Practice question

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