CD70-restricted specific activation of TRAILR1 or TRAILR2 using scFv-targeted TRAIL mutants

Abstract

To combine the CD27 stimulation inhibitory effect of blocking CD70 antibodies with an antibody-dependent cellular cytotoxicity (ADCC)-independent, cell death-inducing activity for targeting of CD70-expressing tumors, we evaluated here fusion proteins of the apoptosis-inducing TNF family member TRAIL and a single-chain variable fragment (scFv) derived from a high-affinity llama-derived anti-human CD70 antibody (lαhCD70). A fusion protein of scFv:lαhCD70 with TNC-TRAIL, a stabilized form of TRAIL, showed strongly enhanced apoptosis induction upon CD70 binding and furthermore efficiently interfered with CD70-CD27 interaction. Noteworthy, introduction of recently identified mutations that discriminate between TRAILR1 and TRAILR2 binding into the TRAIL part of scFv:lαhCD70-TNC-TRAIL resulted in TRAIL death receptor-specific fusion proteins with CD70-restricted activity.

Quantitative analysis of cell surface antigen-antibody interaction using Gaussia princeps luciferase antibody fusion proteins

“…[9][10][11][12][13][14][15] Accordingly, various scFvGpL and GpL-TNFSF ligand fusion proteins proved to be highly suitable for cellular binding studies and tracer applications. We therefore evaluated whether GpL-tagging is also applicable and useful for conventional antibodies.…”

ATVB Distinguished Scientist Award

“…201–205 The constitutive activation of effector T cells by persistent antigen and constitutive signaling via CD27/CD70 interaction leads to exhaustion, demonstrated in patients suffering from B cell non-Hodgkin’s lymphoma. 206 Exhausted T cells are less cytotoxic and incapable of attacking the tumor.…”

Inhibition of IRE1 modifies effect of glucose deprivation on the expression of TNF?-related genes in U87 glioma cells

“…An important role in TNFα signaling is played by a cytokine TNFSF7/CD70, a ligand for TNFRSF27/CD27, which can specifically activate of TRAIL receptors and induce proliferation [36,37]. Its expression is significantly increased in renal cell carcinoma relative to normal kidney tissue [38].…”

“…Moreover, microRNA-30c-2-3p down-regulates of TRADD and CCNe1 in breast cancer and leads to negative regulation of NF-κB signaling as well as cell cycle progression [33]. Great significance in TNFα signaling belongs to cytokine TNFSF7/CD70, a ligand for TNFRSF27/CD27, which can specifically activate TRAIL receptors and induce proliferation [36,37]. Its expression is significantly increased in renal cell carcinoma relative to normal kidney tissue [38].…”