Fig. 7.

Tumor regression by treatment with anti-DR5 mAb KMTR2 in vivo. (A) Growth suppression and tumor regression of established T98SQ1 xenografts by fully human anti-DR5 mAbs, E11 and KMTR2, respectively, in vivo. Nude mice (9 per each group) were injected subcutaneously with 2 × 10⁶ T98SQ1 cells and were allowed to establish tumors. From postimplantation Day 20, mice were treated with either anti-DR5 mAb E11 or KMTR2 (5 mg/kg) or control non-specific human IgG (DNP), administered i.p. daily for 3 consecutive days. Square, control DNP; diamond, E11; circle, KMTR2. Data are shown as the mean ± SE. ***P < .001 (DNP vs E11; DNP vs KMTR2). The experiment was repeated independently 2 times with similar results. (B) Effect of fully human anti-DR5 mAb treatment on survival of mice bearing intracerebral T98SQ1 xenografts. Nude mice were injected intracerebrally with 5 × 10⁵ T98SQ1 cells and were treated from postimplantation Day 20 for 3 consecutive days as described in (A). Mice treated with KMTR2 were sacrificed at various time points and were found to carry no intracerebral tumor at any points. ***P < .001 (DNP vs KMTR2), **P = .003 (DNP vs E11) (log-rank test). The experiment was repeated independently 3 times with similar results. (C) Decreased proliferative activity (MIB-1 index) and increased apoptosis induction (TUNEL positivity) by KMTR2 treatment of T98SQ1 cells in xenografts. Nude mice with established subcutaneous xenografts derived from T98SQ1 cells were treated with either KMTR2 or DNP i.p. for 2 days and were sacrificed on the next day. Tumor tissues were harvested and subjected to either MIB-1 staining or TUNEL assay. (D) Treatment with KMTR2 induces multiple caspase activation in established T98SQ1 xenografts. Tumor lysates were prepared as described in (C) and were subjected to Western blot analyses. Caspase-9, caspase-3, and PARP, a substrate of activated caspase-3, were significantly cleaved upon treatment with KMTR2 but not by control DNP. FL, full length; CL, cleaved form.