Development of pancreatic cancer targeting aptamer and therapeutic application CHOI SUN IL National Cancer Center, Korea JP BIO A Corporation, Korea
[Background of Study] Apta ptamer mer is is “nucleic ac acid id antibody” Aptamer sequence Target binding Binding mechanism 3D structure formation AGA G A A A CAAT A A A - Structure compatibility G T A G T A A A A Target A G AATAC - Electrostatic interaction Definition Single-stranded oligonucleotide molecules Aptamer selection process : SELEX (Systematic Evolution of Ligands by Exponential enrichment) High (pM – nM) Affinity High specificity Nucleic acid Material (long-termstability as dry powder or in solution) In vitro Chemical process Production Wide range of target Target (protein, sugar, ion, cell, toxins, …) Batch to batch Little or no variation Easy and straightforward Modification : site-specific modification possible 20 kDa Size Fast tissue penetration Penetration
Objec Objectiv tive of of study study To o de develop elop apta ptamer mer-ba based sed the therape peutics utics with wi th high high spe specifi cificity and city and ef effi fica cacy for or pa panc ncrea eatic tic ca canc ncer er
The he str strate tegy of of Doli Doligob gobody ody (Drug-oligomer-antibody complex) ③ To enhance the efficacy Drug (Payload) ① Specific targeting ② To enhance the stability Aptamer and optimization for modification Antibody (Supporter) Pancreatic cancer cell
1-1. Cell Cell-SELEX SELEX for or pancr pancrea eatic tic cancer cancer specific specific aptamer ptamer C D H&E Library SQ6 SQ7 SQ8 SQ9 Normal cells (HPNE) 20 μ m Target cells (CMLu-1) 20 μ
1-2. Siz Size-op optim timiza ization tion of of SQ SQ7 : SQ SQ7-1 (32 32 nt nt) SQ7 aptamer structure-based SQ7-1 aptamer internalizing size minimization to SQ7-1 into CFPAC1 cells
2. Aptamer ptamer-antibody antibody comple complex (Oligobo Oligobody dy)
3. Dr Drug ug-conjuga conjugated ted Oligobo Oligobody dy (DO DOligobody ligobody)
Su Summar mmary DOligobody (Drug + Oligomer + Antibody) has anti-cancer effect. VC-MMAE (Payload) Powerful Cell toxicity Selective cleavage (Cathepsin B) Aptamer SQ7-1 (Navigator) High affinity & specificity Internalization Cotinine & Cot-body (Supporter) Humanized anti-cotinine antibody Increase pharmacokinetics
CO CONC NCLS LSIO ION De Develop elopmen ment of t of apta ptamer mer-ba based sed the therape peutics utics for or pa panc ncrea eatic tic ca canc ncer er High Higher er sta stabili bility ty High High spec specificity ificity Higher High er pe pene netr tration tion High af High affinity finity Cell death Drug is released into the cytoplasm Lysosome High ef High efficac ficacy (CathepsinB) → Cell death
Ac Ackn knowl wled edge gemen ment <Ad <Advi visor> sor> * * Dr. . Yun un-Hee Hee Kim Kim, , NC NCC, , GC GCSP SP <Aptame tamer> r> <Lab me memb mbers> rs> Hyun un Jung ung Kim, im, NCC CC Dr. Dr . In-Hoo oo Kim, im, NCC CC, , GCS CSP Yu-Sun Yu un Lee, N Lee, NCC CC Yul ul Min in Lee Lee, N , NCC CC, , JP JP BIO BIO A Dr Dr. . Kyun un Heo eo, , NCC CC Joon K oon Ki i Kim, im, NCC CC Dr. Dr . Youn oun Hoon oon Joo oo, JP , JP BIO BIO A C A Co. Be Benja njamin min, , NCC CC Dr Dr. . Junho unho Chung, Chung, SNU Mi i rim rim Lee, N Lee, NCC CC <Flow w cyto ytome metr try & y & Confoc focal analys ysis> s> <Anima mal experi rime ment t & & ti tiss ssue patho thology> y> Tae ae Sik ik Kim, Kim, NCC NCC Mi i Sun un Par ark, k, NCC CC Mi i Ae K Ae Kim, im, NCC CC Bo Bo Ra K Ra Kim, im, NCC CC
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