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ANTIBODIES
• It is a specialized glycoprotein, produced from activated B
cells (plasma cells) in response to an antigen that triggers its
production .
• Also called ‘Immunoglobulins’ because they immunologically
react with the antigen
MONOCLONAL ANTIBODIES
• These are homogenous preparations of antibodies (or
fragments of antibodies) in which every antibody in the
product is identical in its protein sequence, and thus every
antibody is expected to have the same antigen recognition site,
affinity, biologic interactions, and downstream biologic
effects.
Discovery
The idea of a "magic bullet" was first proposed by Paul Ehrlich,
who, at the beginning of the 20th century, postulated that, a
compound can be made that selectively targeted a disease-
causing agent.
• It was understood that these cancerous
B-cells all produce a single type of
antibody (a paraprotein).
• This was used to study the structure of
antibodies, but it was not yet possible to
produce identical antibodies specific to
a given antigen
In the 1970s, the B-cell cancer - multiple myeloma was known.
Somatic cell hybridization - 1975
• The advent of hybridoma technology by Kohler and Milstein
made it possible to produce large quantities of antibodies with
high purity and monospecificity for a single binding region
(epitope) on an antigen .
Production of monoclonal antibodies
• By HYBRIDOMA TECHNIQUE
• These cells do not have th eenzyme hypoxanthine guanine-
phosphoribosyl transferase (HGPRT).
• This enzyme enables cells to synthesize purines using an
extracellular source of hypoxanthine as a precursor.
• Ordinarily, the absence of HGPRT is not a problem for
the cell because cells have an alternate (de novo)pathway
that they can use to synthesize purines.
• However, when cells are exposed to aminopterin (a folic
acid analog), they are unable to use de novo pathway and
are now fully dependent on HGPRT for survival.
Bcell has the enzyme HGPRT
But B cells die soon
• They do not have the capacity to grow indefinitely
because of their limited life span
Scanning Electron Microscopic
view of a Bcell
CELLS FUSED:
◦ Spleen cells from a mouse that has been immunized with
the desired antigen
◦ Myeloma cells.
FUSION AGENT:
◦ Polyethylene glycol
MEDIUM:
◦ HAT Medium {Hypoxathine-Aminopterin- Thymidine}
Mice are immunized every 2-3 weeks with an antigen
that is prepared for injection
Step 2: Screening of Mice for
Antibody Production
• Blood samples are obtained from mice for measurement of
serum antibodies whose titer is determined with various
techniques, such as enzyme-linked immunosorbent assay
(ELISA) and flow cytometry.
Isolation of antibody producing
spleen cells
•When the antibody titer is high enough, mice are commonly boosted by injecting
antigen without adjuvant intra peritoneally or intravenously (via the tail veins) 3
days before fusion but 2 weeks after the previous immunization.
•If the titer is too low, mice can be boosted until an adequate response is
achieved, as determined by repeated blood sampling.
•Then the mice are euthanized and their spleens removed for in vitro hybridoma
cell production.
Step 4 : Production of hybridomas
Culture medium
Culture medium
• Myeloma cells lack HPGRT (hypoxanthine phospho ribosyl
transferase) enzyme,which is responsible for synthesis of
nucleotides.
• The cells are then screened in HAT (hypoxanthine-
aminopterin-thymidine) medium which blocks the pathway
for nucleotide synthesis.
Step 5 : Screening of hybridomas
Myeloma cells B cells Hybridomas
HAT (hypoxanthine-aminopterin-thymidine )medium
Nucleotide synthesis
pathway blocked
Nucleotide synthesis
pathway blocked
Nucleotide synthesis
pathway blocked
Nucleotide synthesis
pathway blocked
HPGRT gene presentHPGRT gene present
Nucleotides fail to get
synthesized
Nucleotides get synthesized Nucleotides get synthesized
Step 5 : Screening of hybridomas
Myeloma cells B cells Hybridomas
HAT (hypoxanthine-aminopterin-thymidine )medium
Nucleotides fail to get
synthesized
Nucleotides get synthesized Nucleotides get synthesized
Cells die due to lack
of nucleotide
synthesis
Cells die due to
short life span
Cells survive
Step 6 : Culturing Hybridoma Cells
– Monoclones Production
Hybridomas are separated and individually cultured : 1 cell per well
These cells are called as clonal culture. Because each cell in the well is derived
from singe cell and are therefore identical.
After few weeks, when growing cultures can be seen, further screening can be
done for desired antibody.
Step 7 : Screening for desired
antibodies
• Antigens are immobilized in the wells and the antibodies are
transferred (one per well) so that they bind to the complementary
antigen.
• Different antibodies react to different epitopes on the same antigen
Step 8 : Selection and culture of
screened antibodies
Finally, the desired antibodies are grown in mass culture and
are frozen for storage.
Cont’d
Immunoglobulin-G (IgG) molecules are most commonly employed as
the working backbones of current therapeutic monoclonal antibodies,
EVOLUTION OF MONOCLONAL
ANTIBODIES
Murine antibody
• Whole of the antibody is of murine
origin
Major problems associated with murine
antibodies include
• Reduced stimulation of cytotoxicity
• Allergic reactions
• Anaphylactic shock
Chimeric Antibodies
• Chimeric antibodies are those in which the
Fc part of an immunoglobulin is of a
human sequence
• Antibodies are approximately 65% human.
• This reduces immunogenicity and thus
increases serum half-life.
HUMANISED MAB
• Humanised antibodies contain
segments from sources in the
complementary determining regions
(CDR) interspersed among human
derived segments in constant regions
• This results in a molecule of
approximately 95% human origin
Human Monoclonal Antibody
• Human monoclonal antibodies
are produced by transferring
human immunoglobulin genes
into the murine genome, after
which the transgenic mouse is
vaccinated against the desired
antigen, leading to the
production of monoclonal
antibodies
Every monoclonal antibody has the following
components in its name :
Variable-Target Substem-Source Substem-Stem-
Additional words
Ex: Alacizumab pegol is
Ala –ci-zu-mab-pegol
OLD NEW MEANING
-anibi- - Angiogenesis inhibitor
-ba(c)- -ba- Bacterium
-ci(r)- -ci- Circulatory system
-fung- - f u - Fungus
-ki(n)- - k i - Inlterleukin
-les- - Inflamattory lesions
-li(m)- - l i - Immune system
-mul- - Musculoskeletal system
-ne(ur)- -n(e)-* Nervous system
-os- -s(o)- bone
-toxa- -tox(a)- toxin
- - t u - Tumour
-vi(r) -vi- virus
Letter Meaning
- a - Rat
- e - Hamster
- i - Primate
- o - Mouse
- u - Human
- x i - Chimeric
- z u- Humanized
-axo- Rat/mouse hybrid
antibodies named after mid-2017 will not contain the
"zu" and "xi" stems in their generic names.
A second word following the name of the antibody indicates that
another substance is attached.
1)An antibody can be PEGylated – to slow down its degradation by
enzymes and to decrease its immunogenicity .Ex:alacizumab pegol
2)A cytotoxic agent can be linked to an anti-tumor antibody for
drug targeting purposes.
◦ vedotin,(monomethyl auristatin E) which is toxic by itself
but predominantly affects cancer cells if used in
conjugates
Ex:glembatumumab vedotin
3)A chelator for binding a radioisotope can be attached.
◦ Pendetide, a derivative of pentetic acid, in capromab pendetide to
chelate indium-111.If the drug contains a radioisotope, the
name of the isotope precedes the name of the antibody.
Ex: indium (111In) capromab pendetide
Additional Words
MODIFICATIONS
• Fragments typically have a single valence (binding site) for the
antigen, rather than two valences that are characteristic of full-length
antibodies.
TYPES :
• Fragment antigen binding (Fab) – Also called Fab fragments, these
consist of a variable domain and the first constant region each of
heavy and light chain
• Single-chain variable fragment (scFv) – An scFv consists of a light
chain and heavy chain variable region joined by a linker peptide
• Single-domain antibody (sdAb) – An sdAb is an antibody fragment
consisting of a light chain variable region or heavy chain variable
region
• A popular method for producing these fragments is use of a
phage display library that can be used to screen large
collections of potential antibody fragments for their binding to
the antigen and other desired properties.
• Fab fragments lack the Fc component of the antibody (the
remainder of the heavy chain) and thus are not capable of
interacting with Fc receptors or activating complement.So not
useful for cell killing.
Eg : Abciximab
FACTORS REGULATING ANTIBODY-
BASED TUMOR TARGETING
• Antibody Size
The high interstitial pressure in tumor slows the diffusion of molecules from their vascular
extravasation site in a size-dependent manner.
• Tumor Antigens
The valence of an antibody molecule can increase the functional affinity of the antibody
through an avidity effect
• Half life/clearance rate
Half life is in days.This homeostasis is regulated in part by the major histocompatibility
complex (MHC)-class I–related Fc receptor, FcRn (n = neonatal), a saturable, pH-dependent
salvage mechanism that regulates quality and quantity of IgG in serum
• Glycosylation
Glycosylation status of the residue impacts the ability of IgGs to bind effector ligands such
as FcγR and C1q,thus affecting their ability to participate in Fc-mediated functions such as
ADCC and CDC.
Mechanism of Action
• Antibodies can recruit other immune cells and molecules (such
as complement), both of which promote killing of target cells.
• This recruitment is mediated by the Fc (fragment
crystallizable) portion of the antibody, which includes the
heavy-chain second and third constant regions.
• Fc receptors can modulate the
cell killing by antibody-
dependent cellular cytotoxicity
(ADCC) or complement-
dependent cytotoxicity (CDC)
ANTIBODY DEPENDENT CELLULAR
CYTOTOXICITY
• Naturally occurring polymorphisms in FcγRs alter their affinity for
human IgG1 and have been linked to clinical response.
• A polymorphism in the FCGR3A gene results in either a valine or
phenylalanine at position 158 of FcγRIIIa.
• Human IgG1 binds more strongly to FcγRIIIa-158V than FcγRIIIa-
158F, and likewise to NK cells from individuals that are either
homozygous for 158F or heterozygous for this polymorphism.
• The FcγRIIIa-158v was a predictor of early response and was
associated with improved PFS.
• Thus these data suggest that modulating the affinity of MAbs for
FcγRIIIa, FcγRIIa, or both may increase the efficacy of therapeutic
MAbs.
COMPLEMENT-DEPENDENT
CYTOTOXICITY
• MAbs can recruit the complement cascade to kill cells via CDC.
• IgG1 is extremely efficient at fixing complement, in contrast to
IgG2 and IgG4.
• Antibodies activate complement through the classical pathway, by
engaging multiple C1q to trigger activation of a cascade of serum
proteases, which kill the antibody-bound cells.
CDC
• These are mAbs in which two immunoglobulin chains of differing
specificity have been fused into a single antibody molecule.
• This allows the antibody to bring two different antigens (eg, two
proteins) into close physical proximity, which in turn may carry out a
new function
BIFUNCTIONAL ANTIBODIES
(aka "bispecific" antibodies)
Examples:
● Emicizumab binds to two coagulation factors (factor IXa and factor X)
● Catumaxomab binds to the T-cell surface molecule CD3 and epithelial
cell adhesion molecule (EpCAM), a tumor cell surface marker; it also
has an Fc region that can bind to an Fc receptor on macrophages, natural
killer (NK) cells, or dendritic cells. Efficacy has been shown in
malignant ascites.
● Blinatumomab binds to CD3 on T cells and the cell surface protein
CD19, present on precursor B-cell acute lymphoblastic leukemia (ALL)
cells, potentially recruiting cytotoxic T cells to kill the ALL cells.
IMMUNOCONJUGATES
• MAbs that are not capable of directly eliciting antitumor effects,
either by altering signal transduction or directing immune system
cells, can still be effective against tumors by delivering cytotoxic
payloads.
• MAbs have been employed to deliver a wide variety of agents,
including chemotherapy, toxins, radioisotopes, and cytokines .
Antibody Drug Conjugates :
• Gemtuzumab ozogamicin (Mylotarg)
• Ado-trastuzumab emtansine (T-DM1)
• Brentuximab vedotin (SGN-35, Adcetris)
RADIOIMMUNOCONJUGATES
• Two anti-CD20 radioimmunoconjugates have been FDA approved
in non-Hodgkin lymphoma (NHL).
• Ibritumomab (Zevalin) and tositumomab (Bexxar) are murine MAbs
labeled with yttrium-90 (90Y) and iodine-131 (131I), respectively.
• Both are associated with impressive clinical efficacy.
• Although these radioimmunoconjugates are effective therapeutics,
cumbersome logistics surrounding their administration have
significantly limited their use.
ANTIBODIES APPROVED FOR
USE IN SOLID TUMORS
• Targets HER2 protein
• High affinity and
specificity
• 95% human, 5% murine
• Decreased potential for
immunogenicity.
• Increased potential for
recruiting immune
effector mechanisms
HER2 epitopes recognized by
hypervariable murine
antibody fragment
Human
IgG-1
TRASTUZUMAB
OVEREXPRESSION
(PROTEIN)
AMPLIFICATION
(DNA)
IHC FISH
• 25% of breast cancers
• 7% to 34% of gastric cancers.
Trastuzumab: 1 target
4 mechanisms of action
Prevention o f fo rm at io n o f
p95HER2
Inhibition o f c e l l
p ro l i fe ra t i o n
Activation o f ADCC
Inhibition o f
HER2-regulated angiogenesis
Prevention of formation of
p95HER2
Inhibition of c e l l
proliferation
Activation of ADCC
Inhibition of
HER2-regulated angiogenesis
HER2
HerceptinTumour
c e l l
+
ADCCNK c e l l
FcgRIII
• Once bound t o HER2, the Herceptin Fc domain rec ru its
immune c e l l s t o ta rg e t and d e s t ro y the tumour
Herceptin
ADCC is a key mechanism of Herceptin’s
antitumour activity in vivo
ADCC
FcgRIII
• Once bound to HER2, the Herceptin Fc domain recruits
immune cells to target and destroy the tumour
Indications :
• Metastatic breast cancer (Her 2 +)
- First line therapy in combination with paclitaxel
- Second/third line therapy as single agent
• Early stage Breast cancer – adjuvant therapy in node +
• Metastatic gastric or gastroduodenal junc Adenoca
- Alone with cisplatin or capecitabine and 5-FU
Dosage :
• Weekly : 4mg/kg loading f/b 2mg/kg
• 3 weekly : 8mg/kg loading dose f/b 6mg/kg maintenance dose
Side Effects :
• Infusion related symptoms
• Mild GI toxicity
• Cardiotoxicity- dyspnea,peripheral edema,decreased LV function
• Pulmonary toxicity – cough , dyspnea
Caution !!!
• Baseline cardiac function evaluation and monitoring every 3
months
• Withold drug
-if > 16% Absolute decrease in LVEF from normal baseline value
-patient develops clinically significant congestive heart failure
PERTUZUMAB
• Pertuzumab (Perjeta) is a humanized IgG1 MAb that binds to
domain II of HER2 and blocks ligand- dependent dimerization
of HER2 with other members of the EGFR family.
Mechanism of action
• Binding of pertuzumab to Her2 leads to
inhibition of heterodimerisation of
Her2 with other ‘Her’ family members
• Inhibition of these heterodimerisation
process leads to inhibition of
downstream signalling pathways-
MAPK,PI3K,this cell apoptosis
• ADCC
Indications :
• Pertuzumab, in combination with trastuzumab and docetaxel, -
-first-line therapy in HER2- positive metastatic breast cancer
patients.
• Combination therapy –neoadjuavnt in HER2-positive, locally
advanced, inflammatory, or high-risk early breast cancer (>2
cm node negative or node positive).
Dosage :
• Initial dose -840mg iv
• Maintenance dose 420mg 3 weekly
Side Effects:
• Fetal deaths
• Cardiotoxicity
- Withold drug if drop in LVEF < 45% or if LVEF -45-49% with
>10% fall from baseline
- Discontinue drug if cardiac function doesn’t improve after 3
weeks of discontinuation
• Infusion related reactions
• fatigue
• Diarrhea, nausea,vomiting
CLEOPATRA :
• 808 patients
• locally recurrent, unresectable, or metastatic breast cancer
• trastuzumab plus docetaxel with or without the addition of
pertuzumab.
• Inclusion of pertuzumab increased the independently assessed
PFS by 6.1 months from 12.4 to 18.5 (hazard ratio [HR], 0.62
(95% confidence interval [CI], 0.51, 0.75), p <0.0001], with a
trend toward improved overall survival that reached statistical
significance (p = 0.0008) after an additional year of follow-up.
• The addition of pertuzumab did increase rates of grade 3
adverse events (AE), but it did not adversely affect cardiac
function.
• Four-arm, open-label phase II study of 417 patients
randomized to receive trastuzumab plus docetaxel, pertuzumab
plus docetaxel, pertuzumab plus trastuzumab, or the triple
combination.
• The triple combination improved the pathologic complete
response (pCR) rate by 17.8% over the trastuzumab plus
docetaxel arm (39.3% versus 21.5%) in the pertuzumab arm.
ADO-TRASTUZUMAB EMTANSINE
• It is an ADC composed of the anti-HER2 MAb trastuzumab
linked to DM1, a highly potent derivative of maytansine,
through a stable thioether linker
• It is FDA approved for patients with HER2- positive
metastatic breast cancer previously treated with trastuzumab
and taxane chemotherapy.
• EMILIA : In the international phase III study, there was a 3.2-
month improved progression-free survival among patients that
received T-DM1 compared to those receiving standard
treatment with capecitabine and lapatinib.
• The most common side effects in the trial were
thrombocytopenia, transient transaminitis, as well as nausea,
fatigue, myalgias and arthralgias.
CETUXIMAB
• This chimeric IgG1 binds to domain
III of the EGFR, with roughly a
tenfold higher affinity than normal
ligands either EGF or transforming
growth factor α (TGF-α) ligands and
thereby inhibits ligand-induced
activation of this tyrosine kinase
receptor.
• Cetuximab may also function to
downregulate EGFR-dependent
signaling by stimulating EGFR
internalization.
Indications :
• Metastatic colorectal cancer (mCRC) –EGFR expressing cases
along with irinotecan
• Wild type KRAS-first line along with FOLFIRI in mCRC
• Head and neck
- concurrent with Radiation in locally advanced disease
- Along with 5FU and cisplatin in recurrent locoregionally
advanced or metastatic disease
- Monotherapy for recurrent locoregionally advanced or
metastatic disease progressing after platinum based therapy.
Dosage :
• 400mg/m2 loading dose f/b maintenace dose 250mg/m2
weekly
• 500mg/m2 every 2 weeks without loading dose
Side Effects :
• Infusion reactions
• Skin – pruritus,dry skin with pustular acneiform rash
- mainly on face,neck and upper trunk
- resolves on cessation
• Pulmonary toxicity –ILD-cough,dyspnea and pulmonary
infiltrates
• Hypomagnesemia
• Paronchial inflammation
Treatment :
• Skin rash – topical antibiotics-clindamycin/erythromycin
- avoid sun exposure
PANITUMUMAB
• Fully human IgG2 monoclonal
antibody that binds to EGFR.
•
• Binds with 40 fold higher
affinity to EGFR than normal
ligands and thus inhibits EGFR
activation by blocking the
binding of EGF and TGF-α.
• Higher affinity than cetuximab
Indications :
• Monotherapy for advanced CRC followng FOLFIRI.
• Monotherapy for advanced refractory disease in wild type KRAS
mCRC
• First line in wild type KRAS mCRC in combination with FOLFOX
chemotherapy.
Dosage :
• 6mg/kg IV every 2 weeks or
• 2.5mg/kg every week
Side Effects :
• Similar to cetuximab
• Less infusion reactions compared to cetuximab
NECITUMUMAB
• Recombinant human IgG1 monoclonal antibody against EGFR
Indications :
• First line treatment of metastatic squamous NSCLC along with
gemcitabine and cisplatin
Dosage :
• 800mg iv on day 1 and day 8 of a 21 day cycle
Side Effects:
• Infusion reactions
• Pruritus,dry skin
• Cardiopulmonary arrest
• Hypomagnesemia
• Increased risk of venous and arterial thromboembolism
BEVACIZUMAB
• It is a humanized monoclonal antibody targeting VEGF.
• The inhibition of VEGF signaling via bevacizumab treatment
may normalize tumor vasculature, promoting a more effective
delivery of chemotherapy agents.
Indications and Dosage :
• Glioblastoma (GBM) – progressive disease (10mg/kg 2 wkly)
• mCRC –along with 5FU in first line therapy (5mg/kg 2 wkly)
• Non-squamous- NSCLC – along with paclitaxel and
carboplatin (15mg/kg 3 weekly)
• mRCC – along with interferon alpha (10mg/kg 2 wkly)
• Persistent, recurrent, or metastatic cervical cancer (CC)
(15mg/kg 3 weekly)
• Platinum-resistant recurrent epithelial ovarian, fallopian tube
or primary peritoneal cancer (prOC)
• Advanced CRC –along with capecitabine – (7.5mg/kg 3wkly)
Side Effects :
• Gastrointestinal perforation and delayed wound healing
• Bleeding complicatios – epistaxis
• Arterial thromboembolic events
• Hypertension – 5-18%
• Proteinuria with nephrotic syndrome
• Infusion related reactions
• RPLS
Caution !!!
• Atleast 28days after any surgical procedure
• Therapy terminated if patient develop nephrotic syndrome.
interupted if proetinnuria > 2gm/24hrs.
• Discontinue if hypertensive crisis develops
• Pateints with recent hemoptysis > 1/2tsp of blood shouldn’t
recive bevacizumab
RAMUCIRUMAB
• Recombinant fully human IgG1 against VEGFR 2
• Thus inhibition of VEGFR mediated signaling leading to
reduced endothelial permeability , migration and proliferation.
Indications and Dosage :
• Advanced metastatic CRC –along with FOLFIRI after
progression with FOLFOX/XELOX plus bevacizumab
8mg/kg 2weekly with FOLFIRI
• Advanced metastatic gastric cancer-monotherapy or with
paclitaxel after progression on flouropyrimidine or platinum
chemotherapy ( 8mg/kg 2 weekly)
• Advanced metastatic NSCLC – with docetaxel after disease
progreesion with platinum based chemotherapy. (10mg/kg 3
weekly with docetaxel)
Side Effects :
• Similar to bevacizumab
• hypothyroidism
DENOSUMAB
• Denosumab (Xgeva) is a fully human IgG2 monoclonal
antibody that binds human RANK ligand (RANKL) with high
affinity and specificity
Dosage Forms :
• 60mg sc every 6 months
• 120mg sc every 4 weeks
Indications :
• Adults and skeletally mature adolescents who have either
surgically unsalvageable giant cell tumors of the bone (GCTB)
• Supportive care settings to reduce bone metastasis-related
skeletal-related events (SRE).
• To increase bone mass in prostate cancer and breast cancer
patients at high risk for bone fracture due to hormone-ablation
therapies
Adverse Effects
Hypocalcemia, hypophosphatemia, GI upset, arthralgia/back
ache, headache, increased risk of infection, Osteonecrosis of the
Jaw, atypical fracture
Monitoring
Calcium, phosphorus and magnesium
Bone mineral density
Counseling :
• Must be kept in refrigerator until prior to injection
• Remove from refrigerator ~15-30 minutes prior to injection
• Patient must take supplemental calcium and vitamin D to
maintain adequate serum calcium levels during therapy
DARATUMUMAB
• IgG1-k human monoclonal antibody against CD38 which is a
surface glycoprotein expressed on multiple myeloma cells
Indications :
• Multiple myeloma who have received at least 3 prior lines of
therapy including a proteosome inhibitor and an
immunomodulatory agent or who are double refractory to a
proteosome inhibitor and an immunomodulatory agent.
Dosage :
16mg/kg on weekly for week 1-8 ,then
Every 2 weeks for weeks 9-24
Every 4 weeks from week 25 till disease
progression
Side Effects :
• Myelosuppression
• Infusion reactions
• Nasal congestion
• Arthralgias
• Increased risk of infections
Caution !!!
• Give oral corticosteroid 20mg methylprednisolone
-day 1 and 2 of therapy
• Inform blood transfusion centres – false positive coombs
test , can persist upto 6 months after last therapy.
• Prophylaxis for herpes zoster
ANTIBODIES USED IN
HEMATOLOGIC MALIGNANCIES
RITUXIMAB
• Binds to a CD20 protein on the surface of
B cells and causes destruction of B cells
• >90% of NHL and leukemias
Mechanism Of Action
Indications and Dosage :
• Relapsed/refractory low grade FL,B cell NHL as single agent – 375mg/m2
weekly
• CD20+ follicular ,NHL – Along with chemotherapy –
375mg/m2 day1 of chemotherapy
• Maintenance therapy – In FL/ CD20+ NHL –
375mg/m2 every 8 weeks upto 12 doses
• DLBCL - 375mg/m2 day1 of chemotherapy
• CLL – 375mg/m2 one day before 1ST cycle chemo (FC)
cycle 2-6 – 500mg/m2 on day 1
• Non-progressing (including stable disease), low-grade, CD20-positive, B-
cell NHL as a single agent after first-line cyclophosphamide, vincristine, and
prednisone (CVP) chemotherapy. – 375mg/mm2 weekly for 4 weeks at 6
month intervals for maximum of 16 doses.
Side Effects :
• Infusion related reactions
• Tumor lysis syndrome
• Skin reactions –
-pemphigus , stevens johnsons syndrome,lichenoid dermatitis and
toxic epidermal necrolysis
-occurs 1-2 weeks following drug treatment
• Arrhythmias and chest pain
Caution !!!
• Infusion related deaths- risk factors-female gender,pre existing
pulmonary disease,CLL or mantle cell lymphoma
• If high tumor burden ,the first dose can be split into two doses
• If severe skin reactions – stop further therapy
OFATUMUMAB
• It is a fully human IgG1-K monoclonal
antibody that binds to novel epitope of CD20
which encompasses small extracellular loop.
• Mediates antibody dependent cellular
cytotoxicity (ADCC) and stronger complement
dependent cellular cytotoxicity (CDCC) when
compared to rituximab.
Indications:
• Refractory CLL-to fludaribine and alemtuzumab
• Relapsed CLL- combination with fludarabine and cyclophosphamide
• Relapsed or refractory follicular ,B-NHL
Dosage Range :
• Untreated CLL-
Cycle 1 - 300mg on day 1 , 100mg on day 8
Cycle 2 – 1000mg D1 -4 weekly -12 cycles
• Refractory CLL –
300mg –D1 followed 1 week later by
2000mg weekly for 7 doses,followed 4 weeks later by
2000mg every 4 weekly for 4 doses
Side Effects :
• Infusion reactions
• Myelosuppression – neutropenia and thrombocytopenia
• PML
• Increased risk of bacterial,fungal and viral infections
OBINUTUZUMAB
• Novel glycoengineered type II anti CD20 monoclonal antibody
with higher affinity for CD20 than rituximab
Indications :
• Previously untreated CLL-along with chlorambucil
Cycle 1 – 100mg – D1
900mg – D2
1000mg -- D8 and D15
Cycle 2 – 6 , 1000mg D1
• Follicular lymphoma- relapsed/refractory to Rituximab containing
regimen
Cycle 1 – 1000mg –D1 ,D8 and D15
Cycle 2 – 6 , 1000mg D1
1000mg every 2 months for 2 yrs
Side Effects :
• Infusion related reactions
• Myelosuppression with neutropenia and thrombocytopenia
• PML
• Hepatitis B reactivation
• Increased risk of bacterial ,viral and fungal infections
Caution !!!
• Withold antihypertensive Rx for 12hrs prior to obinutuzumab
infusion.
• Screen patients for HBV infection
• Don’t give in patients with active infection as serious bacterial ,
fungal and new or reactivated viral infections.
ALEMTUZUMAB
• Alemtuzumab (Campath-1H) targets the CD52 glycopeptide,
which is highly expressed on T and B lymphocytes.
Indications :
• relapsed or refractory B-cell CLL-who have been treated with
alkylating agents and who have failed fludarabine therapy
• T-cell prolymphocytic leukemia-who failed first line
Dosage :
• 30mg/day iv three times per week for a maximum
of 12 weeks
• Administered as 2hr iv infusion
Side Effects:
• Infusion related
• Immunosuppresion—increased incidence of oppurtunistic
infections-penumocystis,candida,cyptococcus
• Myelosuppression-neutropenia > anemia and thrombocytopenia
BRENTUXIMAB VEDOTIN
Brentuximab vedotin (SGN-35, Adcetris) is an CD30 directed
ADC that is made up of three components :
Approximately 4 molecules of MMAE are conjugated to each
antibody molecule.
Mechanism of action
Indications :
• Systemic, chemotherapy-refractory anaplastic large-cell
lymphomas (sALCL)
• Hodgkin lymphoma who have progressed after an autologous
stem cell transplant (ASCT). Patients ineligible for ASCT must
have failed two prior multidrug chemotherapy regimens.
• Post autologous stem cell transplant consolidation for patients
with hodgkins lymphoma at high risk of relapse or
progression.
Dosage :
1.8mg/kg iv every 3 wks
Side effects :
• Infusion related reactions
• Peripheral neuropathy
Incidence 55%
Resolution or improvement in 88% after BV
• Fatigue
• Myelosuppresion – Neutropenia and anemia
• Nausea ,vomiting , Diarrhea - mild
• Progressive multifocal leucoencephalopathy
CYTOKINE RELEASE
SYNDROME
• CRS is a severe immune reaction that occurs in response to immunotherapy
for certain cancers (eg, lymphoid malignancies), in which positive feedback
leads to progressive elevation in inflammatory cytokines by T lymphocytes
• It can occur in response to a therapeutic mAb or other immune-based
therapies such as chimeric antigen receptor (CAR)-T cells.
• Presentation : fever, headache, nausea, malaise, hypotension, rash, chills,
dyspnea, and tachycardia. Elevations in serum aminotransferases and
bilirubin can be seen, and, in some cases, disseminated intravascular
coagulation (DIC), capillary leak syndrome,
• The largest risk factor for CRS is tumor load. The antibodies most likely to
cause CRS are those that promote T-lymphocyte activation.
Examples: Blinatumomab, Nivolumab, Rituximab
• Prophylaxis for CRS (eg, premedication with acetaminophen
and diphenhydramine) is sometimes incorporated into therapy
protocols.
• Management of CRS depends on the severity and may include
interruption of the infusion, symptomatic treatment,
intravenous fluids, and ventilator and/or pressor support.
• The mAb tocilizumab, directed against interleukin (IL)-6, has
been effective in treating CRS related to chimeric antigen
receptor (CAR)-T cells, which, unlike an mAb, cannot be
discontinued once they have been infused.

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Monoclonal antibodies

  • 1.
  • 2. ANTIBODIES • It is a specialized glycoprotein, produced from activated B cells (plasma cells) in response to an antigen that triggers its production . • Also called ‘Immunoglobulins’ because they immunologically react with the antigen
  • 3.
  • 4. MONOCLONAL ANTIBODIES • These are homogenous preparations of antibodies (or fragments of antibodies) in which every antibody in the product is identical in its protein sequence, and thus every antibody is expected to have the same antigen recognition site, affinity, biologic interactions, and downstream biologic effects.
  • 5. Discovery The idea of a "magic bullet" was first proposed by Paul Ehrlich, who, at the beginning of the 20th century, postulated that, a compound can be made that selectively targeted a disease- causing agent.
  • 6. • It was understood that these cancerous B-cells all produce a single type of antibody (a paraprotein). • This was used to study the structure of antibodies, but it was not yet possible to produce identical antibodies specific to a given antigen In the 1970s, the B-cell cancer - multiple myeloma was known.
  • 8. • The advent of hybridoma technology by Kohler and Milstein made it possible to produce large quantities of antibodies with high purity and monospecificity for a single binding region (epitope) on an antigen .
  • 9. Production of monoclonal antibodies • By HYBRIDOMA TECHNIQUE
  • 10. • These cells do not have th eenzyme hypoxanthine guanine- phosphoribosyl transferase (HGPRT). • This enzyme enables cells to synthesize purines using an extracellular source of hypoxanthine as a precursor. • Ordinarily, the absence of HGPRT is not a problem for the cell because cells have an alternate (de novo)pathway that they can use to synthesize purines. • However, when cells are exposed to aminopterin (a folic acid analog), they are unable to use de novo pathway and are now fully dependent on HGPRT for survival.
  • 11. Bcell has the enzyme HGPRT But B cells die soon • They do not have the capacity to grow indefinitely because of their limited life span Scanning Electron Microscopic view of a Bcell
  • 12. CELLS FUSED: ◦ Spleen cells from a mouse that has been immunized with the desired antigen ◦ Myeloma cells. FUSION AGENT: ◦ Polyethylene glycol MEDIUM: ◦ HAT Medium {Hypoxathine-Aminopterin- Thymidine}
  • 13. Mice are immunized every 2-3 weeks with an antigen that is prepared for injection
  • 14. Step 2: Screening of Mice for Antibody Production • Blood samples are obtained from mice for measurement of serum antibodies whose titer is determined with various techniques, such as enzyme-linked immunosorbent assay (ELISA) and flow cytometry.
  • 15. Isolation of antibody producing spleen cells •When the antibody titer is high enough, mice are commonly boosted by injecting antigen without adjuvant intra peritoneally or intravenously (via the tail veins) 3 days before fusion but 2 weeks after the previous immunization. •If the titer is too low, mice can be boosted until an adequate response is achieved, as determined by repeated blood sampling. •Then the mice are euthanized and their spleens removed for in vitro hybridoma cell production.
  • 16. Step 4 : Production of hybridomas Culture medium Culture medium • Myeloma cells lack HPGRT (hypoxanthine phospho ribosyl transferase) enzyme,which is responsible for synthesis of nucleotides. • The cells are then screened in HAT (hypoxanthine- aminopterin-thymidine) medium which blocks the pathway for nucleotide synthesis.
  • 17. Step 5 : Screening of hybridomas Myeloma cells B cells Hybridomas HAT (hypoxanthine-aminopterin-thymidine )medium Nucleotide synthesis pathway blocked Nucleotide synthesis pathway blocked Nucleotide synthesis pathway blocked Nucleotide synthesis pathway blocked HPGRT gene presentHPGRT gene present Nucleotides fail to get synthesized Nucleotides get synthesized Nucleotides get synthesized
  • 18. Step 5 : Screening of hybridomas Myeloma cells B cells Hybridomas HAT (hypoxanthine-aminopterin-thymidine )medium Nucleotides fail to get synthesized Nucleotides get synthesized Nucleotides get synthesized Cells die due to lack of nucleotide synthesis Cells die due to short life span Cells survive
  • 19. Step 6 : Culturing Hybridoma Cells – Monoclones Production Hybridomas are separated and individually cultured : 1 cell per well These cells are called as clonal culture. Because each cell in the well is derived from singe cell and are therefore identical. After few weeks, when growing cultures can be seen, further screening can be done for desired antibody.
  • 20. Step 7 : Screening for desired antibodies • Antigens are immobilized in the wells and the antibodies are transferred (one per well) so that they bind to the complementary antigen. • Different antibodies react to different epitopes on the same antigen
  • 21. Step 8 : Selection and culture of screened antibodies Finally, the desired antibodies are grown in mass culture and are frozen for storage.
  • 23. Immunoglobulin-G (IgG) molecules are most commonly employed as the working backbones of current therapeutic monoclonal antibodies,
  • 25. Murine antibody • Whole of the antibody is of murine origin Major problems associated with murine antibodies include • Reduced stimulation of cytotoxicity • Allergic reactions • Anaphylactic shock
  • 26. Chimeric Antibodies • Chimeric antibodies are those in which the Fc part of an immunoglobulin is of a human sequence • Antibodies are approximately 65% human. • This reduces immunogenicity and thus increases serum half-life.
  • 27. HUMANISED MAB • Humanised antibodies contain segments from sources in the complementary determining regions (CDR) interspersed among human derived segments in constant regions • This results in a molecule of approximately 95% human origin
  • 28. Human Monoclonal Antibody • Human monoclonal antibodies are produced by transferring human immunoglobulin genes into the murine genome, after which the transgenic mouse is vaccinated against the desired antigen, leading to the production of monoclonal antibodies
  • 29.
  • 30. Every monoclonal antibody has the following components in its name : Variable-Target Substem-Source Substem-Stem- Additional words Ex: Alacizumab pegol is Ala –ci-zu-mab-pegol
  • 31. OLD NEW MEANING -anibi- - Angiogenesis inhibitor -ba(c)- -ba- Bacterium -ci(r)- -ci- Circulatory system -fung- - f u - Fungus -ki(n)- - k i - Inlterleukin -les- - Inflamattory lesions -li(m)- - l i - Immune system -mul- - Musculoskeletal system -ne(ur)- -n(e)-* Nervous system -os- -s(o)- bone -toxa- -tox(a)- toxin - - t u - Tumour -vi(r) -vi- virus
  • 32. Letter Meaning - a - Rat - e - Hamster - i - Primate - o - Mouse - u - Human - x i - Chimeric - z u- Humanized -axo- Rat/mouse hybrid antibodies named after mid-2017 will not contain the "zu" and "xi" stems in their generic names.
  • 33. A second word following the name of the antibody indicates that another substance is attached. 1)An antibody can be PEGylated – to slow down its degradation by enzymes and to decrease its immunogenicity .Ex:alacizumab pegol 2)A cytotoxic agent can be linked to an anti-tumor antibody for drug targeting purposes. ◦ vedotin,(monomethyl auristatin E) which is toxic by itself but predominantly affects cancer cells if used in conjugates Ex:glembatumumab vedotin 3)A chelator for binding a radioisotope can be attached. ◦ Pendetide, a derivative of pentetic acid, in capromab pendetide to chelate indium-111.If the drug contains a radioisotope, the name of the isotope precedes the name of the antibody. Ex: indium (111In) capromab pendetide Additional Words
  • 34. MODIFICATIONS • Fragments typically have a single valence (binding site) for the antigen, rather than two valences that are characteristic of full-length antibodies. TYPES : • Fragment antigen binding (Fab) – Also called Fab fragments, these consist of a variable domain and the first constant region each of heavy and light chain • Single-chain variable fragment (scFv) – An scFv consists of a light chain and heavy chain variable region joined by a linker peptide • Single-domain antibody (sdAb) – An sdAb is an antibody fragment consisting of a light chain variable region or heavy chain variable region
  • 35. • A popular method for producing these fragments is use of a phage display library that can be used to screen large collections of potential antibody fragments for their binding to the antigen and other desired properties. • Fab fragments lack the Fc component of the antibody (the remainder of the heavy chain) and thus are not capable of interacting with Fc receptors or activating complement.So not useful for cell killing. Eg : Abciximab
  • 36. FACTORS REGULATING ANTIBODY- BASED TUMOR TARGETING • Antibody Size The high interstitial pressure in tumor slows the diffusion of molecules from their vascular extravasation site in a size-dependent manner. • Tumor Antigens The valence of an antibody molecule can increase the functional affinity of the antibody through an avidity effect • Half life/clearance rate Half life is in days.This homeostasis is regulated in part by the major histocompatibility complex (MHC)-class I–related Fc receptor, FcRn (n = neonatal), a saturable, pH-dependent salvage mechanism that regulates quality and quantity of IgG in serum • Glycosylation Glycosylation status of the residue impacts the ability of IgGs to bind effector ligands such as FcγR and C1q,thus affecting their ability to participate in Fc-mediated functions such as ADCC and CDC.
  • 37. Mechanism of Action • Antibodies can recruit other immune cells and molecules (such as complement), both of which promote killing of target cells. • This recruitment is mediated by the Fc (fragment crystallizable) portion of the antibody, which includes the heavy-chain second and third constant regions. • Fc receptors can modulate the cell killing by antibody- dependent cellular cytotoxicity (ADCC) or complement- dependent cytotoxicity (CDC)
  • 39. • Naturally occurring polymorphisms in FcγRs alter their affinity for human IgG1 and have been linked to clinical response. • A polymorphism in the FCGR3A gene results in either a valine or phenylalanine at position 158 of FcγRIIIa. • Human IgG1 binds more strongly to FcγRIIIa-158V than FcγRIIIa- 158F, and likewise to NK cells from individuals that are either homozygous for 158F or heterozygous for this polymorphism. • The FcγRIIIa-158v was a predictor of early response and was associated with improved PFS. • Thus these data suggest that modulating the affinity of MAbs for FcγRIIIa, FcγRIIa, or both may increase the efficacy of therapeutic MAbs.
  • 40.
  • 41. COMPLEMENT-DEPENDENT CYTOTOXICITY • MAbs can recruit the complement cascade to kill cells via CDC. • IgG1 is extremely efficient at fixing complement, in contrast to IgG2 and IgG4. • Antibodies activate complement through the classical pathway, by engaging multiple C1q to trigger activation of a cascade of serum proteases, which kill the antibody-bound cells.
  • 42. CDC
  • 43. • These are mAbs in which two immunoglobulin chains of differing specificity have been fused into a single antibody molecule. • This allows the antibody to bring two different antigens (eg, two proteins) into close physical proximity, which in turn may carry out a new function BIFUNCTIONAL ANTIBODIES (aka "bispecific" antibodies)
  • 44. Examples: ● Emicizumab binds to two coagulation factors (factor IXa and factor X) ● Catumaxomab binds to the T-cell surface molecule CD3 and epithelial cell adhesion molecule (EpCAM), a tumor cell surface marker; it also has an Fc region that can bind to an Fc receptor on macrophages, natural killer (NK) cells, or dendritic cells. Efficacy has been shown in malignant ascites. ● Blinatumomab binds to CD3 on T cells and the cell surface protein CD19, present on precursor B-cell acute lymphoblastic leukemia (ALL) cells, potentially recruiting cytotoxic T cells to kill the ALL cells.
  • 45. IMMUNOCONJUGATES • MAbs that are not capable of directly eliciting antitumor effects, either by altering signal transduction or directing immune system cells, can still be effective against tumors by delivering cytotoxic payloads. • MAbs have been employed to deliver a wide variety of agents, including chemotherapy, toxins, radioisotopes, and cytokines . Antibody Drug Conjugates : • Gemtuzumab ozogamicin (Mylotarg) • Ado-trastuzumab emtansine (T-DM1) • Brentuximab vedotin (SGN-35, Adcetris)
  • 46. RADIOIMMUNOCONJUGATES • Two anti-CD20 radioimmunoconjugates have been FDA approved in non-Hodgkin lymphoma (NHL). • Ibritumomab (Zevalin) and tositumomab (Bexxar) are murine MAbs labeled with yttrium-90 (90Y) and iodine-131 (131I), respectively. • Both are associated with impressive clinical efficacy. • Although these radioimmunoconjugates are effective therapeutics, cumbersome logistics surrounding their administration have significantly limited their use.
  • 47.
  • 48.
  • 49. ANTIBODIES APPROVED FOR USE IN SOLID TUMORS
  • 50. • Targets HER2 protein • High affinity and specificity • 95% human, 5% murine • Decreased potential for immunogenicity. • Increased potential for recruiting immune effector mechanisms HER2 epitopes recognized by hypervariable murine antibody fragment Human IgG-1 TRASTUZUMAB
  • 51. OVEREXPRESSION (PROTEIN) AMPLIFICATION (DNA) IHC FISH • 25% of breast cancers • 7% to 34% of gastric cancers.
  • 52. Trastuzumab: 1 target 4 mechanisms of action Prevention o f fo rm at io n o f p95HER2 Inhibition o f c e l l p ro l i fe ra t i o n Activation o f ADCC Inhibition o f HER2-regulated angiogenesis Prevention of formation of p95HER2 Inhibition of c e l l proliferation Activation of ADCC Inhibition of HER2-regulated angiogenesis
  • 53. HER2 HerceptinTumour c e l l + ADCCNK c e l l FcgRIII • Once bound t o HER2, the Herceptin Fc domain rec ru its immune c e l l s t o ta rg e t and d e s t ro y the tumour Herceptin ADCC is a key mechanism of Herceptin’s antitumour activity in vivo ADCC FcgRIII • Once bound to HER2, the Herceptin Fc domain recruits immune cells to target and destroy the tumour
  • 54. Indications : • Metastatic breast cancer (Her 2 +) - First line therapy in combination with paclitaxel - Second/third line therapy as single agent • Early stage Breast cancer – adjuvant therapy in node + • Metastatic gastric or gastroduodenal junc Adenoca - Alone with cisplatin or capecitabine and 5-FU Dosage : • Weekly : 4mg/kg loading f/b 2mg/kg • 3 weekly : 8mg/kg loading dose f/b 6mg/kg maintenance dose
  • 55. Side Effects : • Infusion related symptoms • Mild GI toxicity • Cardiotoxicity- dyspnea,peripheral edema,decreased LV function • Pulmonary toxicity – cough , dyspnea Caution !!! • Baseline cardiac function evaluation and monitoring every 3 months • Withold drug -if > 16% Absolute decrease in LVEF from normal baseline value -patient develops clinically significant congestive heart failure
  • 56. PERTUZUMAB • Pertuzumab (Perjeta) is a humanized IgG1 MAb that binds to domain II of HER2 and blocks ligand- dependent dimerization of HER2 with other members of the EGFR family.
  • 57. Mechanism of action • Binding of pertuzumab to Her2 leads to inhibition of heterodimerisation of Her2 with other ‘Her’ family members • Inhibition of these heterodimerisation process leads to inhibition of downstream signalling pathways- MAPK,PI3K,this cell apoptosis • ADCC
  • 58. Indications : • Pertuzumab, in combination with trastuzumab and docetaxel, - -first-line therapy in HER2- positive metastatic breast cancer patients. • Combination therapy –neoadjuavnt in HER2-positive, locally advanced, inflammatory, or high-risk early breast cancer (>2 cm node negative or node positive). Dosage : • Initial dose -840mg iv • Maintenance dose 420mg 3 weekly
  • 59. Side Effects: • Fetal deaths • Cardiotoxicity - Withold drug if drop in LVEF < 45% or if LVEF -45-49% with >10% fall from baseline - Discontinue drug if cardiac function doesn’t improve after 3 weeks of discontinuation • Infusion related reactions • fatigue • Diarrhea, nausea,vomiting
  • 60. CLEOPATRA : • 808 patients • locally recurrent, unresectable, or metastatic breast cancer • trastuzumab plus docetaxel with or without the addition of pertuzumab. • Inclusion of pertuzumab increased the independently assessed PFS by 6.1 months from 12.4 to 18.5 (hazard ratio [HR], 0.62 (95% confidence interval [CI], 0.51, 0.75), p <0.0001], with a trend toward improved overall survival that reached statistical significance (p = 0.0008) after an additional year of follow-up. • The addition of pertuzumab did increase rates of grade 3 adverse events (AE), but it did not adversely affect cardiac function.
  • 61. • Four-arm, open-label phase II study of 417 patients randomized to receive trastuzumab plus docetaxel, pertuzumab plus docetaxel, pertuzumab plus trastuzumab, or the triple combination. • The triple combination improved the pathologic complete response (pCR) rate by 17.8% over the trastuzumab plus docetaxel arm (39.3% versus 21.5%) in the pertuzumab arm.
  • 62. ADO-TRASTUZUMAB EMTANSINE • It is an ADC composed of the anti-HER2 MAb trastuzumab linked to DM1, a highly potent derivative of maytansine, through a stable thioether linker
  • 63.
  • 64. • It is FDA approved for patients with HER2- positive metastatic breast cancer previously treated with trastuzumab and taxane chemotherapy. • EMILIA : In the international phase III study, there was a 3.2- month improved progression-free survival among patients that received T-DM1 compared to those receiving standard treatment with capecitabine and lapatinib. • The most common side effects in the trial were thrombocytopenia, transient transaminitis, as well as nausea, fatigue, myalgias and arthralgias.
  • 65. CETUXIMAB • This chimeric IgG1 binds to domain III of the EGFR, with roughly a tenfold higher affinity than normal ligands either EGF or transforming growth factor α (TGF-α) ligands and thereby inhibits ligand-induced activation of this tyrosine kinase receptor. • Cetuximab may also function to downregulate EGFR-dependent signaling by stimulating EGFR internalization.
  • 66. Indications : • Metastatic colorectal cancer (mCRC) –EGFR expressing cases along with irinotecan • Wild type KRAS-first line along with FOLFIRI in mCRC • Head and neck - concurrent with Radiation in locally advanced disease - Along with 5FU and cisplatin in recurrent locoregionally advanced or metastatic disease - Monotherapy for recurrent locoregionally advanced or metastatic disease progressing after platinum based therapy. Dosage : • 400mg/m2 loading dose f/b maintenace dose 250mg/m2 weekly • 500mg/m2 every 2 weeks without loading dose
  • 67. Side Effects : • Infusion reactions • Skin – pruritus,dry skin with pustular acneiform rash - mainly on face,neck and upper trunk - resolves on cessation • Pulmonary toxicity –ILD-cough,dyspnea and pulmonary infiltrates • Hypomagnesemia • Paronchial inflammation Treatment : • Skin rash – topical antibiotics-clindamycin/erythromycin - avoid sun exposure
  • 68. PANITUMUMAB • Fully human IgG2 monoclonal antibody that binds to EGFR. • • Binds with 40 fold higher affinity to EGFR than normal ligands and thus inhibits EGFR activation by blocking the binding of EGF and TGF-α. • Higher affinity than cetuximab
  • 69. Indications : • Monotherapy for advanced CRC followng FOLFIRI. • Monotherapy for advanced refractory disease in wild type KRAS mCRC • First line in wild type KRAS mCRC in combination with FOLFOX chemotherapy. Dosage : • 6mg/kg IV every 2 weeks or • 2.5mg/kg every week Side Effects : • Similar to cetuximab • Less infusion reactions compared to cetuximab
  • 70. NECITUMUMAB • Recombinant human IgG1 monoclonal antibody against EGFR
  • 71. Indications : • First line treatment of metastatic squamous NSCLC along with gemcitabine and cisplatin Dosage : • 800mg iv on day 1 and day 8 of a 21 day cycle Side Effects: • Infusion reactions • Pruritus,dry skin • Cardiopulmonary arrest • Hypomagnesemia • Increased risk of venous and arterial thromboembolism
  • 72. BEVACIZUMAB • It is a humanized monoclonal antibody targeting VEGF. • The inhibition of VEGF signaling via bevacizumab treatment may normalize tumor vasculature, promoting a more effective delivery of chemotherapy agents.
  • 73. Indications and Dosage : • Glioblastoma (GBM) – progressive disease (10mg/kg 2 wkly) • mCRC –along with 5FU in first line therapy (5mg/kg 2 wkly) • Non-squamous- NSCLC – along with paclitaxel and carboplatin (15mg/kg 3 weekly) • mRCC – along with interferon alpha (10mg/kg 2 wkly) • Persistent, recurrent, or metastatic cervical cancer (CC) (15mg/kg 3 weekly) • Platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer (prOC) • Advanced CRC –along with capecitabine – (7.5mg/kg 3wkly)
  • 74. Side Effects : • Gastrointestinal perforation and delayed wound healing • Bleeding complicatios – epistaxis • Arterial thromboembolic events • Hypertension – 5-18% • Proteinuria with nephrotic syndrome • Infusion related reactions • RPLS Caution !!! • Atleast 28days after any surgical procedure • Therapy terminated if patient develop nephrotic syndrome. interupted if proetinnuria > 2gm/24hrs. • Discontinue if hypertensive crisis develops • Pateints with recent hemoptysis > 1/2tsp of blood shouldn’t recive bevacizumab
  • 75. RAMUCIRUMAB • Recombinant fully human IgG1 against VEGFR 2 • Thus inhibition of VEGFR mediated signaling leading to reduced endothelial permeability , migration and proliferation.
  • 76. Indications and Dosage : • Advanced metastatic CRC –along with FOLFIRI after progression with FOLFOX/XELOX plus bevacizumab 8mg/kg 2weekly with FOLFIRI • Advanced metastatic gastric cancer-monotherapy or with paclitaxel after progression on flouropyrimidine or platinum chemotherapy ( 8mg/kg 2 weekly) • Advanced metastatic NSCLC – with docetaxel after disease progreesion with platinum based chemotherapy. (10mg/kg 3 weekly with docetaxel) Side Effects : • Similar to bevacizumab • hypothyroidism
  • 77. DENOSUMAB • Denosumab (Xgeva) is a fully human IgG2 monoclonal antibody that binds human RANK ligand (RANKL) with high affinity and specificity
  • 78.
  • 79.
  • 80. Dosage Forms : • 60mg sc every 6 months • 120mg sc every 4 weeks Indications : • Adults and skeletally mature adolescents who have either surgically unsalvageable giant cell tumors of the bone (GCTB) • Supportive care settings to reduce bone metastasis-related skeletal-related events (SRE). • To increase bone mass in prostate cancer and breast cancer patients at high risk for bone fracture due to hormone-ablation therapies
  • 81. Adverse Effects Hypocalcemia, hypophosphatemia, GI upset, arthralgia/back ache, headache, increased risk of infection, Osteonecrosis of the Jaw, atypical fracture Monitoring Calcium, phosphorus and magnesium Bone mineral density Counseling : • Must be kept in refrigerator until prior to injection • Remove from refrigerator ~15-30 minutes prior to injection • Patient must take supplemental calcium and vitamin D to maintain adequate serum calcium levels during therapy
  • 82. DARATUMUMAB • IgG1-k human monoclonal antibody against CD38 which is a surface glycoprotein expressed on multiple myeloma cells
  • 83. Indications : • Multiple myeloma who have received at least 3 prior lines of therapy including a proteosome inhibitor and an immunomodulatory agent or who are double refractory to a proteosome inhibitor and an immunomodulatory agent. Dosage : 16mg/kg on weekly for week 1-8 ,then Every 2 weeks for weeks 9-24 Every 4 weeks from week 25 till disease progression
  • 84. Side Effects : • Myelosuppression • Infusion reactions • Nasal congestion • Arthralgias • Increased risk of infections Caution !!! • Give oral corticosteroid 20mg methylprednisolone -day 1 and 2 of therapy • Inform blood transfusion centres – false positive coombs test , can persist upto 6 months after last therapy. • Prophylaxis for herpes zoster
  • 86. RITUXIMAB • Binds to a CD20 protein on the surface of B cells and causes destruction of B cells • >90% of NHL and leukemias
  • 88. Indications and Dosage : • Relapsed/refractory low grade FL,B cell NHL as single agent – 375mg/m2 weekly • CD20+ follicular ,NHL – Along with chemotherapy – 375mg/m2 day1 of chemotherapy • Maintenance therapy – In FL/ CD20+ NHL – 375mg/m2 every 8 weeks upto 12 doses • DLBCL - 375mg/m2 day1 of chemotherapy • CLL – 375mg/m2 one day before 1ST cycle chemo (FC) cycle 2-6 – 500mg/m2 on day 1 • Non-progressing (including stable disease), low-grade, CD20-positive, B- cell NHL as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy. – 375mg/mm2 weekly for 4 weeks at 6 month intervals for maximum of 16 doses.
  • 89. Side Effects : • Infusion related reactions • Tumor lysis syndrome • Skin reactions – -pemphigus , stevens johnsons syndrome,lichenoid dermatitis and toxic epidermal necrolysis -occurs 1-2 weeks following drug treatment • Arrhythmias and chest pain Caution !!! • Infusion related deaths- risk factors-female gender,pre existing pulmonary disease,CLL or mantle cell lymphoma • If high tumor burden ,the first dose can be split into two doses • If severe skin reactions – stop further therapy
  • 90. OFATUMUMAB • It is a fully human IgG1-K monoclonal antibody that binds to novel epitope of CD20 which encompasses small extracellular loop. • Mediates antibody dependent cellular cytotoxicity (ADCC) and stronger complement dependent cellular cytotoxicity (CDCC) when compared to rituximab. Indications: • Refractory CLL-to fludaribine and alemtuzumab • Relapsed CLL- combination with fludarabine and cyclophosphamide • Relapsed or refractory follicular ,B-NHL
  • 91.
  • 92. Dosage Range : • Untreated CLL- Cycle 1 - 300mg on day 1 , 100mg on day 8 Cycle 2 – 1000mg D1 -4 weekly -12 cycles • Refractory CLL – 300mg –D1 followed 1 week later by 2000mg weekly for 7 doses,followed 4 weeks later by 2000mg every 4 weekly for 4 doses Side Effects : • Infusion reactions • Myelosuppression – neutropenia and thrombocytopenia • PML • Increased risk of bacterial,fungal and viral infections
  • 93. OBINUTUZUMAB • Novel glycoengineered type II anti CD20 monoclonal antibody with higher affinity for CD20 than rituximab
  • 94. Indications : • Previously untreated CLL-along with chlorambucil Cycle 1 – 100mg – D1 900mg – D2 1000mg -- D8 and D15 Cycle 2 – 6 , 1000mg D1 • Follicular lymphoma- relapsed/refractory to Rituximab containing regimen Cycle 1 – 1000mg –D1 ,D8 and D15 Cycle 2 – 6 , 1000mg D1 1000mg every 2 months for 2 yrs
  • 95. Side Effects : • Infusion related reactions • Myelosuppression with neutropenia and thrombocytopenia • PML • Hepatitis B reactivation • Increased risk of bacterial ,viral and fungal infections Caution !!! • Withold antihypertensive Rx for 12hrs prior to obinutuzumab infusion. • Screen patients for HBV infection • Don’t give in patients with active infection as serious bacterial , fungal and new or reactivated viral infections.
  • 96. ALEMTUZUMAB • Alemtuzumab (Campath-1H) targets the CD52 glycopeptide, which is highly expressed on T and B lymphocytes.
  • 97. Indications : • relapsed or refractory B-cell CLL-who have been treated with alkylating agents and who have failed fludarabine therapy • T-cell prolymphocytic leukemia-who failed first line Dosage : • 30mg/day iv three times per week for a maximum of 12 weeks • Administered as 2hr iv infusion Side Effects: • Infusion related • Immunosuppresion—increased incidence of oppurtunistic infections-penumocystis,candida,cyptococcus • Myelosuppression-neutropenia > anemia and thrombocytopenia
  • 98. BRENTUXIMAB VEDOTIN Brentuximab vedotin (SGN-35, Adcetris) is an CD30 directed ADC that is made up of three components : Approximately 4 molecules of MMAE are conjugated to each antibody molecule.
  • 100. Indications : • Systemic, chemotherapy-refractory anaplastic large-cell lymphomas (sALCL) • Hodgkin lymphoma who have progressed after an autologous stem cell transplant (ASCT). Patients ineligible for ASCT must have failed two prior multidrug chemotherapy regimens. • Post autologous stem cell transplant consolidation for patients with hodgkins lymphoma at high risk of relapse or progression.
  • 101. Dosage : 1.8mg/kg iv every 3 wks Side effects : • Infusion related reactions • Peripheral neuropathy Incidence 55% Resolution or improvement in 88% after BV • Fatigue • Myelosuppresion – Neutropenia and anemia • Nausea ,vomiting , Diarrhea - mild • Progressive multifocal leucoencephalopathy
  • 102. CYTOKINE RELEASE SYNDROME • CRS is a severe immune reaction that occurs in response to immunotherapy for certain cancers (eg, lymphoid malignancies), in which positive feedback leads to progressive elevation in inflammatory cytokines by T lymphocytes • It can occur in response to a therapeutic mAb or other immune-based therapies such as chimeric antigen receptor (CAR)-T cells. • Presentation : fever, headache, nausea, malaise, hypotension, rash, chills, dyspnea, and tachycardia. Elevations in serum aminotransferases and bilirubin can be seen, and, in some cases, disseminated intravascular coagulation (DIC), capillary leak syndrome, • The largest risk factor for CRS is tumor load. The antibodies most likely to cause CRS are those that promote T-lymphocyte activation.
  • 104. • Prophylaxis for CRS (eg, premedication with acetaminophen and diphenhydramine) is sometimes incorporated into therapy protocols. • Management of CRS depends on the severity and may include interruption of the infusion, symptomatic treatment, intravenous fluids, and ventilator and/or pressor support. • The mAb tocilizumab, directed against interleukin (IL)-6, has been effective in treating CRS related to chimeric antigen receptor (CAR)-T cells, which, unlike an mAb, cannot be discontinued once they have been infused.

Editor's Notes

  1. An IgG molecule is typically divided into three domains consisting of two identical antigen-binding (Fab) domains connected to an effector or Fc domain by a flexible hinge sequence. Figure 29.1 shows the structure of an IgG molecule. IgG antibodies are comprised of two identical light chains and two identical heavy chains, with the chains joined by disulfide bonds, resulting in a bilaterally symmetrical complex. The Fab domains mediate the binding of IgG molecules to their cognate antigens and are composed of an intact light chain and half of a heavy chain. Each chain in the Fab domain is further divided into variable and constant regions, with the variable region containing hypervariable, or complementarity determining regions (CDR) in which the antigen-contact residues reside. The light and heavy chain variable regions each contain three CDRs (CDR1, CDR2, and CDR3). All six CDRs form the antigen-binding pocket and are collectively defined in immunologic terms as the idiotype of the antibody. In the majority of cases, the variable heavy chain CDR3 plays a dominant role in binding
  2. Fab fragments and single-chain antibodies — The use of antibody fragments instead of full-length antibodies may enhance pharmacokinetic properties and/or the efficiency of penetration into tissues or tumor masses (since fragments are smaller) .
  3. DM4-Ravtansine,soravtansine
  4. VEGF is a critical determinant of tumor angiogenesis, a process that is a necessary component of tumor invasion, growth, and metastasis. VEGF expression by invasive tumors has been shown to correlate with vascularity and cellular proliferation and is prognostic for several human cancers.
  5. Inhibits growth of cd38 expressing tumor cells by inducing apoptosis directly through fc crosslink and adcc Myeloid
  6. CD20 antigen expressed during early pre B cell devlopment until plasma cell stage
  7. Inhibits cell activation and cell cycle progression