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#CD30

2 public questions tagged with this topic.

Immunological Applications

Brentuximab vedotin targets:

CD30 antigen also designated TNFRSF8, 120 kDa type I transmembrane glycoprotein member tumor necrosis factor receptor superfamily characterized by cysteine rich domains extracellularly and TRAF binding motifs intracellularly activating NF-kB, transiently expressed on activated B and T lymphocytes but constitutively highly expressed on Reed-Sternberg giant cells of classical Hodgkin lymphoma and anaplastic large cell lymphoma ALCL, and small subset cutaneous T cell lymphomas, making near tumor specific target with minimal normal tissue expression limited to activated immune cells conferring favorable safety margin. Brentuximab vedotin pioneered antibody-drug conjugate class, comprising chimeric anti-CD30 IgG1 antibody cAC10 variable regions murine grafted onto human constant selected for high internalization rate, conjugated via protease-cleavable valine-citrulline dipeptide plus PABC self-immolative spacer to monomethyl auristatin E synthetic analogue of marine natural product dolastatin 10 derived from sea hare Dolabella auricularia that binds tubulin at vinca domain inhibiting polymerization. This mechanistic insight supports diagnostic and therapeutic applications while reinforcing core immunological and cell biology principles taught in advanced curricula.

Ref: Younes et al NEJM 2010 363:1812 Brentuximab vedotin CD30 MMAE valine citrulline; Seattle Genetics Adcetris approval.

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Immunological Applications

Brentuximab vedotin targets:

Brentuximab vedotin Adcetris exemplifies first approved CD30-directed antibody-drug conjugate transforming management Hodgkin lymphoma systemic anaplastic large cell lymphoma peripheral T-cell lymphoma uniformly expressing CD30 TNFRSF8 120 kDa type I transmembrane signaling TRAF1 TRAF2 TRAF5 activating NF-kB MAPK promoting survival malignant clone. Murine chimeric cAC10 IgG1 human constant murine variable binds ECD residues 19-38 affinity 5 nM complex rapidly internalizes 2-4h CD30-mediated clathrin-dependent endocytosis delivering conjugate lysosomal compartment acidic pH proteases degrade antibody. Each antibody conjugated average four molecules MMAE synthetic analog dolastatin 10 sea hare Dolabella auricularia via protease-cleavable valine-citrulline linker para-aminobenzyl carbamate self-immolative spacer stable plasma half-life 4-6 days cleaved cathepsin B enriched tumor lysosomes releasing free MMAE permeable membranes intracellular. MMAE binds tubulin beta at vinca domain inhibiting polymerization 13 protofilament microtubules suppressing dynamic instability arresting cells G2/M checkpoint activating spindle assembly checkpoint BubR1 Mad2 causing Bcl2 phosphorylation ser70 inactivating antiapoptotic mitochondrial outer membrane permeabilization cytochrome c Smac DIABLO caspase-3 apoptosis intrinsic. Membrane-permeable payload diffuses neighboring CD30-negative supporting reactive cells microenvironment bystander killing enhancing debulking mixed infiltrate characteristic Hodgkin histology few malignant Reed-Sternberg surrounded inflammatory cells. Pivotal phase 2 showed 75 percent objective response 34 percent CR relapsed

Ref: FDA Adcetris Brentuximab Vedotin CD30 Target Label Mechanism; NEJM Brentuximab Hodgkin Lymphoma Efficacy 2012 Younes et al; Trail ADC CD30 Mechanism Review.

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