A versatile pretargeting approach for tumour-selective delivery and activation of TNF superfamily members

作者：He Yuan; van Bommel Peter E; Samplonius Douwe F; Bremer Edwin; Helfrich Wijnand^*

来源：Scientific Reports, 2017, 7(1): 13301.

DOI：10.1038/s41598-017-13530-w

TNFR superfamily (TNFRSF) members have important immunoregulatory functions and are of clear interest for cancer immunotherapy. Various TNFRSF agonists have been clinically evaluated, but have met with limited efficacy and/or toxicity. Recent insights indicate that 'first-generation' TNFRSF agonists lack efficacy as they do not effectively cross-link their corresponding receptor. Reversely, ubiquitous TNFRSF receptor(s) cross-linking by CD40 and Fas agonistic antibodies resulted in dose-limiting liver toxicity. To overcome these issues, we developed a novel pretargeting strategy exploiting recombinant fusion proteins in which a soluble form of TRAIL, FasL or CD40L is genetically fused to a high-affinity anti-fluorescein scFv antibody fragment (scFvFITC). Fusion proteins scFvFITC: sTRAIL and scFvFITC: sFasL induced potent target antigen-restricted apoptosis in a panel of cancer lines and in primary patient-derived cancer cells, but only when pretargeted with a relevant FITC-labelled antitumour antibody. In a similar pretargeting setting, fusion protein scFvFITC: sCD40L promoted tumour-directed maturation of immature monocyte-derived dendritic cells (iDCs). This novel tumour-selective pretargeting approach may be used to improve efficacy and/or reduce possible off-target toxicity of TNFSF ligands for cancer immunotherapy.

• 出版日期2017-10-16