2008
DOI: 10.1158/1078-0432.ccr-08-0670
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Cooperation of the Agonistic DR5 Antibody Apomab with Chemotherapy to Inhibit Orthotopic Lung Tumor Growth and Improve Survival

Abstract: Purpose: Apomab is a fully human monoclonal antibody that induces programmed cell death through the proapoptotic receptor DR5 in various cancer cells but not in normal cells. Several lung cancer cell lines express DR5 and exhibit apoptosis in response to apomab in vitro. Experimental Design: We investigated the efficacy of apomab and its interaction with chemotherapy in xenograft models based on human NCI-H460 non^small-cell lung carcinoma cells. In an established model of s.c. tumor xenografts, apomab or Taxo… Show more

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Cited by 51 publications
(42 citation statements)
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References 33 publications
(26 reference statements)
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“…The safety and tolerability of TRAIL-R2 agonists as single agents in these phase I studies provide a strong foundation for combining them with cytotoxic agents in future clinical trials. Multiple preclinical studies have shown that TRAIL-R2 agonists and chemotherapy or radiation act synergistically to reduce tumor burden in murine models of several solid tumors (14,15,46,47). Chemotherapy and radiation enhance the sensitivity of cancer cells to TRAIL receptor agonists by increasing the expression of TRAIL-R2 and/or Bax, thereby providing additional rationale for therapeutically targeting TRAIL-R2 (15,26,48).…”
Section: Discussionmentioning
confidence: 99%
“…The safety and tolerability of TRAIL-R2 agonists as single agents in these phase I studies provide a strong foundation for combining them with cytotoxic agents in future clinical trials. Multiple preclinical studies have shown that TRAIL-R2 agonists and chemotherapy or radiation act synergistically to reduce tumor burden in murine models of several solid tumors (14,15,46,47). Chemotherapy and radiation enhance the sensitivity of cancer cells to TRAIL receptor agonists by increasing the expression of TRAIL-R2 and/or Bax, thereby providing additional rationale for therapeutically targeting TRAIL-R2 (15,26,48).…”
Section: Discussionmentioning
confidence: 99%
“…The monoclonal antibody PRO95780 (Genentech) is a PARA that specifically targets DR5 (9,10). DR5 is expressed in a wide range of solid tumors and hematologic malignancies (4,(11)(12)(13).…”
mentioning
confidence: 99%
“…DR5 is expressed in a wide range of solid tumors and hematologic malignancies (4,(11)(12)(13). PRO95780 induces apoptosis in a variety of human cancer cell lines and xenograft models both alone and in combination with other antineoplastic agents, but has shown little deleterious effect in nonmalignant cell cultures (3,10,14). Preclinical modeling strongly suggested that the minimal efficacious serum concentration of PRO95780 would be 0.9 to 22 μg/mL, depending on the tumor type (14,15), and that trough concentration (C mins ) at the higher end of this concentration range would be achievable in humans at doses of 10 mg/kg or above administered every 3 weeks.…”
mentioning
confidence: 99%
“…In addition to stimulation by their respective ligands, proapoptotic receptors can be engaged by agonistic antibodies (14). DR5 agonist antibody (PRO95780) binds DR5 tightly and selectively, triggering apoptosis in various types of cancer cells and inhibiting tumor xenograft growth in vivo (15,16).IAP proteins represent the ultimate line of defense against cellular suicide by regulating caspase activity and preventing caspase activation (17). c-IAP1 and c-IAP2 are components of TNF receptor (TNFR) complexes where they modulate apoptotic signaling and caspase-8 activation (18 -20).…”
mentioning
confidence: 99%