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DISSERTATION PROTEIN ENGINEERING THERAPEUTIC STRATEGIES AND TOOLS Submitted by Angeline Ngoc Ta Department of Chemistry In partial fulfillment of the requirements For the Degree of Doctor of Philosophy Colorado State University Fort Collins, Colorado Spring 2019 Doctoral Committee: Advisor: Christopher Snow Chuck Henry Alan Kennan Tim Stasevich Copyright by Angeline Ngoc Ta 2019 All Rights Reserved ABSTRACT PROTEIN ENGINEERING THERAPEUTIC STRATEGIES AND TOOLS Proteins have become an important tool for research development and therapeutics. Proteins complement the use of small molecules as well as overcome challenges that small molecules can- not. The contrasting difference of their diverse functional and structural properties allows for com- plex processes like molecular recognition and catalysis. Through loops, turns, helixes, and sheets, these structural motifs provide a protein with shape and electrostatics to achieve a particular func- tion. Overall, I describe here two examples of functional proteins where the protein’s complex structure plays an important role in the development of new strategies and tools for therapeutics. The first part of this dissertation shows the effects of increased antibody recruitment on targeted cell death through the use of an immunotherapeutic cocktail of cell surface HER2 receptor binding proteins. The second part of this dissertation describes the use of a protein’s chiral environment to develop a new artificial metalloenzyme that selectively catalyses synthesis of the most common N-heterocycle found in FDA approved pharmaceuticals. ii ACKNOWLEDGEMENTS I would like to thank my former research advisor, Dr. Brian McNaughton. He has facilitated in my development as a researcher, presenter, figure maker, and scientist. I am grateful for the guidance, patience, confidence, and skills to adapt and overcome. I would also like to thank my current advisor, Prof. Chris Snow for adopting me into his group. He went from being my out of area committee member, to not being on my committee, to being my advisor. I appreciate your flexibility and the care provided me as I finished up. Thank you to the Snow lab members for your willingness to help and making me feel included. Thank you to my committee members, Prof. Chuck Henry, Prof. Alan Kennan, and Prof. Tim Stesavich. I appreciate your time, feedback, and understanding. Thanks to all my collaborators. Research knows no distance. With a little help from e-mail and Skype I’ve been able to learn a great deal from each of you. Without your expertise, my projects would not have been possible. Thank you to my lab mates. You don’t realize what you have until it is gone. Your constant feedback and willingness to talk science and experiments has helped me progress through my research. I am grateful to have had lab mates who help you celebrate the wins and support you through the losses. A very special thank you to my friends and family. Your outside perspective and encourage- ment was more appreciated than I can express. Finally, I am extremely grateful for my fiancé, Jangir, for being my support. You helped keep me grounded and was there for me every step of the way. I am indebted to your willingness to help and provide me with a different perspective on my research and experiences. I cannot put down in words how much I appreciate your patience and understanding over the years. iii TABLE OF CONTENTS ABSTRACT . ii ACKNOWLEDGEMENTS . iii LIST OF TABLES . vi LIST OF FIGURES . viii Chapter 1 Minimalist Antibodies and Mimetics: An Update and Recent Applications . 1 1.1 Introduction . 1 1.2 Antibodies: Structure, Function, Virtues, and Challenges . 2 1.3 Antibody Fragments . 3 1.3.1 Fab fragments . 5 1.3.2 Single-chain variable fragments (scFv) . 6 1.3.3 Minibodies . 8 1.3.4 Diabodies . 9 1.4 Nanobodies: A camelid-derived scaffold . 10 1.4.1 Recent applications of nanobodies . 11 1.5 Monobodies: A fibronectin-derived scaffold . 15 1.5.1 Recent applications of monobodies . 15 1.6 Summary and Outlook . 17 Chapter 2 Antibody Mimetic Immunotherapeutics and Insight into the Effects of Multi- domain Antibody Recruitment . 19 2.1 What are immunotherapeutics? . 19 2.2 Biologics as immunotherapeutics . 20 2.3 Antibody immunotherapeutics . 20 2.4 Antibody mimetic immunotherapeutics . 22 2.5 An Immunotherapeutic Cocktail of Biologics . 24 2.6 Results and Discussion . 26 2.6.1 An immunotherapeutic cocktail that targets spatially distinct regions on extracellular HER2 leads to an increase in antibody recruitment to HER2-positive breast cancer cells. 26 2.6.2 Increase in antibody recruitment through multi-domain binding to the cell surface does not have a direct correlation to effector cell recruitment and activation for targeted cell death. 29 2.7 Conclusion . 30 2.8 Experimental Details . 31 2.8.1 Protein Expression and Purification . 31 2.8.2 Flow cytometry . 31 2.8.3 Antibody-Dependent Cellular Cytotoxicity . 31 2.9 Supporting Information . 32 2.9.1 Materials . 32 2.9.2 Instrumentation . 34 iv 2.9.3 Western Blot . 35 2.9.4 Flow Cytometry (EC50, siRNA knockdown, Cocktail mixture) . 35 2.9.5 Antibody-Dependent Cellular Cytotoxicity Assay . 36 2.9.6 Protein sequences . 36 2.9.7 Protein expression and purification . 37 2.9.8 Protein gel . 38 2.9.9 Flow Cytometry of mixtures at different concentrations . 39 2.9.10 ADCC Herceptin positive control . 39 Chapter 3 Artificial Metalloenzymes . 40 3.1 Repurposing natural metalloenzymes . 42 3.2 Redesigning metalloenzymes . 45 3.3 Creating new metalloenzymes . 47 3.4 Summary . 49 Chapter 4 Asymmetric δ-Lactam Synthesis with a Monomeric Streptavidin Artificial Metalloenzyme . 50 4.1 Introduction . 50 4.2 Results and Discussion . 51 4.3 Conclusion . 58 4.4 Supporting Information . 58 4.4.1 General methods . 58 4.4.2 Preparation of starting materials . 59 4.4.3 General procedures for dihydropyridone synthesis (racemic) . 60 4.4.4 Product characterizations (racemic) . 62 4.4.5 Copies of NMR spectra . 70 4.4.6 General procedures for asymmetric dihydropyridone synthesis . 100 4.4.7 Analytical data for enantioenriched dihydropyridones (NMR/HPLC) . 102 4.4.8 Product derivatization to piperidines (procedure, characterization, and spectra) . 126 4.4.9 Control experiments and mechanistic studies . 142 4.4.10 Relative rates of bound and unbound catalyst . 144 4.4.11 Preparation of artificial metalloenzyme . 149 4.4.12 Protein sequences . 151 4.4.13 Protein mass spectrometry analysis (TOFMS) . 152 4.4.14 Protein gel . 154 4.4.15 Biotin binding ELISA . 155 4.4.16 Protein data bank . 155 4.4.17 Calculation of initial rates and relative rates . 155 References . 158 v LIST OF TABLES 4.1 Evaluation of organometallic catalysts and artificial metalloenzymes. 53 4.2 N-(Pivaloyloxy)methacrylamide (2a) characterization. 60 4.3 2-Benzyl-N-(pivaloyloxy)acrylamide (2b) characterization. 60 4.4 2-Ethoxy-N-(pivaloyloxy)acrylamide (2c) characterization. 60 4.5 2-(4-Bromobenzyl)-N-(pivaloyloxy)acrylamide (2d) characterization. 61 4.6 2-(4-methoxyphenyl)-N-(pivaloyloxy)acrylamide (2e) characterization. 61 4.7 Methyl 3-((pivaloyloxy)carbamoyl)but-3-enoate (2f) characterization. 61 4.8 6-(4-Methoxyphenyl)-3-methyl-5,6-dihydropyridin-2(1H)-one (4aa) characterization. 62 4.9 3-Methyl-6-phenyl-5,6-dihydropyridin-2(1H)-one (4ab) characterization. 62 4.10 6-(4-Chlorophenyl)-3-methyl-5,6-dihydropyridin-2(1H)-one (4ac) characterization. 62 4.11 3-Methyl-6-(4-(trifluoromethyl)phenyl)-5,6-dihydropyridin-2(1H)-one (4ad) characterization. 63 4.12 6-(3,4-Dimethoxyphenyl)-3-methyl-5,6-dihydropyridin-2(1H)-one (4ae) characteriza- tion. 63 4.13 6-(3-Methoxyphenyl)-3-methyl-5,6-dihydropyridin-2(1H)-one (4af) characterization. 63 4.14 6-(3-Chlorophenyl)-3-methyl-5,6-dihydropyridin-2(1H)-one (4ag) characterization. 64 4.15 3-Methyl-6-(3-(trifluoromethyl)phenyl)-5,6-dihydropyridin-2(1H)-one (4ah) characterization. 64 4.16 3-Methyl-6-(m-tolyl)-5,6-dihydropyridin-2(1H)-one (4ai) characterization. 64 4.17 6-(2-Fluorophenyl)-3-methyl-5,6-dihydropyridin-2(1H)-one (4aj) characterization. 65 4.18 3-Benzyl-6-(4-methoxyphenyl)-5,6-dihydropyridin-2(1H)-one (4ba) characterization. 65 4.19 3-Benzyl-6-phenyl-5,6-dihydropyridin-2(1H)-one (4bb) characterization. 65 4.20 3-Benzyl-6-(4-chlorophenyl)-5,6-dihydropyridin-2(1H)-one (4bc) characterization. 66 4.21 3-Benzyl-6-(4-(trifluoromethyl)phenyl)-5,6-dihydropyridin-2(1H)-one (4bd) characterization. 66 4.22 3-Benzyl-6-(3,4-dimethoxyphenyl)-5,6-dihydropyridin-2(1H)-one (4be) characteriza- tion. 66 4.23 3-Benzyl-6-(3-chlorophenyl)-5,6-dihydropyridin-2(1H)-one (4bg) characterization. 67 4.24 3-Benzyl-6-(3-(trifluoromethyl)phenyl)-5,6-dihydropyridin-2(1H)-one (4bh) characterization. 67 4.25 3-Benzyl-6-(3-fluorophenyl)-5,6-dihydropyridin-2(1H)-one (4bj) characterization. 67 4.26 3-Ethoxy-6-(4-methoxyphenyl)-5,6-dihydropyridin-2(1H)-one (4ca) characterization. 67 4.27 3-(4-Bromobenzyl)-6-(4-(trifluoromethyl)phenyl)-5,6-dihydropyridin-2(1H)-one (4dd) characterization. 68 4.28 3,6-Bis(4-methoxyphenyl)-5,6-dihydropyridin-2(1H)-one (4ea) characterization. 68 4.29 3-(4-Methoxyphenyl)-6-(4-(trifluoromethyl)phenyl)-5,6-dihydropyridin-2(1H)-one (4ed) characterization. 68 4.30 Methyl 2-(6-(4-methoxyphenyl)-2-oxo-1,2,5,6-tetrahydropyridin-3-yl)acetate (4fa) characterization. 69 4.31 Methyl 2-(2-oxo-6-(4-(trifluoromethyl)phenyl)-1,2,5,6-tetrahydropyridin-3-yl)acetate (4fd) characterization. 69 vi 4.32 6-(4-methoxyphenyl)-3-methylpiperidin-2-one (6aa) characterization. 129 4.33 6-(4-chlorophenyl)-3-methylpiperidin-2-one (6ac) characterization. 129 4.34 6-(2-fluorophenyl)-3-methylpiperidin-2-one (6aj) characterization.
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    US010328157B2 (12 ) United States Patent ( 10 ) Patent No. : US 10 , 328 , 157 B2 Zhao ( 45 ) Date of Patent: Jun . 25, 2019 ( 54 ) ACETYLENEDICARBOXYL LINKERS AND 45/ 06 ( 2013. 01 ) ; A61K 47/ 6809 (2017 . 08 ) ; THEIR USES IN SPECIFIC CONJUGATION A61K 47/ 6849 ( 2017 .08 ) ; A61K 47/ 6851 OF A CELL - BINDING MOLECULE ( 2017 . 08 ) ; A61K 47 /6889 ( 2017 .08 ) ; C07C 59 / 76 (2013 . 01 ) ; C07C 233 / 20 ( 2013 .01 ) ; (71 ) Applicant: SUZHOU M -CONJ BIOTECH CO . , C07C 237 /52 (2013 .01 ) ; C070 207 /46 LTD ., Suzhou (CN ) ( 2013 .01 ) ; C07D 277 / 56 (2013 .01 ) ; C07D 309/ 14 ( 2013 . 01 ) ; CO7D 403/ 14 ( 2013 .01 ) ; ( 72 ) Inventor: Robert Yongxin Zhao , Lexington , MA C07D 407 / 12 ( 2013 . 01 ) ; C07D 407/ 14 (US ) ( 2013 .01 ) ; CO7D 413 / 04 (2013 . 01 ) ; C07D ( 73 ) Assignee : HANGZHOU DAC BIOTECH CO . , 413 / 14 ( 2013 .01 ) ; C07D 417 / 12 ( 2013 . 01 ) ; LTD . , Hangzhou ( CN ) C07D 417 / 14 ( 2013 .01 ) ; C07D 493 /04 ( 2013 . 01 ) ; C07D 498 / 14 ( 2013 . 01 ) ; C07D ( * ) Notice : Subject to any disclaimer , the term of this 519 / 00 ( 2013 .01 ) ; C07K 16 / 28 ( 2013 . 01 ) ; patent is extended or adjusted under 35 CO7K 16 / 2863 ( 2013 .01 ) ; COOK 16 / 32 U . S . C . 154 ( b ) by 0 days . ( 2013 . 01 ) ; GOIN 33 /5014 (2013 .01 ) ; A61K 2039/ 505 ( 2013 .01 ); C07K 2317 /24 (2013 . 01 ) ; (21 ) Appl. No. : 15 /423 ,695 YO2A 50 /416 ( 2018 .01 ); YO2A 50 / 466 ( 22 ) Filed : Feb . 3 , 2017 ( 2018 . 01) ; YO2A 50 /473 (2018 .01 ) (58 ) Field of Classification Search (65 ) Prior Publication Data CPC .. A61K 47 /6803 US 2017 /0143845 A1 May 25 , 2017 See application file for complete search history .
  • Ep 2739649 B1

    Ep 2739649 B1

    (19) TZZ ¥_T (11) EP 2 739 649 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07K 14/79 (2006.01) A61K 38/40 (2006.01) 27.09.2017 Bulletin 2017/39 A61K 38/00 (2006.01) A61K 39/44 (2006.01) (21) Application number: 12746240.6 (86) International application number: PCT/US2012/049475 (22) Date of filing: 03.08.2012 (87) International publication number: WO 2013/022738 (14.02.2013 Gazette 2013/07) (54) P97 FRAGMENTS WITH TRANSFER ACTIVITY P97-FRAGMENTE MIT TRANSFERAKTIVITÄT FRAGMENTS DE P97 AVEC ACTIVITÉ DE TRANSFERT (84) Designated Contracting States: (56) References cited: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB WO-A2-02/13873 WO-A2-03/009815 GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR • KARKAN DELARA ET AL: "A Unique Carrier for Delivery of Therapeutic Compounds beyond the (30) Priority: 05.08.2011 US 201161515792 P Blood-Brain Barrier", PLOS ONE, vol. 3, no. 6, June 2008 (2008-06), XP002685120, ISSN: (43) Date of publication of application: 1932-6203 11.06.2014 Bulletin 2014/24 • TANG Y ET AL: "Directing adenovirus across the blood-brain barrier via melanotransferrin (P97) (73) Proprietor: Bioasis Technologies Inc. transcytosis pathway in an in vitro model", GENE Richmond, British Columbia V6X 2W9 (CA) THERAPY, MACMILLAN PRESS LTD., BASINGSTOKE, GB, vol. 14, no. 6, 1 March 2007 (72) Inventors: (2007-03-01), pages523-532, XP002517213, ISSN: • JEFFERIES, Wilfred 0969-7128, DOI: 10.1038/SJ.GT.3302888 South Surrey, BC V4A 2V5 (CA) [retrieved on 2006-11-30] • TIAN, Mei Mei • YANG J ET AL: "Deletion of the GPI pre-anchor Coquitlam, BC V3J 7E6 (CA) sequence in human p97-a general approach for • VITALIS, Timothy generating the soluble form of GPI-linked Vancouver, BC V6Z 2N1 (CA) proteins", PROTEIN EXPRESSION AND PURIFICATION, ACADEMIC PRESS, SAN DIEGO, (74) Representative: Gowshall, Jonathan Vallance CA, vol.