SAFETY AND ADVERSE REACTION OF THERAPEUTIC

ANTIBODIES AGAINST SARs-COV-2

PRESENTED BY: SUPERVISOR:

ANKUSH-17073004 Mrs. PINKI PHOUGAT

PREETI YADAV-17073036 ASSISTANT PROFESSOR
RITIKA-17073043
DEEPA-18073061
B.PHARMACY
Vlll sem 4TH YEAR

BHAGAT PHOOL SINGH MAHILA VISHWAVIDYALAYA SONIPAT

DEPARTMENT OF PHARMACEUTICALEDUCATION AND RESEARCH
SOUTH CAMPUS, BHAINSWAL KALAN
2020-2021
 LIST OF CONTENT

 INTRODUCTION

 POTENTIAL TARGET FOR DEVELOPING COVID-19 THERAPEUTIC

ANTIBODIES - Mechanism

 TYPES OF THERAPEUTIC ANTIBODIES

- Therapeutic polyclonal antibodies
- Therapeutic monoclonal antibodies
- Therapeutic cocktail antibodies

 RECENT FINDINGS ON THE IMMUNOBIOLOGY OF SARs COV-2 INFECTION

 CHALLENGES AND FUTURE ASPECTS

 CONCLUSIONS

 REFERENCES
1. INTRODUCTION

 SARS‑CoV‑2 is a virus of the species severe acute respiratory syndrome–related

coronavirus (SARSr-CoV). It is believed to have zoonotic origins and has close genetic similarity to
bat coronaviruses, suggesting it emerged from a bat-borne virus. However research is still ongoing.

 The Coronavirus disease 2019 (COVID-19) is an emerging infectious disease caused by the
severe acute respiratory syndrome 2 coronavirus (SARS-CoV-2) .

 It was first detected in December 2019 in Wuhan China from bats and crossing the species barrier it
entered human beings.

 The clinical outcome of SARS-CoV-2 infection ranges from asymptomatic, flu-like symptoms, and
pneumonia to acute respiratory distress syndrome , renal failure, and other deadly complications .

 On March 11, 2020, the World Health Organization (WHO) declared the COVID-19 outbreak a
global pandemic.

 Similar to other coronaviruses, SARS-CoV-2 uses its spike (S) protein for receptor binding and
virus entry into the target cells.

 Several recent studies demonstrated that both SARS-CoV and SARS-CoV-2 use the same receptor,
the angiotensin-converting enzyme 2 for cell entry.
 A highly specific antibody can be generated for targeting both host and viral target proteins.

 To defeat the ongoing COVID-19 pandemic, worldwide research efforts have been made at
genome, transcriptome, proteome, and interactome levels to help understand the mechanism of the
disease. Hundreds of antibodies for treating COVID-19 have been developed at in the format of
polyclonal antibodies, monoclonal antibodies, and cocktail antibodies .
2. POTENTIAL TARGET FOR DEVELOPING COVID-19
THERAPEUTIC ANTIBODIES

 Genomics studies have shown SARS-CoV-2 is a novel member of the genus beta coronavirus.

 Genes of SARS-CoV-2 are grouped into 3 categories-

I. Nonstructural
II. Structural and
III. Accessory

 There are 4 structural genes, namely S, E, M, and N, encoding Spike, Envelope, Membrane, and
Nucleocapsid protein respectively –
i. The N protein is responsible for viral genome packing.
ii. The M protein plays a central role in viral morphogenesis, assembly, and egress .
iii. The E protein is critical for viral envelope curvature, maturation, and budding.
iv. The S protein has two subunits, S1 and S2, determining viral entry.
 MECHANISM -

 All proteins encoded by the SARS-CoV-2 genome are potential anti-virus targets for
developing therapeutic antibodies against COVID-19.

 The S protein is the major target for neutralizing antibody development due to the
mechanism of blocking viral entry.

 Immune response to SARS-CoV-2 is an important part of the complex virus-host interactions .

It is a double-edged sword. On one hand, will help clear the virus and block further infection.
On the other hand, high levels of inflammatory cytokines and chemokines such as (TNF-α),
(IL-6), (IL-8), & (IL-10) can amplify tissue damage and even cause cytokine storm, leading to
respiratory/organ failure
.
 The main mechanism of these host targets is anti- inflammation.

 The lifecycleof SARS-CoV-2 and the complex virus-host interactions is the potential targets for
antibody development against COVID-19.

 All targets can be grouped into two categories -

 the anti-virus.Another
 the anti- host category
3. TYPES OF THERAPEUTIC ANTIBODIES

 Therapeutic polyclonal antibodies

 Therapeutic monoclonal antibodies – Drugs safe summary

Drugs adverse reaction

Drugs risk summary

 Therapeutic cocktail antibodies - Drugs safe summary

Drugs adverse reaction

Drugs risk summary

 THERAPEUTIC POLYCLONAL ANTIBODIES
 Therapeutic polyclonal antibodies have been applied to treat infectious diseases since the
1890s.
 Due to the increasing number of SARS-CoV-2 infections and the lack of effective therapies,
convalescent plasma therapy has become very popular currently.

 According to data there are at least 176 registered clinical trials using convalescent plasma for
treating COVID-19 patients.

 Results show convalescent plasma therapy is not only safe but also may help eliminate the virus
and improve clinical symptoms .

 On August 23, 2020, the U.S. Food and Drug Administration authorized the emergency use of
convalescent plasma for the treatment of hospitalized patients of COVID-19 .
 In a retrospective, propensity score-matched, case-control study, the effectiveness of convalescent
plasma therapy with severe or life-threatening COVID-19 meet both oxygen requirement and
survival rate increases .

 A prospective, propensity score-matched study compared the efficacy of COVID-19 convalescent

plasma with the standard of care and data shows decrease in mortality within 28 days, specifically
in patients transfused within 3 days of admission with plasma with an anti-RBD titer.
MAJOR PROBLEM WITH CONVALESCENT PLASMA THERAPY

 Quality control and standardization.

 Optimal dose and time point, as well as the most proper patients, investigation.

 The risk of infecting unknown blood-borne infectious diseases exists, though strict screen
is performed before the collection of plasma.

 Besides, convalescent plasma is not easy to store and deploy compared with other drugs.

 To deal with the above problems, intravenous immunoglobulin (IVIG) has also been proposed to
treat COVID-19 .

 IVIGs are sterile, purified immunoglobulins products from the plasma of approximately a
thousand or more blood donors.

 It is available as either a liquid or lyophilized powder.

 It is very convenient to store and transfer.

 THERAPEUTIC MONOCLONAL ANTIBODIES
 A monoclonal antibody is an antibody made by cloning a unique white blood cell.

 Monoclonal antibodies (mAbs) are produced by B cells and specifically target antigens.

 Therapeutic monoclonal antibodies have been applied to treat human diseases since 1986 when
muromonab-CD3 was approved by FDA for treating acute rejection after a kidney transplant . It
has rapidly become a major part of the pharmaceutical industry for the past 35 years.

 Palivizumab is the first monoclonal antibody approved for infectious disease. In 1998, the FDA
authorized palivizumab to prevent serious lung disease caused by the respiratory syncytial virus
in infants

 It is widely used in the fight against cancer, inflammatory and autoimmune disease.

 The development of therapeutic monoclonal antibodies is currently at the front line of fighting
against the COVID-19 pandemic.

 The U.S. Food and Drug Administration (FDA) has issued an Emergency Use Authorization
(EUA) to permit the emergency use of the unapproved product Bamlanivimab for the treatment of
mild to moderate coronavirus disease 2019 in adults and pediatric.
 According to their targets, we divide the COVID-19 therapeutic monoclonal antibodies into anti-
virus and anti-host categories.
MECHANISM -
ANTI-VIRUS MONOCLONAL ANTIBODY

1. Bamlanivimab :-. Bamlanivimab is an investigational medicine used to treat mild to

moderate symptoms of COVID-19 in non-hospitalized adults and adolescent.
• You will receive one dose of bamlanivimab by IV infusion. The infusion will take 16 – 60 minutes
or longer.

a) Safety summary - The safety of bamlanivimab is based on interim data from one Phase 2 trial of
465 ambulatory (non-hospitalized) subjects with COVID-19.
BLAZE-1 is a randomized, double-blind, placebo-controlled clinical trial in ambulatory adults
with mild to moderate COVID-19 symptoms who had sample collection for the first positive
SARS-CoV-2 viral infection.

b) Adverse reactions - A case of anaphylaxis and other cases of serious infusion-related reactions
were reported include – fever, difficulty breathing, reduced oxygen saturation, chills, fatigue,
arrhythmia , chest pain, weakness, altered mental status, nausea, headache, bronchospasm,
hypotension, hypertension, angioedema, throat irritation, rashes, dizziness, and diaphoresis.

c) Risk summary – Lactation

Pediatric use
Geriatric use
Pregnancy
2 . Sotrovimab: -Sotrovimab is a medication that the FDA is allowing to be given for emergency
use to treat COVID-19. It is used by people 12 years of age and older who have recently
tested positive for coronavirus.
• Sotrovimab is given one time by injection into a vein by a health care professional. It is
infused over 30 minutes.

a) Safety summary - The safety of sotrovimab is primarily based on an interim analysis from
the ongoing Phase 1/2/3 double-blind, placebo-controlled, randomized study enrolled 1,057
non-hospitalized patients with COVID-19 .

b) Adverse Reactions - An infusion reaction may occur while this product is being given and
up to 24 hours after infusion, such as low or high blood pressure,dizziness, slow/fast/irregular
heartbeat, chest pain, trouble breathing, fever, chills, nausea, headache, confusion, sweating,
or muscle pain.

c) Risk summary – Lactation

Pedriatic use
Geriatic use
Pregnancy
3. Ragdanivimab - Regdanvimab is indicated for the treatment of confirmed COVID-19 in adult
patients that do not require supplemental oxygen for COVID-19 and who are at high risk of
progressing to severe COVID-19.
• Administered as an IV infusion via pump over 90 minutes.

a) Safety summary - The safety of regdanvimab is based on interim data from a Phase 2/3 trial of
325 non-hospitalized. Patients with COVID-19 .The efficacy of regdanvimab was assessed in
Study CT-P59 3.2 Part 1 which is a randomized, Double-blind, placebo-controlled clinical trial
studying regdanvimab for the treatment of adult Patients with mild to moderate COVID-19 .

b) Adverse Reactions - Serious hypersensitivity reactions, including anaphylaxis have been

observed rarely .
Infusion related reactions may include fever, dyspnoea, chills, nausea, headache, bronchospasm,
hypotension, angioedema, throat irritation, rash including urticaria, pruritus, myalgia, dizziness.

c) Risk summary – Pregnancy

Breast feeding
Geriatrics use
Renal failure
ANTI – HOST MONOCLONAL ANTIBODIES
1. Itolizumab: - Itolizumab is humanized recombinant anti CD6 mAB of
immunoglobulin G1 isotype that binds to domain 1 of CD6 .
• Administration of single dose by IV infusion.

a) Safety summary - Safety data for itolizumab has been derived mainly from the two
multicenter clinical trials of patients with chronic plaque psoriasis, and from a study of
patients with rheumatoid arthritis.

b) Adverse reactions - Infusion related side effects and others include –

gastriointestinal disorder , metabolism and nutrional disorder , psychriatric
and renal disorder .

c) Risk summary – Pregnancy

Lactation
Geriatric
2. Tocilizumab: - Tocilizumab belongs to a class of drugs known as Interleukin-6 (IL-6) blockers. It
works by blocking IL-6, a substance made by the body that causes swelling  . Tocilizumab
injection comes as a solution (liquid) to be injected intravenously about over 1 hour by a doctor or
nurse in a medical office .

a) Safety summary - Tocilizumab is prescribed to treat moderate to severe active arthritisin

The clinical evaluation of Toclizumab ( ACTEMRA) in hospitalized COVID-19 patients was
based on 4 clinical trials. These included one randomized, controlled, open-label, platform trial
[Randomized Evaluation of COVID-19 Therapy (RECOVERY)] and 3 randomized, double-blind,
placebo-controlled trials] .

b) Adverse reactions - We can categories side effects into –

1) common side effects (respiratory tract infections, headache, hypertension, elevation in liver)
2) reactions of injection site (rash, redness, swelling, itching)
3) associated serious infection (tuberculosis, sepsis, fungal infection)
4) side effects reported in studies (hyper sensitivity reactions, developed cancer, reactivation of
herpes zoster, gastrointestinal perforation in patients with diverticulitis)

c) Risk summary – Pregnancy

Lactation
Geriatric
 THERAPEUTIC COCKTAIL ANTIBODIES
 Therapeutic cocktail antibodies are combinations of two or more monoclonal antibodies.Cocktail
holds all advantages of monoclonal antibodies.

 Antibody cocktail should ideally be administered within 48 to 72 hours of a COVID-19 infection

and before seven days

 This drug has been recommended only for patients above 12 years. It covers the elderly above
the age of 60. It is not recommended for infants and children below 12 years.

 It targets more than one epitope or even binds multiple antigens like polyclonal antibodies. The
synergism and complementarity of each monoclonal antibody make a cocktail a better choice for
treating varying infectious diseases.

 Therapeutic cocktail antibodies have become the frontiers of COVID-19 treatment. The two
monoclonal antibodies both target the spike protein of the virus ,but recognize two different
epitopes.

 Recently, Central Drugs Standards Control Organisation (CDSCO), the Indian drug regulator,
granted emergency use authorization (EUA) to this antibody cocktail in India. The drug marketed
by CIPLA available pan-India from May 24, 2021.
 Bamlanivimabh as shown promising interim results in the phase 2trial and has been
approved by the FDA for emergency use.

 REGN-COV2 is a cocktail of two potent neutralizing antibodies (REGN10933/

Casirivimaband REGN10987/ Imdevimab).
1. Casirivimab/Imedivimab:It is called as REGEN-COV which is given as Single vial which
contains 2 antibodies coformulated in a 1:1 ratio .
• IV infusion strongly recommended; SC injection is an alternative route of administration when IV
infusion is not feasible and would lead to delay in treatment.

a) Safety summary - The safety of REGEN-COV is based on analyses from,COV-2067, a Phase

1/2/3 trial of 6,311 ambulatory (non-hospitalized) subjects with COVID-19.This is a randomized,
double-blind, placebo-controlled clinical trial in subjects with mild to Moderate COVID-19 who
had a sample collected for the first positive SARS-CoV-2 viral Infection determination .

b) Adverse reactions -Serious hypersensitivity reactions, including anaphylaxis and post exposure
prophylaxix have been reported with administration of REGEN-COV

c) Risk summary – Lactation

Pregnancy
Geriatric
Hepatic failure
 
2. Etesevimab/Bamlanivimab:Bamlanivimab and etesevimab together also demonstrated
statistically significant improvements on key secondary endpoints. These results are consistent
with those seen in other data sets from BLAZE-1: in the previous Phase 3 cohort in monoclonal
antibodies.

a) Safety summary - The safety of bamlanivimab administered with etesevimab is primarily based
on Exposure of approximately 1400 ambulatory (non-hospitalized) subjects who received Doses of
bamlanivimab and etesevimab together, at the recommended dose or higher, in BLAZE-1 and
BLAZE-4.

b) Adverse reactions - Serious hypersensitivity reactions, including anaphylaxis, have been

observed
•  Infusion-related reactions have been observed

c) Risk summary – Pregnancy

Breastfeeding
Lactation
4. RECENT FINDINGS ON THE IMMUNOBIOLOGY OF SARs COV-2
INFECTION

 Recent research shows that SARS-CoV-2 infection triggers the induction of both innate and
adaptive immune responses by the infected person.

 SARS-CoV-2 infection activates the humoral immune response, which triggers the production of
different isotypes of virus-specific antibodies.

 The development of the protective adaptive immunity to SARS-CoV-2 infection mainly depends
on the activation of both humoral and cell-mediated immune responses. Thus, the activation of the
CD4-positive T helper cells, which help the B-cells in the process of the production of specific
neutralizing antibodies.

 A recent study investigated the seropositivity rate for IgG and IgM antibodies in some COVID-19
patients 14 days after the onset of symptoms. This study found higher titers of antibodies against
the surface spike protein receptor-binding domain (RBD) compared to the internal nucleocapsid
protein (NP) antigen.

 A lot of studies on chemical drug design or repurposing for the treatment of COVID-19 have been
done . However, only dexamethasone resulted in lower 28-day mortality in a controlled, open-
label trial .
5. CHALLENGES AND FUTURE ASPECTS

1. Antibody-dependent enhancement (ADE) is an unexpected phenomenon that

happened after vaccination or antibody therapies, where the production or
presence of specific antibodies may enhance rather than inhibit viral infection.

2. The second challenge comes from SARS-CoV-2 variants, as mutations might

yield antibody resistance.

3. The third challenge is how to survive drowning in the sea of COVID-19 data and
papers .

Suitable strategies to deal with the ADE problem.

➢ Future studies should also track SARS-CoV-2 variants, especially antibody
resistant variants. Developing monoclonal antibodies with more diverse targets
and formulating cocktail antibodies more flexibly may be proper strategies.

➢ In addition, future studies should keep an eye on the development of a special

COVID-19 therapeutics antibody database.
 6. CONCLUSIONS

 The available therapeutic antibodies for COVID-19 treatment can be divided into three
categories: polyclonal, monoclonal, and cocktail antibodies.

➢ Four products have received EUA from the FDA, i.e. convalescent plasma,
bamlanivimab, REGN-Cov2, and the combination of bamlanivimab and etesevimab.
Currently, hundreds of therapeutic antibodies against COVID-19 are at the preclinical
stage or in clinical trials.

➢ The development of antibody therapeutics for COVID-19 is challenged by the risk of

antibody-dependent enhancement, SARS-CoV-2 variants, and information overload.

➢ The Project focuses on the development and application of therapeutic antibody

therapies for COVID-19 in polyclonal, monoclonal, and cocktail format, addressing
relevant progress, safety, Adverse Reactions, challenges, possible strategies, and
solutions.
7. REFERENCES

 Wu F, Zhao S, Yu B, Chen YM, Wang W, Song ZG, et al. A new coronavirus associated with
human respiratory disease in China. Nature. 2020;579(7798):265–9.

 Dhama, K.; Patel, S.K.; Pathak, M.; Yatoo, M.I.; Tiwari, R.; Malik, Y.S.; Singh, R.; Sah, R.;
Rabaan, A.A.; Bonilla-Aldana, D.K.; et al. An update on SARS-CoV-2/COVID-19 with
particular reference to its clinical pathology,pathogenesis, immunopathology and mitigation
strategies. Travel Med. Infect. Dis. 2020.

 Plante JA, Liu Y, Liu J, Xia H, Johnson BA, Lokugamage KG, et al. Spike mutation D614G
alters SARS-CoV-2 fitness. Nature. 2020;Weisblum Y, Schmidt F, Zhang F, DaSilva J, Poston
D, Lorenzi JCC, et al. Escape from neutralizing antibodies by SARS-CoV-2 spike protein
variants. Elife. 2020;9:61312.

 www.fda.gov

www.clinicaltrials.gov

www.healthaffairs.org
THANK YOU