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Nasdaq: ZYME | zymeworks.com Making a Meaningful DifferenceAccelerating the next generation of therapeutics to improve the standard of care for the most challenging diseases in cancer, autoimmune and inflammatory diseaseOctober 2025
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2 Legal DisclaimerThis presentation and any accompanying oral commentary include “forward-looking statements” or information within the meaning of the applicable securities legislation, including Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. Forward-looking statements in this presentation and the accompanying oral commentary include, but are not limited to, statements that relate to Zymeworks’ expectations regarding implementation of its strategic priorities; expectations regarding future regulatory filings and approvals and the timing thereof; the timing of and results of interactions with regulators; the timing and status of ongoing and future studies and the related data; clinical development of product candidates and enrollment in clinical trials; anticipated preclinical and clinical data presentations; the potential addressable market of zanidatamab and other product candidates; potential safety profile and therapeutic effects of zanidatamab and other product candidates; the commercial potential of technology platforms and zanidatamab and other product candidates; extrapolations or comparisons of results derived from independent studies instead of head-to-head studies are subject to misinterpretation, assumptions or caveats of each study, and may be different from head-to-head comparisons; Zymeworks’ early-stage pipeline; evolution of Zymeworks’ business strategy related to anticipated and potential future royalty streams and existing and potential new partnerships; Zymeworks’ ability to execute new collaborations and partnerships; the anticipated benefits of its collaboration agreements with Jazz, BeiGene and other partners; Zymeworks’ ability to receive any future milestone payments and royalties thereunder; Zymeworks’ ability to satisfy potential regulatory and commercial milestones with existing and future partners; the timing and status of ongoing and future studies and the release of data; anticipated continued receipt of revenue from existing and future partners; Zymeworks’ early stage pipeline; Zymeworks’ strategic priorities; preclinical development progress and expectations for future investigational new drug and foreign equivalent application submissions; and other information that is not historical information. When used herein, words such as “plan”, “believe”, “expect”, “may”, “continue”, “anticipate”, “potential”, “will”, “progress”, “on track”, and similar expressions, or any discussion of strategy, are intended to identify forward-looking statements. In addition, any statements or information that refer to expectations, beliefs, plans, projections, objectives, performance or other characterizations of future events or circumstances, including any underlying assumptions, are forward-looking. All forward-looking statements are based upon Zymeworks’ current expectations and various assumptions, including, without limitation, Zymeworks’ examination of historical operating trends. Zymeworks believes there is a reasonable basis for its expectations and beliefs, but they are inherently uncertain. Zymeworks may not realize its expectations, and its beliefs may not prove correct. Actual results could differ materially from those described or implied by such forward-looking statements as a result of various factors, including, without limitation: Zymeworks’ assumptions and estimates regarding its financial condition may be incorrect; any of Zymeworks’ or its partners’ product candidates may fail in development, may not receive required regulatory approvals, or may be delayed to a point where they are not commercially viable; Zymeworks may not achieve milestones or receive additional payments under its collaborations; regulatory agencies may impose additional requirements or delay the initiation of clinical trials; the impact of new or changing laws and regulations; market conditions; the impact of pandemics and other health crises on Zymeworks’ business, research and clinical development plans and timelines and results of operations, including impact on its clinical trial sites, collaborators, and contractors who act for or on Zymeworks’ behalf; zanidatamab may not be successfully commercialized; Zymeworks’ evolution of its business strategy related to anticipated and potential future milestones and royalty streams and existing and potential new partnerships may not be successfully implemented; clinical trials and any future clinical trials may not demonstrate safety and efficacy of any of Zymeworks’ or its collaborators’ product candidates; Zymeworks may be unable to maintain or enter into new partnerships or strategic collaborations; and the factors described under “Risk Factors” in Zymeworks’ quarterly and annual reports filed with the Securities and Exchange Commission (copies of which may be obtained at www.sec.gov and www.sedarplus.ca). Although Zymeworks believes that such forward-looking statements are reasonable, there can be no assurance they will prove to be correct. Investors should not place undue reliance on forward-looking statements.The above assumptions, risks and uncertainties are not exhaustive. Forward-looking statements are made as of the date hereof and, except as may be required by law, Zymeworks undertakes no obligation to update, republish, or revise any forward-looking statements to reflect new information, future events or circumstances, or to reflect the occurrences of unanticipated events.
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3 Zymeworks: Global Biotech Focused on Targeted Therapies Starting with Patients Driven by Science & Technology Empowered by People •Focusing on challenging, multi-factorial diseases with significant unmet medical needs, including aggressive cancers with historically low survival rates and complex autoimmune and inflammatory disorders that remain difficult to treat•Focused on developing best-in-class multifunctional therapeutics that hold the potential to optimize patient outcomes •Suite of ADC technologies combines the precision of antibodies with the power of potent proprietary payloads for targeted delivery to cells•Clinically validated proprietary MSAT technology, Azymetric™ and suite of MSAT technologies enhance therapy precision, efficacy, and adaptability, targeting complex disease mechanisms •Robust leadership team with decades of experience in drug discovery, development, and commercialization•Renowned scientists and researchers in protein engineering, MSATs, and ADC technologies •Global scope, operating across North America, Europe, and Asia•Productive and efficient organization focused on transformative drug discovery with cash resources of approx. $333.4M1 ADC: antibody-drug conjugate; MSAT: multispecific antibody therapeutic 1.Cash, cash equivalents, and marketable securities as of June 30, 2025
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ProgramTechnologyTargetIndicationDiscoveryPreclinicalPhase 1Phase 2Phase 3Solid Tumor Oncology: Antibody-Drug Conjugates (ADC)ZW191Topo1i ADC | DAR 8 | Fc WTZD06519 PayloadFRαGynecologicalThoracicZW251Topo1i ADC | DAR 4 | Fc WTZD06519 PayloadGPC3Digestive System (HCC)ZW220Topo1i ADC |DAR 4 | Fc MutZD06519 PayloadNaPi2bGynecologicalThoracicSolid Tumor Oncology: Multispecific Antibody Therapeutics (MSAT)ZanidatamabBispecificAzymetric™HER2Multiple indicationsZW209Trispecific TCE | Tri-TCE CostimAzymetric™Novel anti-CD3Conditional CD28DLL3 x CD3 x CD28ThoracicZW239Trispecific TCE | Tri-TCE CostimAzymetric™Novel anti-CD3Conditional CD28CLDN18.2x CD3 x CD28Digestive System Autoimmune & Inflammatory Diseases ZW1528Dual Cytokine BlockerAzymetric™Hetero-Fab | YTEIL4Rα x IL-33ZW1572Dual Cytokine BlockerAzymetric™Hetero-Fab | YTEIL4Rα x IL-31 4 Differentiated Pipeline of Multifunctional Therapeutics NCT06555744NCT07164313 Anticipated IND 2H 2026 Anticipated IND 1H 2026Development partners: Jazz Pharmaceuticals and BeOne
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EFECT™ 2+1 TCE EngineeringZW171Bi-paratopicEngineeringZanidatamab AZYMETRIC™ FcgRIIb selective Azymetric™ TriTCE CostimZW209 Cytokine EngineeringZW1528 nomination ZW220 & ZW251 nominationsNovel Payload Mechanisms & Targeting Moieties Zymelink Hemiasterlin& AuristatinPreCysion Site- Specific Conjugation 20102012201420162018202020222024 20272026 R&D day ‘5x5’ launchedADVANCEexpansion to AIID & HemeOnc Ziihera® approved in 2L HER2-positive BTC Nov 2024 TOPO1i PlatformZW191 5 10+ Years of Pioneering Multifunctional Antibody Development Currently partnered with: Leading the development of next generation antibody-drug conjugates Clinically validated technology drives development of novel multispecific therapeutics Novel Targeting Moieties BTC: biliary tract cancer; TCE: t cell engager; TOPO1i: topoisomerase 1 inhibitor; 2L: second-line.
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6 Recent Accomplishments and Near-Term, Upcoming Milestones 5+ Collaborating with industry leaders to accelerate impactExtended the reach of therapeutic candidates, while validating our innovative approach through strategic partnerships with companies including Jazz, BeOne, GSK, and others. StrategicPartnerships 1Ziihera® (zanidatamab-hrii) (HER2 bispecific antibody)Licensed to Jazz and BeOne2L BTC (IHC3+) U.S. FDA, European Commission, and China NMPA ApprovalPhase 3 1L BTC confirmatory trial ongoingPhase 3 1L GEA top-line PFS readout expected 4Q25 Internally Developed FDA Approved Drug 5Multiple Modalities and Therapeutic AreasClinical Stage Asset in Phase 1 Trials: ZW191FDA IND Clearance Received for ZW251; Phase 1 Trial initiation expected in 20252 INDs Planned in 2026:ZW209 & ZW1528ZW220 remains an IND-ready candidate Nominated Wholly-Owned Candidates 2L: second-line; BTC: biliary tract cancer; 1L: first-line; GEA: gastroesophageal adenocarcinoma; IND: investigational new drug application
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7 Strategic Priorities for 2025 and 2026 Build a diverse and differentiated pipelineExpand solid tumor portfolio with an emphasis on digestive system cancersExpand R&D portfolio into hematology oncology and AIIDMaintain balanced R&D investmentacross wholly-owned clinical candidatesand preclinical research Become a leading, global biotech focused ontargeted therapiesEnable preclinical, clinical, and TMOgroups to manage portfolio ofcandidates across expanded focus areasMaintain and potentially expandR&D portfolio through strategicpartnering effortsContinue to build pipeline of newproduct candidates with validated,strong target profiles Invest in our people,culture & societyHarness global presence rooted inR&D to foster continued innovationin our patient communitiesMaintain an efficient, financially/socially responsible,and productive organization Use strength of balance sheet to grow and broaden wholly-owned pipeline and next-generation technologies Enhanced optionality for partnerships and collaborations to share capital and development risk
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8 Focused Therapeutic Areas Provide Diversity to R&D Portfolio and Enhanced Optionality for Partnering and Retained Product Rights Solid Tumors•Gynecological cancers•Thoracic cancers•Digestive system cancers Hematological Cancers•AML•Multiple myeloma•Lymphoma Autoimmune & Inflammatory Disease•Respiratory diseases•Rheumatoid arthritis•Inflammatory bowel diseases AML: Acute myeloid leukemia
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9 Zanidatamab: $2B+ Peak Sales Potential* •Ziihera® now approved in the U.S. for the treatment of adults with previously treated, unresectable or metastatic HER2+ (IHC3+) 2L BTC. Jazz Pharmaceuticals initiated U.S. launch activities.•European Commission (EC) and NMPA in China approved zanidatamab for previously treated, unresectable or metastatic HER2+ BTC•Confirmatory Phase 3 trial initiated in 1L BTC Entering market first in BTCwith U.S. FDA ApprovalPath to approval in 1L GEA with sBLA with top-line results estimated 4Q 2025 Expanded opportunity across linesof Breast Cancer (BC)1 Broad potential beyond BTC, GEA, and mBC in multiple HER2-expressing indications2 The approval of Ziihera® is the result of over a decade of groundbreaking research and development at Zymeworks Strong Track Record of Meaningful Commercial Partnerships Licensing agreement with Jazz Pharmaceuticals to commercialize Ziihera in U.S., EU, Japan, India, and all other non-APAC territoriesEligible for up to $500M in regulatory milestones and $862.5M in commercial milestonesLicensing agreement with BeOne to commercialize zanidatamab in APAC(except Japan and India)Eligible for up to $144M in development andcommercial milestonesTiered royalties between 10-20% from Jazz and from the high single digits to 19.5% from BeOne sales (up to 20% when royalty reduction of 0.5% reaches cap in the low double-digit millions of dollars) •HER2+/PD-L1 negative: opportunity to address unmet need and replace trastuzumab1•HER2+/PD-L1 positive: opportunity to replace trastuzumab as HER2-targeted therapy of choice1•Opportunity to explore potential in neoadjuvant populations1 01 03 02 04 *Adapted from Jazz Pharmaceuticals’ Guidance sBLA: supplemental biologics license application; NMPA: National Medical Products Administration.1. Pending regulatory approvals, 2. Funda Meric-Bernstam et al, Zanidatamab, a novel bispecific antibody, for the treatment of locally advanced or metastatic HER2-expressing or HER2-amplified cancers: a phase 1, dose-escalation and expansion study, The Lancet Oncology, Volume 23, Issue 12, 2022, Pages 1558-1570, ISSN 1470-2045, https://doi.org/10.1016/S1470-2045(22)00621-0. Expanded opportunity across lines of therapy1•Post T-DXd (Ph3 EmpowHER trial)•Early lines of therapy (neoadjuvant)•Novel combinations1Ongoing trials in early breast cancer:•I-SPY2 Trial (NCT01042379)•MD Anderson collaboration•Phase 2 trial (EmpowHER-BC-208) •Colorectal •NSCLC •Ovarian•Endometrial •Pancreatic •Bladder •Salivary Gland •Ampullary •And other HER2-expressing solid tumors
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EngineeringSet of transferable mutations supporting pure and stable Fc heterodimer formation with exclusive chain pairing duringco-expressionLibraries of constant domain Fab mutations available for kappa/kappa, kappa/lamda and lambda/lambda bispecific LC combinationsFlexibilityCan employ novel or existing antibody paratopes; human (IgG1, IgG2A, IgG4) and mouse frameworks; other CH2 and glyco-engineering approaches. Compatible with linker/payload conjugationHigh-throughput ScreeningBest-in-class activity requires screening of alternative targets, epitopes, sequences, target engagement geometries, and mechanisms of action (blocking, lytic, ADC)Highly ManufacturableAntibody like yields/stability; leveraged by multiple pharma/biotech with various clinical stage programs in development 10 Azymetric™: Adaptable to Different Formats and Applications Tri/Multi specifics T Cell Engagers (TCE) Biparatopic Simultaneous Pathway Blockade1 + 1 Formats 2 + 1 Formats 2 + 2 Formats Bispecific ADCs
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11 Advancing Our Next-Generation Technology in Challenging Diseases Novel Payload Discovery •Our hypothesis on ADC mechanism guidesour approach to novel payload discovery•Four novel payload mechanisms in discovery to help innovation beyond TOPO1i and auristatin platformsOptimal Antibody Formats•Multi-pronged strategy to discover antibodies with enhanced ADC properties•Antibody format (monospecific, biparatopic, or bispecific) dictated by target characteristicsTherapeutic Application •Target, payload mechanism, and antibody format selected for enhanced activity in disease indication Advanced Protein Engineering Solutions•FDA approved, clinically validated, and novel engineering solutions enable plug and play building blocks to address complex biological challenges•Flexibility of Azymetric™ facilitates high throughput multiparameter antibody screening to identify molecules with the desired biologyAddressing Biological Challenges in Indications with High Unmet Need•Designing next generation T cell engagers to overcome biological challenges not addressed with traditional bispecific T cell engagersDriving the Forefront of Next Generation T cell Engagers•Enhancing functionality and specificity to drive deep and durable responses in difficult to treat tumors•Plug and play platforms enable fast development to rapidly address patient need Continued execution against 2027+ IND application strategy Antibody-Drug Conjugates Multispecific Antibody Therapeutics
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12 Zymeworks Topoisomerase ADC Platform ExemplifiesOur Philosophy and Enables Our Pipeline ZD06519 12M.E. Petersen, M.G. Brant et al, Mol Cancer Ther 2024, 23(5):606-618.CDX: cell line-derived xenograft, MTD: maximum tolerated dose, NHP: non-human primates, PDX: Patient-derived xenograft, TK: Toxicokinetic -2-101237 8 9 10 cLogD 1 nM pIC50 SK-BR-3 hydrophobicitypotency Exatecan DXd ZD06519SN-38 Not potent enough Too hydrophobic Too hydrophilic Too potent ZD06519 DXd Exatecan A-1743332 SuperTopoi AZ14170132 SHR9265 Ed-04 SN38 7. 5 8.0 8.5 9.0 9.5 10.0 10.5pIC50Potency Moderate potency to enable higher ADC dose Bystander activeZW191 first in human trial (NCT0655574)ZW251 expected to enter clinic in 2025 ~100 payloads prepared and tested in vitro ADC properties:monodispersity, plasma stability, hydrophilicity In vitro potency: target-dependency and bystander activity Robust efficacy in multiple CDX and PDX models MTD in NHPs: DAR8: ≥30 mg/kgDAR4: ≥120 mg/kg Payloads conjugated as DAR4 and DAR8, multiple mAbs Payload synthesis & screening Conjugation of select payloads ADC characterization In vivo efficacy & PK NHP toxicology& TK ADC in vitro potency Lead selection and application NNO OHO Me F HNOOHO O Antibody-Drug Conjugates
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12 Zymeworks’ Engineering Approach: Key Expertise in Format and Geometry Screening to Identify Differentiated Activity Potential best-in-class activity requires screening of epitopes, affinities and target engagement geometriesUnique flexibility of Azymetric™enables format and affinity optimization for potential best-in-class attributesDiscovery of unique biology and differentiation to combination approaches 13 ZanidatamabOptimization of affinity and format for highest biparatopic activityUnique biparatopic MOASuperior activity to combination ZW1528 (IL4Rα x IL33)IgG-like format, manufacturability and PKIL4Ra and IL33 blockade equivalentto bivalent benchmarksUnique bispecific activity,potentially superior to combination ZW209 (CD28 TriTCE)Discovery of novel format to prevent non-specific T cell activationConditional CD28 activationSynapse optimization for balancedSignal 1 plus Signal 2 BiparatopicMulti-Cytokine Blocker Trispecific T Cell Engager Increased Complexity Multispecific Antibody Therapeutics Mod: Mechanism of Action: MSLN: Mesothelin, PK: Pharmacokinetic, TCE: T Cell Engager, TriTCE: Trispecific T Cell Engager,
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0 20 40 60 80 100 0 5000010000 015000 020000 025000 030000 0 5-Year Survival, 2014-2020 (%) US Incidence, 2024 NSCLC (ZW220, ZW191) SCLC (ZW209)Pancreas Esophageal (zanidatamab)Liver(ZW251) AMLStomach (zanidatamab) Ovary (ZW191, ZW220) MMLarynx TNBC CRC HR+ HER2- BC Prostate Oral Cavity and Pharynx Melanoma NHLBladderRCCEndometrial (ZW191, ZW220) SarcomaCervicalSmall Intestine ThyroidHR+ HER2+ BCHLHR- HER2+ BCCLLTestis BoneVulvaALLCMLAnal Brain Mesothelioma Therapeutic focus areas | ZYME Development Programs 14 Maintain Focus on Cancers with Highest Unmet Medical Need: Increase GI Tract and Thoracic Cancer Coverage and Expand to Heme-Onc Cancers SEER*Explorer, accessed 10 Oct 2022.AML: AML: Acute myeloid leukemia, CRC: colorectal cancer; MM: Multiple myeloma, NSCLC: Non-small cell lung cancer, SCLC: Small cell lung cancer, NHL: non-Hodgkin lymphoma
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A balanced portfolio of ADCs targeting clinically validated FRα and NaPi2b, along with a T cell engager targeting MSLN, ensures comprehensive coverage and risk mitigation for ovarian cancer and NSCLC, providing a diversified therapeutic focus on ovarian and lung cancers. Ovarian Cancer Log(TPM + 1) MSLNFOLR1NaPi2b mRNA Expression Profile of Select Cancer Target in Ovarian Cancer (N=421) 15 Target Selection Driven by Expression Profile, Biology and Clinical Precedence TCGA bulk RNA-sequencing data were obtained from TCGA-OV, workflow STAR – Counts from https://portal.gdc.cancer.gov/ repository. The median TPM (Transcript per Million) for each gene in each patient was plotted on a violin plot using ggplot21. This dataset contains 421 samples (patients) from Ovarian Serous Cystadenocarinoma (OV) and 521 sample from lung adenocarcinoma.The width of the shape/violins indicates the density of samples TPM: transcripts per million 1.Wickham H (2016).ggplot2: Elegant Graphics for Data Analysis. Springer-Verlag New York. ISBN 978-3-319-24277-4,https://ggplot2.tidyverse.org. ADC: antibody-drug conjugate; TCE: t cell engager; NSCLC: non-small cell lung cancer Selection of an ADC or TCE strategy is driven by target expression, biology including internalization rate, clinical precedence and differentiation to prior therapeutic programs MSLN, FOLR1 and NaPi2b are each expressed at higher level than other targets pursued in ovarian cancer or NSCLC
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16 ZW191ADC Designed to TargetFRα-Expressing TumorsSignificant Patient Need •FRα is found in ~75% of high-grade serous ovarian carcinomas2 and ~70% of lung adenocarcinomas.3Initiated Phase 1 clinical trialin 2H 2024 (NCT06555744) Optimized Design1•ADC targeting FRα -expressing tumors including ovarian cancer, other gynecological cancers, and NSCLC.•Comprised of a humanized IgG1 antibody conjugated to a novel camptothecin-based topoisomerase 1 inhibitor payload technology, ZD06519.•Drug-to-antibody ratio ~8.•Validated peptide cleavable linker sequence.Differentiated Profile•Differentiated anti-tumor activity in preclinical tumor models with a breadth of FRα expression.1•Favorable safety profile in nonhuman primate (NHP) toxicology studies.1•Favorable PK and is well-tolerated in NHP at exposure levels above those projected to be efficacious.•Opportunity to treat broader range of FRα-expressing cancers. 1. Lawn S et al. Abstract # 2641 Presented at AACR 2023.2. Köbel, M., Madore, J., Ramus, S. et al. Br J Cancer 111, 2297–2307 (2014).3. O'Shannessy DJ, et al., Oncotarget. 2012 Apr; 3(4):414-25.
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FRa-Expressing Cancers Estimate of Newly DiagnosedFRα+ Patients In Key Indications Lung 14%-74% Ovarian 39%-75% Endometrial 50% 17 FRα-expressing Cancers Represent a Significant Commercial Opportunity1-7 020,00040,00060,00080,000100, 000120, 000 NSCKC Ovarian Endometrial USEUJapan FRα: folate receptor alpha; NSCLC: non-small cell lung cancer; TNBC: triple negative breast cancer1. Senol S, et al. Int J Clin Exp Pathol. 2015;8(5):5633-5641; 2. Omote S, et al. Med Mol Morphol. 2018;51(4):237-243; 3. Oza AM. SGO. 2021; 4. O’Shannessy DJ, et al. Oncotarget. 2012;3(4):414-425; 5. Nunez MI, et al. J Thorac Oncol. 2012;7(5):833-840; 6. D’Angelica M, et al. Mod Pathol. 2011;24(9):1221-1228; 7. Scaranti M, et al. Nat Rev Clin Oncol. 2020;17(6):349-359. NSCLC Potential best-in-class opportunity in FRα-high ovarian cancerPotential first and best-in-class inFRα-high endometrial, NSCLC, TNBC, and FRα-mid/low solid tumors
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01020300 500 1000 1500 2000 Time post dose (Days) Mean Tumour Volume ± SEM (mm3) 01020300 500 1000 1500 2000 2500 Time post dose (Days) Mean Tumour Volume ± SEM (mm3) 0 2040600 500 1000 1500 Time post dose (Days) Mean Tumour Volume ± SEM (mm3) 18 ZW191: Key Design Considerations ZW191’s Novel mAb Drives Superior Internalization, Payload Delivery, and Tissue Penetration Wong J et al., Abstract #3127 presented at American Association for Cancer Research annual meeting 2024 Lawn S. et al. Abstract # 1862 presented at American Association for Cancer Research annual meeting 2024 Anti-tumor Activity Across Multiple Tumor Types And Range of FRα Expression (PDX models) Ovarian Cancer ZW191, 6 mg/kg CTG-1602 CTG-1703 CTG-3718 CTG-0958 CTG-0947 CTG-2025 CTG-1301 CTG-3383 CTG-0703 -100 -50 0 50 100 Best Response (% change from baseline) ZW MIRV CTG-1602 CTG-1703 CTG-3718 CTG-0958 CTG-0947 CTG-2025 CTG-1301 CTG-3383 CTG-0703 -100 -50 0 50 100 Best Response (% change from baseline) ZW MIRV LU6802FRα H-Score 145UT5321FRα H-Score 220 NSCLCEndometrial Internalization of AF488 labelled antibodies to KB-Hela cells after 24 hrs at 100 nM; Mass-spec. quantification of internalized payload following 24-hour treatment of IGROV-1 cells with 10 nM of ADCs comprising ZW191 mAb or other FRα-targeted mAbs conjugated to n auristatin payload; Tumor spheroid penetration of AF488 labelled antibodies as quantified by high content imaging of spheroid layers at 24 hours post-treatment at 50 nM. ZW191 mAb (from ZW191)Mirvetuximab (from ElahereTM)Farletuzumab (from MORAb-202)SRP1848-H01 (from STRO-002)F131 (from PRO1184)Non-targeted control mAb Tumor Spheroid Penetration10L18 v17716 (Mirvetuximab) v31629 (Farletuzumab) v39156 (SRP1848-H01) v39088 (F131) Palivizumab 0 200 400 600 800 1,000 1,200CorrectedAF488 Mean Intensity JEG-3 SpheroidPlacental Choriocarcinoma Cell Line 50 nM 24 hours 10L18v17716 (Mirvetuximab)v31629 (Farletuzumab)v39156 (SRP1848-H01) v39088 (F131) Palivizumab Mean fluorescence intensitySpheroid center CTG-1703FRα H-Score 20CTG-0958FRα H-Score 110 v36675 (hu10L18) v17716 (Mirvetuximab) v31629 (Farletuzumab) v39156 (SRP1848-H01) v39088 (F131) Palivizumab 0 10,000 20,000 30,000 40,000 AF488 Mean Intensity KB-HeLaCervical Carcinoma Cell Line100 nM Treatment 24 hours v36675 (hu10L18)v17716 (Mirvetuximab)v31629 (Farletuzumab) v39156 (SRP1848-H01) v39088 (F131) Palivizumab AF488 mean fluorescence intensity v30384-MTvc044 v17716-MTvc044 v31629-MTvc044 v39156-MTvc044 v39088-MTvc044 v21995-MTvc044 0 5,000 10,000 15,000nM in cell IGROV-1Intracellular Payload Payload in cell (nM) InternalizationPayload Delivery mirvetuximab soravtansine, 6 mg/kg 0 20 400 500 1000 1500 2000 Time post dose (Days) Mean Tumour Volume ± SEM (mm3)
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19 ZWI-ZW191-101: Preliminary Clinical ResultsBest percent change in target lesion size from baseline (n=27) Best responseZW1911.6 mg/kg (n=3) ZW1913.2 mg/kg (n=3) ZW1914.8 mg/kg (n=4) ZW1916.4 mg/kg (n=7) ZW1918.0 mg/kg (n=4) ZW1919.6 mg/kg (n=3) ZW191 6.4-9.6 mg/kg(n=14)Total(n=24) PR, n (%)a02 (67)1 (25)4 (57)2 (50)3 (100)9 (64)12 (50)cPR, n (%)02 (67)1 (25)3 (43)1 (25)04 (29)7 (29)SD, n (%)1 (33)1 (33)2 (50)3 (43)2 (50)05 (36)9 (38)PD, n (%)2 (67)01 (25)00003 (13)aPR includes confirmed and unconfirmed. The 5 participants with unconfirmed PR are all awaiting confirmation. Note: Percentages are out of gynecological cancer (OC and EC) participants.cPR: confirmed partial response; EC, endometrial cancer; OC, ovarian cancer; PD: progressive disease; PR: partial response; RECIST v1.1: Response Evaluation Criteria in Solid Tumors version 1.1; SD: stable disease Preliminary efficacy for response-evaluable participants with gynecological cancer 27 participants were response-evaluable by having at least 1 post-baseline scan. Response based on RECIST v1.1 (response and progression defined as -30% and +20% change from baseline, respectively).EC: endometrial cancer; FRα:folate receptor alpha; LC: non-small cell lung cancer; OC: ovarian cancer; RECIST v1.1: Response Evaluation Criteria in Solid Tumors, version 1.1Data cutoff: September 10, 2025 LoRusso P. et al. Abstract # LB-A011 Presented at AACR-NCI-EORTC 2025. Presented at 2025 AACR-NCI-EORTC Conference on Molecular Targets and Cancer Therapeutics
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20 ZWI-ZW191-101: Preliminary Clinical Results Presented at 2025 AACR-NCI-EORTC Conference on Molecular Targets and Cancer Therapeutics Duration of treatment and overall response (n=41) CA-125: cancer antigen 125; EC: endometrial cancer; FRα:folate receptor alpha; LC: non–small cell lung cancer; OC: ovarian cancer; PD, progressive disease; PR, partial response; SD, stable disease; OOR: overall response rate; uPR: confirmed partial response; cPR: confirmed partial response Data cutoff: September 10, 2025 Key Highlights•ZW191 has been safely administered during dose escalation up to 11.2 mg/kg, with the majority of participants still on treatment.•Low rates of dose modifications, dose delays, and Grade ≥3 AEs. 7 participants reported Grade ≥3 TRAEs – the most common were anemia, neutropenia, and thrombocytopenia. No discontinuations due to AEs.•Preliminary efficacy is promising, starting at 3.2 mg/kg Q3W•ORRs (uPR + cPR) between 6.4 mg/kg to 9.6 mg/kg were: 53% (overall) and 64% (GYN cancers)•Anti-tumor activity is observed across all FRα expression levels LoRusso P. et al. Abstract # LB-A011 Presented at AACR-NCI-EORTC 2025.
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21 Differentiation is Critical for ZW191 in the CompetitiveFRα ADC Space for TOPO1i * Denotes use of exatecan payload | ^ Denotes use of Fc-silenced antibody A novel design to target FRαPotential best-in-class antibodyThe ZW191 antibody was selected for enhanced internalization, payload delivery, and tumor penetration.1 Topoisomerase I inhibitor (TOPO1i) payload mechanismTOPO1i containing ADCs have proven to be an effective mechanism to treat ovarian cancers.2,3 Moderate payload potency A moderate potency TOPO1i payload (ZD06519) was selected for ZW191 to enable a higher protein dose, which may be advantageous for target engagement, tumor penetration, and drug exposure.5 Exatecan is 3-10X more potent than the ZW191 payload. Moderate antibody-linker stabilityA ‘designed instability’ approach was taken with ZW191; all approved ADCs feature an element of linker instability.4 Strong bystander activityStrong bystander activity is beneficial when treating tumors with low and heterogenous expression of FRα.1 1.Lawn S et al. Abstract # 2641 Presented at AACR 2023; 2.Meric-Bernstam F, et al., Journal of Clinical Oncology202341:17; 3.Moore K, et al., j.annonc.2023.09.1924; 4.Colombo R, Barnscher SD, Rich JR. Cancer Res 2023, 83 (7). Abstract #1538 presented at AACR 2023 5.Lawn S. ZW191: A Potential Best-in-Class TOPO1i ADC for Treatment of FRα-Expressing Solid Tumors, Presented at World ADC London 2023. The balance between drug-linker stability and payload potency differentiates ZW191 from other FRα-TOPO1i ADCs Drug-Linker Stability Payload Potency ZW191 MBK-103*^ BAT8006* PRO1184*^ AMT-151* AZD5335
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Part 1: Dose Escalation Part 2: Dose Optimziation/Expansion MTD/RD determined Treatment until disease progression, unacceptable toxicity, or withdrawal of consent ZW191: Global Phase 1 Study in FRα-Expressing Solid Tumors (NCT06555744) Open-label, FIH, dose-escalation study (N~145) aOvarian cancer includes primary peritoneal and fallopian tube cancers. bPart 2 will be initiated at dose levels (RDEs) based on the SMC’s comprehensive analysis of safety, tolerability, clinical PK, PD, and preliminary antitumor activity data from Part1. The Part 2 selected doses will be decided at SMC meetings and could be the MTD or RDEs based on comprehensive analysis of safety, tolerability, clinical PK, PD, and antitumor activity data from Part 1. The RDE dose levels may vary across the tumor types in Cohorts 1, 2, and 3. cTimed from cycle 1 day 1. Q6W (every 6 weeks) for the first 4 assessments and then Q9W (every 9 weeks) thereafter. ClinicalTrials.gov ID: NCT06555744. CT/MRI: computed tomography/magnetic resonance imaging; DLT: Dose Limiting Toxicity; FIH: First-in-human; FRα: folate receptor alpha; IHC:immunohistochemistry; IV: intravenous; MTD: maximum tolerated dose; NSCLC: non-small cell lung cancer; RD: Recommended Dose.. Eligibility/Screening Assessments (occur within 28 days prior to Cycle 1 Day 1)ScreeningTreatment PeriodFollow-up21-Day DLT Observation PeriodEvery 6 or 9 WeekscFollow-up 30 days postlast dose of ZW191CT/MRI Cohort 2: Endometrial Cohort 3: Nonsquamous NSCLC n=20 FRα expressing(+).Dose LevelTBD n=20FRα expressing(+).DoseLevelTBD Part 2b: Dose Expansion Endometrial cancer and non-squamous NSCLC Part 2a: Dose Optimization Ovarian cancera Cohort 1: Ovariana OvariancancerRandomized1:1 into2 Dose LevelsDose LevelA (n=20)Dose LevelB (n-=20) Cycle 1 day 1 ZW191 dose IV 22 FRα expression will be evaluated retrospectively in Part 1.
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23 ZW251ADC Designed to Target Glypican 3-Expressing Hepatocellular Carcinoma (HCC)Significant Patient Need •GPC3 is expressed in 76% of HCC, with highexpression observed in ~55% of HCC2•HCC is the most common type of primary liver cancer and the third leading cause of cancer deaths globally1 Differentiated Profile•Strong preclinical activity in models with a breadth of GPC3 expression1•Exhibited comparable PK to a clinical-stage antibody comparator; PK unaffected by conjugation•Noteworthy tolerability and no mortality observed in a repeat dose NHP toxicology study up to 60 mg/kg (DAR 8) or 120 mg/kg (DAR 4) Optimized Design•Potential first-in-class ADC designed to treat GPC3-expressing HCC with a new MOA•Composed of a humanized IgG1 antibody conjugated to a novel camptothecin-based topoisomerase 1 inhibitor, ZD06519•Intermediate drug-to-antibody ratio ~4•Validated peptide cleavable linker sequence 1. https://www.cancer.gov/types/liver/what-is-liver-cancer/causes-riskfactors#:~:text=Worldwide%2C%20liver%20cancer%20is%20the,the%20incidence%20of%20HBV%20infection2. Wang HL et al., Arch Pathol Lab Med 2008;ADC: Antibody Drug Conjugate; DAR: Drug to antibody ratio; GPC3: Glypican-3; HCC: Hepatocellular Carcinoma; NHP: Non-human Primates; PK: Pharmacokinetics. Initiated Phase 1 clinical trialin 2H 2025 (NCT07164313)
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24 HCC Epidemiology and Current TreatmentHCC BurdenStandard of Care for Systemic HCC As a first-in-class TOPO1-based ADC for HCC, ZW251 offersthe potential of anew MOA for patients, and an opportunity to improve upon the current standard of care •Globally 6th most common cancer and third most common cause of death from cancer•In the US, most patients receive IO-VEGF or IO-IO combinations in 1L; multi-targeted TKIs are a 2L option 3.58.215.63134.1 21.625.46590.797.1 020406080100Liv erLun gColonBr eastProstate Percent 5-Year Relative Survival, US (2013-2019) All S tages Finn RS et al NEJM 2020; Abou-Alfa GK et al NEJM Evid 2022; Yoo C et al Liver Cancer 2021 WHO. International Agency of Cancer Research. Cancer Today. 2020. Available at: https://gco.iarc.fr/today/home. Accessed October 2023 SEER. Cancer Stat Facts. National Cancer Institute. Available at https://seer.cancer.gov/statfacts/ 0 25 50 75 100 02468 ORR (%) mPFS (months) Standard of Care, ORR & PFS atezolizumab + bevacizumab1L, IMbrave150durvalumab + tremelimumab1L, HIMALAYA sorafenib or lenvatinib2L retrospective
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0 1020300 500 1000 1500 2000 Days a+er dosing Tumour Volume (mm3, Mean ± SEM) 0 10 20 300 1000 2000 3000 Days a*er dosing Tumour Volume (mm3, Mean ± SEM) 25 ZW251: Potential Utility in Hepatocellular Carcinoma HCC: Hepatocellular carcinoma; PDX: patient derived xenograft; MTD: maximum tolerated dose; T1/2: half-life; GLP: good laboratory practiceMadera L et al., Abstract #2658 presented at AACR 2023; Madera L et al, presentation at World ADC 2023; Madera L et al., Abstract #177 presented at EORTC-NCI-AACR 2024.ADC: Antibody Drug Conjugate; GPC3: Glypican-3; HCC: Hepatocellular Carcinoma; MTD: Maximum Tolerated Dose; NHP: Non-human Primates; PDx: Patient-derived xenograph; PK: Pharmacokinetics. Differentiated Modality Demonstrates Anti-tumor ActivityRobust ADC Internalizationand Cytotoxicity ZW251 internalized in HCC cell line Tumor spheroid cytotoxicity in HCC cell lineInternalization visualized after 24-hour treatment Impressive Tolerability and Dose-proportional PK in NHP DoseMTDT1/2 (day)20 mg/kg≥ 120 mg/kg4.660 mg/kg4.8120 mg/kg5.4 Vehicle ZW251, 8 mg/kg HCC PDXGPC3 H-Score: 288HCC PDXGPC3 H-Score: 84 Anti-tumor activity of ZW251 against hepatocellular carcinoma patient derived xenografts expressing high and low GPC3 Non-GLP toxicology study in non-human primates dosed 3 times every 3 weeks Total IgG in NHP serumZW251 0.00010.0010.010.11101001,000 0 20 40 60 Concentration (nM) % Cytotoxicity Cytotoxicity assessed by cell line spheroids (treatment over 4 days) On track for clinical studies in mid-2025
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26 ZW220ADC Designed to TargetNaPi2b-Expressing Ovarian Cancer and NSCLCSignificant Patient Need•NaPi2b is found in ~83% of ovarian serous adenocarcinomas2 and ~77% of NSCLC adenocarcinomas2 Differentiated Profile•Strong preclinical activity in models with a breadth of NaPi2b expression2•Encouraging tolerability in repeat dose NHP toxicology studies1•Desirable PK and is well tolerated at high doses•First-in-class ADC potential for NaPi2b-expressing solid tumors Optimized Design1•ADC targeting NaPi2b-expressing solid tumors•Comprised of a humanized IgG1 antibody conjugated to a moderate potency topoisomerase I inhibitor payload technology with bystander activity, ZD06519•Intermediate drug-to-antibody ratio ~4•Validated peptide cleavable linker sequence•FcγR silenced to potentially minimize toxicities driven by cellular uptake via FcγR 1. Hernandez Rojas A et al., Abstract #1533 presented at AACR 2023.2. Lin K, et al. Clin Cancer Res. 2015;21(22):5139–5150 (prevalence% basedon 26 cases of ovarianserousadenocarcinomasand 31 cases of non-smallcelllungadenocarcinomas).ADC: Antibody Drug Conjugate; NaPi2b: Sodium-dependent phosphate transporter 2b; NHP: Non-human Primates; NSCLC: non-small cell lung cancer; PK: Pharmacokinetics IND-ready candidate
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27 NaPi2b is Overexpressed in Multiple Cancers with High Unmet Medical Need Ovarian1)Banerjee et al. 2023. ESMO #1452)Richardson et al. 2022. SGO #763)Levan et al. 2017. BMC Cancer4)Lin et al. 2015. Clin Cancer Res5)Lopes dos Santos et al. 2013. PLoS OneEndometrial/uterine1)Horsley et al. 2024. Cancer Res #5085NSCLC (adeno)1)Horsley et al. 2024. Cancer Res #50852)Heynemann et al. 2022. Clin Lung Cancer3)Yu et al. 2018. IASLC #126364)Zhang et al. 2017. Tumor Biology5)Lin et al. 2015. Clin Cancer ResThyroid1)Hakim et al. 2021. Anal Cell Pathol2)Lin et al. 2015. Clin Cancer ResColorectal1)Liu et al. 2018. Biomed PharmacotherBladder1)Ye et al. 2017. Cell Death DisBreast1)Lopes dos Santos et al. 2013. PLoS One2)Kiyamova et al. 2011. Exp Oncol Renal/kidney1)Lopes dos Santos et al. 2013. PLoS OneOvarian (serous) Endometrial/uterine NSCLC (adeno) Thryoid Colorectal Bladder Breast Renal/kidney 0 10 20 30 40 50 60 70 80 90 100 NaPi2b % Positivity by IHC Range:64-96%Range:66-84%Range:68-91% Range:20-30% 83%81%77%80% 54%53% 25%21% Cancer indication
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01020304050600 500 1,000 1,500 2,000 2,500 Time post dose (Days) Tumor Volume (mm3) 01020300 250 500 750 1,000 Time post dose (Days) Tumor Volume (mm3) 28 ZW220: Potential Utility in Multiple CancersZW220 Efficiently Internalizes and Co-localizes with LysosomesAnti-tumor Activity in Ovarian and Lung Cancer Models Anti-tumor activity of ZW220 and lifastuzumab vedotin against ovarian and lung patient derived xenografts (PDXs) expressing NaPi2b NSCLC PDXNaPi2b H-Score: 180Ovarian PDXNaPi2b H-Score: 115 VehicleZW220 (6 mg/kg)lifastuzumab vedotin (6 mg/kg) ZW220 (mAb) internalization in Ovarian Cancer cell line 15 min4 hrs16 hrs24 hrs15 min4 hrs16 hrs24 hrs15 min4 hrs16 hrs24 hrs 0 10,000 20,000 30,000 40,000 Internalized FluorescenceGeometric Mean (FITC-A) OVCAR-3Internalization timecourse Upifitamab Lifastuzumab ZW220 mAb ZW220 mAbupifitamablifastuzumab Lysosomal trafficking of ZW220 mAb 051015202530354045 100 1,000 10,000 Time (days post dose) Total Ab Concentration (ug/mL) Group 5 (v38594-30mg/kg/dose)Group 6 (v38594-60mg/kg/dose)Group 7 (v38594-90mg/kg/dose) Dose1 Dose2 Dose3 ZW220 (30 mg/kg) ZW220 (60 mg/kg) ZW220 (90 mg/kg) Total IgG in NHP serum Impressive Tolerability and Dose-proportional PK in NHP DoseMTDT1/2 (day)30 mg/kg≥ 90 mg/kg10.360 mg/kg9.890 mg/kg8.0 Non-GLP toxicology study in non-human primates dosed 3 times every 3 weeks *ZW220 Fc wt surrogate used in non-GLP NHP study mAb: monoclonal antibody; PDX: patient derived xenograft; MTD: maximum tolerated dose; T1/2: half-life; GLP: good laboratory practiceHernandez Rojas A et al., Abstract #1533 presented at AACR 2023; Hernandez Rojas A et al. Presentation at World ADC 2023; Hernandez Rojas A et al. Eur. J. Cancer (2024), 211, 114535.
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29 ZW209Trispecific T cell engager (TriTCE) Designed to Target DLL3-expressing Solid TumorsSignificant Patient Need •DLL3 is expressed on the surface of SCLC and other neuroendocrine tumors but rarely on the surface of normal cells.•SCLC accounts for about 15% of all lung cancer diagnoses in the U.S. each year.1On track for IND submission 1H 2026 Differentiated Profile•Clean expression profile and absence of on-target, off-tumor side effects observed for DLL3 x CD3 bispecifics provides ideal TriTCE Co-stim target profile.•Long term cytotoxicity at low effector to T cell ratios, increased T cell proliferation, survival, and anti-tumor activity with reduced cytokine release.•Validated responsiveness of DLL3-expressing tumors to TCE modality. Optimized Design•Potential first-in-class TriTCE that targets DLL3-expressing tumor cells, and CD3 and CD28 on T cells.•TriTCE with potentially optimized TAA, CD3, CD28 binding affinity andgeometry usingAzymetric™ and EFECT™ platforms.•Leverages obligate cis-T cell binding and conditional CD28 engagement to prevent unintended T cell activation, while enabling tumor-targeted cytotoxicity. 1. https://www.yalemedicine.org/conditions/small-cell-lung-cancer#:~:text=There%20are%20two%20primary%20forms,and%20improving%20quality%20of%20life.DLL3: Delta-like ligand 3; SCLC: Small Cell Lung Cancer; TAA: tumor-associated antigen; TriTCE: Tri-specific T Cell Engager.
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Percentage of Patients with DLL3+ Tumors (%) 30 DLL3 is an Ideal Target to Evaluate TriTCECo-stim Platform, with Opportunities in Multiple Cancers 68% 37% 17% 17%64% 12%13% 77% 8% SCLCNEPCGEP NECLCNEC(N = 1050)(N = 13)(N = 47)(N = 94) 85%77%77%74%TPS ≥ 1%TPS ≥ 25% TPS ≥ 50% TPS ≥ 75% Responsiveness of DLL3-expressing tumors to TCE modality validated with Imdelltra™ and other DLL3 bispecific TCEs; however, opportunity for improved responses remainsDLL3 is expressed on the surface of SCLC and other neuroendocrine tumors but rarely on the surface of normal cellsClean expression profile and absence of on-target, off-tumor side effects observed for DLL3 x CD3 bispecifics provides ideal TriTCE Co-Stim target profile Adapted from: Rojo F et al Lung Cancer 2020. International real-world study of DLL3 expression in patients with small cell lung cancer. Puca L et al. Delta-like protein 3 expression and therapeutic targeting in neuroendocrine prostate cancer. Sci Transl Med. 2019. 11: eaav0891. Liverani C et al Endocrine Pathol 2021. Diagnostic and Predictive Role of DLL3 Expression in Gastroenteropancreatic Neuroendocrine Neoplasms. 32:309-27. Hermans BCM et al. DLL3 expression in large cell neuroendocrine carcinoma (LCNEC) and association with molecular subtypes and neuroendocrine profile. Lung Cancer 2019. 138:102-8. DLL3: Delta-like Ligand 3; GEP NEC: Gastroenteropancreatic Neuroendocrine Cancer; LCNEC: Large Cell Neuroendocrine Cancer; NEPC: Neuroendocrine Prostate Cancer; SCLC: Small Cell Lung Cancer TCE, T cell engager; TPS: Tumor Proportion Score.
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31 CD28 Co-stimulatory T Cell Engager Approaches 1Stein et al., Journal ClinicalOncology(2023); 2Seung et al., Nature (2022); 3 Promsoteet al., Nature Communications (2023)TAA: tumor-associated antigens, TMDD: Target-mediated drug disposition CD28 x TAA +/- PD1Limitations:Initial clinical activity for CD28-TAA +PD1, but potential toxicity due to autoreactive T cells1 CD28 x TAA + CD3 x TAA Limitations:•Optimized for single agent activity and strong CD28 agonism, potential for similar toxicity to CD28-TAA and difficult to optimize by dose adjustment•Exposure of two molecules at required dose levels potentially suboptimal First Generation:•High affinity CD3 and CD28superagonist paratopes2,3 •T cell binding, activation and TMDDobserved in periphery2,3 •Target-independent activity and T cell activation Zymeworks’ Next Generation Solution:•Balanced low affinity CD3 and CD28 engagement•Conditional CD28 binding that only binds in cis with CD3 engagement •Strict target-dependent activity and T cell activation•Identified via Azymetric™ screening of various antibody geometries and CD3 and CD28 paratope affinities Bispecific CD28 T cell Engagers TrispecificCD28 T cellEngagers
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Antibody Concentration (pM) % T Cell : T Cell Bridging 101 1021031041050 10 20 30 32 ZW209: Mediates Enhanced and Sustained CytotoxicityConditional Binding of CD28, Requiring Co-engagement of CD3; Obligate Cis Binding ZW209 demonstrates conditional CD28 binding and target-dependent anti-tumor activity CD28-KOJurkat CD3-KOJurkat Improved Cytotoxicity Over Bispecifics in Low E:T ConditionsImproved T Cell Proliferation, Memory T Cell Expansion and Sustained Cytotoxicity T cells +Tumor cells T cells Only T cell Proliferation Repeat Challenge Assay ZW209ZW209 CD28null AMG 757Irrelevant Ab 0100101102103104105 0 5000 10000 15000 20000 Antibody Concentration (pM) ZW209 ZW209 CD3null ZW209 CD28null ZW209ZW209Positive Control TrispecificPalivizumab Trans Binding Control Irrelevant mAb ZW209Positive Control TrispecificPalivizumab Tumor Cell Cytotoxicity (%) Assay Day3691215180 50 100 T Cell +Tumor CellT CellOnly ZW209 ZW209 CD28null T Cell +Tumor CellT CellOnly AMG 757 1001011021031040 50 100 COR-L279 1001011021031040 50 100 NCI-H510A Tumor Cell Survival (%) Antibody Concentration (pM) ZW209DLL3xCD3xHAAMG 757RG6524BI 764532PalivizumabZW209 ZW209 CD28null AMG 757†(DLL3xCD3) BI 764532⧧(DLL3xCD3) RG6524＊(DLL3xCD3xCD137) Irrelevant mAb ZW209DLL3xCD3xHAAMG 757RG6524BI 764532PalivizumabZW209DLL3xCD3xHAAMG 757RG6524BI 764532Palivizumab Lau D, et al. Presented at: AACR. 2025 (Abstract 7318). † AMG 757 (DLL3/CD3 BiTE) produced in-house, ⧧ BI 764532 (DLL3/CD3 bispecific TCE) produced in-house, ＊ RG6524 (DLL3/CD3/CD137 trispecific TCE), § CD3xCD28xTAA CODV Analog is a CD3xCD28xMSLN trispecific with the same format as the Sanofi Trispecific containing a CD3xCD28 CODV-Fab; produced in-house. ⧲ TGN1412 (hIgG4; biosimilar produced in-house) Naïve TCM TEM TEMRA % Change from Day 0 ZW209 ZW209 CD28 null AMG 757 †-100% 0% 100% 200% 300% 400%
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33 ZW209: Mediates Enhanced Anti-Tumor Activity and Favorable Safety Profile in In Vitro and Animal StudiesWell Tolerated in Non-Human Primates Note: Peak 10 mg/kg surrogate values are male with ↑ CRP Transient, Minor Increases in Serum Cytokine Post-Dosing ZW209 (10 mg/kg)DLL3 TriTCE Cyno surrogate (10 mg/kg) IL-6 IL-10 MCP-1 IL-2 051015202530350 700 1400 2100 2800 Days Post-Tumor Implant Tumour Volume (mm3) Tumour Volume (mm3) NCI-H82 Donor G (CE0007358) Legend PBMC Donor 2 051015202530350 700 1400 2100 2800 Days Post-Tumor implant Tumour Volume (mm3) Tumour Volume (mm3) - NCI-H82 Donor G V2 LH01 C3E5 Fab (v41086) 051015202530350 500 1000 1500 2000 2500 Days Post-Tumor Implant Tumour Volume (mm3) Tumour Volume (mm3) - NCI-H82 Donor H V2 LH01 C3E5 Fab (v41086) ZW209 2.85nmol/kg 051015202530350 700 1400 2100 2800 Days Post-Tumor implant Tumour Volume (mm3) Tumour Volume (mm3) - NCI-H82 Donor G AMG757 (v38589) 051015202530350 500 1000 1500 2000 2500 Days Post-Tumor Implant Tumour Volume (mm3) Tumour Volume (mm3) - NCI-H82 Donor H V2 LH01 C3E5 Fab (v41086) ZW209 2.85nmol/kg 051015202530350 500 1000 1500 2000 2500 Days Post-Tumor Implant Tumour Volume (mm3) Tumour Volume (mm3) - NCI-H82 Donor H AMG757 (v38589) AMG757 2.85nmol/kg 051015202530350 500 1000 1500 2000 2500 Days Post-Tumor Implant Tumour Volume (mm3) Tumour Volume (mm3) - NCI-H82 Donor H V2 LH01 C3E5 Fab (v41086) ZW209 2.85nmol/kg 051015202530350 500 1000 1500 2000 2500 Days Post-Tumor implant Tumour Volume (mm3) Tumour Volume (mm3) NCI-H82 Donor H (CE0010039) Untreated 051015202530350 500 1000 1500 2000 2500 Days Post-Tumor Implant Tumour Volume (mm3) Tumour Volume (mm3) - NCI-H82 Donor H V2 LH01 C3E5 Fab (v41086) ZW209 2.85nmol/kg UntreatedZW209 2.85 nmol/kg AMG 757 2.85 nmol/kg ZW209 Mediates Enhanced Anti-Tumor Activity In Vivo Compared to Benchmark Bispecific TCE in Humanized SCLC ModelsPBMC Donor 1 Lau D, et al. Presented at: AACR. 2025 (Abstract 7318). † AMG 757 (DLL3/CD3 BiTE) produced in-house
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- AD-VAN-CE Portfolio: Progressing “First In Class” Therapeutics 1.Focus on novel “first in class” multi-functional therapeutics: novelty of modality, mechanism of action (MoA), and/or targeting strategy. Disruptive therapeutics with high potential benefit to patients.2.Build on competitive edge in ADCs and protein engineering: cross complementary MoA and pathway axes across Zyme portfolio.3.Continue to focus on select therapeutic opportunities in solid tumors: expand portfolio coverage with GI tract and thoracic cancers.4.Expand technology application to Heme-Onc, Autoimmune and Inflammatory Disease: targeted areas conducive to multi-functional therapeutic intervention; overlap with company expertise. Antibody-Drug Conjugates•Novel Payload(s) – beyond TOPO1i •Bispecific/Biparatopic(s)•Novel Targets and Target Pairs•Payload modalities beyond cytotoxics Cell EngagersCytokine Engineering•Multispecific T Cell Engagers•Multi-antigen targeting•Conditional activation•Novel targets (e.g. proteomics)•Intracellular antigens •Tumor specific cytokine activation •Combination Checkpoint Inhibition/cytokine activation•Chemokine incorporation•Multi-cytokine blockade (Autoimmune) ADCs: Antibody Drug Conjugates; GI: Gastrointestinal; MoA: mechanism of action. 34
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35 ZW1528Bispecific Designed to Address Respiratory InflammationSignificant Patient Need •Mixed-type COPD patients are hospitalized 2-3.6 times more often than those with other COPD phenotypes1On track for IND submission 2H 2026 Differentiated Profile•Potently blocks two complementary pathways of respiratory inflammation: IL-4Rα and IL-33•Targets three cytokines in a single biologic•Offers a unique approach that leverages clinically validated targets•Demonstrates high manufacturability and incorporates half-life extending Fc modifications•Aligns with requirements for successful AIID therapeutics Optimized Design•IL-4Rα x IL-33 bispecific molecule that inhibits multiple pathways within complex pathophysiology of inflammation in diseases such as mixed-type COPD•In-house antibody discovery of novel anti-IL4Rα and IL-33 paratopes•Native IgG-like geometry Anti-IL4Rα Anti-IL-33 IgG4 YTE 1. https://pubmed.ncbi.nlm.nih.gov/25844673/#:~:text=Measurements%20and%20main%20results:%20Of,%3C%200.05%20for%20all%20comparisons).AIID: Autoimmune and inflammatory disease, COPD: Chronic obstructive pulmonary disease
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36 Bispecific Antibody Therapeutics as the Potential Answerto Complex Biology of AIID and Hematology Oncology Patients Clinical ScienceClinically validated targetsBenefits of combination Inconvenience and costof clinical implementation TechnologyClinically validated platformCompatibility with Fc modifications (HLE) High efficacy, convenient, cost-effective solution Zymeworks’ differentiated multifunctional therapeutics provide opportunity to improve upon existing treatment approaches and current standard of care in areas of high unmet need •Serious, difficult-to-treat diseases (e.g., ALL, cHL, MM, COPD, and NHL)•Contribution of multiple (targetable) pathways•Large patient population•Restricted access to advanced therapeutics•Urgent need for treatments in refractory or multidrug-resistant cases•Poor outcomes ALL:Acute lymphocytic leukemia , cHL: Classical Hodgkin Lymphoma, MM: Multiple myeloma, COPD: Chronic obstructive pulmonary disease, NHL: non-Hodgkin lymphoma, HLE: Half-life extension.
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37 ZW1528: A Potential New Treatment Option in COPD Effectively Blocks of IL-4/13 and IL-33 Signaling Potently blocks two complementary pathways of respiratory inflammation, while aligning with requirements for successful AIID therapeutics Effectively Blocks Complementary Pathways of Immune ActivationDemonstrates Biomarkers of IL-4Rα/IL-33 Blockade in NHP Up to 6 Weeks After Single Administration IL-1310-2 100 102 104 10600.0 0.2 0.4 0.6 0.8 1.0 Concentration (pM) IL-4 blockade, OD620nm ZW1528 (IL-4Ra x IL-33) Dupilumab (IL-4Ra) Control mAb Itepekimab (IL-33) Blockade of IL-4/13 Blockade of IL-3310-210010210410600.0 0.5 1.0 1.5 Concentration (pM) IL-33 blockade, OD620nm ZW1528 (IL-4Ra x IL-33)Dupilumab (IL-4Ra)Control mAbItepekimab (IL-33)10-210010210410600.0 0.5 1.0 1.5 Concentration (pM) IL-33 blockade, OD620nm ZW1528 (IL-4Ra x IL-33)Dupilumab (IL-4Ra)Control mAbItepekimab (IL-33) 10-2100 102 104 10600.0 0.5 1.0 1.5 Concentration (pM) IL-33 blockade, OD620nm ZW1528 (IL-4Ra x IL-33) Dupilumab (IL-4Ra)Control mAb Itepekimab (IL-33) 10-210010210410600.0 0.2 0.4 0.6 0.8 1.0 Concentration (pM) IL-4 blockade, OD620nm ZW1528 (IL-4Ra x IL-33)Dupilumab (IL-4Ra) Control mAbItepekimab (IL-33) Unstimulated IL-33IL-13 IL-13 + 33DupilumabDupi + IteZW1528 0 1 2 3 4 CCL2 expression, log2 fold change Pre-dose48 hours anti-hIgG4anti-hIgG4 CD20 0102030-1.0 -0.5 0.0 0.5 1.0 Days post treatment NHP Serum IgE, Log2 Fold Change
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38 Multiple Candidates in Development Offer Strategic Pivot Points ZW191 ZW220 ZW251ZW209 ZW1528 Phase 1 Clinical Development Preclinical Development Pipeline Resource Allocation Partnership Optionality Combination Approaches Accelerated Developmentinto Phase 2/3 Decision Pathway FactorsOptimal doseTolerability and safetyEarly signs of anti-tumor activity Proof of targeted therapy: strong relationship between expression levels and anti-tumor activityCompetitive landscape
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39 Executive Summary With nominationof ZW209, 5x5solid tumorportfolio construction is 18 months ahead of schedule Additional solid tumor research focusedon digestive system cancers, including CRC and PDAC ADVANCE portfolio broadly diversified into hematological cancers and AIID in additionto solid tumors with initial IND planned for 2H 2026 for ZW1528 R&D organizational structure in place to drive continued progress in both ‘5x5’ and ADVANCE portfolios Enhanced optionalityfor partnerships and collaborations to share capital and development risk Strong financial positionto provide opportunityfor retaining certain product rights Clear decision-making processes to advanceor cease development activities on product candidates based on clinical data generated Recent approval of zanidatamab demonstrates our experience and abilitiesto develop unique and differentiated therapeutics with clinically meaningful benefits for patients
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40 Meaningful Catalyst Events Anticipated Throughout 2025 & 2026 2025 2026EMA and NMPA granted approval of zanidatamab for BTC, expanding patient access and potential royalties payable to ZymeworksInitial royalty revenue for Ziihera® from Jazz collectedIND cleared for ZW251 (GPC3) with first-in-human studies planned to initiate in 2025 Initial royalty revenue for Ziihera® from BeiGene collectedPivotal Phase 3 top-line PFS data readout in 1L GEAforzanidatamab targeted by our partner Jazz in 4Q 2025 Expected IND submission for ZW209 (DLL3) in 1H 2026Expected regulatory submission for ZW1528 (IL4R x IL-33) in 2H 2026Jazz to potentially launch zanidatamab for 1L GEA in the U.S. in 2026 pending regulatory approval CASH1RUNWAY FORECAST INTO 2H 2027 WHEN COMBINED WITH RECEIPT OF CERTAIN ANTICIPATED REGULATORY MILESTONE PAYMENTS 1 Cash, cash equivalents, and marketable securities.Illustrative. Key news flow only. BTC: Biliary Tract Cancer; GEA: Gastroesophageal adenocarcinoma; GPC3: Glypican-3; sBLA: supplemental biologics license application; PFS: Progression-Free Survival
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Nasdaq: ZYME | zymeworks.com Company ContactsInvestor RelationsShrinal InamdarSenior Director, Investor Relationsir@zymeworks.com+1 604 678 1388 Media RelationsDiana PapoveSenior Director, Corporate Communicationsmedia@zymeworks.com+1 604 678 1388