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

Abstract

• SGN-CD19B is broadly active in vitro against malignant B-cell lines, including doublehit and triple-hit lymphoma cell lines.• SGN-CD19B shows significant antitumor activity in vivo in preclinical models of B-NHL and B-cell-derived acute lymphoblastic leukemia.Patients with relapsed/refractory B-cell malignancies such as non-Hodgkin lymphoma (B-NHL) or acute lymphoblastic leukemia 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 with 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 mg/kg (3 mg/kg drug equivalents); combination with rituximab decreased the curative dose to 100 mg/kg (1 mg/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 1 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 cross-linking 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.

CD19-targeted immunotherapies for treatment of patients with non-Hodgkin B-cell lymphomas

“…SGN-CD19B has been preclinically evaluated in 3 murine B-NHL models as a single agent and in combination with rituximab. Durable tumor regression was observed in all three models and were enhanced in the rituximab combination therapy [33].…”

Loncastuximab tesirine, an anti-CD19 antibody-drug conjugate, in relapsed/refractory B-cell acute lymphoblastic leukemia

“…Loncastuximab tesirine is a novel CD19-targeted humanized ADC delivering SG3199, a potent cytotoxic DNA minor groove interstrand cross-linking PBD dimer warhead. 11,15 In this open-label, dose-escalation, phase 1 trial, 35 patients with R/R B-ALL received loncastuximab tesirine in the dose-escalation portion of the study.…”

Perspectives of Fc engineered antibodies in CD19 targeting immunotherapies in pediatric B-cell precursor acute lymphoblastic leukemia

“…2 In addition, CD19 antibody drug conjugates (ADC) are tested in clinical trials. 18-20 In our opinion, Fc engineered antibodies may offer certain advantages over blinatumomab or CD19 CAR T cells because Fc engineered antibodies are easy to apply and show only limited toxicity.…”