rituximab in n - isfahan university of medical sciences · rituximab chimeric antibodies ......

Rituximab in N.SDr. Alaleh Gheissari

Prof. of Pediatrics

Pediatric Nephrologist

IUMS

Monoclonal Antibodies

”4

◉ 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.

5

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.




◉ 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.

8



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Mechanism Of Action

1- Complement-

dependent

cytotoxicity

2- Antibody-

dependent cellular

cytotoxicity

3- Induction of

apoptosis

11

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

12

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

13

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.

14

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.

15

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.

16

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.

17

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.

18

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




◉ 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

23

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

24

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

25

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

26

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.

27

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.

28

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.

29

• 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.

30

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

32

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.

33

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

34

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

35

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

rituximab in n - isfahan university of medical sciences · rituximab chimeric antibodies ......

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