This document discusses antibody combinations for treating COVID-19. It begins by providing background on innate and adaptive immunity, as well as active and passive immunity. It then summarizes clinical trial results showing that antibody combinations like REGEN-COV (casirivimab and imdevimab) can reduce viral levels, medical visits, and hospitalizations in non-hospitalized COVID patients. For hospitalized patients, a RECOVERY trial found Regeneron's monoclonal antibody cocktail improved outcomes when added to usual care. The document thus outlines how antibody combinations represent an effective therapeutic approach for both non-hospitalized and hospitalized COVID-19 patients.

1. ANTIBODY
COMBINATION
Dr Prashant Bhatia

2. immunity
◦ Innate immunity
◦ Adaptive immunity
◦ A) active immunity
◦ B )passive immunity

3. Innate
immunity
◦ the immune system that is present when you are born
◦ It is your body's first line of defense against germs
-physical barriers, such as skin and mucous
membranes
- special cells and proteins that can recognize and kill
germs
◦ The problem – No memory
◦ It does not communicate any information about the
germ to the rest of the body
◦ Without this information, the body cannot prepare
itself to fight this germ if it should reinfect the
body.

4. Adaptive
immunity
◦ protection that your body builds when it meets and
remembers antigens
◦ When your body recognizes antigens, it produces
antibodies to fight the antigens
◦ It takes about 14 days for your body to make
antibodies
◦ the body memorizes this fight so that if its meets
the same antigen again, it can recognize and attack
more quickly
◦ Antibody production is one of the most important
ways that immunity is developed.

5. Active
immunity
◦ antibodies that develop in a person's own immune
system after the body is exposed to an antigen
through a disease or when you get an immunization
◦ this type of immunity lasts for a long time.

6. Passive
immunity
• antibodies given to a person to
prevent disease or to treat disease
after the body is exposed to an antigen
• passive immunity is given from mother
to child through the placenta before
birth, and through breast milk after
birth
• it can also be given medically through
blood products that contain antibodies,
such as immune globulin
• this type of immunity is fast acting but
lasts only a few weeks or months.

7. NIH
Covid treatment guidelines

8. COVID-19 Therapy by Illness Phase
Antiviral
therapies
Immune
modulator
therapies
Healthy, no
infection
Not hospitalized, no limitations
Not hospitalized, with
limitations
Hospitalized, no
active medical
problems
Hospitalized, not
on oxygen
Hospitalized, on
oxygen
Hospitalized, high
flow oxygen/non
invasive ventilation
Hospitalized,
mechanical
ventilation/ECMO
Exposed /
Asymptomatic Infected
Early Symptomatic Hospital Admission ICU Admission
No Illness
Remdesivir
Convalescent Plasma
Baricitinib +
remdesivir
Dexamethasone +
remdesivir
Monoclonal Antibodies
• Bamlanivimab
• Bamlanivimab +
etesevimab
• Casirivimab +
imdevimab
EUA issued
FDA approved
Dexamethasone
Dexamethasone + tocilizumab
https://www.covid19treatmentguidelines.nih.gov/therapeutic-management/;
https://www.uptodate.com/contents/covid-19-management-in-hospitalized-adults

9. Humanized
mice
◦ Humanized mouse is a general term that refers to a
mouse that has been engrafted with something from
a human. This could be a short strand of human
DNA, human tissue, a human tumor, a humanized
immune system, or parts of the human microbiome.

11. quiz
◦ How many years back was passive immunity first
practised
◦ 125 years back
◦ Who wast the first doctor to practice it
◦ Dr Paul Ehrlich
◦ Which disease was it first used
◦ diptheria

12. Pitfalls of
passive
immunization
Serumsickness
Variation in antibody titres
Variable epitope specificity
TRALI
TACO
Anaphylactic reactions
Febrile nonhemolytic reactions
Hemolytic reactions
Hypothermia
Metabolic complications
Transfusion-transmitted infections
Thrombotic events
Theoretical risk of antibody mediated enhancement of
infection and suppressed long-term immunity

13. antibody-
dependent
enhancement
◦ ADE can occur via two distinct mechanisms.
◦ First pathogen- specific antibodies could increase infection by
promoting virus uptake and replication in Fcγ receptor-
expressing immune cells as is seen in dengue haemorrhagic
virus
◦ SARS- CoV and SARS- CoV-2 in vitro evidence amassed to date
indicate that these non- lymphotropic coronaviruses are unable
to productively replicate within haematopoietic cells
◦ Alternatively, ADE can be mediated via increased immune
activation by Fc- mediated effector functions or immune
complex formation
In the case of respiratory virus infections the
resulting immune cascade can contribute to lung
disease

15. CONVALESCENT
PLASMA
THERAPY

18. Why
neutralizing
antibodies
◦ In the trial by Chen et al., patients with persistently
high nasopharyngeal RNA shedding on day 7 were
more likely to be hospitalized than those with lower
levels (12% vs. 0.9%)
◦ This finding suggests that persistent SARS-CoV-2
replication in the nasopharynx portends progression
of Covid-19, which may be limited by early antibody
treatment or by a rapid autologous immune response.

19. Earlier use of Mab
◦ Palivizumab, a neutralizing mAb to the fusion protein
of RSV, was initially approved in 1998 as a prophylaxis
for severe RSV infection in high- risk infants
◦ During the Ebola virus disease outbreak in
the Democratic Republic of the Congo in 2018, an
open label RCT (PALM) investigated four
intravenously administered treatments in 681 patients
actively infected with Ebola virus
◦ the antiviral remdesivir, the triple mAb cocktail
ZMapp, the single mAb MAb114, and the triple mAb
combination REGN- EB3
◦ After an interim analysis, the first two treatments
were discontinued
◦ MAb114 monotherapy and REGN- EB3 were
superiorwith respect to the primary outcome, patient
mortality

20. What is an Emergency Use Authorization (EUA)?
◦ An Emergency Use Authorization (EUA) is a mechanism to facilitate the availability and use of
medical countermeasures, including vaccines, during public health emergencies, such as the
current COVID-19 pandemic. Under an EUA, FDA may allow the use of unapproved medical
products, or unapproved uses of approved medical products in an emergency to diagnose, treat, or
prevent serious or life-threatening diseases or conditions when certain statutory criteria have been
met, including that there are no adequate, approved, and available alternatives. Taking into
consideration input from the FDA, manufacturers decide whether and when to submit an EUA
request to FDA.
◦ Once submitted, FDA will evaluate an EUA request and determine whether the relevant statutory
criteria are met, taking into account the totality of the scientific evidence about the vaccine that is
available to FDA.

21. Casirivimab and Imdevimab are a novel combination of two
SARS CoV-2-neutralizing antibodies
Adapted from https://www.regencov.com/hcp/resources
Screened 1000s of SARS-CoV-2 Spike-specific Abs from
VelocImmune mice and convalescent humans and identified
as Casirivimab (CAS) and Imdevimib (IMD)
CAS and IMD simultaneously bind to different regions of the
viral Spike RBD without interference and block the virus from
binding to ACE2 receptor
The Cocktail of two noncompeting mAbs with different
epitopes reduces the probability of viral escape.
The combination was evaluated in preclinical animal studies
and is also being studied in clinical trials

23. ◦ Data is available on REGEN-COV in various patient populations:
◦ Non-hospitalized patients: Data from an ongoing seamless trial assessed the effect of REGEN-COV
on reducing viral load and patient medical visits in high-risk, non-hospitalized patients
◦ Hospitalized patients: Initial data for futility analyses evaluated REGEN-COV based on the ability to
reduce incidence of death or mechanical ventilation in hospitalized patients on low-flow oxygen
◦ Prevention of symptomatic disease: Phase 3 data assessing the ability of REGEN-COV to reduce the
risk and burden of COVID-19 infection among household contacts of SARS-CoV-2 infected individuals

24. Phase 1-2 trial
◦ Key Inclusion Criteria: • Onset of COVID-19
symptoms ≤7 days before randomization • SpO2
≥93% on room air
◦ Key Exclusion Criteria: • Hospitalization before or
at randomization due to COVID-19 • Prior, current,
or planned future use of any of the treatments
specified in the protocol
◦ Interventions: • Single IV infusion of: • CAS plus
IMD 2,400 mg (CAS 1,200 mg and IMD 1,200 mg),
• CAS plus IMD 8,000 mg (CAS 4,000 mg and IMD
4,000 mg), or • Placebo • Administered ≤3 days
after receiving a positive result on a SARS-CoV-2
virologic test
◦ Primary Endpoint: • TWA change in NP VL from
baseline to Day 7 Secondary Endpoints: • COVID-
19-related medical visits including hospitalization
or ED, urgent care, or physician
office/telemedicine visit within 28 days of
treatment • Safety • Symptom improvement

26. Phase 1-2 trial
interim analysis
◦ Primary endpoint evaluated in modified full
analysis set of participants with detectable virus
at baseline (n = 221)
◦ TWA change in NP VL at Day 7 was greater
among the participants who received CAS plus
IMD (-1.74 ± 0.11 log10 copies/mL; 95% CI, -
1.95 to -1.53) than among those who received
placebo (-1.34 ± 0.13 log10 copies/ mL; 95%
CI, -1.60 to -1.08)
◦ participants with a negative serum antibody
status at baseline, TWA change in VL was
greater among those who received CAS plus
IMD (-1.94 ± 0.13 log10 copies/mL; 95% CI, -
2.20 to -1.67) than among those who received
placebo (-1.37 ± 0.20 log10 copies/ mL; 95%
CI, -1.76 to -0.98).

27. Secondary
outcome
◦ The percentage of participants who had COVID-
19- related medical visits within 28 days of
treatment was lower in the CAS plus IMD arms
than in the placebo arm
◦ Among participants with negative serum
antibody status at baseline, the percentage of
those who had COVID-19-related medical visits
within 28 days of treatment was lower in the
CAS plus IMD arms All CAS plus IMD doses
◦ The safety profile of CAS plus IMD was similar to
the profile of the placebo; 2 hypersensitivity or
infusion related reactions of grade 2 severity or
higher were reported in both the CAS plus IMD
8,000 mg arm and the placebo arm. • The mean
half-life for b

30. https://doi.org/10.1101/2021.05.04.442663 doi: bioRxiv preprint
B.1.351 and B.1.617 S protein-mediated entry was efficiently inhibited
by Imdevimab and by a cocktail of Casirivimab and Imdevimab,
termed REGN-COV

32. Definition of
High-Risk
Patients
High-risk is defined as patients who meet at least one
of the following criteria:
◦ Have a body mass index (BMI) ≥35
◦ Have chronic kidney disease
◦ Have diabetes
◦ Have immunosuppressive disease
◦ Are currently receiving immunosuppressive
treatment
◦ Are ≥65 years of age
◦ Are ≥55 years of age AND have
◦ cardiovascular disease, OR
◦ hypertension, OR
◦ chronic obstructive pulmonary disease/other
chronic respiratory disease.

33. ◦ Are 12 – 17 years of age AND have
◦ BMI ≥85th percentile for their age and gender
based on CDC growth
charts, https://www.cdc.gov/growthcharts/clinica
l_charts.htm,OR
◦ sickle cell disease, OR
◦ congenital or acquired heart disease, OR
◦ neurodevelopmental disorders (e.g., cerebral
palsy), OR
◦ a medical-related technological dependence, for
example, tracheostomy, gastrostomy, or positive
pressure ventilation (not related to COVID-19),
OR
◦ asthma, reactive airway or other chronic
respiratory disease that requires daily medication
for control.

34. Phase-3 trial
◦ Double-blind, Phase 3 RCT in outpatients with
mild to moderate COVID-19 (n = 4,180 for
modified full analysis subset of the Phase 3
trial)
◦ Key Inclusion Criteria: • Onset of COVID-19
symptoms ≤7 days before randomization •
SARS-CoV-2 PCR positive at baseline • Criteria
only for the modified full analysis: • Aged ≥18
years • ≥1 risk factor for severe COVID-19
◦ Interventions: • Single IV infusion of: • CAS 600
mg plus IMD 600 mg, • CAS 1,200 mg plus IMD
1,200 mg, or
◦ Placebo Endpoint: • Proportion of participants
with COVID19-related hospitalization or all-
cause death through Day 29

35. Study design
◦ Number of Participants: • CAS 600 mg plus IMD
600 mg (n = 736) vs. placebo (n = 748) • CAS 1,200
mg plus IMD 1,200 mg (n = 1,355) vs. placebo (n =
1,341)
◦ Participant Characteristics: • Median age was 50
years. • 35% of the participants were
Hispanic/Latinx and 5% were Black or African
American.
◦ Median duration of symptoms prior to enrollment
was 3 days (IQR 2–5 days).4

36. Study
outcomes
◦ Percentage of participants with COVID-19-related
hospitalization or all-cause death through Day 29
◦ 7 of 736 (1.0%) in the CAS 600 mg plus IMD 600 mg
arm vs. 24 of 748 (3.2%) in the placebo arm (P =
0.0024)
◦ 18 of 1,355 (1.3%) in the CAS 1,200 mg plus IMD
1,200 mg arm vs. 62 of 1,341 (4.6%) in the placebo
arm (P < 0.0001)
◦ Percentage of participants who died
◦ 1 of 827 (0.1%) in the CAS 600 mg plus IMD 600 mg
arm • 1 of 1,849 (0.05%) in the CAS 1,200 mg plus
IMD 1,200 mg arm • 5 of 1,843 (0.3%) in the
placebo arm

37. Interpretation
◦ There was a 2.2% absolute reduction and a
70% relative risk reduction in COVID-19-related
hospitalizations or all-cause deaths in
participants who received CAS 600 mg plus IMD
600 mg compared to those who received
placebo
◦ There was a 3.3% absolute reduction and a
71% relative risk reduction in COVID-19 related
hospitalizations and all-cause deaths in
participants who received CAS 1,200 mg plus
IMD 1,200 mg compared to those who received
placebo.

38. PHASE 3 TRIAL
REGEN-COV™
(CASIRIVIMAB
WITH
IMDEVIMAB)
ANTIBODY
COCKTAIL IN
NON-
HOSPITALIZED
COVID-19
PATIENTS
◦ All doses (8,000 mg, 2,400 mg and 1,200 mg)
had similar efficacy across all endpoints
◦ significantly shortened the duration of
symptoms by 4 days
◦ significantly reduced the risk of hospitalization
or death by 70% (1,200 mg intravenous [IV])
and 71% (2,400 mg IV) compared to placebo
◦ also met all secondary endpoints in the Phase 3
outcomes trial, including the ability to reduce
symptom duration
◦ In addition, a companion Phase 2 trial showed
that even the lowest doses tested (IV: 300 mg;
subcutaneous [SC]: 600 mg) had significant viral
load reductions over the first 7 study days,
comparable to the 2,400 mg and 1,200 mg IV
doses.

39. RECOVERY
trial Regeneron’s
monoclonal antibody
combination for
hospitalised COVID-
19 patients
◦ Between 18 September 2020 and 22 May 2021, 9785
patients hospitalised with COVID-19 were randomly
allocated to receive usual care plus the antibody
combination treatment (casirivimab 4g with
imdevimab 4g by intravenous infusion) or usual care
alone as part of the RECOVERY trial
◦ Of these, about one-third were seronegative at
baseline (ie they had not mounted a natural antibody
response of their own
◦ one-half were seropositive (ie they had already
developed natural antibodies)
◦ one-sixth had unknown serostatus

40. Results
◦ Among patients who received usual care alone,
28-day mortality was twice as high in those who
were seronegative (30%) vs. those who were
seropositive (15%) at study entry.
◦ Among patients who were seronegative at
baseline the antibody combination significantly
reduced the primary outcome of 28-day
mortality by one-fifth compared with usual care
alone
◦ 24% of patients in the antibody combination
group died vs 30% of patients in the usual care
group; rate ratio 0·80; 95% confidence interval
0·70–0·91; p=0·001)

41. ◦ Treatment in seronegative patients differed from that in
seropositive patients
◦ Combining the larger seropositive group with the seronegative
patients, there was no significant effect on 28-day mortality (overall
20% of patients in the antibody combination group died vs 21% of
patients in the usual care grouprate ratio 0·96; 95% confidence
interval 0·86–1·03; p=0·17)
◦ For the seronegative patients, the duration of hospital stay was
four days shorter (median 13 days vs. 17 days) among those allocated
to the antibody combination than the usual care group
◦ Proportion of patients discharged alive by day 28 was greater
(64% vs. 58%; rate ratio 1·19, 95% confidence interval 1·08 to 1·30)
◦ Seronegative patients not on invasive mechanical ventilation at
baseline, the risk of progressing to the composite endpoint of
invasive mechanical ventilation or death was lower among those
allocated to the antibody combination than the usual care group

42. Effect on delta plus variant
◦ The new Delta plus variant has been formed due to a mutation ..
Delta Plus (AY.1) is resistant to monoclonal antibodies cock tail

43. THANK
YOU