 
  
  
  
 
  
  
  
  
  
Stored serum for pharmacokinetics 
  
Xb 
X 
X 
X 
X 
X 
X 
X 
Stored serum for immunogenicityc 
 
X 
 
 
 
X 
X 
X 
X 
Notes. a) Elements of each panel are listed in Section 7.1.1 
b) PK sample on Day 0 includes baseline (pre-infusion), 1 hour (+/- 15 min) after the end of the infusion, and 6 hours (+/- 30 min) after the end of 
the infusion.   
c) Serum will be collected for immunogenicity assessment for subjects at the time of an AE suggestive of hypersensitivity reaction (including 
serum sickness) even if the AE does not coincide with a visit in which immunogenicity assessment is planned. 
6.3.2 
Location of Study Drug Administration 
The study drug will be administered in the PPD Phase 1 Clinic in Austin, Texas.  Subjects will 
be asked to arrive on the unit at least 60 minutes prior to scheduled time of study drug 
administration.   
 

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6.3.3 
Randomization 
An order for randomization to SAB-176 or placebo will be entered into CRIS.  A blinded 
treatment allocation is determined by the pharmacy as discussed in Section 5.1. 
 
6.3.4 
Study Day -1 to Day 0 - Baseline Evaluation 
Prior to study drug administration, a baseline evaluation will be performed, including the 
following: 
 
6.3.4.1 Interval History and Exam 
An interval medical history will be performed. This will include: 
• Any new medical conditions since screening visit 
• Any new medications since screening visit 
• Allergies 
• Participation in any other research protocols within the last month or since the screening 
visit, whichever is longer 
 
6.3.4.2 Assessment of Baseline Symptoms 
The presence of any baseline symptoms will be elicited and documented. 
 
6.3.4.3 Laboratory Testing 
The following clinical laboratory tests will be performed and documented: 
• CBC with differential 
• Reticulocyte Count 
• PT/PTT 
• Chemistry panel 
• Urinalysis  
• Urine biomarkers  
• Quantitative Immunoglobulins (IgG level) 
• Rheumatoid factor 
• Serum or urine pregnancy test for women of child-bearing potential 
• Stored serum for pharmacokinetics and immunogenicity (16 ml blood) 
(Elements of each panel are listed in Section 7.1.1) 
Only the pregnancy test must be resulted prior to initiation of study drug infusion. 
 
6.3.5 
Study Day 0: Study Drug Administration 
SAB-176 or placebo will be prepared as noted in Section 5.3. The blinded bag of SAB-176 
diluted in sterile normal saline or placebo (sterile normal saline) will be provided to blinded 
study staff for dose administration. 
 
A peripheral IV will be placed.  The dose will be administered as an IV infusion.  For each dose, 
the subject’s actual administration time will be recorded in the source documents. 

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6.3.6 
Study Day 0: Peri-Administration Assessments 
After study drug administration, subjects will remain in the trial unit for 6 hours after the end of 
infusion.  Monitoring will be performed in a setting with emergency medications, resuscitation 
equipment and appropriately trained personnel to intervene if needed. The following procedures 
will occur: 
• Vital signs: prior to start of infusion, and then approximately 15 and 30 minutes after 
the start of the infusion, and every 30 minutes thereafter until the end of the infusion 
• Pharmacokinetic Evaluation approximately 1 hour (+/- 15 min) after the end of the 
infusion.  The PK sample (8 ml blood) will be obtained from a separate venipuncture 
(i.e. not through the infusion IV).  
• 
 Vital signs post-dosing will be captured hourly for 6 hours and again at 12h. 
• Pharmacokinetic Evaluation approximately 6 hours (+/- 15 min) after the end of the 
infusion.  The PK sample (8 ml blood) will be obtained from a separate venipuncture 
(i.e. not through the infusion IV).  
• Any adverse events occurring during the infusion will be recorded 
 
6.3.7 
Study Day 1 
6.3.7.1 Interval History and Exam 
An interval medical history will be performed.  This will include: 
• Any new medical conditions 
• Current prescription and OTC medications  
• Vital signs 
• Physical exam as needed to evaluate new symptoms/complaints 
 
6.3.7.2 Assessment of Symptoms 
The presence of any symptoms will be elicited and documented. 
 
6.3.7.3 Laboratory Testing 
• Stored serum for pharmacokinetics (8 mL blood) 
 
6.3.8 
Study Day 2 
6.3.8.1 Interval History and Exam 
An interval medical history will be performed. This will include: 
• Any new medical conditions 
• Current prescription and OTC medications  
• Vital signs 
• Physical exam as needed to evaluate new symptoms/complaints 
 

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6.3.8.2 Assessment of Symptoms 
The presence of any symptoms will be elicited and documented. 
 
6.3.8.3 Laboratory Testing 
The following clinical laboratory tests will be performed and documented: 
• CBC with differential 
• Reticulocyte count  
• PT/PTT 
• Chemistry panel 
• Urinalysis  
• Quantitative Immunoglobulins (IgG level) 
• Rheumatoid factor 
• Urine biomarkers  
• Stored serum for pharmacokinetics  
(Elements of each panel are listed in Section 7.1.1) 
 
6.3.9 
Study Day 3 (+1) 
6.3.9.1 Interval History and Exam 
An interval medical history will be performed. This will include: 
• Any new medical conditions 
• Current prescription and OTC medications  
• Vital signs 
• Physical exam as needed to evaluate new symptoms/complaints 
 
6.3.9.2 Assessment of Symptoms 
The presence of any symptoms will be elicited and documented. 
 
6.3.9.3 Laboratory Testing 
The following clinical laboratory tests will be performed and documented: 
• CBC with differential 
• Reticulocyte count  
• PT/PTT 
• Chemistry panel 
• Urinalysis  
• Quantitative Immunoglobulins (IgG level) 
• Rheumatoid factor 
• Urine biomarkers  
• Stored serum for pharmacokinetics (8 mL blood) 
(Elements of each panel are listed in Section 7.1.1) 
 

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6.3.10 
Study Day 7 (+/-1) 
6.3.10.1 Interval History and Exam 
An interval medical history will be performed. This will include: 
• Any new medical conditions 
• Current prescription and OTC medications 
• Vital signs 
• Physical exam as needed to evaluate new symptoms/complaints 
 
6.3.10.2 Assessment of Symptoms 
The presence of any symptoms will be elicited and documented. 
 
6.3.10.3 Laboratory Testing 
The following clinical laboratory tests will be performed and documented: 
• CBC with differential 
• Reticulocyte count 
• PT/PTT 
• Chemistry panel 
• Urinalysis  
• Quantitative Immunoglobulins (IgG level) 
• Rheumatoid factor 
• Urine biomarkers  
• Stored serum for pharmacokinetics & immunogenicity (16 mL blood) 
(Elements of each panel are listed in Section 7.1.1) 
 
6.3.11 
Study Day 21 (+/- 1) 
6.3.11.1 Interval History and Exam 
An interval medical history will be performed. This will include: 
• Any new medical conditions 
• Current prescription and OTC medications 
• Vital signs 
• Physical exam as needed to evaluate new symptoms/complaints 
 
6.3.11.2 Assessment of Symptoms 
The presence of any symptoms will be elicited and documented. 
 
6.3.11.3 Laboratory Testing 
The following clinical laboratory tests will be performed and documented: 
• Quantitative Immunoglobulins (IgG level) 
• Rheumatoid factor 
• Stored serum for pharmacokinetics & immunogenicity (16 mL blood) 

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6.3.12 
Study Day 42 (+/- 2) 
6.3.12.1 Interval History and Exam 
An interval medical history will be performed. This will include: 
• Any new medical conditions 
• Current prescription and OTC medications 
• Vital signs 
• Physical exam as needed to evaluate new symptoms/complaints 
 
6.3.12.2 Assessment of Symptoms 
The presence of any symptoms will be elicited and documented. 
 
6.3.12.3 Laboratory Testing 
The following clinical laboratory tests will be performed and documented: 
• CBC with differential  
• Reticulocyte count 
• PT/PTT 
• Chemistry panel 
• Urinalysis  
• Quantitative Immunoglobulins (IgG level) 
• Rheumatoid factor 
• Urine biomarkers  
• Stored serum for pharmacokinetics & immunogenicity (16 mL blood) 
(Elements of each panel are listed in Section 7.1.1) 
 
6.3.13 
Study Day 90 (+/- 7) 
6.3.13.1 Interval History and Exam 
An interval medical history will be performed. This will include: 
• Any new medical conditions 
• Current prescription and OTC medications 
• Vital signs 
• Physical exam as needed to evaluate new symptoms/complaints 
 
6.3.13.2 Assessment of Symptoms 
The presence of any symptoms will be elicited and documented. 
 
6.3.13.3 Laboratory Testing 
The following clinical laboratory tests will be performed and documented: 
• CBC with differential 
• Reticulocyte count  

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• PT/PTT 
• Quantitative Immunoglobulins (IgG level) 
• Rheumatoid factor 
• Stored serum for pharmacokinetics & immunogenicity (16 mL blood) 
 
7 
MEASURES OF SAFETY, EFFICACY, AND COMPLIANCE 
7.1 
Safety Evaluations 
7.1.1 
Laboratory Evaluations 
All laboratory evaluations (except reference endpoint assays) will be performed at a CLIA-
certified clinical laboratory.  Blood samples will be collected from subjects as noted in the 
schedule of assessments.  Abnormal labs thought to be erroneous may be repeated once. 
 
On the designated days, the following laboratory tests will be performed: 
• CBC with differential: white cell count (to include absolute neutrophil, and lymphocyte 
counts), hemoglobin, hematocrit, and platelet count 
• Reticulocyte count 
• Prothrombin Time (PT) and Partial Thromboplastin Time (PTT) 
• Chemistry panel: Na, K, total CO2, BUN, creatinine, glucose, ALT, AST, total 
bilirubin, LDH, CPK, and estimated GFR by the CKD-EPI equation) 
• Routine urinalysis (includes protein, glucose, ketones, hemoglobin, urobilinogen, 
leukocyte esterase, nitrite, pH, specific gravity, RBCs, WBCs) 
• Urine biomarkers (quantitative albumin, quantitative protein, β2-microglobulin, and 
creatinine) 
• Serum or urine pregnancy test (females of childbearing potential only) 
• Quantitative Immunoglobulins (IgG level) 
• Rheumatoid factor 
 
7.1.2 
Physical Examinations 
A brief physical examination will be conducted at screening to ensure there are no medical 
conditions that would increase a subject’s risk for participation in this study.  Symptom-targeted 
physical examinations will be conducted at all other visits as needed to evaluate new complaints 
and possible AEs. 
7.1.3 
Vital Signs, Including SaO2 
At each visit, vital signs assessments (BP, HR, temperature, respiration rate, oxygen saturation). 
7.2 
Measures of Pharmacokinetics and Immunogenicity  
As noted in the schedule and text above, 8 mL or 16 mL of blood will be obtained for evaluation 
of pharmacokinetics and immunogenicity.  It is anticipated this will be in a serum separator tube 
(this tube may change without amending the protocol). Serum will be collected for 
immunogenicity assessment for subjects at the time of an AE suggestive of hypersensitivity 
reaction (including serum sickness) even if the AE does not coincide with a visit in which 
immunogenicity assessment is planned. 

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Pharmacokinetics evaluations will be performed by PPD.  As SAB-176 cannot be differentiated 
from human IgG, the pharmacokinetics evaluations will use Hemagglutination Inhibition assays.  
 
This protocol will evaluate immunogenicity in several assays: 
1. anti-IgG antibodies using rheumatoid factor  
2. Anti-Drug (anti-SAB-176) Antibody (performed at SAB Biotherapeutics) 
7.3 
12-Lead ECG 
A 12-lead ECG will be obtained according to the Schedule of Assessments. 
 
The ECGs will be measured using and ECG machine that calculates the heart rate and measures 
PR, QRS, QT, and QTcF. 
 
Subjects will be required to lie quietly in a supine position for at least 5 minutes.  
8 
RISKS AND BENEFITS 
8.1 
Potential Risks 
8.1.1 
Risks of SAB-176 
The risks of SAB-176 are largely unknown. However, a previous Phase 1 study of SAB-301 
(anti-Middle Eastern Respiratory Syndrome virus immunoglobulin) derived from Tc bovines was 
shown to be safe and well tolerated at the highest dose of 50 mg/kg proposed in this study. It is 
anticipated that the risks will be similar to SAB-301 and human derived IVIg with some unique 
considerations for proteins of animal origin as discussed below. 
 
Based on human IVIg, common side effects may include: 
• Headache 
• Injection site reaction 
• Nausea 
• Urticaria 
• Fatigue 
• Arthralgia 
• Pyrexia   
 
Less common side effects may include:  
• Vomiting 
• Back pain 
• Rash 
 
Serious side effects seen with human IVIg that could be seen with SAB-176 include: 
• Hyperproteinemia, with resultant changes in serum viscosity and electrolyte imbalances 
may occur in patients receiving IVIg therapy (6). Humans routinely receive up to 1-2 
grams/kg of human-derived IVIg to treat Guillain-Barre syndrome and other immune 
related neuropathies.  Therefore, the addition of 50 mg/kg IgG as SAB-176 is a relatively 

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small amount and is unlikely to cause AEs related to increased viscosity. 
• Aseptic Meningitis Syndrome (AMS) has been reported with IVIg treatments, especially 
with high doses or rapid infusion. This risk is anticipated to be minimized given the low 
amount of protein and relatively slow infusion. 
• Hemolysis, either intravascular or due to enhanced RBC sequestration, can be seen with 
human IVIG. This risk is anticipated to be low given the lack of exposure of the cows to 
human RBC antigens.   
• Volume overload has been reported with human IVIg.  This risk is anticipated to be 
minimized given the low amount of protein and small total volumes administered. 
 
There may be unique risks given the animal origin of the IVIg. SAB-176 is a human IgG so it is 
anticipated the risk with SAB-176 would be less, though there may be residual animal proteins. 
The most similar product would be an animal polyclonal antibodies to non-human proteins e.g. 
Horse Heptavalent Botulism Antitoxin.  
(http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProduc
ts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM345147.pdf) 
 
There is the risk of off-target binding of the IVIg. In the worst case, this could cause immune 
activation (cytokine storm).  The tissue cross reactivity assays do not predict any off-target 
binding, and this has not been seen in any other animal IVIg (of Fab fragment) preparations, so 
this risk is considered low.  
For Horse Heptavalent Botulism Antitoxin, the most common adverse reactions in all healthy 
subjects were headache (9%), pruritus (5%), nausea (5%), and urticaria (5%). Other adverse 
reactions reported in less than 4% of subjects included pyrexia and throat discomfort. All 
reported adverse reactions were considered mild or moderate. No serious adverse reactions were 
reported.  Two moderate acute allergic reactions that required premature termination of the 
infusion and treatment were reported. Reactions were predefined as mild if the subject was aware 
but could tolerate the symptoms. Moderate reactions were predefined as discomfort enough to 
interfere with normal daily activity.  
The development of antibodies to bovine proteins and potential for food allergies is a theoretical 
concern.  There is precedent for animal antibodies (or Fab fragments) being obtained from 
animal plasma and given to humans.   
• Rabbit Anti-thymocyte Globulin [Thymoglobulin] 
(http://products.sanofi.ca/en/thymoglobulin.pdf) 
• Horse Anti-thymocyte Globulin [Atgam] 
(http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/Approved
Products/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM199603.pdf) 
• Horse Heptavalent Botulism Antitoxin  
(http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/Approved
Products/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM345147.pdf) 
• Sheep Digoxin Immune Fab [DigiFab] 
(http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/Approved
Products/LicensedProductsBLAs/FractionatedPlasmaProducts/ucm117626.pdf) 

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• Sheep Digoxin Immune Fab [DigiBind] 
(http://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=19044) 
• Sheep Crotalidae Polyvalent Immune Fab [CroFab] 
(http://www.crofab.com/documents/CroFab-Prescribing_Information.pdf) 
 
Upon review of these package inserts, the development of anti-drug antibodies was noted only in 
Horse Heptavalent Botulism Antitoxin (11 of 271 subjects).  There was no warning in any of 
these products concerning the development of allergies to other animal proteins, nor of any food 
allergies. As SAB-176 is a transgenic human IgG, the risk should be even further minimized. 
However, given the American diet is often heavy in bovine products (milk and/or beef, including 
derivatives), there is the risk of development of anti-bovine antibodies that is stimulated with 
repeated exposure.  Given the data above and the lack of precedent for the development of food 
allergies after exposure to similar products, it is anticipated this risk with SAB-176 is very small.   
 
Patients exposed to topical bovine thrombin products (previously used in surgical procedures e.g. 
fibrin glue) have developed antibodies towards bovine thrombin and contaminating bovine factor 
V; these antibodies can cross react with human clotting factors and may cause coagulopathy (7). 
In that series, postoperative coagulation abnormalities were more common in patients with 
antibodies to human coagulation proteins. SAB-176 clinical lots contain less than 5 ppm (parts 
per million) of bovine plasma proteins, but the clinical significance of this level of bovine 
contaminants is not known. Regardless, the serial assessment of PT/PTT in the study will 
monitor for any coagulation abnormalities in the subjects receiving SAB-176.  
 
As SAB-176 is bovine derived, it may contain galactose-alpha-1,3-galactose (alpha-Gal) 
glycosylation of the IgG.  In other products, the alpha-Gal glycosylation has been shown to be 
the source of immune based hypersensitivity reactions.  For example, the epidermal growth 
factor receptor (EGFR) inhibitor cetuximab is a monoclonal antibody with alpha-Gal 
glycosylation. Cetuximab, while a marketed product, has been associated with hypersensitivity 
reactions, including anaphylaxis.  In most subjects that had hypersensitivity reaction to 
cetuximab, IgE antibodies were present in pretreatment samples (8). This study is designed to 
start with very small doses, with close monitoring for similar hypersensitivity reactions.  
 
Lastly, SAB’s Tc-bovine production system and the US cattle population have a negligible risk 
for transmissible bovine spongiform encephalopathy (BSE), also known as “Mad Cow 
Disease”.  Only three reported cases of BSE infection in cattle have been documented in the US 
in the last decade.  Risk assessments for infectious diseases were completed on the production 
herd, and documented procedures are in place to reduce or eliminate certain infectious diseases 
in the production animals.  All inputs (feed, medications, and vaccines) have been evaluated for 
the transmission of viral and BSE agents. The manufacturing process was also evaluated for the 
clearance and removal of viruses and BSE. Virus removal has been validated. The BSE Western 
blot analysis was done to demonstrate clearance and removal of prions.  
 
There may be additional risks not apparent or predicted by preclinical testing. 

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8.1.2 
Risk of Intravenous Catheter 
The primary risks of the placement of an intravenous catheter include local discomfort; 
occasional bleeding or bruising of the skin at the site of needle puncture; hematoma; and, rarely, 
infection or fainting. To reduce the risk of injury from a fall, the subject will be closely 
monitored and asked about these symptoms before being allowed to stand up. 
8.1.3 
Risks of Phlebotomy 
The primary risks of phlebotomy include local discomfort, occasional bleeding or bruising of the 
skin at the site of needle puncture, hematoma and, rarely, infection or fainting.  At the time of 
enrollment and during study visits, each subject will be asked about participation in other 
research studies, to ensure that blood draws do not exceed 450 mL over any 8-week period for 
adults, for all research protocols combined. 
8.2 
Potential Benefits 
 
Subjects will not benefit directly from participation in this protocol. 
8.3 
Alternatives 
As there is no benefit to the subject for enrollment in this protocol, the alternative to participating 
in this protocol is not to participate. 
9 
RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS, AND DATA 
9.1 
Intended Use of the Samples/Specimens/Data 
Samples and data collected under this protocol will be used to determine the safety and 
pharmacokinetics of SAB-176. 
9.2 
Storage of Samples/Specimens/Data  
Samples will be stored for the reasons noted above. 
9.3 
Storage of Genetic Samples 
No samples are being stored for genetic testing on the subjects. 
9.4 
Tracking Samples 
Samples will be tracked by a commercial software program. 
9.5 
Use of Samples/Specimens/Data at the Completion of the Protocol 
Samples will be maintained for further laboratory testing for up to 5 years after completion (or 
closure) of the protocol for the purpose stated in Section 9.1.  No long-term storage of samples 
will occur in this study. 
9.6 
Reporting Loss or Destruction of Samples/Specimens/Data  
Any loss or unanticipated destruction of locally maintained samples (for example, due to freezer 
malfunction) or data (for example, misplacing a printout of data with identifiers) will be reported 
to the site IRB.  

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10 
ASSESSMENT OF SAFETY  
Regulatory requirements, including FDA regulations and ICH Guideline for Good Clinical 
Practice, set forth safety monitoring and reporting responsibilities of Sponsors and Investigators 
to ensure the safety and protection of human subjects participating in clinical trials. 
10.1 
Toxicity Scale 
All AEs that occur during the study should be assessed according to the DAIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), 
Version 2.1 (July 2017). 
 
Some grade 1 laboratory parameters on the DAIDS Toxicity Table may fall within the lab 
reference range for normal values.  If so, these normal values will not be reported as grade 1 
adverse events.   
 
10.1.1 
Causality 
Causality (likelihood that the event is related to the study agent) will be assessed 
considering the factors listed under the following categories:  
 
Definitely Related:    
• Reasonable temporal relationship 
• Follows a known response pattern 
• Clear evidence to suggest a causal relationship 
• There is no alternative etiology 
 
Probably Related: 
 
• Reasonable temporal relationship 
• Follows a suspected response pattern (based on similar agents) 
• No evidence of a more likely alternative etiology 
 
Possibly Related: 
 
• Reasonable temporal relationship 
• Little evidence for a more likely alternative etiology 
 
Unlikely Related: 
 
• Does not have a reasonable temporal relationship  
OR 
• Good evidence for a more likely alternative etiology 
 
Not Related: 
 
• Does not have a temporal relationship 
OR 
• Definitely due to an alternative etiology 
 

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Note: Causality assessment is based on available information at the time of the 
assessment of the AE.  The Investigator may revise the causality assessment as 
additional information becomes available. 
10.2 
Recording/Documentation 
At each contact with the subject, information regarding AEs will be elicited by appropriate 
questioning and examinations and will be immediately recorded on a source document.  Source 
documents will include: progress notes, laboratory reports, consult notes, phone call summaries, 
survey tools, and data collection tools.  Source documents will be reviewed in a timely manner 
by the research team.  All reportable AEs that are identified will be recorded in Medidata Rave.  
The start date, the stop date, the severity of each reportable event, and the PI’s judgment of the 
AEs relationship to the study agent/intervention will also be recorded in Medidata Rave. 
10.3 
Definitions 
Adverse Event (AE): Any untoward or unfavorable medical occurrence in a human subject, that 
includes any abnormal sign (e.g. abnormal physical exam or laboratory finding), symptom, or 
disease, temporally associated with the subject’s participation in the research, whether or not 
considered related to the research. 
 
Adverse Reaction (AR): An adverse event that is caused by an investigational agent (drug or 
biologic). 
 
Suspected Adverse Reaction (SAR): An adverse event for which there is a reasonable 
possibility that the investigational agent caused the adverse event.  ‘Reasonable possibility’ 
means that there is evidence to suggest a causal relationship between the drug and the adverse 
event.  A suspected adverse reaction implies a lesser degree of certainty about causality than an 
adverse reaction, which implies a higher degree of certainty. 
 
Serious adverse event (SAE): Any adverse event that results in one or more of the following 
outcomes: 
• Death 
• Life-threatening (i.e. an immediate threat to life) event 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• Congenital anomaly/birth defect 
• Medically important event* 
 
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately life 
threatening or result in death or hospitalization, but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed above. 
 
Unexpected Adverse Event: An AE is unexpected if it is not listed in the Investigator’s 
Brochure or Package Insert (for marketed products) or is not listed at the specificity or severity 
that has been observed.  It is the responsibility of the IND Sponsor to make this determination. 

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Serious and Unexpected Suspected Adverse Reaction (SUSAR): A SUSAR is a suspected 
adverse reaction that is both serious and unexpected.  
 
Unanticipated Problem (UP): Any incident, experience, or outcome that is: 
1. Unexpected in terms of nature, severity, or frequency in relation to 
a. The research risks that are described in the IRB-approved research protocol, informed 
consent document, Investigator’s Brochure, or other study documents; and 
b. The characteristics of the subject population being studied; and 
2. Possibly, probably, or definitely related to participation in the research; and 
3. Places subjects or others at a greater risk of harm (including physical, psychological, 
economic, or social harm) than was previously known or recognized. (Per the IND 
Sponsor, an AE with a serious outcome will be considered increased risk.) 
 
Unanticipated Problem that is not an Adverse Event (UPnonAE): An unanticipated problem 
that does not fit the definition of an adverse event, but which may, in the opinion of the 
Investigator, involve risk to the subject, affect others in the research study, or significantly 
impact the integrity of research data.   
 
Protocol Deviation: Any change, divergence, or departure from the IRB-approved study 
procedures in a research protocol. Protocol deviations are designated serious or non-serious and 
further characterized as: 
1. Those that occur because a member of the research team deviates from the protocol 
2. Those that are identified before they occur, but cannot be prevented 
3. Those that are discovered after they occur 
 
Serious Protocol Deviation: A deviation that meets the definition of a SAE or compromises the 
safety, welfare, or rights of subjects or others. 
 
Non-Compliance: The failure to comply with applicable SAB policies, IRB requirements, or 
regulatory requirements for the protection of human subjects.  Non-compliance is further 
characterized as: 
1. Serious: Non-compliance that: 
a. Increases risks or causes harm to participants 
b. Decreases potential benefits to participants 
c. Compromises the integrity of the study 
d. Invalidates the study data 
2. Continuing: Non-compliance that is recurring 
3. Minor: Non-compliance that is neither serious nor continuing 
 
10.4 
Adverse Event Reporting 
10.4.1 
Expedited Reporting to the site IRB 
 
Unanticipated problems that are either AEs or non-AEs (as defined by Section 10.3) and Serious 
Protocol Deviations will be reported within seven calendar days of Investigator awareness.  
Serious Adverse Events that are possibly, probably, or definitely related to the research will be 

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reported to the site IRB within seven calendar days of Investigator’s awareness, regardless of 
expectedness. 
10.4.2 
Annual Reporting to the site IRB  
The following items will be reported to the site IRB in summary at the time of Continuing 
Review: 
• Serious and non-serious unanticipated problems  
• SAEs that are possibly, probably, or definitely related to the research 
• SAEs that are not related to the research 
• All AEs. 
• Serious and Non-Serious Protocol deviations 
• Serious, continuing, and minor non-compliance 
• Any trend or event that, in the opinion of the Investigator, should be reported 
10.4.3 
Investigator Reporting Responsibilities to the Sponsor  
Adverse Events: Line listings, frequency tables, and other summary AE data will be submitted to 
the IND Sponsor when needed for periodic safety assessments, review of IND annual reports, 
review of IND safety reports, and in the preparation of final study reports. 
 
SAEs (whether or not they are also UPs) must be reported on the Safety Expedited Report Form 
(SERF) and sent to the Sponsor Clinical Safety Office (CSO) by fax or e-mail attachment. 
Deaths and immediately life threatening SAEs must be reported within one business day after the 
site becomes aware of the event. All other SAEs must be reported within three business days of 
site awareness. 
 
SPONSOR CLINICAL SAFETY OFFICE CONTACT INFORMATION:  
 
SAB Biotherapeutics, Inc.  
ATTN: Clinical Safety Office 
2301 E. 60th St. North 
Sioux Falls, SD 57104 
 
Phone: 605-679-6980 
Fax: 888-680-0864 
E-mail: safetyreporting@sabbiotherapeutics.com 
 
Non-Serious AEs that are UPs must also be reported on the SERF and sent to the CSO by fax or 
e-mail attachment no later than seven calendar days of site awareness of the event. The UPs that 
are not AEs are not reported to the Sponsor CSO. 
 
Pregnancy: Although pregnancy itself is not an AE, events that meet SAE criteria during 
pregnancy, delivery, or in the neonate (e.g., congenital anomaly/birth defect) are reportable on 
the SERF.  Pregnancy and pregnancy outcome data (e.g. delivery outcome, spontaneous or 
elective termination of the pregnancy) will be reported to the CSO within three business days of 
the site’s awareness via email or fax. 
 

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10.5 FOLLOW-UP OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
AEs that occur following enrollment of the subject (by signing the informed consent) are 
followed until the final outcome is known or until the end of the study follow-up period. 
 
SAEs that have not resolved by the end of the follow-up period are followed until the final 
outcome is known.  If it is not possible to obtain the final outcome for an SAE (e.g. the subject 
is lost to follow-up), the reason that a final outcome could not be obtained will be recorded by 
the Investigator on the AE case report form (CRF), if the CRF is still open, and the SERF as 
applicable. 
 
SAEs that occur after the study follow-up period that are reported to the Investigator and are 
assessed to be possibly, probably, or definitely related to the study agent must be reported to the 
CSO, as described above. 
10.6 
Sponsor’s Reporting Responsibilities 
Serious, unexpected, suspected adverse reactions (SUSARs) as defined in 21 CFR 312.32 will be 
reported to FDA and all participating Investigators as IND Safety Reports.  The sponsor will also 
submit a brief report of the progress of the investigation to the FDA on an annual basis as 
defined in 21 CFR 312.33. 
11 CLINICAL MONITORING STRUCTURE 
11.1 
Site Monitoring Plan  
As per ICH-GCP 5.18 and FDA 21 CFR 312.50, clinical protocols are required to be adequately 
monitored by the study sponsor.  Study monitoring will be conducted according to the “NIAID 
Intramural Clinical Monitoring Guidelines” or similar guideline currently in use. Monitors under 
contract to SAB or CRO will visit the clinical research site to monitor aspects of the study in 
accordance with the appropriate regulations and the approved protocol.  The objectives of a 
monitoring visit will be: 
1) To verify the existence of signed informed consent documents and documentation of the 
ICF process for each monitored subject;  
2) To verify the prompt and accurate recording of all monitored data points and prompt 
reporting of all SAEs; 
3) To compare Medidata Rave data abstracts with individual subject records and source 
documents (subject charts, laboratory analyses and test results, physicians’ progress 
notes, nurses’ notes, and any other relevant original subject information);  
4) To help ensure Investigators are in compliance with the protocol.  The monitors also will 
inspect the clinical site regulatory files to ensure that regulatory requirements (Office for 
Human Research Protections-OHRP), FDA, and applicable guidelines (ICH-GCP) are 
being followed.  During the monitoring visits, the Investigator (and/or designee) and 
other study personnel will be available to discuss the study progress and findings of the 
monitoring visit. 
 
A specific protocol monitoring plan will be discussed with the PI and study staff prior to 
enrollment.  The plan will outline the frequency of monitoring visits based on such factors as 
study enrollment, data collection status and regulatory obligations.  

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11.2 
Data and Safety Monitoring 
11.2.1 
Investigator Safety Monitoring 
The Investigator or designee may interrupt the administration of study drug to an individual 
subject, or enrollment into this study if indicated for unanticipated problems or AEs.  In addition, 
the Investigators are responsible for: 
• Protecting the safety and welfare of subjects 
• Evaluating subject safety, including physician assessment of AEs for seriousness, 
severity, and causality 
• Notifying the sponsor of SAEs and immediately-reportable events 
• Providing detailed written reports, including confirmatory tests promptly 
following immediate initial reports 
• Informing the IRB of SAEs 
11.3 
Safety Review and Communications Plan (SRCP) 
A Safety Review and Communication Plan (SRCP) has been developed for the protocol.  The 
SRCP is an internal communications document between the PI and the IND Sponsor Clinical 
Safety Office (CSO), which delineates the safety oversight responsibilities of the PI, the CSO, 
and other stakeholders.  The SRCP also includes the overall plan for conducting periodic safety 
surveillance assessments. 
11.4 
Safety Monitoring Plan 
PPD has established through their Safety Monitoring Plan a process that defines a committee 
charged with reviewing the accumulating data as the trial progresses to monitor safety, 
effectiveness and trial conduct. The Safety Monitoring Plan will be developed by a safety 
specialist from PPD’s pharmacovigilance group.  This plan then would be reviewed by the 
principle investigator, a medical monitor from PPD, as well as medical monitors and subject 
matter experts (e.g. pharmacokinetic, biostatistics, etc.) identified by the sponsor. While the 
committee could have up to ten members, including project and study managers, there will be a 
core committee designated of at least four members that are charged with authorizing study 
advancement. The plan will be included in the Trial Master File at the end of the study. 
11.5 
Sponsor Medical Monitor 
A Medical Monitor representing the IND Sponsor will be appointed for oversight of safety in 
this clinical study.  The Sponsor Medical Monitor will be responsible for performing safety 
assessments as outlined in a Safety Review and Communications Plan (SRCP). 
11.6 
Treatment Interruption or Discontinuation 
A subject’s study drug infusion may be discontinued at any time at the subject’s request or at the 
discretion of the Investigator or the Sponsor.  The following may be justifiable reasons for the 
Investigator to discontinue a subject from SAB-176 infusion: 
• The subject was erroneously included in the study (i.e., was found to not have met the 
eligibility criteria) 
• The subject experiences an intolerable AE 
• The subject is unable to comply with the requirements of the protocol 

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• The subject participates in another investigational study without the prior written 
authorization of the Sponsor 
 
The criteria for slowing or stopping a given infusion is discussed in Section 5.3 
11.7 
Pausing Rules 
If any of the following criteria are met at any time the study will be paused to further enrollment 
until assessed by the sponsor medical monitor: 
• Any SAE as defined in Section 10.3 that can be possibly, probably, or definitively 
attributed to the study drug 
• Three or more subjects in the same cohort experiencing the same Grade 2 or higher adverse 
effect that can be possibly, probably, or definitively attributed to the study drug 
• Two or more subjects develop the same or clinically similar Grade 3 AE or laboratory 
abnormality 
• Two or more subjects develop a serum creatinine ≥Grade 2 toxicity (≥1.8 mg/dL) 
• Two or more subjects develop ≥1.5-fold increase in serum creatinine level from baseline 
• Two or more subjects develop GFR <70 mL/min, irrespective if serum creatinine is normal 
range or Grade 1 
• Two or more subjects develop a serum creatinine ≥Grade 2 toxicity in PT and/or PTT (i.e. 
one grade 2 PT and one grade 2 PTT would meet this pausing rule) 
The sponsor medical monitor can request information needed (such as a listing of graded AEs) 
and unblinded randomization scheme (directly from the site investigational pharmacy group) to 
evaluate the data.  For individual subject unblinding, the site will follow their unblinding 
procedures per SOP-AUSCLN-506. The sponsor medical monitor will ultimately make the 
decision to either resume the study or stop the study. 
 
If the trial is stopped due to unacceptable adverse events or stopping criteria, the IRB will be 
notified. 
11.8 
Dose Escalation Rules 
When the results from the Day 7 visit for the last subject in a cohort (e.g., Cohort 1) are available 
safety parameters will be analyzed to determine the overall safety of that dose-level (e.g., 1 
mg/kg). If any of the following criteria are met, the corresponding dose-level is not considered 
“acceptably safe”, and the study will not proceed to the next higher dose group (as the review is 
blinded, this will be across treatment arms). 
• Any SAE that can be possibly, probably, or definitively attributed to the study drug 
• Any immediate hypersensitivity or cytokine storm events 
• Two or more subjects with asymptomatic positive anti-IgG (rheumatoid factor)  
• One or more subjects with positive anti-IgG (rheumatoid factor) with associated 
rheumatologic symptoms (i.e. arthralgia, myalgia, etc.)  
• Two or more subjects across all cohorts experience the same Grade 3 or higher adverse 
effect that can be possibly, probably, or definitively attributed to the study drug 

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• Three of the first 10 subjects (30%) experience the same grade 2 or higher adverse effect 
that can be possibly, probably, or definitively attributed to the study drug or any time 
thereafter 30% of enrolled subjects have the same grade 2 or higher ‘related’ AE. 
• Two or more subjects across cohorts develop a serum creatinine ≥ Grade 2 toxicity (≥1.8 
mg/dL) or doubled from baseline (whichever is lower) 
 
If any of the above criteria are met at any time, then the medical monitor will evaluate unblinded 
study data and make a determination about continuation of the study and/or amendment of the 
protocol. 
11.9 
Study Endpoints 
11.9.1 
Primary Endpoint 
• 
Type and frequency of AEs experienced by subjects receiving SAB-176 at escalating 
dose-levels, as compared to placebo 
 
11.9.2 
Secondary Endpoints 
• 
Pharmacokinetic profile of intravenously administered SAB-176 in healthy adults 
• 
Hemagglutination Inhibition (HAI) 
• 
Microneutralization (MN) 
• 
Frequency and concentrations of antibodies caused by SAB-176, as measured by: 
Anti-IgG antibodies using rheumatoid factor  
Anti-SAB-176 
12 ETHICS/PROTECTION OF HUMAN SUBJECTS 
12.1 
Informed Consent Process 
Informed consent is a process where information is presented to enable persons to voluntarily 
decide whether or not to participate as a research subject.  It is an on-going conversation between 
the human research subject and the researchers about the essential information about the study, 
which begins before consent is given and continues until the end of the subject's involvement in 
the research.  Discussions of essential information about the research will include the study's 
purpose, duration, experimental procedures, alternatives, risks, and benefits. Subjects will have 
the opportunity to ask questions and have their questions answered. 
 
The participants will sign the informed consent document prior to any procedures being done 
specifically for the study.  The participants may withdraw consent at any time throughout the 
course of the trial.  A copy of the informed consent document will be given to the participants for 
their records.  The researcher will document the signing of the consent form in the subject’s 
medical record.  The rights and welfare of the participants will be protected by emphasizing to 
them that the quality of their medical care will not be adversely affected if they decline to 
participate in this study. 
12.2 
Subject Confidentiality 
All records will be kept confidential to the extent provided by federal, state and local law. Study 
monitors and other authorized representatives of the Sponsor may inspect all documents and 

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records required to be maintained by the Investigator, including but not limited to, medical 
records.  Records will be kept locked and all computer entry and networking programs will be 
done with coded numbers only.  Clinical information will not be released without written 
permission of the subject, except as necessary for monitoring by IRB, the FDA, or the sponsor’s 
designee. 
13 
DATA MANAGEMENT AND MONITORING 
13.1 
Data Management Responsibilities 
The Investigator is responsible for assuring that the data collected is complete, accurate, and 
recorded in a timely manner.  Source documentation (the point of initial recording of 
information) should support the data collected in the electronic data system, and must be signed 
and dated by the person recording and/or reviewing the data.  All data should be reviewed by the 
Investigator and signed as required electronic signature. 
13.2 
Data Capture Methods 
Study data will be collected at the study site and maintained in an electronic data system 
(Medidata Rave).  This data will be completed on an ongoing basis during the study.  Data will 
be entered into electronic data systems by authorized individuals.  Corrections to electronic data 
systems will be tracked electronically (password protected or through an audit trail) with time, 
date, individual making the correction, and what was changed. 
13.3 
Types of Data 
Source documents include, but are not limited to, the subject’s medical records, laboratory 
reports, ECG tracings, x-rays, radiologist’s reports, subject’s diaries, biopsy reports, ultrasound 
photographs, progress notes, pharmacy records, and any other similar reports or records of 
procedures performed during the subject’s participation in the study. 
13.4 
 Source Documents and Access to Source Data/Documents 
Source documents include all recordings of observations or notations of clinical activities, and all 
reports and records necessary for the evaluation and reconstruction of the clinical trial.  Data 
from Medidata Rave will be collected directly from subjects during study visits and telephone 
calls, or will be abstracted from subjects’ medical records.  The subject’s medical record must 
record his/her participation in the clinical trial and, after unblinding, study treatment/vaccination 
(with doses and frequency) or other medical interventions or treatments administered, as well as 
any adverse reactions experienced during the trial. 
13.5 
Record Retention 
The Investigator is responsible for retaining all essential documents listed in the ICH Good 
Clinical Practice Guideline.  All essential documentation for all study subjects are to be 
maintained by the Investigators in a secure storage facility for a minimum of three years.  The 
FDA requires study records to be retained for up to two years after marketing approval or 
disapproval (21 CFR 312.62), or until at least two years have elapsed since the formal 
discontinuation of clinical development of the investigational agent for a specific indication.  
These records are also to be maintained in compliance with IRB, state, and federal medical 

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records retention requirements, whichever is longest.  All stored records are to be kept 
confidential to the extent required by federal, state, and local law. 
 
 
 

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14 
REFERENCES 
1. 
W. W. Thompson et al., Mortality Associated With Influenza and Respiratory Syncytial 
Virus in the United States. JAMA 289, 179-186 (2003). 
2. 
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blood products for Spanish influenza pneumonia: a future H5N1 treatment? Ann Intern 
Med 145, 599-609 (2006). 
3. 
J. H. Beigel et al., Anti-influenza immune plasma for the treatment of patients with 
severe influenza A: a randomised, double-blind, phase 3 trial. Lancet Respir Med 7, 941-
950 (2019). 
4. 
R. Davey et al., Anti-influenza hyperimmune intravenous immunoglobulin for adults 
with influenza A or B infection (FLU-IVIG): a double-blind, randomised, placebo-
controlled trial. The Lancet Respiratory Medicine 7,  (2019). 
5. 
FDA. Guidance for industry estimating the maximum safe starting dose in initial clinical 
trials for therapeutics in adult healthy volunteers. (U.S. Dept. of Health and Human 
Services, Food and Drug Administration, Center for Drug Evaluation and Research, 
Rockville, MD :, 2005). 
6. 
B. A. Steinberger, S. M. Ford, T. A. Coleman, Intravenous immunoglobulin therapy 
results in post-infusional hyperproteinemia, increased serum viscosity, and 
pseudohyponatremia. Am J Hematol 73, 97-100 (2003). 
7. 
Insight Flu IVIg Pilot Study Group, INSIGHT FLU005: An Anti–Influenza Virus 
Hyperimmune Intravenous Immunoglobulin Pilot Study. The Journal of infectious 
diseases 213, 574-578 (2016). 
8. 
C. H. Chung et al., Cetuximab-induced anaphylaxis and IgE specific for galactose-α-1, 3-
galactose. New England journal of medicine 358, 1109-1117 (2008).