Dreier, Nicole

Howald, AnnaBianca

Kretzschmar, Titus

Landi, Marco

Marti, Andrea

Molitor, Julia

Phillips, Douglas

Shamshiev, Japar

Steinwand, Miriam

Szabo, Emese

Weller, Michael

Winnewisser, Camilla

English

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N E U RO - O N CO LO G YAbstractsANGI-12. EFFICACY OF THE PENTRAwBODY DLX1008, AMONOVALENT ANTIBODY FRAGMENT WITH LOWPICOMOLAR AFFINITY TO VEGF-A, IN HUMAN GLIOMAMODELS IN VITRO AND IN VIVOEmese Szabo1, Douglas Phillips2, Japar Shamshiev2, Miriam Steinwand2,Nicole Dreier2, AnnaBianca Howald2, Marco Landi2, AndreaMarti2,Camilla Winnewisser2, Julia Molitor2, Titus Kretzschmar2, andMichaelWeller1; 1Laboratory ofMolecular Neuro-Oncology, Department ofNeurology, University Hospital and University of Zurich, Zurich,Switzerland; 2Delenex Therapeutics AG, Schlieren, SwitzerlandAngiogenesis mediated by vascular endothelial growth factor (VEGF) is ahallmark of glioblastoma. Moreover, VEGF may exert tumor-intrinsic sur-vival properties mediated both by VEGF receptors 1 and 2. Althoughvarious VEGF inhibitors have shown limited clinical activity in glioblastoma,notably determined by responses on neuroimaging and prolongation ofprogression-free survival (PFS), no VEGF antagonist has so far been demon-strated to unequivocally improve overall survival in any clinical setting in glio-blastoma. Based on response rates and improved PFS, although not overallsurvival (OS), the 149 kDa anti-VEGF-A IgG antibody bevacizumab(Avastinw) is approved in the US and Japan for recurrent glioblastoma andin Japan for newly diagnosed glioblastoma. However, it is not approved inthe EU. Here we characterize DLX1008, a 26 kDa anti-VEGF-A singlechain antibody fragment which binds with 22 pM and 27 pM affinity tomouse and human VEGF-A, respectively. In vitro, in a tube formation assaywith human cerebral microvascular endothelial cells (HCMEC), it was dem-onstrated that DLX1008 is at least as active as Avastinw. In addition,DLX1008 showed superiority to Avastinw in the inhibition of VEGF-Abinding toVEGF-R1 inELISAbya factorof around10. In vivo,DLX1008 sig-nificantly improved survival in amouse orthotopicU87 xenograftmodel com-pared to vehicle control (p ¼ 0.00026) and significantly inhibited tumorgrowth in a mouse subcutaneous U87 xenograft model compared to vehiclecontrol (p ¼ 0.0021). In summary, thesedatawarrant further clinical develop-ment of DLX1008 in a biomarker-driven approach to glioblastoma.DLX1008 may provide improved clinical benefit in glioblastoma, especiallyin overall survival, due to higher affinity and smaller size leading to improvedtumor penetration.Neuro-Oncology 17:v41–v44, 2015.doi:10.1093/neuonc/nov207.12Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2015.

ANGI-12EFFICACY OF THE PENTRA®BODY DLX1008, A MONOVALENT ANTIBODY FRAGMENT WITH LOW PICOMOLAR AFFINITY TO VEGF-A, IN HUMAN GLIOMA MODELS IN VITRO AND IN VIVO

http://doc.rero.ch/record/292481/files/nov207.12.pdf

ANGI-12EFFICACY OF THE PENTRA®BODY DLX1008, A MONOVALENT ANTIBODY FRAGMENT WITH LOW PICOMOLAR AFFINITY TO VEGF-A, IN HUMAN GLIOMA MODELS IN VITRO AND IN VIVO

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