EFTA00586577.pdf

OH2 Laboratories Re-engineering Drug Discovery Company Overview February 2015 David Levy, Ph.D. General Manager and Chairman OH2 Laboratories, LLC Confidential and Proprietary EFTA00586577 Introductions: The OH2 Laboratories Team Board of Managers David Levy, Ph.D. Chairman and General Manager, OH2 Founder, Digit Wireless, LLC Founder, TH, Inc Design Engineer, Apple Marc Rioult, Ph.D Managing Director, 3DMatrix Senior Licensing Officer, MIT TLO Kevin Munnelly, Ph.D. President & CEO, Gen9 GM, Life Technologies, VP and GM, BioTrove Steve Yang, Ph.D. Director, Sentilaia Consultant, McKinsey Scientific Advisory Board Shuguang, Zhang, Ph.D. Lab Head, MIT 170 publication 36 patents and pending patents Founder, 3D Matrix Many awards Robert Langer, D.Sci. David H. Koch Institute Professor, MIT 1,250 Publications 1,050 patents Many awards Many, many Companies Alex Rich, M.D. Professor of Biophysics, MIT 550 Publications Many awards David Jin, M.D. Practicing Oncologist and Researcher 2012 Top Chief Medical Officer in America 2014 Leading Physicians in the World OH2 Laboratories, LLC Confidential and Proprietary EFTA00586578 Significance of Our Work About 50% of medications function by GCPR signaling. 99% of them were "lucky": They worked prior to science understanding GPCRs. Imagine if we could now target-design medications to signal through specific GPCR receptors... OFI2 Laboratories, LLC Confidential and Proprietary EFTA00586579 What We Do We produce GPCRQTY, mAbc1TY, and ReceptorcITY : synthetic materials created with our patented algorithms to target-design stable water-soluble variants of any desired protein, especially membrane proteins, while maintaining the functionality of the original. The result is a foundational technology: a fundamental tool that opens many doors. OH2 Laboratories, LLC Confidential and Proprietary EFTA00586580 Monetization The ability to produce stable water-soluble versions of proteins that are naturally insoluble brings value to several areas: • Drug Discovery • Research Tools • Diagnostics • mAB-Similar Products • Autoimmune/Allergy Therapy • Viral Therapeutics • Molecular Sensors OH2 is a holding company, ultimately intending to form subsidiaries to monetize each. OH2 Laboratories, LLC Confidential and Proprietary EFTA00586581 Drug Discovery 151P GPCRQTY provides a critical revitalization of drying pharma pipelines: — Addresses compounds with poor solubility (over 40% of drugs) offering increased efficacy and faster, cheaper development. — Enables novel drug candidates for GPCR-mediated diseases: Prostate cancer (GPR68/OGR1) Cancer metastasis (CXCR4) Leukemia (P2Y8/P2 R Y8) Bipolar disorder (GPRS 78) Osteoarthritis (GPR22) Breast Cancer (CXCR4) Parkinson's (GPCR 37) Asthma (CCR3.CXCR2) Ovarian Cancer (OGR1) Autism (GPCR 63) Lung cancer (GPR87) Alzheimer's (GPR3) Arteriosclerosis (GPRS 176) Colon cancer (MASI ) Diabetes (GPCR 21) (Plus over 700 others and the list grows almost daily.) OH2 Laboratories, LLC Confidential and Proprietary EFTA00586582 Research Tools Providing GPCRQTY, mAbc1TY, and ReceptorQTY products to research laboratories, enables others to explore the benefits of water-soluble proteins. OH2 Laboratories, LLC Confidential and Proprietary EFTA00586583 Diagnostics GPCRQTY materials maintains ligand binding ability to specific antigens/receptors is a low-cost and stable medium enabling a new class of novel, low-cost diagnostics. OH2 Laboratories, LLC Confidential and Proprietary EFTA00586584 mAB-Similar Products mAbQT't' offers new molecular therapeutics: — Target-designed to be similar to monoclonal antibodies, but easier to produce. — Engineered to reduce mAb aggregation and increase long- term storage. OH2 Laboratories, LLC Confidential and Proprietary EFTA00586585 Autoimmune/Allergy Therapy GPCRQTY can be used as a decoy therapy (similar to Enbrel/Etanercept). This approach can theoretically be used for any disease or condition associated with GPCR signaling. OH2 Laboratories, LLC Confidential and Proprietary EFTA00586586 Viral Therapeutics ReceptorsQTY can be use to trap viruses including: HIV, Ebola, Marburg & Lassa - for rapid reduction of viral loads. OH2 Laboratories, LLC Confidential and Proprietary EFTA00586587 Molecular Sensors Due to their stability, low-cost and high degree of molecular selectivity, Receptorsc/TY can be used to create ultra- sensitive bionic detectors. (e.g. a chip-based bionic nose.) OH2 Laboratories, LLC Confidential and Proprietary EFTA00586588 The Science - Using CXCR4 as an example The following 7 slides explains how we can produce CXCR4QTY , a functional soluble CXCR4 variant. • Re-Coding CXCR4 • Comparing Structures • Comparing Solubility • Thermal Stability • Circular dichroism Spectra • Natural SDF1 ligand Binding • X-Ray Diffraction The variant structure was target-designed, not by trial and error. OH2 Laboratories, LLC Confidential and Proprietary EFTA00586589 Coding CXCR4QTY from CXCR4 TMHMM posteror probabilities for WI 1.2 7 distinctive Trans membrane helices 0 Trans membrane helices! I 0.8 0.6 0.4 0.2 0 1.2 0.8 0.6 0.4 0.2 0 50 100 transmembrane 150 200 inside TMHMM posterior probabilities for MT 250 300 960 outside 50 100 160 200 250 900 960 transmembrane kakis — outside — EFTA00586590 Comparing Structures - Natural & CCR4 Variant, Superimposed The two structures are nearly identical. View #1 View #2 Laboratories, LLC Confidential and Proprietary EFTA00586591 Natural CXCR4 Hydrophobic Regions Comparing H2O Solubility Designed Variant CXCR4QTY Hydrophobic Regions Od: Loboratcrie, LLC Confidential and Proprietary EFTA00586592 Native CXCR4 and CXCR4 variant "1 The CD spectra Molecular models CD spectrum of natural CXCR4 and water-soluble CXCR4 QTY A Native protein 8 6 B QTY variant 4 0 I 0 4 3 0a) 2 • 2 0 £ 1 0 0 0 • 0 -1 0 O 6 15499°) -2 • • O / -4 -2 • -3 WI -6 \pow/ -8 195 205 215 225 235 245 Wavelength (nm) 195 205 215 225 235 245 Wavelength (nm) Red, Native CXCR4 Blue, CXCR4QTY variant The structures are nearly The same. EFTA00586593 Thermal Stability of Water-soluble CXCR4QTY, Tm 67°., A 10 0• I ▪ -lo- ot - -30 - 5 15 25 35 45 55 65 -10- -127 -14- -16- -le• N -20- N Z• -22- -24- -32- B 200 210 220 230 240 250 260 0 20 40 60 Wavelength Temperature (C) ea 100 OH2 Laboratories, LLC Confidential and Proprietary EFTA00586594 Ligand-binding of CXCR4QTY with its natural ligand CXCL12 ELISA-style binding assay CXCR4 QTY-CXCL12 1,2 1 ■ • MEN 0,8 • ■ • 0,6 • 0,4 • 0 0,2 ■ 0 ■• ■ <0 CP N'N Qr N<,P • b (0. 4 ). ,ek s Log CXCL12 [nM] The natural SDF1a ligand-binding assay. The SDF1a binds to the native CXCR4 - 1.00nM. The SDF1a binds to the designed code made CXCR4 variant - 80nM. OH2 Laboratories, LLC Confidential and Proprietary EFTA00586595 X-ray diffraction of crystal of water-soluble CXCR4QTY OHz Laboratories, LLC Confidential and Proprietary EFTA00586596 First Patent Issued 111111111111111111111111 (12) United States Patent Zhang et al. (lo) Patent No.: US 8,637,452 82 (45) Date of Patent: Jan. 28, 2014 (54) WAFER St/1.1;111.E MEMBRANE PROTEINS AND METHODS FOR THE PREPARATION AND USE THEREOF 2011/0028700 Al 212011 Heal 2011/0046351 Al 2/2011 Weir et al. 201110112037 Al 5/2011 Warne et al. 2012/0165507 Al 6/2012 Jazayeri-Dezfuly et al. (75) Inventors: Shugnang Zhang, Lexington, MA (US); FOREIGN PATENT DOCUMENTS Alexander Rich, Cambridge, MA (US); Karol na Corin. Irvine, CA (US); Lotto EP 1270724 A2 • 2/2003 Cl2N 15/12 T.1Cgler. Linkoping (SE) WO WO 2007/089899 • 2/2007 C07K 14/705 WO 2008/114020 A2 9/2008 (73) Assignee: Massachusetts Institute of Technology, Cambridge. MA (US) WO WO WO 2011/095625 AI 8/2011 20121066330 Al 5/2012 2012/098413 Al 7/2012 WO 2012/120315 A2 9/2012 Zhang, S and Tao Fei, Design Code for Design code of detergent-free G protein-coupled receptors substituting hydrophobic amino acids using non-ionic amino acids and uses thereof. MIT case No. 16938X (To be filed in 2014) 0H2 Laboratories, LLC Confidential and Proprietary EFTA00586597 Shuguang Zhang, Ph.D. Inventor of self-assembling Peptide nanofiber scaffolds . 4 14A r ta 2 , A •ingle papInfr .16 amino adthi I lb.uvoil, µ Wok III..,- 1,1111,nn IM.,IT.hl Academic Biography • Institute: Center for Bits and Atoms, MIT • Alma mater: PhD, Biochemistry & Molecular Biology, Department of Biological Sciences, University of California, B.S., Sichuan University, China. • Award: Winner of R&D100 award for peptide matrix, Wilhelm Exner Medal of Austria. Fellow of US National Academy of Inventors, Fellow of American Institute of Medical & Biological Engineering. • Foreign Member of the Austrian Academy of Sciences in Vienna, Fellow of the American Institute of Medical & Biological Engineering, Honorary Professor of China University of Petroleum and Sichuan & Shanghai Jiaotong University. • 16 issued patents and 20 pending patent applications. • Published over 170 scientific papers. Business Biography • Co-founder of biotech startups 3-D Matrix., Ltd. (7777:JP), IPO in Japan in 2011 October on JASDAQ (current valuation • - $800 millions September 2014). • Co-Founder and Board member of Molecular Frontiers Foundation, a global organization with objective to early identify breakthroughs in science and to stimulate young people's interests in science. OH) Laboratories, LLC Confidential and Proprietary EFTA00586598 Robert S. Langer, Sc.D. Father of controlled drug release & tissue engineering Academic Biography ■ Institutions: David H. Koch Institute Professor at the Massachusetts Institute of Technology ■ Alma mater: Cornell University (Sc.D.), Massachusetts Institute of Technology (B.C.) • Awards: Priestley Medal, US National Medal of Science, 10th Annual Heinz Award in the category of Technology, Economy and Employment, Charles Stark Draper Prize, Lemelson-MIT Prize, Albany Medical Center Prize in Medicine and Biomedical Research, Millennium Technology Prize. ■ Member of US National Academy of Sciences, of Engineering and of Institute of Medicine. K Considered a pioneer of many new technologies, including transdermal delivery systems, which allow the administration of drugs or extraction of analytes from the body through the skin without needles or other invasive methods, and the creation of engineered blood vessels and vascularized engineered muscle tissue. K Maintained a research laboratory at MIT, which is the largest biomedical engineering lab in the world, maintaining about $10 million in annual grants and over 100 researchers. K Held more than 1020 granted or pending patents. K Authored more than 1,100 scientific papers. Business Biography K Participated in the founding of multiple technology companies. K Co-Founders for over 25 biotechnology companies. K Board members, scientific advisors and consultants for -100 entities. K Generated over $100 billion biotech business worIgivyyMarmyy. Confidential and Proprietary EFTA00586599 Alexander Rich, M.D. Discover of structures of collagen, RNA double helix, tRNA, Z-DNA Academic Biography K Institutions: The William Thompson Sedgwick Professor of Biophysics at MIT since 1958. K Alma mater: A.B. Harvard University and an M.D. from Harvard Medical School. K Awards: US National Medal of Science, MIT James Killian Award, Linus Pauling Medal, Lewis Rosenstiel Award, William Procter Prize, Lomonosov Medal. Passano Award, Bower Award and the Welch Award. K Member of US National Academy of Sciences, Institute of Medicine and Philosophical Society. Foreign member of French Academy of Sciences, Russian Academy of Sciences and Pontifical Academy of Sciences. K 5 Honorary Ph.D. from ETH-Zurich, Weizmann Institute of Science. Freie University-Berlin, Federal University of Rio de Janerio and Sichuan University, China. K Discovered nuclei acid hybridization. RNA double helix, DNA-RNA hybrid double helix, molecular structure of collagen, of tRNA, of DNA-anticancer drug complexes and polyribosomes. K Determined the molecular structure of left-handed double helix Z-DNA. This was the first single crystal structure of any form of DNA, published on the cover of Nature in Dec 1979. After 26 years of attempts, Rich and colleagues finally determined molecular structure of the junction of B-DNA and Z-DNA. Their results were again published on the cover in Nature in Oct 2005. ■ Editorial board of more than 20 journals including Science, PNAS, J.Mol. Biol., EMBO J.. RNA and Genomics. Business Biography ■ Co-Founder and the Co-Chairman of the Board of Directors of Repligen Corporation (NASDAQ: RGEN), a biopharmaceutical company since 1981. ■ Co-Founder and Board of Directors , Alkermes , Inc. (NASDAQ: ALKS) and has been its director since 1987. ■ Co-Founder 3DMatrix, Inc., Tokyo, Japan, 2002; Co-Founder and Board of Directors for Profectus BioSciences, Inc. 2004; Co-Founder, Beaver Biosciences, Guangzhou, China, 2009. ■ Scientific Advisor for 11 biotech companies. EFTA00586600 Next Steps/Raise Our next step is to demonstrate our process on 14 GPCRs simultaneously, as a final proof of concept. This work will take 4 months. At that milestone, we will publish scientific papers, raise money to form our first spin out company. Current raise: $800K in convertible notes at a 30% discount to Series A OH2 Laboratories, LLC Confidential and Proprietary EFTA00586601