TapImmune (TPIV) Increasing the Potency of Nucleic Acid-Based Immunotherapeutic(s) using PolyStart Expression System
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1 TapImmune (TPIV) Increasing the Potency of Nucleic Acid-Based Immunotherapeutic(s) using PolyStart Expression System Robert Florkiewicz, Ph.D. & Glynn Wilson, Ph.D. 1
2 2
3 Immunotherapy Landscape Monoclonal Antibodies In Vivo: Herceptin (tratuzumab), Perjeta (pertuzumab) Roche/Genentech Keytruda (pembrolizamab) Merck Yervoy (ipilimumab) BMS/Mederax T-cell Stimulation Ex Vivo: T-Cell isolation and Transfer (e.g., Lion, Juno, Kite) Dendritic Cell isolation and Transfer (e.g., Dendreon, NW Bio, Prima BioMed, TPIV (PolyStart)) T-cell Stimulation* In Vivo: Antigen Approaches: ONTY, GALE, IMUC, antigen express Antigens + Prime/Boast W/PolyStart TM + Antigen Presentation: TPIV Small Molecules In Vivo: Agonists Antagonists 3
4 Immunotherapy Targets Strategic Overview Targeting Cancer and Infectious Disease by Synergistically Stimulating a Patient s: CD4 + Helper T-cells CD8 + Killer T-cells Antigen presentation across a broad patient population Simply put, our therapeutic objective is to simultaneously stimulate the in vivo or ex vivo production of antigenic peptide specific Helper T-Lymphocytes (HTLs) and Cytotoxic T-Lymphocytes (CTLs), that synergistically and selectively kill unwanted cells, thereby providing stronger and longer therapeutic benefit to a Patient Note: antigen presentation may be stimulated by vaccine formulations comprising selected synthetic peptides, nucleic acid expression vectors encoding selected antigenic peptides, or otherwise by modulating the antigen presentation pathway. 4
5 TapImmune: Immunotherapy Strategy Peptide-TAA Targeted Compositions CD4 + T-Helper and CD8 + Cytotoxic T-Killer Cells Cooperate Synergistically to Exterminate Tumor Cells Tumor cell APC-CD40 + MHC Class I *INFγ [IL-2] CD8 + T-Cell Effector-Cytotoxic Killer T-Cell TCR +, CD40L + Ab and Mφ mediated CD4 + T-Helper Cell TCR +, CD40L + Class I mediated B-cell CD40 + Class II mediated *Proprietary Peptide(s) and/or PolyStart TM Nucleic Acid Expression System/Vector [IL-12] Dendritic Cell Professional APC MHC Class I and II CD40 + 5
6 Immunotherapy Targets Identify an indication of commercial interest (e.g., breast/ovarian cancer) Identify a Tumor Associated Antigen (TAA) differentially expressed by cancer cells Identify potential MHC Class I or Class II peptide epitopes Screen Patient samples and select peptide(s) associated with a measurable immune response for further evaluation 6
7 Immunotherapy Targets Evaluate patient samples and select specific antigenic peptide epitopes for further development Initial selection is based upon T-cells isolated from a group of patients screened for the ability to interact with specific peptide epitopes 7
8 Mid-Stage Pipeline - Multiple Shots on Goal Indication Design Preclin. Phase 1 Phase 2 Sponsors/ Collaborators Triple-Negative Breast Cancer Dose & Boost Safety Enrolling Phase 2 HER2/neu Folate Receptor-α TPIV200 TPIV110 TPIV100 Ovarian Cancer (platinumsensitive) Triple-Negative Breast Cancer Ovarian Cancer (platinum-resistant) Her2/neu Breast Cancer DCIS Breast Cancer Time to progression Time to progression Combo with durvalumab (anti PD-L1) Preparing Phase 1/2 Preparing Phase 2 Enrolling Phase 2 Enrolling Phase 2 Enrolling Phase 2 IND update Start in 2017 Fully Funded Fully Funded 8
9 Advancing Our Therapeutic Opportunity Pipeline: Additional indications and targets (TAAs) Nucleic acid expression technology PolyStart 9
10 Features of PolyStart *Overcomes expression level deficiencies associated with any current nucleic acid-based delivery systems by providing four moles of primary translation products for one mole of mrna, thereby enhancing antigen specific immunogenicity, potency. A Novel vaccine technology, cost effective polygenic nucleic acid-based, co-linear polystart TM technology, functionally distinct from conventional single target monoclonal antibody mediated immunotherapies such as Herceptin. Co-linear Polystart TM technology, directs the enhanced synthesis of a linear peptide antigen array () comprising multiple proprietary T-cell peptide epitopes (appropriate to killer CD8 + and/or long term helper CD4 + T-cells). Versatile and Dynamic, synergistically enhances killing of unwanted cells, simultaneously providing multiple T-cell mediated target opportunities to kill cancer cells (e.g., breast, colorectal) or virally infected cells (e.g., SARS, small pox). T-cell epitopes effectively identified directly from patient samples or by in silico generated algorithm (rapid plug-and-play design). Adjuvant affect, can be built in, mediated by co-expressed cytokine(s), PAMPs etc. Flexible, administered as a standalone formulation or incorporated into a viral delivery system (e.g., VACV, Adenovirus). Vaccine technology, broadly applicable in conjunction with T-cell peptide based immunization modalities (e.g., prime and boost paradigms). 10
11 Features of PolyStart Professional Antigen Presenting Cell (e.g., DC) Distinct Intracellular Pathways Mediate The Proliferation of Cognate T-ells CTLs Proliferate Seek and Destroy Tumor Cells CD8 + T-Cell Helper T-Cells provide cytokines and some cell killing CD4 + T-Cell Peptides MHC Class II CD4 + response *PolyStart Proteasome Peptides MHC Class I CD8 + response Golgi Endosome lysosome nucleus Endoplasmic reticulum conventional, steady state representative diagram 11
12 Nucleic Acid-Based Technology: State of the Art Typical approaches and key features include: Manufactured using Prokaryotic cells Copy number and selection (antibiotic free) Eukaryotic promoter/enhancer elements Translation (1X, codon optimized) Suitable for clinical trials/fda familiarity Williams, Vaccine 1:225,
13 PolyStart and Poly-Antigen Array () Infectious Disease Target(s) PolyStart portion derived from hfgf2 Portion (CTL epitopes) mrna (one mole) 5.CUG.CUG CUG..AUG..()..TAA 3 4 aa Note: Nuclear and cytosolic Localization possible NH Translation 2 NH 2 (four moles) NH 2 NH 2 VAR gene ID F1L GB AAA VAR/MPV gene ID G5R NP_ VAR/MPV gene ID QiL NP_ Matrix Protein M1 Influenza A GenBank AAA Control peptide VAR gene ID F11L AAA evntilmdnkglgvrlat(g 4 S) 2 ksltilddnlykvyngi(g 4 S) 2 rtddglldrlydltrya(g 4 S) 2 pltkgilgvftltvps(g 4 S) 2 kivnslsnldfrl NH 2 - YTDIEMNRLGK VSVG epitope tag - Note: the Poly-Antigen Array () portion is a modular design for rapid straight forward replacement 13
14 TapImmune: Nucleic Acid-Based Technology Stimulating selected peptide MHC Class I:CD8 + T-cell response TapImmune Advantage (PolyStart TM and ) Translation enhanced 4 fold (1 mrna : 4 primary translation products) PolyStart Nucleic Acid () 14
15 Exemplary Intracellular Expression of r and rtap1 Transfected COS-1 cells, transient expression A. pcdna3 MG132 [10µΜ] kda *Novel provides four translation products from one mrna Amino Acids MW (kda) B. pcdna3tap1 - + C. Transient or stable expression format kda IP with tag antibody Immunoblot with tag antibody 2 Visualize by chemiluminesence 15
16 Functional T Cell Antigens from MTI- Product ELISPOT assay, CD8 + T-cells derived from HLA-A2 Tg mice 16
17 PolyStart Summary: Infectious Disease Confirmed overall strategic design Characterized selected Infectious disease target small pox Four primary translation products detected Confirmed functional MHC Class I peptide presentation, in vitro (i.e., ex vivo) Flexible, replacing nucleic acid domain encoding antigenic peptide epitopes Next step, expand characterization to include oncology targets, utilizing clinical trial amenable plasmid vector backbone (e.g., Nano-Plasmid (NTC)) 17
18 PolyStart Her2/neu Poly-Antigen Array () A. Strategy PolyStart Portion Poly Antigen Array Portion Epitope Tag/ Stop Portion Cla1, Hpa1 Xho1 Not1 Apa1 Mfe1 / Xba1 Pme1/Xba1 Mlu1, Cla1 CUG1 CUG2 CUG3 AUG 5 3 B. Design PolyStart Portion Portion (T-cell epitopes) mrna (one mole) Translation (four moles) 5.CUG.CUG CUG..AUG..()..TAA 3 NH 2 NH 2 NH 2 NH2 4 aa Note: nuclear and cytosolic localization possible C. Her2/neu: 4 MHC Class II and one MHC Class I T-cell Epitopes NH2- vvqgnleltylptnaslsflqdi(g 4 S) 3 vliahnqvrqvplqrlrivrgtq(g 4 S) 3 fgslaflpesfdgd(g 4 S) 3 slpdlsvfqnl QVIRGRILhnga(G 4 S) 3 ggkvpikwmalesilrrrfthqsgsypydvpdyagsypydvpdyagsypydvpdya- Note: PolyStart derivative of Nano-Plasmid vector from Nature Technology Corporation 18
19 PolyStart Mediated Expression of Her2/neu and FRA kda 38 Transfected HeLa Cells: Immunoprecipitation / Immunoblot Analysis Her2/neu FRA Negative Control : Her2/neu Amino Acids Predicted MW (kda) ? 214 Amino Acids 284 : FRA 24.6 Predicted MW (kda) *Each novel provides four primary translation products from one mrna 19
20 Her2/neu 4+1 : More Than Four Fold Increase In Expression Quantifying Relative Expression Levels Note: Band 4* represents the single AUG initiated primary translation product incorporating the previously shown Her2/neu 4+1 derived T-cell epitopes and therefore represents 1 mole of protein for 1 mole of mrna. However, in this analysis, with the simultaneous addition of 3 CUG initiated primary translation products (i.e., bands 1, 2 and 3), the calculated expression level is 6.25 moles of protein for 1 mole of mrna. 20
21 PolyStart Her2/neu Poly-Antigen Array () NetCTL2.1 analysis of potential embedded HLA Class I analysis of the four Her2/neu HLA Class II peptides 21
22 PolyStart Folate Receptor Alpha Poly-Antigen Array () A. Strategy PolyStart Portion Poly Antigen Array Portion Epitope Tag/ Stop Portion Cla1, Hpa1 Xho1 Not1 Apa1 Mfe1 / Xba1 Pme1/Xba1 Mlu1, Cla1 CUG1 CUG2 CUG3 AUG 5 3 B. Design PolyStart Portion Portion (T-cell epitopes) mrna (one mole) Translation (four moles) 5.CUG.CUG CUG..AUG..()..TAA 3 NH 2 NH 2 NH 2 NH2 C. FRA: 5 MHC Class II T-cell Epitopes 4 aa Note: nuclear and cytosolic localization possible NH2 iawartellnvcmnakhhkekpgpe(g 4 S) 3 klheqcrpwrknaccstntsqea(g 4 S) 3 qeahkdvsylyrfnwnhcge MApack(G 4 S) 3 cspnlgpwiqqvdqswrkervlnvp(g 4 S) 3 sgagpwaawpfllslalmllwllsgsypydvpdyagsypydv PDYAGSYPYDVPDYA- 22
23 Expression of Her2/neu or FRA Focusing on MHC Class II Expression Construct 1b: Portion is Her2/neu 4+1 with 3XHA tag, VSVGss, 3XStrep Tag, Her2/neu4+1(GS), LAMP TM/CTY PolyStart Portion Her2/neu 4+1(GS) LAMP Portion TM/CYT Cla1, Hpa1 Xho1 Not1 Apa1 Mfe1 CUG1 CUG2 CUG3 AUG EcoR1/Xba1 Xba1/Pme1 Mlu1, Cla1 5 3 Intracellular trafficking - taking advantage of PolyStart but uncoupled from potentially confounding NH2 co-linear extended amino acid sequence 23
24 Indirect Immunofluorescence: Intracellular Localization 24
25 TapImmune: next steps and partnering opportunities Project: Design: Evaluate immunogenicity of PolyStart expression vector(s) encoding either multiple Folate Receptor Alpha (FRA) or Her2/neu CD4 + or yet to be determined peptide epitopes containing embedded CD8 + epitopes. (a) Prepare peptide specific CD8 + T-cells isolated from the appropriate HLA restricted Tg mice and/or human donors, peptide immunization; (b) Evaluate ability of isolated T-cells to recognize matched MHC Class I presented peptide complex by ELISPOT assay, transfected cell system; (c) Identify transgenic animal model (e.g., HLA-A2 Tg mice), subdermal PolyStart nucleic acid immunization and isolate T-cells, perform ELISPOT assay using appropriately matched HLA restricted/transfected animal cell cultures. Further: Evaluate PolyStart cassette in context of one or another expression system of choice (e.g., RNA, viral, yeast) and/or encoding CD8 + T- cell epitopes of interest. 25
26 Intellectual Property Assets Related to PolyStart Title: A Chimeric Nucleic Acid Molecule with Non-AUG Translation Initiation Sites U.S. Patent Application No. 14/660,924 filed , issued as U.S. Patent No. 9,364,523 U.S. Divisional Patent Application No. 15/180,852 filed (method claims, ID, IM and IV delivery)) U.S. C2 Patent Application No ,619 filed , issued May 23, 2017 as U.S. Patent No. 9,655,956 B2 U.S. Continuation Patent Application No. 15/222,627 filed (Note allowed subject mater, any ) International Patent Application No. PCT/US2015/627 filled Entitled: Nucleic Acid Molecule Vaccine Compositions and Uses Thereof (National Phase entry 9/2016) Indian (IN) Patent Application No Canadian (CA) Patent Application No. 2,942,501 European (EP) Patent Application No Brazil (BR) Patent Application No. BR Chinese (CN) Patent Application No. not yet assigned Australian (AU) Patent Application No. AU New Zealand (NZ) Patent Application No Japanese (JP) Patent Application No. not yet assigned 26
27 Patent No. 9,364,523 A Chimeric Nucleic Acid Molecule with Non-AUG Translation Initiation Sites Issued Claim 1 1. A chimeric nucleic acid molecule, comprising a multiplex translation initiation (MTI) sequence comprising from two to about five translation initiation sites operatively linked in frame to a nucleic acid molecule encoding a fusion protein comprising from two to about ten eukaryotic folate receptor-alpha (FRα) antigenic peptides, wherein at least one of the MTI translation initiation sites is a non-aug translation initiation site and the MTI allows the production of more than one mole of fusion protein per mole of mrna. mrna (one mole) 5.CUG.CUG CUG..AUG..()..TAA 3 4 aa NH Translation 2 NH 2 (four moles) NH 2 NH 2 27
28 PolyStart a versatile nucleic acid expression technology Concluding: Strategic design Data showing expression, trafficking Data showing processing and presentation Intellectual property assets 28
29 END THANK YOU Technology: Robert Florkiewicz, Ph.D, Sr Director Molecular Biology and Virology Business: *Peter L. Hoang, President & CEO (904)
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