Brentuximab vedotin (sgn 35)
Post on 12-Nov-2014
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Brentuximab Vedotin (SGN-35)A new option for relapsed lymphoma patients
Christian Schwarm
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Anaplastic Large-Cell Lymphoma
T-cell based, lymphatic cancer Subtle symptoms lead to late stage
diagnoses Most common in young males Hallmark cells, CD30 positive Treatment: Chemotherapy (CHOP) Inital cure rate 70-80%
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Hodgkin‘s Lymphoma
B-cell based lymphatic cancer
Usually confined to lymphoid tissues
Primarily affects young people
Reed-Sternberg cells, CD30 positive
Treatment: Chemotherapy
(ABVD,BEACOPP) Radiation therapy
~ 85% patients cured Relapses usually require
stem cell transplants
NOTABLE CASES
Delta Goodrem Michael C. Hall
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Using antibodies in cancer therapy
Monoclonal antibodies alone (i.e. Rituximab)- not very effective unless combined with normal chemotherapy
Linked to radioisotopes Antibody-drug conjugate (ADC)
- deliver agent to target cells- highly toxic agents can be used- current focus of research- SGN-35
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SGN-35
SGN-35:modified monoclonal antibody
Carries microtubule inhibitor (MMAE)
Induces apoptosis through CD30 binding
Figure 1: Structure and pathway of actionof SGN-35
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Why make CD30 the target?
Limited expression on healthy tissues High expression levels in Hodgkin‘s
lymphoma and anaplastic large cell lymphoma (ALCL)
Important role on signaling pathway for cell survival (NF-κB activation)
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Biological activity of SGN-35 I NF-κB indirectly
inhibited=> Apoptosis
Introduction of
MMAE stops proliferation
Acts on cancer cell environmentFigure 2: Induction of apoptosis in CD30+ cells by SGN-35
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Biological activity of SG-35 II
MMAE diffuses into microenvironment- HRS cells surrounded by supportive CD4+ T-Cells (act as T-regulatory cells)
HRS cells posess constituitively activated NF-κB- no induction of apoptosis- stimulus to proliferate vs. activity of MMAE
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Successful treatment
B.Vedotin significantly increases response rate
At most effective dose:-HL: 34% CR, 40% PR- ALCL: 57% CR,30%PR
Increases chance of succesful stem cell transplant
Figure 3: Overall response of Hodgkin‘s Lymphoma and ALCL to different dosesof SGN-35 Hodgkin‘s Lymphoma ALCL
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Further benefits
Reduced side effects to standard chemotherapy or radiation
Current studies using SGN-35 in combination with standard chemotherapy to reduce toxicity of treatment in primary disease
Less toxic alternative in non-curative situations
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References
Katz J, Janik J, Younes A (2011)., Brentuximab Vedotin, Clin Cancer Res 2011; 17:6428-6436
Stein H, Foss H-D, Dürkop H, Marafioti T, Delsol G, Pulford P, Falini B (2000)., CD30+ anaplastic large cell lymphoma: a review of ist histopathologic, genetic and clinical features, Blood 2000; 96:3681-3695
Constans M, Sureda A, Terol M, Arranz R, Caballero M, Iriondo A, Jarque I, Carreras E, Moraleda J, Carrera D, León A, López A, Albó C, Díaz-Mediavilla J, Fernández-Abellán P, García-Ruiz J, Hernández-Navarro F, Mataix R, Petit J, Pascual M, Rifón J, García-Conde J, Fernández-Ranada J, Mateos M, Sierra J, Conde E (2003)., Autologous stem cell transplantation for primary refractory Hodgkin‘s disease: results and clinical variables affecting outcome, Annals of Oncology 14: 745-751
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