brentuximab vedotin (sgn 35)

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