Toxicology and pharmacokinetic studies in mice and nonhuman primates of the nontoxic, efficient, targeted hexameric Fasl: CTLA4-FASL

Efi Makdasi, Shira Amsili, Alexandra Aronin, Tatyana B. Prigozhina, Kobi Tzdaka, Yosi Meir Gozlan, Liat Ben Gigi–Tamir, Jitka Yehudith Sagiv, Fanny Shkedy, Noam Shani, Mark L. Tykocinski, Michal Dranitzki Elhalel*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Cytotoxic T-lymphocyte antigen 4 (CTLA4)-FasL, a homo-hexameric signal converter protein, is capable of inducing robust apoptosis in malignant cells of the B-cell lineage expressing its cognate B7 and Fas targets, while sparing nonmalignant ones. This fusion protein's striking proapoptotic efficacy stems from its complementary abilities to coordinately activate apoptotic signals and abrogate antiapoptotic ones. A limiting factor in translating FasL or Fas receptor agonists into the clinic has been lethal hepatotoxicity. Here, we establish CTLA4-FasL's in vivo efficacy in multiple murine and xenograft models, for both systemic and subcutaneous tumors. Significantly, good laboratory practice (GLP) toxicology studies in mice indicate that CTLA4-FasL given repeatedly at doses up to five times the effective dose was well-tolerated and resulted in no significant adverse events. An equivalent single dose of CTLA4-FasL administered to nonhuman primates was also well-tolerated, albeit with a moderate dose-dependent leukopenia that was completely reversible. Interestingly, monkey peripheral blood mononuclear cells were more sensitive to CTLA4-FasL–induced apoptosis when tested in vitro. In both species, there was short-term elevation in serum levels of IL6, IL2, and IFNg, although this was not associated with clinical signs of proin-flammatory cytokine release, and further, this cytokine elevation could be completely prevented by dexamethasone premedication. Liver toxicity was not observed in either species, as confirmed by serum liver enzyme levels and histopathologic assessment. In conclusion, CTLA4-FasL emerges from animal model studies as an effective and safe agent for targeted FasL-mediated treatment of B7-expressing aggressive B-cell lymphomas.

Original languageAmerican English
Pages (from-to)513-524
Number of pages12
JournalMolecular Cancer Therapeutics
Issue number2
StatePublished - Feb 2020
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2020 American Association for Cancer Research.


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