Non-confidential Technical Introduction to the Affimer® Technology for Therapeutics and Reagents Dr. Alastair Smith Chief Executive, Avacta Group plc Introduction Avacta Group plc AIM: AVCT • 80 staff over two sites: • 1300 m2 of bespoke laboratory, production and logistics space in Wetherby. • 790 m2 of bespoke laboratory space in Cambridge. • Balance sheet to support existing plans. Wetherby • Experienced management team with interests aligned to shareholders. • Strongly supportive shareholder base. Cambridge London Shareholders >5% . IP Group plc 24.8% Lombard Odier 11.4% Aviva 9.6% Baillie Gifford 7.2% Ruffer LLP 7.1% Fidelity 5.9% J O Hambro 5.7% © Avacta Group plc 2 Leadership Team Dr Alastair Smith, CEO Dr Matt Johnson, CTO Mr Tony Gardiner, CFO • Over 10 years experience as a public • Genetics & Microbiology Molecular • Joined Avacta from AHR, an company CEO Biology international architecture practice • Was a leading UK biophysicist - founded • 8 years at Abcam becoming global • Chief Financial Officer of AIM listed Avacta in 2006 Head of R&D Fusion IP plc 2007 – 2011 which was acquired by IP Group plc in 2014 • World class scientific and technical • Joined Avacta in 2014 knowledge with a highly commercial • Joined Avacta in 2016 mindset Dr Philippe Cotrel, CCO Dr Amrik Basran, CSO • Over 20 years’ commercial experience in senior • Over 10 years’ experience of both the biotech and positions in Amersham Pharmacia Biotech, Oxford pharma industries Glycosciences, Affymetrix and Abcam • Director of Protein Biosciences at Domantis, Head of • Commercial Director of Abcam since 2008 – grew Topical Delivery (Biopharm) at GSK revenue from £36.7m to £144m over a 7-year period • Joined Avacta in 2013 • Joined Avacta in 2016 © Avacta Group plc 3 Affimer Technology Affimer®: A proprietary protein scaffold with key technical benefits What is an Affimer? Binding Surface • Based on a naturally occurring proteins (cystatins) and engineered to stably display two loops which create a binding surface. • Loops are randomised to create large libraries of diversity ~1010 and Affimers are selected by phage display. Key Benefits • Smaller (14 kDa), simpler (no disulphide bridges and no post- translational modifications), more robust (thermally and chemically) than antibodies. • High affinity (single digit nM) Affimers generated for new targets in a few weeks • Exquisite specificity obtained by control of phage selection process. • Easily modified (chemically and as fusion proteins) and easily manufactured in bacterial, yeast or mammalian systems with high expression yields. • Intracellular survival and activity. • Core Affimer protein is non-immunogenic. © Avacta Group plc 4 Core Intellectual Property Broad IP coverage across the cystatin protein family First Generation • Acquired from the Medical Research Council and Leeds University UK in 2012. • Based on human stefin A with multiple mutations to reduce dimerisation and prevent binding to cathepsin. • Patents granted in EU, US, Asia; Priority date: 2006. • Current technology for therapeutic programmes. Second Generation • Affimer technology based on plant cystatin consensus sequence; high stability suitable for challenging applications in research and diagnostics. • IP exclusively licensed to Avacta by Leeds University; Priority date: 2014. Third Generation • Developed in-house and based on human stefin A with improved biophysical properties and minimal mutations from human sequence for therapeutics; broad claims based on protein engineering and not on a specific sequence. • Priority date: July 2017. • New technology for future therapeutic programmes. © Avacta Group plc 5 Avacta’s Business Model Low down-side risk with significant up-side potential of therapeutics 1 Reagents 2 Therapeutics Building a profitable reagents Building a pipeline of Affimer business through licensing drug candidates in immuno- oncology for partnering © Avacta Group plc 6 Affimer® Therapeutics • Opportunities for Affimer Therapeutics • Avacta Therapeutics Strategy • Pipeline and Research Collaborations • Affimer Therapeutic Molecule Formats • PD-L1 Programme Update: In-vitro activity, in-vivo efficacy and Affimer/PD-L1 co-crystal structure • Affimer Technology Immunogenicity • Pharmacokinetics and Half-life Extension 7 Opportunities for Affimer Therapeutics A novel class of therapeutics with favourable drug properties Affimer-Drug Respiratory Ocular Conjugates o Small size (relative to antibodies) o Potential for a significantly lower dose, o Adaptable for topical delivery in front- favors extravasation/tissue lower cost of goods, lower systemic of-eye conditions and intravitreal & penetration. target engagement with potentially sub-retinal injection for back-of-eye fewer systemic side effects and therapeutics. May have differentiated PK/ADME properties particularly beneficial for treating: increased patient convenience. o Target tissues include cornea, vitreous humor, neurosensory retina (retinal o fibrotic diseases and fibrotic tumors o Can be engineered for high affinity ganglion and photoreceptors) and (breast and pancreatic tumors, uterine and specificity, and low/null systemic RPE/choroidal layers. fibroids). availability. o poorly or abnormally vascularized tissues o Ability to tune duration of action and and tissues with high interstitial pressures. o Stability allows longer duration of reduce frequency of injection for o Tunable serum half-life - can be used action than small molecules. protein therapeutics generally. to limit toxicity in peripheral tissues o Protease stability in diseased lung o Improved intra-ocular pharmacokinetics and improve therapeutic index. (protease inhibitor scaffold). through intravitreal half-life extension by fusion with HA-binding Affimers o Bi-paratopic and bispecific formats to o Non-toxic metabolic products (amino improve both specificity and acids). o Small molecular weight and internalisation. o Thermal stability for nebulisers. compactness of Affimers allows for higher molar loading and better/ o Site directed labeling and biophysics o Attributes suggest compatibility with consistent release kinetics over time to improve manufacturability. inhalable powders/particles. for implantable drug eluting devices. TM o New Approaches: AfDC program o With ability to optimize particle size, o Opportunity for gene delivery for exploring linker/warhead morphology, hygroscopicity, electrical charge and density per application. constitutively expressing recombinant combinations for TME drug release Affimer drug product in eye. with bystander effects. o Exemplars include anti-VEGF Affimers for o PD-L1 Affimer to target tumor and inhibit wet AMD, and bispecific anti-Factor D/C5 PD-1 axis coupled to highly potent drug and anti-b-amyloid Affimers for dry AMD. ablating tumor associated macrophages. © Avacta Group plc 8 Opportunities for Affimer Therapeutics A novel class of therapeutics with favourable drug properties Gene Delivery Dermatological Oral/GI o Small size means recombinant coding o Dermal and transdermal delivery o pH stability + enteric coating or sequence amenable to wide range of embodiments. suppository for intraluminal delivery viral or other coding sequence o Transdermal – skin is the most accessible to large or small intestines. delivery platforms. organ of the body with a large surface o pH stability for intraluminal or area. o Ease of cellular expression and submucusal (endoscopic) delivery to secretion. o Needle-free topical application routes esophagus. - small molecular weight, compactness o Flexible formatting. and stability of Affimers may be o Potential for selective GPCR agonist o Anticipate high specific activity of secreted exploited to enhance the dermal and antagonists for inflammatory gut recombinant Affimers. diseases. permeability of Affimers and o Potential for generating Affimers that associated proteins. o Potential for use in drug eluting alter intracellular targets. o Amendable to fusion protein formats devices (esophageal and intestinal o Modify epigenetics, mitotic activity, and/or use of penetrant enhancers. stents and collars). viability, or other characteristics. o May enable penetration of the stratum o Exploring engineered Affimers and o Cell surface retained embodiments for corneum and entry into the viable formulations strategies permitting epidermis. altering cell trafficking, cellular half- systemic exposure from orally dosed life, immunogenicity or other function. o Readily adaptable to Affimers. o Secreted IO Affimers from engineered microneedle/dermal rollers, CAR-T or ACTR cell therapies. noninvasive jet injectors and electroporation for delivery. o Targeting moieties for viral delivery to o Should be able to achieve delivery of specific cells. Affimers at >1mg/cm2. © Avacta Group plc 9 Avacta Therapeutics Strategy Leveraging Affimer key benefits to create differentiated medicines In-house Pipeline Proof-of-Concept Research Collaborations • Immune-checkpoint inhibitors (combinations, • Gene delivery (Moderna Tx Inc) bispecifics, biparatopics) • CAR-T (Memorial Sloan Kettering) • T-cell engagers • Drug conjugates (Glythera) • Agonists Key Benefit of Affimers Key Benefits of Affimers Ease of creating and manufacturing “multimers” Small size, stability and ease of production by cells that combine multiple Affimers © Avacta Group plc 10 In-house Pipeline Leveraging Affimer key benefits to create differentiated medicines T-cell Engagers Agonists T-cell Tumour Targeting Immune Activators GITR, CD27 CD3e CD19 Other Potential Targets: