A Multi-center, Double-blinded, Randomized, Placebo-controlled, Phase II Study to Evaluate the Safety, Tolerability and Efficacy of a Topical Application of DLX105 Onto Lesional Skin in Patients With Mild-to-moderate Psoriasis Vulgaris

In this study, the safety, tolerability and efficacy of DLX105 administered topically onto the psoriatic lesion of mild-to-moderate psoriasis patients will be investigated.

Start Date01 Aug 2013

Sponsor / Collaborator

Cell Medica Switzerland AG

EUCTR2013-001885-41-DE / Not yet recruitingNot Applicable

A multi-center, double-blinded, randomized, placebo-controlled, phase II study to evaluate the safety, tolerability and efficacy of a topical application of DLX105 onto lesional skin in patients with mild-to-moderate psoriasis vulgaris

Start Date11 Jul 2013

Sponsor / Collaborator

Cell Medica Switzerland AG

NCT01624376 / CompletedPhase 2

A Randomized, Double-blind, Placebo-controlled Phase I/IIa Study in Patients With Abdominal or Perianal Fistulizing Crohn's Disease to Explore the Safety, Tolerability and Preliminary Efficacy of Locally Administered DLX105.

The primary objective of this study is to investigate the safety and tolerability of locally administered DLX105 in treating enterocutaneous fistulas in Crohn's Disease patients.
The study will consist of a screening period of approx. 2 weeks, a 4-week treatment period and a 2-week follow-up period. An end-of study visit is scheduled on Day 43, 2 weeks after the last study visit.

Start Date01 Jun 2012

Sponsor / Collaborator

Cell Medica Switzerland AG

100 Clinical Results associated with Cell Medica Switzerland AG

0 Patents (Medical) associated with Cell Medica Switzerland AG

Literatures (Medical) associated with Cell Medica Switzerland AG

01 Jul 2018·Cancer Research

Abstract 4: Antitumor activity of DLX1008, a single chain antibody fragment binding to VEGF-A, in in vivo preclinical models of Kaposi sarcoma and glioblastoma

Author: Eason, Anthony B. ; Szabó, Emese ; Droste, Miriam ; Sin, Sang-Hoon ; Dittmer, Dirk P. ; Shamshiev, Abdijapar ; Phillips, Douglas J. ; Weller, Michael

AbstractBackground:Angiogenesis mediated by vascular endothelial growth factor (VEGF) is a hallmark of several cancers. Efficacy of VEGF inhibitors could be increased by improving affinity or tumor penetration, for example by reducing the size of the drug. Recently, the exceptionally stable anti-VEGF single chain variable fragment (scFv) brolucizumab (RTH258, ESBA1008, Novartis) completed phase 3 clinical trials in ophthalmology and was shown to be more efficacious than the larger aflibercept. The same molecule, named DLX1008, is currently in pre-clinical development in gliobastoma and Kaposi sarcoma (KS) by Cell Medica. KS is the most angiogenic cancer known to date. Carcinogenesis is induced by KS-associated herpesvirus (KSHV) and compromised of endothelial cells expressing high levels of VEGFR. KS is unique because angiogenesis (growth of non-tumor endothelial cells) as well as proliferation of the primary tumor cells are dependent on VEGF. No VEGF antagonist has yet been demonstrated to unequivocally improve overall survival in either KS or glioblastoma, which may be due to limited tumor penetration.Methods:Binding affinity to VEGF-A was determined by kinetic exclusion assay (KinExA).For in vivo studies, we used the L1T2 model of KS, whereby KSHV-positive human cells (L1T2/ ATCC® VR-1802™) are implanted subcutaneously onto NGS mice, and the U87 model of glioblastoma, where human glioblastoma cells (U87/ ATCC® HTB-14™) are implanted subcutaneously or intracranially onto SWISS nude mice. Tumor growth was followed by caliper measurements and pathology evaluated by histochemistry or imaging.Results:DLX1008 binds to VEGF-A165 with a KD of 1.05 pM. Bevacizumab binds with a KD of 32.4 pM. Hence, the affinity of DLX1008 to human VEGF is around 30-fold tighter than that of bevacizumab.DLX1008 reduced growth of L1T2 cells in vivo (p ≤ 0.007 by mixed effects model, n = 10) compared to vehicle control at 15 mg/kg once daily 5x/week and (p≤0.001, n = 10) in a second biological repeat. Imaging showed that the tumor died from the inside out in response to DLX1008. DLX1008 reduced the growth of U87 cells subcutaneously implanted in vivo (p ≤ 0.0021 by ANOVA, n = 10) and improved median survival of mice intracranially implanted with U87 cells (p ≤ 0.00026) compared to control scFv at 50 mg/kg twice daily. Staining of intracranial U87 tumors showed decreased CD31-positive blood vessel density as well as decreased p-VEGFR1 immunoreactivity in vascular structures and glioma cells.Conclusions:The high affinity, highly stable scFv DLX1008 shows highly reproducible anti-tumor activity in in vivo preclinical models of KS and glioblastoma. Efficacy was attributable to reduced angiogenesis. Its small size offers advantages in tissue penetration and distribution as compared to bevacizumab. DLX1008 is an excellent antibody to advance into clinical trials.Citation Format: Anthony B. Eason, Sang-Hoon Sin, Emese Szabó, Douglas J. Phillips, Miriam Droste, Abdijapar Shamshiev, Dirk P. Dittmer, Michael Weller. Antitumor activity of DLX1008, a single chain antibody fragment binding to VEGF-A, in in vivo preclinical models of Kaposi sarcoma and glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4.

01 May 2018·Journal of Pharmacology and Experimental TherapeuticsQ3 · MEDICINE

Antitumor Activity of DLX1008, an Anti-VEGFA Antibody Fragment with Low Picomolar Affinity, in Human Glioma Models

Q3 · MEDICINE

Article

Author: Weller, Michael ; Marti, Andrea ; Szabó, Emese ; Phillips, Douglas J ; Shamshiev, Abdijapar ; Droste, Miriam ; Kretzschmar, Titus

Angiogenesis mediated by vascular endothelial growth factor (VEGF) is a hallmark of glioblastoma. Based on the response rate and improved progression-free survival, although not on overall survival, the 149-kDa anti-VEGF-A IgG antibody bevacizumab (Avastin) has been approved in the United States and Japan for recurrent glioblastoma and in Japan for newly diagnosed glioblastoma; however, it is not approved in the EU. Here we characterize the biologic activity of DLX1008, a 26-kDa anti-VEGF-A single-chain antibody fragment that shows 30-fold stronger affinity to human VEGF-A than bevacizumab. The small molecular size of DLX1008 is predicted to result in improved target coverage over bevacizumab. DLX1008 showed superiority to bevacizumab in the inhibition of VEGF-A binding to VEGF receptor (VEGFR) 1 in enzyme-linked immunosorbent assay by a factor of around 10 and comparable efficacy for the inhibition of VEGF-A-stimulated VEGFR2 dimerization. In a tube-formation assay with human cerebral microvascular endothelial cells, DLX1008 was at least as active as bevacizumab. In vivo, DLX1008 delayed growth in a mouse subcutaneous U87 xenograft model (P = 0.0021) and improved survival in a mouse orthotopic U87 xenograft model (P = 0.00026). Given the exceptionally high affinity and small molecular size of DLX1008, these data warrant further clinical development of DLX1008 as an antiangiogenic agent in glioblastoma.

100 Deals associated with Cell Medica Switzerland AG

100 Translational Medicine associated with Cell Medica Switzerland AG

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Drug(Targets)	Indications	Global Highest Phase

DLX-105 ( TNF-α )	Uveitis More	Discontinued
DLX-2751 ( TNF-α )	Hidradenitis Suppurativa More	Pending
Therapeutic Antibody Fragments(Cell Medica Switzerland Ag) ( VEGF )	Neoplasms More	Pending
DLX-2560 ( TNF-α )	Skin Diseases More	Pending
DLX-521 ( ALK )	Solid tumor More	Pending

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