TABLE 1

Preclinical and clinical therapeutics targeting death receptors

Molecular Target Reagent Principle Company/Reference Experimental Effects Clinical Trial/Status
TRAIL receptors HGS-ETR1 Agonistic TRAIL-R1 mAb HGSI/CAT Apoptosis induction in various tumor cell lines and tumor xenografts, synergistic with anticancer drugs Phase 2, no hepatic or hematological toxicity with up to 10 mg/kg i.v.
HGS-ETR2 Agonistic TRAIL-R2 mAb HGSI/CAT Apoptosis induction in tumor cell lines Phase 1
HGS-TR2J Agonistic TRAIL-R2 mAb HGSI/KNBWY Apoptosis induction in tumor cell lines Phase 1
PRO1762 Soluble human Apo2L/TRAIL Amgen/Genentech Apoptosis induction in tumor cell lines, no side effects in cynomolgus monkeys and mice, synergistic with anticancer drugs Phase 1
TRA-8 Agonistic TRAIL-R2 mAb Sankyo Co., Ltd. Apoptosis induction in tumor cell lines Preclinical
CD95/Fas CD95-Fc Humanized CD95 Fc-decoy construct ApoGenix Inhibition of CD95 signaling Preclinical, first intended for spinal cord injury
TNF Recombinant TNF-α Combination of TNF and chemotherapy Eggermont and ten Hagen, 2001 Apoptosis induction in tumor-associated blood vessels Approved for isolated limb perfusion therapy in melanoma
HUMIRA (Adalimumab) Recombinant human IgG1κ mAb against TNF-α CAT/Abbott Inhibition of TNF-α FDA approved for rheumatoid arthritis, psoriasis, ankylosing spondylitis, and Crohn's disease
Infliximab (Remicade) Mouse/human TNF-α antibody Centocor/Schering-Plough Anti-inflammatory, also induces apoptosis in macrophages FDA approved for rheumatoid arthritis and Crohn's disease
Enbrel (Etanercept) Recombinant TNF-R2/IgG fusion protein Amgen/Wyeth Anti-inflammatory in rheumatoid arthritis, Crohn's disease, and other inflammations Approved for United States, some patients with severe side effects (infections, neurologic, and hematologic disorders)
CDP571 Mouse/human TNF-α antibody Celltech Disappointing results in Crohn's disease Phase 3 for rheumatoid arthritis stopped
ISIS 104838 2′-O-Methoxyethyl antisense construct against TNF-α ISIS Improvement of rheumatoid arthritis-associated symptoms Phase 2 for rheumatoid arthritis, Crohn's disease, psoriasis