This document provides an overview of monoclonal antibodies (mAbs), including their history, production, nomenclature, mechanisms of action, and applications. Some key points: - mAbs were first discovered in 1975 and are produced by introducing human antibody genes into mice or other animals. The first therapeutic mAb was approved in 1985. - mAbs approved by the FDA target various diseases including cancer, infections, autoimmune/inflammatory conditions, and more. During the COVID-19 pandemic, several mAbs have been approved to treat and prevent the disease. - mAb names provide information on their target (e.g. CD3, TNF, IL-6), source/derivatization (human,

1. Presentation by
Devi Pravallika. K

2. HISTORY
 Emil von Behring and Kitasato Shibasaburo
discovered in 1890 that diphtheria and tetanus
toxins were neutralized in the bloodstream of animals
by substances they called antitoxins, which were
specific for the respective toxin.
 Behring received the first Nobel Prize in Physiology or
Medicine for their find in 1901. A year after the
discovery, Paul Ehrlich used the
term antibodies (German Antikörper) for these
antitoxins.

3. HISTORY….
 In 1975, the monoclonal antibody (mAb) technique
was created by Georges Köhler, César Milstein, and
Niels Kaj Jerne using a mouse x mouse hybridoma.
 They shared the Nobel Prize in Physiology of Medicine
in 1984 for the discovery.
 Eight years later, in 1992, the US FDA approved the
first therapeutic mAb muromonab-CD3 (trade name
Orthoclone OKT3) to reduce acute rejection in
patients with organ transplants.

4. INTRODUCTION
 As of now, there are more than 100 mabs have been
approved by FDA.
 These target various tumors, cancers, bacteria, virus,
autoimmune disorders, toxins and even for drug
antidotes(eg., Idarucizumab).
 Right now the pandemic that’s affected everyone, the
SARS COV-19 has got several mabs approved for its
prophylaxis and mitigation.

5. So what is mAb???...
 Monoclonal antibody or simply mAb is an antibody
synthesized from a single type of cell(thus,
monoclonal) while our endogenously produced
antibodies are polyclonal(produced by a number of
distinct B lymphocytes and therefore have slightly
different specificity for the target Ag.

6. How are these produced exactly?
Monoclonal antibodies are produced by introducing
human genes that produce antibodies into mice or
another suitable mammal.
The mice then are vaccinated with the desired antigen.
This causes the immune cells of the mice to produce
the desired human antibody.

8. NOMENCLATURE
 The first mab was approved in 1985 is named as
MUROMONAB-CD3 which depicts as
 Muro- murine originated(mice)
 Mon- monoclonal
 Ab- antibody
 CD3- against CD3 i.e., against immunity and is
approved for preventing tranplantation rejections.

9. Nomenclature…
 Later in 2006, WHO introduced nomenclature system
for mabs.
 This includes
❶ Prefix- any random
❷Infix- includes their target with a second
substem depicting their source-chimeric(xi)/
humanized(zu)/ completely human(u) &
❸suffix- mab

10. SOME INFLIXES WITH THEIR
TARGETS
 Ba: bacterial
 Ci: cardiovascular
 De: metabolic or endocrine pathways
 Eni: enzyme inhibition
 Fung: fungal
 Ki: cytokine and cytokine receptor
 Nen: nervous system
 Os: bone
 Li: immune system
 Tu: tumor
 Tox: toxin
 Vi: viral

11. Nomenclature…
 Eg: Adalimumab
 Here, lim stands as infix which indicates (lymphocytes as
in) immune system being the target.
 U indicates it’s completely human derived & mab denotes
it’s a monoclonal antibody.
 This is TNF blocker approved to use in various
autoimmune conditions like Rheumatoid arthritis,
Ankylosing Spondylitis, Crohns Disease, Ulcerative Colitis
& Psoriatic Spondylitis.

12. Nomenclature…
 Later in 2017, two changes were made to this.
1. To remove the source as both human and animal
derived can produce allergic reaction.
2. To add four alphabets which have no meaning to
differentiate between mabs produced by different
companies(biosimilars).

14. TOX(toxin)
BEZLOTOXUMAB: Pseudo-membranous colitis by
Clostridium difficile (Clostridioides difficile) infection.
A single molecule of bezlotoxumab neutralizes Toxin B
by binding its two Fab regions to two epitopes within
the N-terminal half of the Toxin B.
OBILTOXAXIMAB: Anthrax by Bacillus anthracis.
It is designed to attach to a component of the anthrax
toxin called ‘anthrax protective antigen’ that allows the
toxin to enter cells.

15. NE/N(nervous system)
 ERENUMAB, EPTINEZUMAB, GALCANEZUMAB &
FREMANEZUMAB: Prophylaxis of migraine.
These mabs acts by blockage of Calcitonin Gene
Related Peptide(CGRP) receptors expressed in the
trigeminal system – both fibres and ganglia. Inhibition
of the effects of CGRP could theoretically reduce the
compensatory vasodilation in ischemic-related
conditions.

16. VI(viral)
 PALIVIZUMAB: Respiratory Syncytial Virus
It helps prevent RSV in children less than 24 months
old who are at high risk for getting RSV & not used to
treat the symptoms.
It is directed to bind to an epitope in the antigenic site
of the F protein of respiratory syncytial virus (RSV).

17. CI/C(circulatory system)
 ABCIXIMAB: Abciximab binds to the glycoprotein
(GP) IIb/IIIa receptor of human platelets and inhibits
platelet aggregation by preventing the binding of
fibrinogen, von Willebrand factor, and other adhesive
molecules.
 CAPLACIZUMAB: It is a von Willebrand factor (vWF)-
directed antibody fragment used to treat acquired
thrombotic thrombocytopenic purpura (aTTP).

19.  EMICIZUMAB: It restores the function of missing
activated factor VIII (FVIII) by bridging FIXa and FX
to facilitate effective haemostasis in patients with
haemophilia A. It is approved for the routine
prophylaxis of bleeding episodes in patients with
haemophilia A with or without FVIII inhibitors.

20. EMICIZUMAB

21.  IDARUZUMAB: It targets direct thrombin inhibitor
dabigatran, by binding to dabigatran and its
acylglucuronide metabolites with higher affinity than
the binding affinity of dabigatran to thrombin,
neutralizing their anticoagulant effect.

22.  ALIROCUMAB & EVOLOCUMAB: PCSK9 inhibitors.
These bind to proprotein convertase subtilisin kexin
type 9 (PCSK9). PCSK9 binds to the low-density
lipoprotein receptors (LDLR) on the surface of
hepatocytes to promote LDLR degradation within the
liver.
 BROLUCIMAB: It inhibits VEGF-A, used as an
intravitreal injection Age Related Macular
Degeneration.
OC(over cholesterol)

24. OS(bone)
 DENOSUMAB: Osteoporosis by preventing fractures
by Inhibiting RANL ligand and preventing osteoclast
activity.
 ROMOSOZUMAB: Osteoporosis by preventing
fractures via sclerostin inhibition, thus inhibits
osteoclast activity.
 BUROSUMAB: X-linked hyperphosphotemia
it binds to Fibroblast Growth Factor-23, a member of
FGF family involved in phosphate and vitamin D
metabolism and regulation.

25. KI/K(leukotriene)
 IXEKIZUMAB,IL-17
 SECUKINUMAB,IL-17
 USTEKINUMAB,IL-12,23
 RISANKINUMAB,IL-23
 GUSELKUMAB,IL-23
 TILDRAKIZUMAB,IL-23
All these are used for PS(plaque psoriasis).

26. LI/L(immune system)
 TNF-alpha inhibitors: ADALIMUMAB,
CERTOLIZUMAB
ETANERCEPT
INFLIXIMAB
GOLIMUMAB
These are used in autoimmune conditions like
Rheumatoid Arthritis, Crohns Disease and Psoriasis

27.  P- SELECTIN: CRIZANLIZUMAB-tmca
It acts against the adhesion molecule P-selectin
causing vaso-occlusion. Thus, it’s used to reduce the
number of pain crises (sudden, severe pain that may
last several hours to several days) in adults and
children 16 years of age and older with sickle cell
disease, reduce the frequency of vaso-occlusive crises
(VOCs).

28.  CD4- IBALIZUMAB
It is a viral-entry inhibitor that coats CD4-positive
cells, the main target of HIV infection. By blocking
viral entry into CD4 cells, ibalizumab creates a barrier
for HIV. Ibalizumab leads to conformational changes
of the CD4 T cell receptor–gp120 complex
thus preventing HIV fusion and entry. Therefore,
ibalizumab is classified as an entry inhibitor.

29. IL-17 RA
 IL-17 RA- BRODALUMAB
Brodalumab binds to the interleukin-17 receptor and
so prevents interleukin 17 (IL-17) from activating the
receptor. This mechanism is similar to that of another
anti-psoriasis antibody, ixekizumab.

30.  IL-4R alpha antagonist- DUPILUMAB
 It is approved for Atopic Dermatitis.
 Dupilumab is of immunoglobulin G4 subclass that
inhibits IL-4 and interleukin-13 (IL-13) signaling by
specifically binding to the IL-4 receptor alpha subunit.
By blocking the IL-4R alpha subunit, dupilumab
inhibits IL-4 and IL-13 cytokine-induced responses,
including the release of proinflammatory cytokines,
chemokines, and immunoglobulin E.

31.  IFN-alpha- EMPALUMAB
Emapalumab is the first global approval for the
treatment of pediatric and adult patients with primary
hemophagocytic lymphohistiocytosis (HLH) with
refractory, recurrent, or progressive disease or
intolerance to HLH therapy. It acts by binding and
neutralising IFN-γ.

32. C5
 Eculizumab: Eculizumab is a recombinant humanized
monoclonal antibody used to reduce the risk of
hemolysis in paroxysmal nocturnal hemoglobinuria
(PNH) and atypical hemolytic uremic syndrome
(aHUS). It targets complement protein C5. Binding to
this protein prevents the activation of a complement
terminal complex.
 Ravulizumab: Ravulizumab-cwvz binds to
complement protein 5 (C5) and blocks its activation by
complement pathway convertases, thus inhibiting the
formation of the terminal complement complex.

33. IMMUNE CHECK POINT INHIBITORS
 Immune checkpoints are made by some types of
immune system cells, such as T cells, and some cancer
cells. These checkpoints help keep immune responses
from being too strong and sometimes can keep T cells
from killing cancer cells. When these checkpoints are
blocked, T cells can kill cancer cells better. Examples of
checkpoint proteins found on T cells or cancer cells
include PD-1/PD-L1 and CTLA-4/B7-1/B7-2. Some
immune checkpoint inhibitors are used to treat cancer.

36. ●PD1 : NIVOLUMAB- Hodgkins lymphoma, Non-
Small Cell Lung Cancer(NSCLC)
PEMBROLIZUMAB- NSCLC, Head &Neck
tumors
CEMIPLIMAB- Squamous cell Ca of skin
●PD-L1 : ATEZOLIZUMAB- Urothelial & breast Ca
AVELUMAB- Merkel cell Ca
DERVALUMAB- Bladder Ca
●CTLA-4: IPILIMUMAB- Malignant melanoma

37. ASTHMA
 Ig-E: OMALIZUMAB
Omalizumab binds to free IgE in the serum, forming
trimers and hexamers and thus inhibiting IgE from
binding to its receptos on mast cells and basophils
and thus their respective inflammatory mechanisms.
 IL-5: RESLIZUMAB
MEPOLIZUMAB
BENRALIZUMAB

39. mAbs approved for COVID
ROCHE’S COVID COCKTAIL: this consists of two mabs
1. CASIRIVIMAB & 2. IMDEVIMAB
This cocktail has to be administered in patients with
mild to moderate infection of Covid and do not
require oxygen, but are at high risk of developing
severe stage of COVID.
MOA: these block COVID virus from entering human
cells.

40.  Criteria : Only for high risk patients i.e,
Age >59yrs;
Obese people;
Patients with chronic lung disease including asthma;
NIDDM & IDDM;
Patients with CKD;
Immunosuppressed(on chemotherapeutics for cancers, BMD
or organ transplantation, immune deficiencies, HIV);
Severe CVDs;
liver disorders;
Sickle cell anaemia;
Thalassemia.

41.  CDSCO approved for restricted emergency use for the
treatment of mild to moderate COVID-19 in adults &
paediatric patients with laboratory confirmed
infection and are at high risk of hospitalisation.
 Efficiency : it is proven to reduce hospitalisation by
upto 70% in eligible candidates(12yrs and above,
weight>40kg, not hospitalised patients and do not
require o2 supplementation when administered within
3-4 days or 7days of onset of symptoms as soon as
possible.

42.  Safety profile: safe for patients with Chronic Kidney
Disease, Chronic Liver Disease and
immunosuppressed as well.
 Adverse Drug Reactions: possible side effects includes
fever, difficulty in breathing, chills, fatigue, nausea,
headache, throat irritation & rashes
severe hypersensitivity reactions rarely occur.

43. IL-6Receptor
 Tocilizumab
 Sarilumab
Both of these are approved for the treatment of
rheumatoid arthritis and other autoimmune
conditions
• Satralizumab: it is used in neuromyelitis optica
spectrum disorder (NMOSD). NMOSD is a rare,
chronic autoimmune disease that causes inflammation
in the central nervous system. This can lead to damage
of the optic nerves, spinal cord, and/or brain.

44.  Interleukin (IL)-6 is a pleiotropic, proinflammatory
cytokine produced by a variety of cell types, including
lymphocytes, monocytes, and fibroblasts.
 Infection by SARS-CoV induces a dose-dependent
production of IL-6 from bronchial epithelial cells.
 COVID-19-associated systemic inflammation and
hypoxemic respiratory failure can be associated with
heightened cytokine release, as indicated by elevated
blood levels of IL-6, C-reactive protein (CRP), D-
dimer, and ferritin.

45.  It is hypothesized that modulating IL-6 levels or the
effects of IL-6 may reduce the duration and/or severity
of COVID-19.
 There are two classes of Food and Drug
Administration (FDA)-approved IL-6 inhibitors: anti-
IL-6 receptor monoclonal antibodies (mAbs) (e.g.,
sarilumab, tocilizumab) and anti-IL-6 mAbs (i.e.,
siltuximab). These drugs have been evaluated in
patients with COVID-19 who have systemic
inflammation.

46.  Tocilizumab and sarilumab should be used with
caution in groups of patients with COVID-19 that have not
been adequately studied in clinical trials. This includes
patients who are significantly immunosuppressed,
particularly those who have recently received other biologic
immunomodulating drugs, and those with:
 Alanine transaminase levels >5 times the upper limit of
normal
 A high risk for gastrointestinal perforation
 An uncontrolled serious bacterial, fungal, or non-SARS-CoV-
2 viral infection
 Absolute neutrophil counts <500 cells/µL
 Platelet counts <50,000 cells/µL
 Known hypersensitivity to the drug

47.  Tocilizumab and sarilumab should only be given in
combination with a course of dexamethasone (or an
alternative corticosteroid at a dose that is equivalent to
dexamethasone 6 mg)
 the Panel recommends sarilumab only when
tocilizumab is not available or is not feasible to
use (BIIa) because the evidence for the efficacy of
tocilizumab is more extensive than that for sarilumab

48.  Adverse Effects
 The primary laboratory abnormalities reported with
tocilizumab treatment are elevated liver enzyme levels
that appear to be dose dependent. Neutropenia or
thrombocytopenia are uncommon. In randomized trials,
no excess secondary infections were seen among patients
who received combination therapy compared to study
controls. Additional adverse effects, such as serious
infections (e.g., tuberculosis [TB], bacterial or fungal
infections) and bowel perforation, have been reported.

49. Drug name Dosing regimen Comments
Tocilizumab Tocilizumab 8 mg/kg actual
body weight (up to 800 mg)
administered as a single IV
dose
•In clinical trials, a third of
the participants received a
second dose of tocilizumab 8
hours after the first dose if no
clinical improvement was
observed.
Sarilumab Use the single-dose, pre-
filled syringe (not the pre-
filled pen) for SQ injection.
Reconstitute sarilumab 400
mg in 100 cc 0.9% NaCl and
administer as an IV infusion
over 1 hour.
•Use as an alternative if
tocilizumab is not available
or not feasible to use (BIIa).
•In the United States, the
currently approved route of
administration for sarilumab
is SQ injection. In the
REMAP-CAP trial, the SQ
formulation was used to
prepare the IV infusion.