Avacta : Targeting the Tumor Microenvironment – June 2024 presentation deck

Targeting the Tumor Microenvironment

Avacta Therapeutics

June 2024

Avacta is challenging the current drug delivery models to expand the reach of highly potent therapeutics using peptide drug conjugates

REVOLUTIONARY

Approach

ROBUST

Pipeline

INNOVATIVE

R&D team

Avacta leverages a key protease (fibroblast activation protein-α,FAP) in the TME as a tumor-specific release mechanism enabling delivery of potent warheads directly to the TME with clinical POC achieved

The FAP-enabled drug release mechanism is used in small molecule peptide drug conjugates (PDC) and biologic-targetedapproaches in the

pre|CISION™ ADC and Affimer™ -DC(AffDC) programs

The R&D leadership team have >15 years industry experience each, over 40 INDs and drug approvals, with expertise in cancer biology, chemistry, clinical, and business development

© Avacta Group plc 2024

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The Avacta Therapeutics Research and Development Team

Christina Coughlin,

MD, PhD

Chief Executive Officer

and Head of R&D

Chris is an oncologist and

immunologist, trained at the University of Pennsylvania

She has >18 years of industry

experience including >30

oncology INDs and approvals across small molecules to cell therapy in oncology

Simon Bennett,

DPhil

Chief Business Officer

Simon is a biochemist with

more than 26 years'

commercial experience in

biopharmaceuticals, supporting business development and corporate development

Simon has been involved in over 80 commercial deals across geographies

Karen Harrison,

MBA

Chief Operating Officer

Karen has >30 years' experience in building successful teams and delivering all operational aspects of her teams

Karen's focus is on value creation and global reach of companies, delivering transformational operational planning

David Jones,

DPhil

VP and Head of Biology

David trained at the

University of Birmingham in the science of oncology modeling with expertise in

both in vitro and in vivo

modeling of cancer

biology

David has worked in

models of human disease with more than 15 years' industry experience

Francis Wilson,

DPhil

VP and Head of Chemistry

Francis trained in medicinal

chemistry at Oxford

University

Francis has >30 years'

experience in industry with

multiple companies and

programs advanced across multiple therapeutic areas including the science of biologic-small molecule conjugations

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© Avacta Group plc 2024

Avacta is Combining Two Innovations to Deliver Potent Warheads to the TME

pre|CISION™ technology

The pre|CISION peptide prevents cellular entry of the warhead and is only released in the TME

pre|CISION peptide

The pre|CISION™ platform enables first-in-classpeptide drug conjugates (PDC) that

boost efficacy and minimize off-target toxicity with clinical proof-of-concept

warhead

Affimer® technology

Next-generation biotherapeutic class to surpass the limitations of antibody cancer therapies

Variable loop	Affimers® are a novel class
regions

of biologics, based on the Stefin A protein, with a best-in-classtherapeutic protein binder at 1/10th the size of an mAb

Next-gen pre|CISION ADC therapeutics

Combining the highly tumor-specific release mechanism of pre|CISION with the biologic advantages of an Affimer create a novel class of Affimer Drug Conjugates

© Avacta Group plc 2024

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FAP is the Ideal Tumor-Selective Enzyme that can be Leveraged to

Deliver Warheads to the TME

FIBROBLAST

ACTIVATION

PROTEIN-α (FAP)

Cancer Associated

Fibroblast (CAF)

Cell membrane

FAP is an enzyme selectively expressed in human cancers1

Member of the DASH family of serine proteases2,3, which are not specific to tumor tissue which includes:

DPP-IV	DPPII	DPP8	DPP9	Prolyl
Endopeptidase
(DPP4)	(DPP2)
		(PREP)

FAP is found on the cell surface of cancer-associatedfibroblasts (CAF) in the TME and on the tumor

cell membrane in some cases

Over-expression of FAP in the TME is associated with poor prognosis: increased metastasis and lower overall survival3

1 Gorrell MD, et al. Structure and function in dipeptidyl peptidase IV and related proteins. Adv Exp Med Biol. 2006;575:45-54. Epub 2006/05/17. doi: 10.1007/0-387-32824-6_5 | 2.Rosenblum JS, et al..

Prolyl peptidases: a serine protease subfamily with high potential for drug discovery. Current opinion in chemical biology. 2003;7(4):496-504.. doi: S136759310300084X [pii]. | 3. Liu F, et al. Fibroblast

activation protein overexpression and clinical implications in solid tumours: a meta-analysis. PLoS One. 2015;10(3):e0116683. doi: 10.1371/journal.pone.0116683. PMID: 25775399; PMCID:

© Avacta Group plc 2024	5

FAP-Targeted Therapies Will Reach a Broad Patient Population With High Unmet Need

Cancer Associated Fibroblast (CAF)

FAP

A cell surface protease upregulated in many solid tumors predicts poor prognosis

UPS	PDAC
Undifferentiated	Pancreatic ductal
pleomorphic Sarcoma	Adenocarcinoma

Immunohistochemistry

using a monoclonal

antibody recognizing FAP

with robust expression

across multiple tumor types

The pre|CISION™ platform leverages this tumor-specificity by linking a FAP-cleavable peptide substrate to a cytotoxic warhead, preventing cell entry

The cleavage of the pre|CISION™ peptide is highly specific to FAP and not cleaved by any other human enzyme

FAP expression is easily quantified by standard IHC methods and FAPI-PETimaging in the clinic

1. Kessler L, et al. J Nucl Med. 2022 Jan;63(1):89-95. doi: 10.2967/jnumed.121.262096 | 2. Cohen SJ et al. 2008 Pancreas 37(2):154-158 DOI: 10.1097/MPA.0b013e31816618c | 3. Zboralski, D et al. Eur J Nuc Med Mol
Imaging 2022. 49. 10.1007/s00259-022-05842-5 | 4. Warli SM,. World J Oncol. 2023;14(2):145-149. doi: 10.14740/wjon1564 | 5. Kawase T, et al. BMC Gastroenterol. 2015;15:109. doi: 10.1186/s12876-015-0340-0	6
© Avacta Group plc 2024

The Spatial Organization of the FAP+ CAF in the Tumor Optimizes Warhead Delivery

*

*

TNBC: IF TNBC: IF (multiplex)

Avacta, internal data (unpublished)

*

*

PDAC: IF (multiplex)

FAP expression is highest at the tumor- stroma interface (arrows) with lower

expression in the distal cancer associated fibroblasts (CAF) population (asterisks)

Pan-cytokeratin (tumor cells)

Alpha-smooth muscle actin (CAF)

FAP (CAF)

FAP is overexpressed at the tumor-stroma interface

Triple negative breast cancer (TNBC) and pancreatic ductal adenocarcinoma (PDAC) are indications with known high FAP expression in multiple studies^

^ Dziadek S, . Comprehensive analysis of fibroblast activation protein expression across 23 tumor indications: insights for			© Avacta Group plc 2024	7
biomarker development in cancer immunotherapies. Front Immunol. 2024;15:1352615. doi: 10.3389/fimmu.2024.1352615

The Subset of CAFs with High FAP Expression are Localized with Tumor Cells and Vessels

TNBC

Avacta, internal data (unpublished)

PDAC

FAP (CAF)

CD31 (blood vessels)

PanCK (cancer cells)

CoCo-localization- ofofvessels,FAP+	The close proximity of vessels, FAP+ CAFs, and cancer cells, allows pre|CISION
CAFsanddtumorcells	enabled warheads to be readily delivered, cleaved, and taken up in the TME

© Avacta Group plc 2023	8

pre|CISION Delivery

© Avacta Group plc 2024	9

Cleavage of the pre|CISION Peptide Occurs at FAP+ CAFs and

Concentrates the Warhead in the TME

pre|CISION peptide

Released Warhead (extracellular)

pre|CISION -Enabled Warhead Cannot Enter Cells

FAP

Tumor-specific and membrane- bound protease expressed in the CAF population

Released Warhead

Enters Local FAP+ or FAP- Cells