Dr. Robert Langer - Simposio Internacional 'Terapias oncológicas avanzadas'

• 1. Biomaterials and biotechnology:From the discovery of the firstangiogenesis inhibitors to thedevelopment of controlled drugdelivery systems and the foundationof tissue engineeringDr. Robert S. LangerDavid H. Koch Institute ProfessorMassachusetts Institute of Technology

2. Anti-angiogenesis(Dormant Tumor)New CapillariesT A F 3. TUMORPOLYMER1.5mm4mm1mm 4. The agent to be released is a smallmolecule with a molecular weight no largerthan a few hundred. One would not expectthat macromolecules e.g. proteins, could bereleased because of their extremely smallpermeation rates through polymers.Adv. Poly. Sci., 1977 5. 10 20 30 40 50 60 70 80 90 100Days% Protein Released908070605040302010LysozymeSoybean Trypsin InhibitorAlkaline PhosphataseCatalaseLanger & Folkman, Nature, 1976 6. 806040200Cumulative Percent release0 10 20 30 40 50Days 7. TUMORPOLYMER1.5mm4mm1mm 8. Rabbit corneal pocket assay-CDI+CDILanger et al, Science, 1976 9. Angiogenesis inhibitors approved for clinical useDate Approved Drug DiseaseFebruary 2004 Avastin (Bevacizumab) Colorectal CancerNovember 2004 Tarceva (Erlotinib) Lung CancerDecember 2004 Macugen Macular DegenerationDecember 2005 Nexavar (Sorafenib) Kidney CancerDecember 2005 Revlimid Myelodysplastic SyndromeJanuary 2006 Sutent (Sunitinib) Gastric (GIST), Kidney CancerJune 2006 Lucentis Macular DegenerationMay 2007 Torisel (CCI-779) Kidney CancerNovember 2007 Nexavar (Sorafenib) Hepatocellular CarcinomaFebruary 2008 Avastin Breast CancerMay 2009 Avastin GlioblastomaNovember 2010 Afinitor Giant Cell AstrocytomaApril 2011 Zactima (Vandetanib) Medullary Thyroid CancerMay 2011 Sutent Pancreatic Neuroendocrine TumorsNovember 2011 Eylea (Aflibercept) Macular DegenerationJanuary 2012 Axitinib (AG-013736) Kidney CancerJuly 2012 Afinitor Breast CancerSeptember 2012 Eylea (Aflibercept) Central Retinal Vein OcclusionJanuary 2013 Avastin Metastatic Colorectal CancerFebruary 2013 Pomalyst (Pomalidomide) Multiple MyelomaApril 2014 Cyramza Advanced Stomach CancerAugust 2014 Avastin (Bevacizumab) Cervical Cancer 10. Overview of targeted therapiesTechnology Example ApproveddrugsPayloadSinglemoleculesHumira 20 1 moleculeNanoparticleconjugates0 103 - 105molecules 11. Coating nanoparticles withpolyethylene glycol (PEG)PEG chainsBiodegradable core + drugs 12. 1 5 50 500 5000Diameter(nm)Intensity 13. In vitro phagocytosis of surface-modifiedpolymeric particlesRat alveolar macrophages - 1hrPolymericparticleswithout PEGPEG(20,000 M.W.Single chain)PEG(5000 M.W.Single chain)PEG(5000 M.W.Triple chain) 14. Gref, R., Minamitake, Y., Peracchia, M., Trubetshoy, V.Torchillin, V., Langer, R. Biodegradable long-circulatingpolymeric nanospheres, Science, 263: 1600-1603, 1994. 15. Targetingmolecule 16. Manufacture: Pre-clinical, clinicaland commercial scale-upScale up for pre-clinical,clinical and commercialdevelopmentCurrent manufacturing scalesLaboratory 1-10 gTox 500 gPhase 1 5 kg 17. Human PK Data and clinical efficacy: (A) PK profile of Bind-014 at differentdoses (B)PK profile of BIND-014 versus DTXL at same dose. (C) PK Data (D)MRI of patient after treatment0 20 40 60100000100001000100101Time (hr)Total Docetaxel Concin Plasma (ng/mL)BIND-014; 30 mg/m2Taxotere; 30 mg/m20 5 10Before After Before After100000100001000100Time (hr)Total Docetaxel Concin Plasma (ng/mL)3.5 mg/m27 mg/m215 mg/m230 mg/m2 18. Accurin targeted nanoparticles are engineeredfor optimal targeting by two complementarymechanismsEPR onlyEPR + bindingLabeled Accurins administered to a mouse with two PC3 prostate xenografttumors: PSMA- and PSMA+ 19. Accurin targeted nanoparticles increasetumor drug targeting and improve efficacyScience Translational Medicine, April 2012,Hrkach et alClinical Cancer Research, June 2012, Zamboni et alTargeted nanoparticles demonstrate significant increase in tumor drug concentrations overparent drug (docetaxel)Targeted nanoparticles result in tumor regression compared to tumor growth for parent drugand non-targeted nanoparticles 20. Genetic medicine DNA Turn Genes on siRNA Turn Genes off 21. The gene medicine bottleneck:DeliveryThere are only three problems ingene therapy: delivery, delivery, anddelivery.Inder Verma, 1999 22. Previous approaches Lipids (no more than 30 were used) Our approach chemical libraries usingnovel synthesis approaches more than1,000 used 23. 1000s of new polymers and lipid-likematerials developedOOOO OO OO OOOOOO OOOOOOOOOO OO OOOOOOO OO O OOO OOOOOOOO O OOO OO OOOOOO OOOOOOO OO OOOOOOOOOOOOOOOOOOOOOO OOOOO OO O OOABCDEFJKLMOPQRSTUZAAO OO OBBO OO OO OF OO OOOFFFO OOO OIIJJKKLLOO O O O O O OOO OOOF OFFFFFFFPPO NH2OOOO NH2O NH2O NH2O NH2NH2ONH2OO NH2ONH2ONH2OONH2ONH2OONH2ONH2ONH2NH2OONH2OOONH2O123456789101112131415161718HOHO NH2NH2OHNH2OHNH2OHHONH2OHHOHO NH2NH2HO NH2HOHOHONH2NH2OHNH2HOOHNH2HONH2HOONH2OHNH2NH2HONH2NH2OHHONH2HONH2HOHONH21920212223242526272829303132333435363738396364656667NH2NH2NH2NH2NH2NH2NH2NH2NH2NH2NH2NH2NH2NH2NH2NH2NH2NH2NH2NH24041424344454647484950515253545556575859NHHNNHHNNHH60 N6162NHHN NHSi NH2OOSi NH2OOONHNHNHNHNHHNOOHNHNONHNHOOONHHNNHNHN NHSNH268697071727374N NH2NNH2NN NH2N NH2NNH2NH2N NH2NHONH2NHONH2NNH2N NH2N NH2HOHON NH2NNH2ONNH2O N NH2O N NH28788899091929394NH2FFFFFFN NH2NHNNNH2757677787980818283848586 24. Formulations induce long duration,reversible knockdown in mice, rats, guineapigs, and primates1.81.61.41.21.00.80.60.40.20.00 10 20 30 40 50 60 70 80 90 100 110Time (d)Relative FVII ProteinsiCont siFVII 25. LP-siCont 2.5 LP-siApoB 2.5 LP-siApoB 6.25mg/kg mg/kg mg/kg1.40.80.0Lipoprotein Relative to Pre-Dose 26. Fully reversible, specific liverknockdown1.81.61.41.21.00.80.60.40.20.00 10 20 30 40 50 60 70 80 90 100 110Time (d)Relative FVII ProteinsiCont siFVIIDose 1 Dose 2 Dose 3No evidence of reduced activity upon repeat administration 27. Improved lipidoid librariesH2N NH2O+ R90 oCCreated library of 150 new compoundsR ROH HO 10 different commercially available epoxide-terminatedtails Selection of amines from original lipidoid librarywith bias towards good performing amines fromprevious libraries Tested FIRST IN VITRON NHO OHR R 28. 2-3 orders of magnitude more efficientdelivery of siRNA in mice APO E independentNHONHNNNNHO NHONHOONH1.210.80.60.40.20PBS 1mg/kgsiLuc0.1mg/kg0.03mg/kg0.01mg/kg0.003mg/kg6 mg/kg 3 mg/kg 1.5mg/kgC12-200 LNP01Relative FVII ExpressionDose (Entrapped siRNA Content) 29. Single dose knockdown of TTR inPrimates at 3 weeks 34. Prototype deviceSilicon Nitrideor DioxideCathodeSiliconActiveSubstance Anode 35. Reservoir activation SEM of a reservoir electrode systembefore application ofan electric potential 36. Reservoir activation SEMs taken after application of 1.04 volts vs. SCE in PBS 37. Single compound release403020100Release Rate1 2 3 4 5 6 7Time (days)Fluorescein (ng/min) 38. Multiple compound releaseTime (Hours)60403020100Release Rate50Fluorescein (ng/min)45Ca++ (5xNCi/min)10 20 30 40 50 60 70 39. Clinical trial Chips are communicated with over a specialfrequency called the Medical ImplantCommunications Service Band, approved by boththe FCC and the FDA. A patient or doctor enters a special computer codeto administer or change the dose. Bidirectional communications link between the chipand receiver enables the upload of statusinformation, including confirmation of dose delivery,battery life, etc. 40. Clinical trial 8 patients PTH (compliance with injections is 25%) Small office procedure to implant Some pharmacokinetics (less variability)and Ca, PINP, CTX measures as dailyinjections 41. Gates Foundation grantsPhase I: Feasibility Granted in December 2012, term: 13 months Purpose: to develop a personal fertility control systemwith emphasis for use by women living in DevelopingWorld countries as a means to effectively plan theirfamilies Amount: $1,579,750Phase II: Detail Design Granted in January 2014, Term: 13 months Purpose: to develop a personal system that enableswomen to regulate their fertility Amount: $4,614,648