title: C-type lectin-like molecule-1 (CLL1)-targeted TRAIL augments the tumoricidal activity of granulocytes and potentiates therapeutic antibody-dependent cell-mediated cytotoxicity.
abstract: The therapeutic effect of anti-cancer monoclonal antibodies stems from their capacity to opsonize targeted cancer cells with subsequent phagocytic removal, induction of antibody-dependent cell-mediated cytotoxicity (ADCC) or induction of complement-mediated cytotoxicity (CDC). The major immune effector cells involved in these processes are natural killer (NK) cells and granulocytes. The latter and most prevalent blood cell population contributes to phagocytosis, but is not effective in inducing ADCC. Here, we report that targeted delivery of the tumoricidal protein tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to granulocyte marker C-type lectin-like molecule-1 (CLL1), using fusion protein CLL1:TRAIL, equips granulocytes with high levels of TRAIL. Upon CLL1-selective binding of this fusion protein, granulocytes acquire additional TRAIL-mediated cytotoxic activity that, importantly, potentiates antibody-mediated cytotoxicity of clinically used therapeutic antibodies (e.g., rituximab, cetuximab). Thus, CLL1:TRAIL could be used as an adjuvant to optimize the clinical potential of anticancer antibody therapy by augmenting tumoricidal activity of granulocytes.
authors.affiliation: a University of Groningen; University Medical Center Groningen (UMCG) ; Department of Surgery; Translational Surgical Oncology ; Groningen , The Netherlands.
authors.forename: Valerie R
authors.initials: VR
authors.lastname: Wiersma
authors.forename: Marco
authors.initials: M
authors.lastname: de Bruyn
authors.forename: Ce
authors.initials: C
authors.lastname: Shi
authors.forename: Marloes J M
authors.initials: MJ
authors.lastname: Gooden
authors.forename: Maartje C A
authors.initials: MC
authors.lastname: Wouters
authors.forename: Douwe F
authors.initials: DF
authors.lastname: Samplonius
authors.forename: Djoke
authors.initials: D
authors.lastname: Hendriks
authors.forename: Hans W
authors.initials: HW
authors.lastname: Nijman
authors.forename: Yunwei
authors.initials: Y
authors.lastname: Wei
authors.forename: Jin
authors.initials: J
authors.lastname: Zhou
authors.forename: Wijnand
authors.initials: W
authors.lastname: Helfrich
authors.forename: Edwin
authors.initials: E
authors.lastname: Bremer
mesh_terms: D000912:Antibodies, Neoplasm / Q000276:immunology* / Q000494:pharmacology; D000920:Antibody-Dependent Cell Cytotoxicity; D005260:Female; D006098:Granulocytes / Q000276:immunology*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D037181:Lectins, C-Type / Q000276:immunology*; D008297:Male; D008565:Membrane Proteins / Q000276:immunology*; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology*; D020298:U937 Cells
chemical_list: D000912:Antibodies, Neoplasm; C470184:CLECL1 protein, human; D037181:Lectins, C-Type; D008565:Membrane Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human
keywords: ADCC; ADCC, antibody-dependent cell-mediated cytotoxicity; ADCP, antibody-dependent cellular phagocytosis; CLL1; CLL1, C-type lectin-like molecule-1; TRAIL; TRAIL, TNF-related apoptosis-inducing ligand; antibody-therapy; granulocyte; leukocyte; scFv, single-chain variable fragment