Ab-XTEN & Ab-XTEN-Drug Conjugates    XTEN    • Long, tunable PK enables up to once-a-month dosing           Difficult to c...
AbFr-XTEN: Product Formats    Monovalent AbFr                                          IgG                        Drug Con...
XTEN Prevents Aggregation of scFv                Abs (215 nm)                                                Size Exclusio...
Bispecific scFv-XTEN-scFv                        EGFR   Her2    SDS/PAGE    160                                           ...
AbFr-XTEN Multimers    Binding site: anti-EGFR Vhh    Linker: 144AA                                                       ...
AbFr Multimers are Well-Behaved                                                                                           ...
Chemical Conjugation to scFv          XTEN                                          medium    short medium      long      ...
Cell Binding of aHer2-XTEN-AF          Isotype control          Trastuzumab block         XTEN288                        X...
Tumor Uptake of aHer2-XTEN                                   60                                                           ...
In Vivo Targeting                                                             IgG                                         ...
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Website antibodies

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  • VS2010_12_03 AX10_07
  • Website antibodies

    1. 1. Ab-XTEN & Ab-XTEN-Drug Conjugates XTEN • Long, tunable PK enables up to once-a-month dosing Difficult to conjugate • Long PK maximizes efficacy and minimizes toxicity Hydrophobic Low Drug Load • Clinically validated in 2 products Fc-receptor mis-targeting ADCC/CDC • Non-immunogenic Bivalent • Biodegradable (safer than PEG) Monospecific No EPR effect • 3 publications 4 protein chains Ab-XTEN • Genetic fusion to Ab fragments & mimetics Easy, specific conjugation Highly hydrophilic • scFv, dAbs, Darpins, Nanobodies, Centyrins, Adnexins, etc. High Drug Load • Single protein chain, manufactured in E. coli No FcR mis-targeting No ADCC/CDC Mono- or Multi-valent Ab-XTEN-Drug Mono- or Multi-specific EPR effect • Specific conjugation to cytotoxic drugs via free thiols 1 protein chain • Many available drugs to choose from • Drug release via linker cleavage or XTEN degradation1
    2. 2. AbFr-XTEN: Product Formats Monovalent AbFr IgG Drug Conjugate Target binding Cytokine Blockers Receptor Blockers Tumor-Drug Delivery Antiviral Bispecific AbFr C1 Binding Multifunctional Fusion Recycling ADCC Tumor-Specific Toxin Tumor-Specific IL2 Combination Products Immune activators • Large number of product opportunities • Common discovery platform2
    3. 3. XTEN Prevents Aggregation of scFv Abs (215 nm) Size Exclusion Chromatography Monomer aHer2 Dimer Volume (ml) XTEN stabilizes the scFv and thus enables clinical use of scFv3
    4. 4. Bispecific scFv-XTEN-scFv EGFR Her2 SDS/PAGE 160 aEGFR aHer2 110 1.0 Normalized Absorbance 60 Normalized Abs. (OD405 nm) GFP 0.5 20 Control 10 0.0 0.0001 0.01 1 100 10000 bscFc Concentration (nM) Versabody Concentration (nM) • High-affinity, specific binding to EGFR and Her2 • Single protein chain manufactured in E. coli4
    5. 5. AbFr-XTEN Multimers Binding site: anti-EGFR Vhh Linker: 144AA Monomer Tetramer Hexamer Dimer Monomer 220 kD 160 kD Dimer 110 kD 80 kD Tetramer Hexamer Single Chain, multivalent, half-life, expressed in E. coli cytoplasm5
    6. 6. AbFr Multimers are Well-Behaved EGFR Binding 1.6 B SA HRP Analytical SEC Profiles V Strept-HRP V EGFR-Fc 44 kDa 17 kDa 660 kDa 160 kDa 1.3 kDa 1.2 ELISA Signal GFP Anti-GFP 0.8 1 STD Monomer 0.4Normalized A215 Dimer 0.75 Tetramer Hexamer 0 0.5 Control Monomer Dimer Tetramer Hexamer 25 0.25 Plasma Stability 0 10 15 20 Days 0 1 3 7 Retention Volume (ml) VHH hexamer 50% pooled cyno plasma in PBS, 37C, Anti-GFP-HRP detection AbFr Multimers show avidity, no aggregation and good plasma stability6
    7. 7. Chemical Conjugation to scFv XTEN medium short medium long SEC short long 44kDa 2 5 2 5 2 5 158kDa Absorbance 680nm 670kDa short med long aHer2 aHer2 aHer2 Elution Volume XTEN allows control of hydrodynamic radius and half-life7
    8. 8. Cell Binding of aHer2-XTEN-AF Isotype control Trastuzumab block XTEN288 XTEN576 XTEN864 Protocol: SKOV incubated with AF680-labeled scFv-XTEN fusion proteins Cell binding detected by FACS XTEN length has little influence on cell binding8
    9. 9. Tumor Uptake of aHer2-XTEN 60 Protocol: SKOV tumor model Fluorescence (Fold Increase) 50 3 mice per group 40 Day 0: Inject labeled protein 24hr 30 48hr Day 1&2: In vivo imaging 20 10 0 Long Medium Short Herceptin Long-chain XTEN facilitates tumor uptake of aHer2 fragment9
    10. 10. In Vivo Targeting IgG aHer2-XTEN Trastuzumab A1 A2 A3 A1 A2 A3 Tumor Inject labeled Heart protein 3 day Kidney left distribution Kidney right Image organs Liver 1 Liver 2 Lungs Protocol: SKOV3 tumor model, n=3 Spleen Proteins labeled with AF680 • aHer2-XTEN576 shows specific tumor accumulation • Trastuzumab shows significant background staining of normal tissues10

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