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Therapeutic potential of SGN-CD19B, a PBD-based anti-CD19 drug conjugate, for treatment of B-cell malignancies

Maureen C. Ryan, Maria Corinna Palanca-Wessels, Brian Schimpf, Kristine A. Gordon, Heather Kostner, Brad Meyer, Changpu Yu, Heather Van Epps and Dennis Benjamin

Key points

  • SGN-CD19B is broadly active in vitro against malignant B-cell lines, including double-hit and triple-hit lymphoma cell lines

  • SGN-CD19B shows significant anti-tumor activity in vivo in preclinical models of B-NHL and B-ALL

Abstract

Patients with relapsed/refractory B-cell malignancies such as non-Hodgkin lymphoma (B-NHL) or acute lymphoblastic leukemia (B-ALL) have a poor prognosis. Despite measurable clinical activity with new targeted therapies, many patients do not achieve a complete or durable response suggesting an opportunity to improve upon existing therapies. Here we describe SGN-CD19B, a pyrrolobenzodiazepine (PBD)-based anti-CD19 antibody drug conjugate (ADC) being investigated for treatment of B-cell malignancies, which has improved potency compared to other ADCs. CD19-expressing tumor cells rapidly internalize SGN-CD19B and the released PBD drug induces DNA damage, resulting in G2-M cell cycle arrest and cell death. SGN-CD19B demonstrated activity against a broad panel of malignant B-cell lines and induced durable regressions in mice bearing xenografts derived from these B-cell malignancies. A single dose of SGN-CD19B induced durable regressions at 300 mcg/kg (3 mcg/kg drug equivalents); combination with rituximab decreased the curative dose to 100 mcg/kg (1 mcg/kg drug equivalents). These doses are significantly lower than the level of drug required with other ADC payloads. In cynomolgus monkeys, SGN-CD19B effectively depleted CD20+ B-lymphocytes in peripheral blood and lymphoid tissues confirming that SGN-CD19B is pharmacodynamically active at well-tolerated doses. In summary, preclinical studies show SGN-CD19B is a highly active ADC, which releases a DNA-crosslinking agent rather than a microtubule-inhibitor. The distinct mechanism of action, broad potency and potential to combine with rituximab suggest that SGN-CD19B may offer unique clinical opportunities in B-cell malignancies. A Phase 1 clinical trial is in progress to investigate the therapeutic potential of SGN-CD19B in relapsed/refractory B-NHL [NCT02702141].

  • Submitted April 12, 2017.
  • Accepted August 28, 2017.