Safety and antitumor activity of recombinant soluble Apo2 ligand

TLDR

TNF and Fas ligand induce apoptosis but are too toxic, whereas Apo2 ligand (TRAIL) can trigger tumor cell apoptosis and is expressed in many tissues, suggesting it may spare normal cells. The study aimed to evaluate Apo2L’s therapeutic potential by producing a potent soluble form in bacteria. A recombinant soluble Apo2L was produced in bacteria to yield a potently active protein. In vitro, normal cells were resistant and Apo2L showed cytostatic or cytotoxic effects on 32 of 39 cancer cell lines; in vivo, repeated IV injections in primates were non‑toxic, and in mice Apo2L reduced tumor incidence, induced apoptosis, suppressed progression, improved survival, and synergized with 5‑FU or CPT‑11 to achieve tumor regression or complete ablation, demonstrating potent anticancer activity with minimal toxicity.

Abstract

TNF and Fas ligand induce apoptosis in tumor cells; however, their severe toxicity toward normal tissues hampers their application to cancer therapy. Apo2 ligand (Apo2L, or TRAIL) is a related molecule that triggers tumor cell apoptosis. Apo2L mRNA is expressed in many tissues, suggesting that the ligand may be nontoxic to normal cells. To investigate Apo2L's therapeutic potential, we generated in bacteria a potently active soluble version of the native human protein. Several normal cell types were resistant in vitro to apoptosis induction by Apo2L. Repeated intravenous injections of Apo2L in nonhuman primates did not cause detectable toxicity to tissues and organs examined. Apo2L exerted cytostatic or cytotoxic effects in vitro on 32 of 39 cell lines from colon, lung, breast, kidney, brain, and skin cancer. Treatment of athymic mice with Apo2L shortly after tumor xenograft injection markedly reduced tumor incidence. Apo2L treatment of mice bearing solid tumors induced tumor cell apoptosis, suppressed tumor progression, and improved survival. Apo2L cooperated synergistically with the chemotherapeutic drugs 5-fluorouracil or CPT-11, causing substantial tumor regression or complete tumor ablation. Thus, Apo2L may have potent anticancer activity without significant toxicity toward normal tissues.