Rituximab in N - Isfahan University of Medical Sciences · Rituximab Chimeric Antibodies ......
Transcript of Rituximab in N - Isfahan University of Medical Sciences · Rituximab Chimeric Antibodies ......
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Rituximab in N.SDr. Alaleh Gheissari
Prof. of Pediatrics
Pediatric Nephrologist
IUMS
Monoclonal Antibodies
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◉ An antibody produced by a
single clone of cells is called
monoclonal antibody: A
PURE TYPE of ANTIBODY
◉ This kind of proteins are used
by immune system to identify
and neutralize foreign
objects.
”
◉ Derived from a single B cell
clone.
◉ No Batch to Batch
variations. Effectiveness of
Ab is much more
predictable.
◉ Enable the development of
secure immunoassay
systems.
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RituximabChimeric Antibodies
◉ In one approach, mouse DNA
encoding the binding portion of
a monoclonal antibody was
merged with human antibody-
producing DNA in living cells,
and the expression of this
chimeric DNA through cell
culture yielded partially mouse,
partially human monoclonal
antibody
.
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Rituximab
◉ Rituximab is a chimeric
monoclonal antibody of the
immunoglobulin G1 (IgG1) sub-
class, comprising a murine
variable region (Fab region) and a
human constant region (Fc
region)6
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Rituximab◉ Directed against the B-
cell specific antigen CD20
expressed only by pre-B
and mature B cells.
◉ Hematopoietic stem cells
and plasma cells are
spared due to their lack
of the CD20 antigen;
thus, serum
immunoglobulin levels
typically remain stable.
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◉ CD20 is suspected to play a
significant role in the
regulation of cell-cycle
initiation and differentiation
of the B-cell lineage, evident
by a rapid B-cell depletion
after treatment, which can be
maintained for 6 to 12
months.
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Mechanism Of Action
1- Complement-
dependent
cytotoxicity
2- Antibody-
dependent cellular
cytotoxicity
3- Induction of
apoptosis
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Mechanism Of Action
In addition to a direct depletion of B cells by various mechanisms, rituximab
may also act on other immune cells such as:
◉ Autoreactive T-effector cells,
◉ Regulatory T cells,
◉ Monocyte-derived macrophages
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Mechanism Of Action
With an increased understanding of the intricate interaction between B
cells and other immune cells, rituximab therapy may be used to
indirectly:
◉ Decrease the production of T-cell modulating cytokines,
◉ Interfere with the presentation and processing of autoantigens,
◉ Reduce activation of autoreactive T cells
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Mechanism Of Action
◉ B‐cell depletion by rituximab may block T‐cell activation induced by
B cells or B‐cell‐derived factors
◎ Results in change of T‐cell cytokine production responsible for the
development of nephrotic syndrome.
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Mechanism Of Action
More simply, B‐cell depletion by rituximab may reduce B‐cell cytokines
responsible for the development of nephrotic syndrome.
B‐cell depletion by rituximab may also change regulatory T‐cell functions,
inducing changes in T‐ and B‐cell cytokine production.
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Adverse Effects1- Mild, infusion-
related reactions that
manifest as fever,
chills, headache,
weakness, nausea,
pruritus, and rash
2- Increased
infections
3- Black box warnings:
◉ Tumor lysis syndrome,
◉ Fatal infusion
reactions,
◉ Severe
mucocutaneous
reactions:
Stevens-Johnson Syndrome and
Toxic Epidermal Necrolysis.
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Adverse Effects◉ Hepatitis B reactivation,
◉ Progressive multifocal leuko-encephalopathy infection,
◉ Hypersensitivity reactions (such as anaphylaxis, serious pulmonary
events, cardiac arrhythmias, and renal failure),
◉ Hematological abnormalities (cytopenias and hemolytic anemia),
◉ Gastrointestinal perforation and obstruction.
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Adverse Effects◉ Formation of human anti-chimeric antibodies (HACAs).
◉ The development of HACAs has been seen at a higher incidence in
patients with autoimmune diseases when compared to those with
lymphoma.
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Nephrotic Syndrome
◉ Unclear Pathogenesis
◉ The most common chronic glomerular disease in children
◉ Approximately 80 % : Minimal Change Nephrotic Syndrome,
◉ Mostly SSNS
◉ Up to 50 % of these SSNS patients, develop frequently
relapsing nephrotic syndrome (FRNS) ◎ four relapses per year or at least two within 6 months of the initial
presentation 19
N.S
Pathogenesi
s20
Old
◉ Primarily a disorder of T cell
function
◉ Impaired T-regulatory Function
Old and New
Concepts New
◉ Maintaining T cell activation in
autoimmune diseases
◎ B cells induce T cell
activation,
◎ Mediate antibody-
independent autoimmune
damage,
◎ Express costimulatory
molecules and cytokines21
Rituximab induced B-Cell
Depletion◉ B cell apoptosis,
◉ Antibody-dependent
cellular cytotoxicity or
phagocytosis,
◉ Suppressing interactions
between B cells and T
cells
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◉ Treg cells induce remission
in nephrotic syndrome
◉ Rituximab enhances the
number and function of Treg
cells
◎ Rituximab maintenance
of remission in patients
with nephrotic
syndrome is due to the
restoration of T-reg22
Researches in Rituximab
◉ Uncontrolled studies in small cohorts suggest that rituximab may
induce disease remission in forms of INS unresponsive to
prednisone and calcineurin inhibitors
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Change of the course of steroid‐dependent nephrotic
syndrome after rituximab therapy.Benz K, et al. Pediatr. Nephrol. 2004; 19: 794–7.
◉ Rituximab treatment for SDNS with idiopathic thrombocytopenic
purpura (ITP) induced long‐term remission in both nephrotic
syndrome and ITP
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Rituximab treatment for (PTLD) induces complete
remission of recurrent nephrotic syndrome.
Nozu K et al. Pediatr. Nephrol. 2005; 20: 1660–63
◉ Rituximab treatment for recurrent nephrotic syndrome with
post‐transplant lymphoproliferative disorder (PTLD) after renal
transplantation induced a long‐term remission in both nephrotic
syndrome and PTLD
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Rituximab therapy in early recurrent focal segmental
sclerosis after renal transplantation.
Apeland et al. Nephrol. Dial. Transplant. 2008; 23: 2091–4.
◉ Reported a case of sustained remission after rituximab in children
with early recurrent nephrotic syndrome after renal transplantation
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Rituximab in patients with the steroid‐resistant nephrotic
syndrome.
Bagga et al. N. Engl. J. Med. 2007; 26: 2751–2.
◉ Treated five children with refractory SRNS with rituximab and four
patients had complete remission.
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Rituximab for refractory focal segmental
glomerulosclerosis.
Nakayama at al. Pediatr. Nephrol. 2008; 23: 481–5
◉ Rituximab induced complete remission in two children with
refractory SRNS with FSGS.
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Successful treatment of collapsing FSGS with a
combination of rituximab, steroids and ciclosporin.
Kaito et al. Pediatr. Nephrol. 2010; 25: 957–9
◉ Kaito et al. reported the efficacy of rituximab for refractory
SRNS with collapsing FSGS.
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• Gilbert et al. Pediatr. Nephrol. 2006
Hofstra et al. Nephrol. Dial. Transplant. 2007
Smith GC. Pediatr. Nephrol. 2007
◉ Rituximab induced long‐term remission at substantial rates
in children with refractory FRNS/SDNS.
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Rituximab in Children with Resistant Idiopathic Nephrotic
Syndrome, Controlled Trial Study
J Am Soc Nephrol. 2012 Jun; 23(6): 1117–1124
◉ 31 eligible assigned to receive rituximab in double doses in
addition to prednisone and calcineurin inhibitors and were
compared with 15 patients randomly assigned to standard therapy
◉ These data do not support the addition of rituximab to prednisone and
calcineurin inhibitors in children with resistant idiopathic nephrotic
syndrome 31
Rituximab in children with steroid-dependent nephrotic
syndrome.
Horebeek et al. Acta Clinica Belgica, 2017
◉ RTX was an effective and safe therapeutic option in our cohort of
children with difficult-to-treat SDNS, resulting in a significant
reduction of yearly relapses in the absence of severe adverse
events and facilitating the reduction of other immunosuppressive
medication
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Rituximab efficacy in pediatric patients with refractory
nephrotic syndrome.Alaifan et al. Int J Res Med Sci. 2017
◉ The effectiveness of rituximab is most observed in steroid
depended nephrotic syndrome patients since it decreases the
frequency of relapses and steroid dependency.
◉ However, it has been shown that it is less effective in steroid
resistant nephrotic syndrome cases and was associated with
significant numbers of relapses.
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The efficacy of rituximab in treatment of childhood SRNS,
SDNS: A systematic review and Meta-analysis.
Mohammadjafari et al. J Pediatr Rev. 2013;1(2)2-12
◉ RTX was an effective and safe therapeutic option in our cohort of
children with difficult-to-treat SDNS, resulting in a significant
reduction of yearly relapses in the absence of severe adverse
events and facilitating the reduction of other immunosuppressive
medication
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Rituximab seems to be
an effective new
treatment for childhood
refractory nephrotic
syndrome.
Rituximab is a promising
treatment for
complicated FRNS/
SDNS in children.
patients treated with
rituximab in the
RNRNS01 trial had
relapsed by 19 months
after randomization
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Zytux v.s MabThera
◉ The first batch of Zytux™, the
biosimilar, with generic name of
Rituximab was launched in Iran
market on 18 January 2014 by
Aryogen Biopharma.
◉ International Journal of Hematology-
Oncology and Stem Cell Research 2018.
12(2):84-91.
◉ A Double-Blind, Randomized
Comparison Study between Zytux™ vs
MabThera® in Treatment of CLL with
FCR Regimen: Non-Inferiority Clinical
Trial. Toogeh et al
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