Practice question

Antibody-drug conjugates engineered targeted chemotherapy combining precision monoclonal antibody recognition lethal payload potency too toxic systemic administration alone narrow therapeutic index causing severe myelosuppression neuropathy. Monoclonal antibody component typically humanized IgG1 kappa 150 kDa produced CHO cells reduced fucosylation enhancing Fc gamma receptor affinity binds tumor-associated antigen nanomolar affinity CD30 120 kDa TNFRSF8 Hodgkin Reed-Sternberg anaplastic large cell HER2 185 kDa tyrosine kinase amplified breast adenocarcinoma CD33 67 kDa sialic acid-binding Ig-like lectin AML blasts undergoing rapid receptor-mediated internalization clathrin-mediated endocytosis forming early endosome pH 6.0 trafficking lysosome pH 4.5 acidic hydrolases cathepsin B L cleaving linker releasing drug. Cytotoxic cargo microtubule inhibitors MMAE 718 Da synthetic dolastatin 10 analog binding vinca site near beta-tubulin interface preventing polymerization causing mitotic arrest G2/M maytansinoid DM1 DM4 binding near vinblastine site suppressing dynamic instability DNA minor groove alkylator calicheamicin gamma1 double-strand breaks Bergman cyclization diradical abstracting deoxyribose hydrogens. Linker chemistry governs stability plasma cleavable valine-citrulline dipeptide substrate cathepsin B para-aminobenzyl carbamate self-immolative spacer disulfide reduced glutathione enriched tumor noncleavable SMCC thioether requiring complete antibody degradation generating lysine adduct retaining potency. Average drug-antibody ratio 3.5-4 balanced maintaining solubility pharmacokinetics delivering sufficient payload conjugation