Despite the many advances in the treatment of hematological malignancies over the past decade, outcomes in refractory lymphomas remain poor. One potential strategy in this patient population is the specific targeting of IL-2R-α (CD25), which is over-expressed on many lymphoma and leukemic cells, using antibody drug conjugates (ADCs). ADCT-301 is an ADC composed of human IgG1 HuMax®-TAC against CD25, stochastically conjugated through a dipeptide cleavable linker to a pyrrolobenzodiazepine (PBD) dimer warhead with a drug-antibody ratio (DAR) of 2.3. ADCT-301 binds human CD25 with picomolar affinity. ADCT-301 has highly potent and selective cytotoxicity against a panel of CD25-expressing human lymphoma cell lines. Once internalized, the released warhead binds in the DNA minor groove and exerts its potent cytotoxic action via the formation of DNA interstrand cross-links. A strong correlation between loss of viability and DNA cross-link formation is demonstrated. DNA damage persists, resulting in phosphorylation of histone H2AX, cell cycle arrest in G2/M and apoptosis. Bystander killing of CD25-negative cells by ADCT-301 is also observed. In vivo, a single-dose of ADCT-301 results in dose-dependent and targeted antitumor activity against both subcutaneous and disseminated CD25-positive lymphoma models. In xenografts of Karpas 299, which expressed both CD25 and CD30, marked superiority over brentuximab vedotin (Adcetris®) is observed. Dose-dependent increases in DNA cross-linking, -H2AX and PBD payload staining were observed in tumors in vivo indicating a role as relevant pharmacodynamic assays. Together these data support the clinical testing of this novel ADC in patients with CD25-expressing tumors.
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