Abstract
Patients with relapsed or refractory B-cell non-Hodgkin lymphoma (r/r NHL) have a poor prognosis. Despite measurable clinical activity seen with new targeted therapies, most r/r NHL patients do not achieve a complete or durable response suggesting there is room to improve upon existing clinical candidates.
Here we describe SGN-CD19B, a new CD19-targeted antibody-drug conjugate (ADC), which demonstrates potent preclinical activity against B-cell malignancies. SGN-CD19B is composed of a humanized antibody (hBU12ec) conjugated to a DNA-cross linking pyrrolobenzodiazepine (PBD) dimer drug (SGD-1882) via a protease-cleavable linker. Fluorescence microscopy studies showed that SGN-CD19B is rapidly internalized and traffics to lysosomes within hours of binding to CD19-positive tumor cell lines. Following uptake, SGN-CD19B induces DNA damage as measured by phosphorylation of histone 2AX. This damage subsequently leads to G2-M cell cycle arrest, caspase-3/7 activation, formation of cleaved poly ADP-ribose polymerase and cell death.
The antitumor activity of SGN-CD19B was evaluated in preclinical studies using lymphoma and leukemia cell lines. In vitro cytotoxicity studies showed that SGN-CD19B was highly active on a broad panel of CD19+ tumor cell lines with IC50 values ranging from 0.007 to12 ng/ml. SGN-CD19B displayed compelling anti-tumor activity in 4 separate xenograft models of B-cell malignancies including two models of diffuse large B-cell lymphoma (NHL-DLCL2 and RL), one model of Burkett's lymphoma (Ramos) and one model of B-cell acute lymphoblastic leukemia (B-ALL; Nalm-6). Amongst the NHL xenograft models, SGN-CD19B induced significant, dose-dependent tumor growth delay and survival benefit at ≥100 mcg/kg. At 300 mcg/kg, 100% of treated mice achieved complete and durable tumor regressions in 3 of 3 lymphoma models tested. In a disseminated model of B-ALL, a significant dose-dependent increase in survival was observed in mice treated with ≥10 mcg/kg of SGN-CD19B. At 100 mcg/kg, 10/10 mice survived for >115 days while the maximal survival for untreated and control groups was ≤37 days.
The ability of SGN-CD19B to deplete normal B-cells was examined in conjunction with single-dose toxicology studies in monkeys. SGN-CD19B was tolerated up to 250 mcg/kg without severe toxicity. Reductions in peripheral CD20+ B-lymphocytes were observed at dose levels as low as 10 mcg/kg and higher. The magnitude and duration of B cell depletion was dose-dependent. CD20+ B-lymphocytes were also depleted from lymphoid tissues, which showed minimal to marked, dose-dependent decreases in the number and size of lymphoid follicle germinal centers at doses ≥30 mcg/kg. Normal lymphoid architecture was restored within 16 weeks and circulating CD20+ B-lymphocytes returned to normal levels within 8-12 weeks of dosing.
Together, these data demonstrate that SGN-CD19B exhibits antitumor activity against a broad panel of CD19+ B-cell malignancies and causes durable remissions in preclinical models of NHL and B-ALL. SGN-CD19B is pharmacodynamically active in cynomolgus monkeys, resulting in 100% depletion of CD20+ B-lymphocytes at well-tolerated doses. Clinical trials are planned to further evaluate SGN-CD19B in r/r NHL.
Disclosures
Ryan: Seattle Genetics, Inc.: Employment. Schimpf:Seattle Genetics, Inc.: Employment. Anderson:Seattle Genetics,Inc: Employment. Zeng:Seattle Genetics, Inc: Employment. Emmerton:Seattle Genetics, Inc.: Employment. Miyamoto:Seattle Genetics, Inc.: Employment. Kostner:Seattle Genetics, Inc.: Employment. Yu:Seattle Genetics, Inc.: Employment. Van Epps:Seattle Genetics, Inc.: Employment. Tatalick:Seattle Genetics, Inc.: Employment. Benjamin:Seattle Genetics, Inc: Employment.
Targeted Therapies in Adult B-Cell Malignancies