Rina K Dukor BioTools, Inc.
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1 Novel Techniques for Structure Elucidation of Blockbuster Drugs: A Close Look at Biologics and Chirality Rina K Dukor BioTools, Inc. FIU webinar January 15, 2013
2 BIOTOOLS: Headquarters, R&D, applications lab, contract work & manufacturing Jupiter, FL Tel: (561) Fax: (561) Research Associated with: Syracuse University Syracuse, NY International: Europe - BioTools Europe ROW - distributor network Sales and Support: near Chicago Website: info@btools.com
3 - Moved to Jupiter, FL in Received SBIR grants from DOD and NSF - Received JUPITER FUND loan - Over 15 interns and students trained
4 BioTools Product Lines Contract Lab VCD Raman VCD Bio Raman IR Diagnostics BioIR Accessories
5 CORE TECHNOLOGY: Vibrational Spectroscopy Vibrational Circular Dichroism (VCD) Raman Optical Activity (ROA) Raman Spectroscopy of Proteins /Biomolecules and pharmaceuticals FT-IR Spectroscopy of Proteins and other Biomolecules
6 Instrument Products ChiralRAMAN-2X (ROA) ChiralIR-2X (VCD) PROTA-2X (FTIR)
7 Definitions of VOA
8 Slide courtesy of Prof. Hamada Univeristy of the Air, Japan
9 VIBRATIONAL OPTICAL ACTIVITY Differential Interaction of a Chiral Molecule with Left and Right Circularly Polarized Radiation During Vibrational Excitation VIBRATIONAL CIRCULAR DICHROISM RAMAN OPTICAL ACTIVITY Differential Absorption of Left and Right Differential Raman Scattering of Left Circularly Polarized Infrared Radiation and Right Incident and/or Scattered Radiation
10 The IR spectra of enantiomers are identical, but their VCD spectra are opposite in sign (1R)-(+)-camphor (1S)-(-)-camphor
11 FT-VCD Measurements
12 FT-VCD Instrumental Layout Photoelastic Modulator (PEM) Optical Filter R L Detector Polarizer Sample Cell Process & Display VCD Lock-in Amplifier (LIA) I AC IR I DC
13 3 types of pharmaceuticals chiral protein-based & other biopharmaceuticals small organic, non-chiral
14 Top 10 Blockbuster Drugs LIPITOR Pfizer high cholesterol: $12.5 billion 2.PLAVIX Bristol-Meyers Squibb & Sanofi-Aventis heart disease $9.5 billion chiral!!! and protein-based! 3.ADVAIR DISKUS GlaxoSmithKline asthma: $7.7 billion 4.ENBREL Amgen rheumatoid arthritis: $6.2 billion 2.DIOVAN Novartis heart failure: $6.0 billion 3.REMICADE J&J / Merck - rheumatois arthritis: $5.9 billion 4.AVASTIN Roche / Genentech - cancer: $5.7billion 8. RITUXAN Roche / Genentech lymphoma, leukemia, rh. Arthritis: $5.6 b 9.HUMIRA Abbott - rh. Arthritis: $5.5 b 10. SEROQUEL AstraZeneca depression: $5.1 billion Source: FiercePharma; 11/09/10
15 Chirality
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18 R-(-)- and S-(+)-Carvone R-(-)-carvone smells like spearmint S-(+)-carvone smells like caraway seeds The fact that the two enantiomers are perceived as smelling differently is proof that olfactory receptors must contain chiral groups, allowing them to respond more strongly to one enantiomer than to the other. Not all enantiomers have distinguishable odors.
19 Thalidomide - Teratogenic mechanism (S)-thalidomide: Teratogenic and causes birth defects (R)-thalidomide: Effective against sickness Thalidomide is racemic it contains both (S)- and (R) enantiomers in equal amounts. The enantiomers can interconvert in vivo that is, if a human is given pure (R)-thalidomide or (S)-thalidomide, both isomers can be found in the serum therefore, administering only one enantiomer will not prevent the teratogenic effect in humans. The mechanism of its biological action is being debated. Approved by FDA as THALOMID for treatment for leprosy and myeloma.
20 Chiral Drugs Two critical parameters are a must-know: Absolute Configuration (R or S; L or D) Enantiomeric Purity (%ee) (1R)-(+)-camphor (1S)-(-)-camphor
21 Use of VCD in Pharma Astra-Zeneca, BMS, GSK, Eli Lilly, Wyeth (now Pfizer), J&J, Roche, Amgen, Boehringer-Ingelheim, Organon (now Schering-Plough / Merck), Sanofi-Aventis, Pfizer, Merck, Abbott, Cell Therapeutics, Solvay Pharma, Neurocrine, Novartis, Sepracor, Abbott, Sunovion, Gilead, BioGenIdec, United Therapeutics, Cayman, Firminech, Syngenta, US naval Research labs and US FDA among others We estimate that close to 5000 AC s have been done in the past few years Now, ~ AC s ever year!!!!!! 21
22 Use of VCD in Patents As of January 2012, there are 105 patent applications filed with US PTO for new molecular entities where AC is determined with VCD!
23 Supramolecular chirality (fibrils..) Other uses of VOA Binding of active site (Structure-Based Design of Novel Inhibitors of the MDM2 p53 Interaction by Amgen) Reaction monitoring and %EE Structure of Biologics: proteins, peptides, glycoproteins, sugars, nucleic acids
24 Proteins & Disease TARGETS THERAPEUTICS Most drugs on the market are directed towards correcting protein malfunction About 10,000 disease related proteins could be targeted About 500 proteins have been targeted to date Blood factors, growth factors, interferons, interleukin, monoclonal antibodies Fastest-growing new therapeutic area; $50-70B market ~ 75 FDA approved ~ 500 in R&D
25 Top Ten Biologics ENBREL (TNF blocker IgG fusion protein) Amgen RA: $7.4 billion 2. REMICADE (TNF blocker-antibody) J&J RA: $6.2 billion 3. RITUXAN (antibody) Roche (Genentech) NHL: $5.5 billion 4. AVASTIN (antibody) Roche colon cancer: $4.8 billion 5. HERCEPTIN (antibody) Roche (Genentech) breast cancer: $4.7 billion 6. HUMIRA (antibody) Abbott RA $4.5 billion 7. LOVENOX (heparin) Samofi-Aventis anticoagulant: $4.0 billion 8. LANTUS (insulin) Sanofi-Aventis diabetes: $3.6 billion 9. ARANESP (erythropoietin) Amgen anemia: $3.1 billion 10. GARDASIL (vaccine) Merck cervical cancer - $2.8 billion Source: knol.google.com
26
27 Many questions There are many types of questions / problems in development and manufacturing of pharmaceuticals ranging from confirmation of starting materials, structure elucidation, formulation, process control, quality control. and many can be solved using spectroscopy
28 Chiral and Bio-pharmaceuticals are Proteins: very unique Structure is very sensitive to perturbation of any kind and to physical state and structure is related to function Formulation is a key Stability / storage Chiral: Two critical parameters are a must-know: absolute configuration and enantiomeric purity BioTools provides answers w/ VCD, ROA & FTIR!
29 Conventional Structural Techniques: Atomic Resolution X-RAY Crystallography great precision Disadvantages - must have a crystal/solid state Nuclear Magnetic Resonance (NMR) Advantage: solution state Disadvantages time, cost, larger amount of samples Computational Methods Advantages: quick, easy for small system Disadvantages - reliability in question, scaling up is problematic
30 Conventional Structural Techniques: Low Resolution Optical Spectroscopy long-term use : UV absorption, fluorescence, Circular Dichroism newer techniques : FT-IR, Raman Advantages: conformationally sensitive to secondary structure and sometimes to tertiary structure; fast, low cost Disadvantages: not site specific - averages
31
32 Advantages of Vibrational Spectroscopy Secondary and tertiary structure (backbone and side chain conformations) From low to very high concentrations Not limited by physical state of samples liquid, solid, gel, colloid
33
34
35
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37 Question posted: IF we do not see any differences (say in CD or FTIR data) does it mean there are no differences in structure or the TECHNQUE is not sensitive enough?
38 FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH OFFICE OF MEDICAL POLICY DRAFT GUIDANCES RELATING TO THE DEVELOPMENT OF BIOSIMILAR PRODUCTS PART 15 PUBLIC HEARING FRIDAY MAY 11, 2012
39 Comments from HOSPIRA From a quality considerations perspective, Hospira has three primary recommendations. First, FDA mentions extra crystallography and multidimensional NMR methods to assess three-dimensional structure but other methods, for example, vibration circular dichroism, hydrogen exchange, Raman spectroscopy, and Fourier transform infrared spectroscopy can also be considered based on the molecule being studied. The emphasis should be placed on using the correct method as appropriate for the molecule.
40 VCD / ROA in Pharma Amgen, Astra-Zeneca, BMS, GSK, Eli Lilly, Wyeth/Pfizer, J&J, Roche, Novartis, Boehringer- Ingelheim, Organon (Akzo Nobel, now Merck), Merck, Pfizer, Abbott, Cell Therapeutics, Solvay, Neurocrine, Sanofi-Aventis, and many many more! VCD is accepted by regulatory agencies as proof of Absolute Configuration Finally, VCD is now used as a tool for AC and not just a research technique! ROA several in biopharma
41 Absolute Configuration with VCD & ROA VOA provides unambiguous determination of Absolute Configuration in solution No need for crystallization Solution phase sampling only Ab-initio calculations require only ground electronic state calculation Solution conformation obtained from analysis Software for VCD calculation is now commercially available (Gaussian98/ Software for ROA calculations is also now commercially available from Gaussian and is also available from Dalton
42 Absolute Configuration with VCD / ROA compare experimental spectrum with an ab initio calculation of selected enantiomer
43 Absolute Configuration Example: VCD ε x Observed Calculated H N N N Molar Absorptivity, ε Observed Calculated Collaboration with Dr. Edwin Kellenbach, Organon Wavenumber (cm -1 )
44 BIOLOGICS: -Proteins - Nucleic Acids - Carbohydrates / Glycoproteins - Viruses
45 PROTEINS Spectroscopic techniques of choice For structure elucidation and formulation (stability) studies: -CD -FT-IR -Raman
46 IR / VCD RAMAN/ROA I II skeletal stretches III I III
47 Characteristic IR Bands of Peptide Group
48 Hundreds of (biopharma companies are using vibrational spectroscopy (mostly IR and ROA) for characterization of proteins in development, formulation (largest use), solving problems in manufacturing and QC
49 What Applications / Information Can be Obtained? Experimental evaluation of predicted secondary structure (e.g. homology building) New protein structure determination: structural proteomics Analysis of effects resulting from site-directed mutagenesis Characterization of structural changes under different conditions (e.g. formulations, presence of drugs, inhibitors, temperature effects, ph) Comparability Studies Biomembrane proteins QA/QC, manufacturing and regulatory screening
50 Questions: Is there a conformational difference after formulation with excipients? Is conformation of protein API the same in solution and solid? Does protein conformation change during storage / transport? Aggregation manufacturing, product activity & quaility and most important immunogenicity Degradation tyr-tyr ; Si leakage (from stoppers) Glycosylated proteins Is crystallinity / polymorphism of excipients important? Most commonly used techniques are IR and to some extent Raman but are problematic when spectra of excipients interfere
51 Aggregation of Human IgG1 CAUSES OF SOLUBLE & INSOLUBLE AGGREGATES: - temperature - shear force - freeze-thawing - ph - high concentration -- long term storage Work and slides courtesy of Dr. Tiansheng Li Amgen, Inc.
52
53 Protein Amyloid Fibril Formation and Structure In collaboration with Professor Igor Lednev and Dr. Dimitri Kurouski (slides courtesy of Dr. Kurouski)
54 Amyloid fibrils are insoluble protein aggregates that have: Cross-β-sheet structure Core structure is highly resistant to hydrogen exchange Various morphologies Found in organs and tissues of patients with various neurodegenerative diseases such as Alzheimer s disease, Parkinson s disease, Huntington s disease, prion disease, type II diabetes, etc. Are believed to be: Toxic species that cause appearance and progress of neurodegenerative diseases Storage of misfolded proteins that lost their physiological functions G. Merlini and V. Belotti, 54 New Engl. J. Med.,2003
55 Amyloid plaque in the human brain Amyloid fibrils imaged using electron microscopy 55
56 Fibril polymorphism: microscopy Calcitonin Mouse Amylin Transthyr Insuli Prion etin n H. Bauer et al.; J. Struct. Biol. 1995; C. S. Goldsbury et al.; J. Struct. Biol. 1997; J. Jimenéz et al.; PNAS 2002; M. Anderson et al.; J. Mol. Biol. 2006; I. Cardoso et al.; J. Mol. Biol
57 J. Am. Chem. Soc. 129, (2007) 57
58 Normal and Reversed Supramolecular Insulin Fibrils Normal: Soution Film Reverse: Solution Film 58
59 Can ph determine formation of tape-like or ribbon-like fibrils? High ph Native insulin Partially unfolde d protein? Low ph Protofilament/ Protofibril D. Kurouski, R. Lombardi, R. K. Dukor, I. K. Lednev and L. A. Nafie, Chem. Commun., 2010, Mature 59 fibrils
60 Insulin fibrils have left-handed twist in solution ph is above 2.4 a b c a 250 nm 50 nm 100 nm Amplitude AFM (a), SEM (b) and (c) images of insulin fibrils grown at ph 2.5, 70 ⁰C. Insulin fibrils have left-handed twist in solution ph is below 2.1 a b c 100 nm 100 nm 100 nm SEM images of (a-c) of binary insulin fibrils prepared at ph 1.5, 70 ⁰C. 60
61 hirality visible for microscopy ph 2.5 Δ A x VCD Chirality visible for VCD ph IR ph 1.5 Absorbance ph Wavenumber (cm -1 ) 61
62 Native insulin denaturation Partially unfolded protein aggregation Proto- Filaments Height: ~1.5 nm intertwining LH? nvcd ph ph RH? Unstable, requires pairing Parallel aggregation Chirality visible for VCD Proto-fibrils Chirality visible for microscopy Height: ~4 nm intertwining LH nvc D RH? rvcd Height: ~1.5 nm Parallel aggregation Fibrils Height ~8 nm LH nvcd RH? rvcd Height: ~2 nm D. Kurouski, X. Lu, R. K. Dukor, L. A. Nafie and I. K. Lednev, Biophys. J., 2012, in press 62
63 63
64 Conclusions The innovative, academic techniques of VCD and ROA are now making significant impact on how structure is currently solved in pharmaceutical companies Many more applications to come from these sensitive tools Don t be afraid to go after your scientific passion!
65 Acknowledgments Prof. Larry Nafie, Prof. Tess Freedman, Dr. Xiaolin Cao, Dr. Shengli Ma, Rosina Syracuse University Dr. Tiansheng LI, Amgen Dr. Alla Polozova, MedImmune Dr. Edwin Kellenbach, Organon (now SP / Merck) Dr.Igor Lednev and Dimitry Kurousky (U of Albany) All Founders and original adapters of VOA All present and past All customers and collaborators for inspiring us to create and innovate! Funding: DOD, NSF, NASA, Johnson Pharmaceutical R&D, Amgen, and the CASE Center, Syracuse University YOU for listening!
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