ReNeuron : Presentation

TARGETED DELIVERY OF THERAPEUTIC PAYLOADS USING STEM-CELL DERIVED EXOSOMES

Sam Thomas - Group Leader- Cell Biology - Research

Cell 2023, London UK

08 November 2023

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© ReNeuron Group plc 2023 All rights reserved

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Introduction

ReNeuron's seven proprietary cell lines and Conditional Immortalisation Technology.

Distinct Exosome Profiles influence cellular tropism.

Recent in vivo validation of CustomEX™ targeting capabilities.

Confirmation of targeted delivery of a therapeutic payload in vivo using the CustomEX™ platform.

© ReNeuron Group plc 2023 All rights reserved

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Why stem cell exosomes?

Limitations around current delivery platforms

o Safety - Viral vectors have been plagued by side effect issues. Viral vectors and LNP's , both have immunogeneic properties that are problematic

o Efficiency of loading and delivery - Limitations on the type, size of cargo and the efficient delivery of therapeutic dose (endosomal escape)

1. Tissue/cell targeting - Lipid Nanoparticles & HEK derived exosomes have limited targeting abilities with delivery mainly to the liver.

Stem cell exosomes - targeted delivery platform for complex drug modalities

1. Safety - Naturally occurring nanoparticles released by all cells for the purpose of intercellular communication - non immunogenic

1. Efficiency of loading and delivery - Proven ability to carry and deliver more than one bio-active cargo simultaneously including proteins and nucleic acids

1. Tissue/cell targeting - Critically, they target recipient cells via specific surface proteins that are determined by their cell of origin

EXOSOME CELL SOURCE IS AN IMPORTANT CONSIDERATION FOR TARGETED DRUG DELIVERY

© ReNeuron Group plc 2023 All rights reserved

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CustomEX™ - A customisable, exosome platform optimisedfor specific targeting capabilities

Competitors - Single cell line approach

o Single cell line, single outcome

o 'One size fits all'

ReNeuron - Portfolio of stem cell derived exosomes

o Exosomes have functional properties based on parent stem cell line

o Multiple conditionally immortalised exosome producer lines allows candidates to be chosen for their ability to target specific tissues and cell types

ReNeuron - Know-how and IP

o 15+ years of experience in CLD and GMP manufacture of stem cells

o IP around conditional immortalization and production of stem-cell derived exosomes and loading

o 10+ years of clinical safety data for conditional immortalization technology

© ReNeuron Group plc 2023 All rights reserved

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CustomEX™ - A customisable, exosome platform optimisedfor specific targeting capabilities

Competitors - Single cell line approach

o Single cell line, single outcome

o 'One size fits all'

ReNeuron - Portfolio of stem cell derived exosomes

o Exosomes have functional properties based on parent stem cell line

o Multiple conditionally immortalised exosome producer lines allows candidates to be chosen for their ability to target specific tissues and cell types

ReNeuron - Know-how and IP

o 15+ years of experience in CLD and GMP manufacture of stem cells

o IP around conditional immortalization and production of stem-cell derived exosomes and loading

o 10+ years of clinical safety data for conditional immortalization technology

© ReNeuron Group plc 2023 All rights reserved

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Conditional Immortalisation - The ReNeuron Advantage

	ReNeuron's c-mycER technology
		Cell proliferation
Add 4-OHT

c-mycER

No proliferation

Remove 4-OHT

Banking of candidate lines

Add 4-OHT

Banking

• Standard stem cell exosomes have significant

barriers to their clinical translation

• Heterogeneity

• • Scale
• Consistent and Scalable Exosome Production through Conditional Immortalisation of the producer cell line
• • Stable producer cell line - Consistent phenotype maintained over multiple passages
  • Fully qualified xeno-free GMP process - tightly controlled USP with strict release criteria
  • Scalability - produced to a commercially relevant scale in multi-tier tissue culture flasks
  • Stable exosome product at 4 oC, -80oC
  • Safe: No c-MycERTAM within exosomes

CONDITIONAL IMMORTALISATION TO PRODUCE CONSISTENT EXOSOMES AT A CLINICALLY

RELEVANT SCALE

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In vitro data highlighting exosome targeting is dependenton cell source

Exosome biology influences tropism and delivery of cargo - selection of exosome type is an importantconsideration.

• Previous results indicated that the CustomEX™ products were distinct in their protein expression profiles and uptake profiles in a panel of cell lines suggesting that exosome biology influences tropism and therefore may result in better delivery of a therapeutic cargo.

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Main Tissue Distribution Similar Irrespective of CellSource Following Systemic Administration

EV1

EV2

EV3

EV4

*Note 1 animal had a missed injection and was excluded from the analysis.

• Zr-89labelled exosomes mainly traffickedto the liver and spleen (and to a lesser extent the kidney).
• This signal was retained up to 120h timepoint.
• Biodistribution to the liver, spleen and kidney was further confirmed at the experimental end point (120h) using gamma counting outputs of the selected tissues/organs.
• This also indicated that the distribution follows the same pattern irrespective of exosome cell source.
• This potentially indicates that no differences in biodistribution will be observed when carrying out a radioactive PET/CT study due to limits in resolution and due to the whole organ/tissue being quantified.

© ReNeuron Group plc 2023 All rights reserved

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Main Tissue Distribution Similar Irrespective of CellSource Following Systemic Administration

*Note 1 animal had a missed injection and was excluded from the analysis.

• Zr-89 labelled exosomes mainly traffickedto the liver and spleen (and to a lesser extent the kidney).

• This signal was retained up to 120h timepoint.

• Biodistribution to the liver, spleen and kidney was further confirmed at the experimental end point (120h) using gamma counting outputs of the selected tissues/organs.

• This also indicated that the distribution follows

the same pattern irrespective of exosome cell source.

• This potentially indicates that no differences in biodistribution will be observed when carrying out a radioactive PET/CT study due to limits in resolution and due to the whole organ/tissue being quantified.

© ReNeuron Group plc 2023 All rights reserved

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