www.delenex.com ® PENTRA Body The Platform: Rapid Discovery of Highly Potent Femtomolar to Low Picomolar Antibody Fragments Nicole Dreier, Douglas Phillips, Japar Shamshiev, Miriam Steinwand, Verena Strassberger, Stefanie Grabulovski, Anna Bianca Howald, Marco Landi, Andrea Marti, Camilla Winnewisser, Julia Molitor, Titus Kretzschmar Delenex: The PENTRA®Body Company • • • Key Advantages of PENTRA®Bodies Clinical stage therapeutic antibody company, founded in 2009 Focused on dermatology and oncology Proprietary PENTRA®Body platform: highly attractive and validated • • Highly stable Highly potent (≤ 600 femtomolar (IL-1b)) without lengthy affinity maturation Small, excellent tissue penetration GMP production at low cost of goods Clinical study in dermatology established proof-of-concept of topical administration Safe and well tolerated • • • PENTRA®Bodies are: • Antibody fragments of about 25 kDa • Building blocks are single-chain format, can be assembled into other formats (e.g. IgG, Fab, bispecific) • Pipeline The ® PENTRA Body PENTRA®Bodies Standard mAb Other Antibody Fragments/Scaffolds Molecular weight 25 kDa 150 kDa < 20 kDa Plasma half-life ~1 day ~3 weeks ~minutes to hours high very low likely high fM to low pM pM nM no no required Tissue penetration Potency Affinity maturation Platform CDRs typically obtained by rabbit immunization; may also be obtained from library display, IgGs etc. Frameworks Product (Target) Indication DLX105 (TNFα) Psoriasis (intradermal) Psoriasis (topical) Hidradenitis Suppurativa Ophthalmology DLX2751 (TNFα) Lead Preclinic 1b/2a 2 Single B cell sorting completed Human spleen derived VLlinker-VH antibody library (> 107) completed Highly potent, highly stable 25 kDa humanized PENTRA®Bodies without affinity maturation ESBA105 Antigen-independent selection in yeast for highly stable VL / VH combinations Psoriasis (topical) Hidradenitis Suppurativa DLX2323/2681 Acne (IL-1β) Acute gout DLX3003 (IL-17A) Psoriasis DLX1008 (VEGF-A) Kaposi Sarcoma, Rosacea Oncology (Glioblastoma) Ophthalmology Protein-based immunization Laser Lymph node cell isolation Rapid screening for neutralizing antibodies Masterset of novel, very stable VL-linker-VH human antibody frameworks HRP Cells Anti-rabbit-IgG target RNA isolation RT-PCR Sequencing of VH & VL ESBA1008/RTH258 ELISA screening Signal Rabbit-IgG target VEGF: High Potency DLX1008 for Glioblastoma Two clinical studies performed: • Intradermal injection of anti-TNFα DLX105 • Local inhibition of TNFα gave a clinical response in mild-to-moderate plaque psoriasis • DLX105 has an excellent safety profile • Systemic exposure with anti-TNFα antibodies is obviously not required for a therapeutic effect in psoriasis • Study results offer an option for topical therapies based on antibodies • DLX1008 binds human and mouse VEGF-A with 27 and 22 pM monovalent affinities (KD), resp. DLX1008 (=ESBA1008, RTH258) is in phase II clinical trials in wet AMD (Novartis) High unmet medical need in glioblastoma Anti-VEGF IgG Avastin® (bevacizumab, Roche) approved for glioblastoma in US, but not in Europe • • • • Topical administration of anti-TNFα DLX105 • mRNA levels of key pro-inflammatory biomarkers were significantly decreased compared to placebo (e.g. TNFα, p< 0.001) • Clinical readout (PASI score) did not show a significant difference from placebo • The translation of these biological effects into a meaningful clinical response is dependent on the concentration of locally-deposited DLX105 and most likely requires improved penetration into deeper dermis • Longer treatment periods (as is the case for etanercept), increasing drug concentration in the dermis and/or a more potent follow-on anti-TNFα PENTRA®Body might result in clinical efficacy Binding of DLX1008 to human VEGF: Quartz Crystal Microbalance Coated DLX1008, VEGF165 as analyte DLX1008 expected to be superior to bevacizumab due to good tissue distribution and high affinity combined with its small size Fast to market approach identified, development started IL-17A: High Potency DLX3003 for Psoriasis • In vitro neutralization of IL-17A IC50 of ≤ 5.1 pM determined by highly sensitive cell-based assay (patent application filed) • 600 IL - 6 , p g /m l TNFα: Clinical Proof-of-Concept with DLX105 No affinity maturation required, 6 months from start to hit Topical treatment of mild-to-moderate psoriasis Use of anti-IL-17A PENTRA®Bodies beyond systemic anti-IL-17A IgG antibodies • • 400 D LX3003 c o n tro l s c F v 200 0 0 .1 1 10 100 1000 10000 100000 A n tib o d y , p M The single-chain anti-TNFα antibody DLX105 induces a clinical response in psoriasis patients when administered intradermally presented at the 41st Annual ADF meeting in Cologne, Germany, 2014, March 13 Patrick Brunner1, Athanasios Tsianakas2, Claudia Berger3, Georg Stingl1, Thomas Luger2, Thomas Jung3 1 Dept. of Dermatology, DIAID, Med. Univ. Vienna, Austria, 2 Dept. of Dermatology, Univ. Münster, Germany, 3 Delenex Therapeutics AG, Zürich, Switzerland IL-1β: ≤ 600 Femtomolar (IC50) DLX2681 PENTRA®Body 1 29 pM Outlook: 2 0 • • • PENTRA®Bodies can be formatted into 52 kDa bispecific format without any loss of potency Simultaneous binding to both targets Parallel neutralization of two targets offers benefits in a variety of diseases Prokaryotic expression suitable 100 1000 10000 100000 • • Reformatting Tendency towards smaller • antibody fragments in ADC field PENTRA®Body properties are ideal for ADCs: − small − tissue penetrating − high affinity PENTRA®Bodies allow sitespecific toxin conjugation a m u 100 100 100 22°C 100 100 100 37°C 100 99.6 99.3 IgG and Fab formats possible without any loss of potency 25 kDa PENTRA®Bodies • Have a unique combination of: − high stability − femtomolar to low picomolar potency − excellent tissue penetration − rapid discovery − solid patent protection • Are suitable building blocks for other formats e.g. bispecific constructs, ADCs • Are clinically validated in phase II studies tr n o 4°C C day 14 o n D LX2681 ki D LX2323 n day 7 b /k , ls 1 g 0 cF m v, g /k 1 g 0 m g /k g g g 1 0 1 m m g g /k /k g g /k m .1 A n tib o d y , p M g 10000 /k 1000 m 100 0 10 g 1 g 0 .1 /k 0 .0 1 g 0 0 a day 0 Summary As Building Blocks Antibody Drug Conjugates • 10 A n tib o d y , p M Bispecific PENTRA®Bodies • 1 30 pM ® PENTRA Bodies % monomer content (by HPLC analysis) after storage temperature 200000 0 .1 PENTRA®Body 500 a D LX105 Section 1 Title 400 0 PEN TR A Body 2 1000 800 1 ® 400000 Ila r is m ® PEN TR A Body 1 D LX2323 1500 g 600000 D LX2681 2000 1 800000 1200 C soluble TNFa • In vitro activity m IC50 In vitro neutralization of soluble TNFa In vivo efficacy: inhibition of human IL-1β induced IL-6 production in mice .1 Antibody 62 times more potent than canakinumab (Ilaris®, Novartis) Highly stable antibody fragment Potently inhibits hIL-1b induced inflammation in mice Potential indications for topical / systemic administration − Acne vulgaris − Flaring gouty arthritis − others, such as hidradenitis suppurativa 0 • • Substantially improved potency compared to DLX105 (factor of 10) Differences in inhibition of transmembrane TNFα Leads for confirmatory clinical studies in psoriasis • IL - 6 , p g /m l • IC50 of ≤ 600 fM: best-in-class • • PENTRA®Bodies C e ll s u r v iv a l TNFα: Next Generation • IL -6 , p g /m l Topical administration of the single-chain anti-TNFα antibody DLX105 suppresses TNFα and Th17 cytokines in psoriatic skin presented at the 44th Annual ESDR Meeting in Copenhagen, Denmark, 2014, September 11 Athanasios Tsianakas1, Patrick Brunner2, Kamran Ghoreschi3, Claudia Berger4, Karin Loser1, Martin Röcken3, Georg Stingl2, Thomas Luger1, Thomas Jung4 1 Dept. of Dermatology, Univ. Münster, Germany, 2 Dept. of Dermatology, DIAID, Med. Univ. Vienna, Austria, 3 Dept. of Dermatology, Univ. Tübingen, Germany, 4 Delenex Therapeutics AG, Zürich, Switzerland Delenex Therapeutics AG Wagistrasse 27 8952 Schlieren Zurich Switzerland www.delenex.com [email protected]