Generation Bio — ESGCT 30th Annual Congress (October 2023)
23 slides from Generation Bio's conference presentation, Oct 26, 2023
Slide 1: A cell-targeted lipid nanoparticle technology with enhanced cell selectivity for in vivo DNA delivery
A cell-targeted lipid nanoparticle technology with enhanced cell selectivity for in vivo DNA delivery Dr. Matt Stanton ESGCT 30th Annual Congress
Slide 2: Forward Looking Statements
Forward Looking Statements Any statements in this presentation about future expectations, plans and prospects for the company, including statements about our strategic plans or objectives, our technology platform, including our rapid enzymatic synthesis (RES) technology, our research and clinical de
Slide 3: GBIO is bringing DNA to non-viral genetic medicines
GBIO is bringing DNA to non-viral genetic medicines siRNA- mRNA- DNA- GalNAc LNP LNP Redosable Redosable Redosable Loss of function Gain of function Gain of function Durable Transient Durable 3
Slide 4: GBIO is bringing DNA to non-viral genetic medicines
GBIO is bringing DNA to non-viral genetic medicines siRNA- mRNA- DNA- GalNAc LNP LNP Redosable Redosable Redosable Loss of function Gain of function Gain of function Durable Transient Durable POTENTIAL HAS BEEN LIMITED BY INNATE IMMUNITY TO NUCLEIC ACIDS 4
Slide 5: Solving innate immunity to DNA has never been done
Solving innate immunity to DNA has never been done DNA LNP IMMUNE STIMULATION NON-SPECIFIC DELIVERY No known modifications to make Off-target delivery drives innate DNA immune-quiet immune stimulation 5
Slide 6: We have made deep investments in our platform to solve this problem
We have made deep investments in our platform to solve this problem CARGO MANUFACTURING DELIVERY 6
Slide 7: Enabling innate immunity solutions at cargo and delivery level
… enabling innate immunity solutions at cargo and delivery level iqDNA ctLNP IMMUNE QUIET DNA MULTI-TISSUE Immune-quiet DNA Avoids off-target clearance by avoids innate immunity the liver and spleen 7
Slide 8: Unlike RNA platforms, we started with no known chemistry solutions to DNA innate immunity
Unlike RNA platforms, we started with no known chemistry solutions to DNA innate immunity DNA INNATE IMMUNITY siRNA IFN-alpha 1500 2’ ribose chemical modifications Empty LNP Mean Concentration DNA-LNP 1000 (pg/ml) 500 mRNA 0 Uridine chemical modifications/purity 8
Slide 9: iqDNA profile is conserved across species, including human PBMCs
iqDNA profile is conserved across species, including human PBMCs Transduced hPBMCs 2500 ceDNA iqDNA IL-6 TNF-α 80000 2000 mRNA 300 Repeat Study First Study IL-6 (pg/mL) 60000 ceDNA ceDNA 1500 iqDNA iqDNA 200 pg/mL Untreated pg/ml 40000 1000 100 20000 500 max un t 0 0 0 PreDose 6 hr. 24 hr. ceDNA iqD
Slide 10: ctLNP platform enables access to new tissues and cell types
ctLNP platform enables access to new tissues and cell types Cell-targeted delivery avoids off-target clearance by liver and spleen ctLNP SPECIFIC DELIVERY
Slide 11: Stealth LNP profile supports targeting to tissues and cell types beyond the liver
Stealth LNP profile supports targeting to tissues and cell types beyond the liver Stealth LNP persists in circulation and Setting the stage for cell and avoids liver and spleen uptake tissue-selective delivery Long serum half-life w/o GalNAc available for ligand-directed extraction 10 2 10 1 50% (of
Slide 12: In vivo targeted delivery could transform access to cell therapies
In vivo targeted delivery could transform access to cell therapies Ex vivo cell therapy requires a Our goal is to modify target highly complex, expensive and cells in vivo using selective and lengthy process re-dosable ctLNPs 12
Slide 13: Targeting platform is a modular system built on our foundational stealth LNP technology
Targeting platform is a modular system built on our foundational stealth LNP technology, capable of targeting a wide variety of extra-hepatic tissues ctLNP Targeting Platform VH Select Immune Cell Targeting VL LIGAND BIOLOGY Oncology Small format ligand discovery, Immunology panning, cell biology fo
Slide 14: Stealth LNP controls show low/no uptake and expression in human immune cells in hPBMC mice
Stealth LNP controls show low/no uptake and expression in human immune cells in hPBMC mice (mRNA cargo) Enhanced blood exposure avoids off target Control conjugation does not affect basal clearance & available for targeting immune cell uptake Whole Blood PK 100 hPBMC Stealth LNP Parent Non-stealth L
Slide 15: Stealth LNP carrying mRNA maintains prolonged PK profile and avoids clearance in NHP
Stealth LNP carrying mRNA maintains prolonged PK profile and avoids clearance by liver and spleen in NHP Majority of drug remains in circulation, Enhanced blood T½ with stealth LNP in NHP avoiding biodistribution to the liver or spleen Whole Blood PK NHP mRNA BioD at 6hr SOI EOI (0.5mpk; mLuc) 10 2
Slide 16: Validated bioconjugation platform to discover and characterize cell targeted LNP conjugates
Validated bioconjugation platform to discover and characterize cell targeted LNP conjugates Small format ligand/conjugate discovery Site-specific conjugation chemistry Single chain VHH Single domain Optimization Parameters antibodies antibodies • Linker chemistry • Linker length Binding affinity (oc
Slide 17: Stealth LNP conjugates targeting human T cells demonstrate dose dependent, receptor specific uptake in vitro
Stealth LNP conjugates targeting human T cells demonstrate dose dependent, receptor specific uptake in vitro Efficient conjugation of protein Conjugated LNP uptake and expression is ligands maintains LNP stability dose dependent and target specific High Conjugation Efficiency High Specificity Dose R
Slide 18: Validation of T cell targeted ctLNPs sets stage for in vivo POC experiment in hPBMC mice
Validation of T cell targeted ctLNPs for analytical quality and in vitro uptake/expression sets stage for in vivo POC experiment in hPBMC mice Blood and Spleen flow cytometry 0.5mpk i.v. injection • ctLNP anti-huCD3ε • ctLNP anti-huY 24hrs • ctLNP anti-huX • ctLNP anti-huHer2 CRL (Non-targeting Ctrl
Slide 19: T cell targeting LNP conjugates induce uptake and expression of mRNA cargo in vivo
T cell targeting LNP conjugates induce uptake and expression of mRNA cargo in vivo GFP expression in circulating T cells Anti-Her2-ctLNP Anti-CD3ε-ctLNP Non-targeting control (hPBMC mice; 0.5mpk; 24hrs post dose) 100 Evidence of T cell depletion 80 hPBMC huCD3+ cells %GFP+DiD+ 60 40 Anti-huY-ctLNP A
Slide 20: Off-target cell type uptake & expression remains at baseline with successful T cell engagement
Off-target cell type uptake & expression remains at baseline with successful T cell engagement GFP Expression in GFP Expression in Splenic Myeloid & B cells Circulating Myeloid cells 100 100 100 %GFP+/DiD+ Mu-myeloid Cells %GFP+/DiD+ muMyeloid Cells %GFP/DiD+ huCD19+ cells 80 80 80 60 60 60 40 40 40
Slide 21: T cell targeted ctLNP demonstrates selective uptake and expression across a dose range in vivo
T cell targeted ctLNP demonstrates selective uptake and expression across a dose range in vivo Efficient T cell transduction Minimal off target cell uptake across dose range and expression 10000 70% of T cells 100 T cells T cells Myeloid Cells Myeloid cells 8000 80 gMFI of GFP+ cells %GFP+DiD+ cells
Slide 22: Next steps are focused on therapeutic translation of extra-hepatic targeting platform
Next steps are focused on therapeutic translation of extra-hepatic targeting platform Evaluate Translate Continued expression and T cell optimization of PD/efficacy of targeted stealth LNPs, therapeutic ctLNPs to targeting transgenes in non-human ligands, and humanized primates conjugation mouse mod
Slide 23: Thank You
Thank You Questions & Answers
Generation Bio — ESGCT 30th Annual Congress (October 2023) on 6ix