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Poly Specific Antibodies

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Poly Specific Antibodies ABSTRACT TERRENCE MCGARTY This Report details the current efforts on the development of poly-specific antibodies (PolyAb) which are logical extensions of monoclonal Ab. PolyAb present an interesting tool to address a variety of disease directly and via the transmission of therapeutics. POLY SPECIFIC ANTIBODIES TGL 181, DECEMBER 2020 1 | P a g e Notice This document represents the personal opinion of the author and is not meant to be in any way the offering of medical advice or otherwise. It represents solely an analysis by the author of certain data which is generally available. The author furthermore makes no representations that the data available in the referenced papers is free from error. The Author also does not represent in any manner or fashion that the documents and information contained herein can be used other than for expressing the opinions of the Author. Any use made and actions resulting directly or otherwise from any of the documents, information, analyses, or data or otherwise is the sole responsibility of the user and The Author expressly takes no liability for any direct or indirect losses, harm, damage or otherwise resulting from the use or reliance upon any of the Author's opinions as herein expressed. There is no representation by The Author, express or otherwise, that the materials contained herein are investment advice, business advice, legal advice, medical advice or in any way should be relied upon by anyone for any purpose. The Author does not provide any financial, investment, medical, legal or similar advice in this document or in its publications on any related Internet sites. Furthermore, this document contains references to and quotes from papers and documents under the premise of Fair Use in order to present ideas and understandings in context. The Author has attempted to make any and all references to such material separate from those of the author per se and has referenced the source expressly in all cases. These documents are for the dissemination of ideas and have no commercial intent. The Author would appreciate any communications relating to these documents and these should be sent to: [email protected]. Terrence P. McGarty, Copyright © 2021, all rights reserved. This document is in DRAFT form and is solely for technical review and evaluation and it not intended for any commercial use. 2 | P a g e Contents 1 Introduction ............................................................................................................................. 6 2 Antibody Basics ..................................................................................................................... 10 2.1 Basic Antibody ............................................................................................................... 10 2.2 T Cell Mechanics ........................................................................................................... 13 3 MAB ...................................................................................................................................... 15 3.1 Immune System Architecture ......................................................................................... 16 3.2 Mab Development .......................................................................................................... 21 3.3 Cell Fusion ..................................................................................................................... 25 3.3.1 Common Cell Fusion .............................................................................................. 27 3.3.2 Disparate Cell Fusions ............................................................................................ 28 3.3.3 Synkaryon ............................................................................................................... 28 3.4 MAb Types ..................................................................................................................... 29 3.4.1 Murine Monoclonal Ab........................................................................................... 30 3.4.2 Human Monoclonal Ab........................................................................................... 30 3.4.3 Transgenic Mice...................................................................................................... 30 3.5 Mab Application ............................................................................................................. 30 3.6 Issues with Ab Approaches ............................................................................................ 34 4 Bi-specifics ............................................................................................................................ 37 4.1 General Constructs ......................................................................................................... 38 4.2 Various Implementations ............................................................................................... 41 4.2.1 Fc Based Formats .................................................................................................... 41 4.2.2 Fragment Based, Fab .............................................................................................. 45 4.2.3 PreClinical............................................................................................................... 48 4.3 Production ...................................................................................................................... 53 4.4 Comparisons and Analyses ............................................................................................ 59 5 Tri-specifics ........................................................................................................................... 61 5.1 Formats ........................................................................................................................... 62 5.2 Production ...................................................................................................................... 63 3 | P a g e 5.3 Usage .............................................................................................................................. 67 6 Productions Issues ................................................................................................................. 71 6.1 Targeting ........................................................................................................................ 71 6.2 Design............................................................................................................................. 72 6.3 Cell Fusion ..................................................................................................................... 73 6.4 Chromatography ............................................................................................................. 75 7 Treatments ............................................................................................................................. 76 7.1 Prostate Cancer ............................................................................................................... 77 7.2 Bladder Cancer ............................................................................................................... 79 7.3 Hematological Malignancies .......................................................................................... 81 7.4 COVID-19 Virus ............................................................................................................ 85 8 Observations .......................................................................................................................... 87 8.1 Production and Scaling................................................................................................... 87 8.2 Targeting ........................................................................................................................ 87 8.3 Immune responses .......................................................................................................... 90 8.4 Comparisons ................................................................................................................... 90 9 Appendix – Poly Specific Options Production ...................................................................... 92 9.1 Fc based Formats ............................................................................................................ 92 9.1.1 Dual Variable Domains Ig (DVD-Ig) ..................................................................... 92 9.1.2 scFv-Ig Fusions ....................................................................................................... 93 9.1.3 scFv-Fc Fusions ...................................................................................................... 93 9.1.4 DART ...................................................................................................................... 93 9.1.5 BEAT ...................................................................................................................... 93 9.1.6 XmAb ...................................................................................................................... 94 9.2 Fragment Based .............................................................................................................. 94 9.2.1 BiTE ........................................................................................................................ 94 9.2.2 TandAb ..................................................................................................................
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