Drozitumab, a human antibody to death receptor 5, has potent anti-tumor activity against rhabdomyosarcoma with the expression of caspase-8 predictive of response

Wednesday, October 26, 2011 — Poster Session III
10:00 a.m. – Noon	Natcher Conference Center	NCI	CLIN/CULT/AGING/DISPREV-12

Authors

• ZG Kang
• JJ Chen
• YK Yu
• B Li
• SY Sun
• BL Zhang
• L Cao

Abstract

We evaluated the efficacy and selectivity of drozitumab, a death receptor DR5-targeted therapeutic antibody, in RMS preclinical models. A panel of 11 RMS cell lines was used for in vitro studies and selected RMS cell lines were also evaluated in mice tumor modes. The molecular marker predictive of response to drozitumab was interrogated. We report that DR5, but not DR4, persisted at high levels and on the surface of all RMS cell lines. Drozitumab was effective in vitro against the majority of RMS cell lines and there was a strong correlation between caspase-8 expression and the sensitivity to drozitumab, which induced the rapid assembly of DISC and the cleavage of caspase-8 only in sensitive cells. More importantly, caspase-8 catalytic activity was both necessary and sufficient for mediating the sensitivity to drozitumab. Furthermore, drozitumab had potent anti-tumor activity against established RMS xenografts with a specificity predicted from the in vitro analysis. Our study provides the first preclinical evaluation of the potency and selectivity of a death receptor antibody in rhabdomyosarcoma. Drozitumab is effective, in vitro, against the majority of RMS cell lines that express caspase-8 and, in vivo, may provide long-term control of RMS.

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