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Extending the Boundaries of Targeted Cancer Therapies Patrick Amstutz, CEO January 2026 Nasdaq, SIX Swiss Exchange: MOLN
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Disclaimer This presentation contains forward looking statements. Any statements contained in this presentation that do not describe historical facts may constitute forward-looking statements as that term is defined in the Private Securities Litigation Reform Act of 1995, as amended, including without limitation: implied and express statements regarding the clinical development of Molecular Partners’ current or future product candidates; expectations regarding timing for reporting data from ongoing clinical trials or the initiation of future clinical trials; the potential therapeutic and clinical benefits of Molecular Partners’ product candidates and its RDT and Switch-DARPin platforms; the selection and development of future programs; Molecular Partners’ collaboration with Orano Med including the benefits and results that may be achieved through the collaboration; and Molecular Partners’ expected business and financial outlook, including anticipated expenses and cash utilization for 2026 and its expectation of its current cash runway. These statements may be identified by words such as “aim”, "anticipate", “expect”, “guidance”, “intend”, “outlook”, “plan”, “potential”, “will” and similar expressions, and are based on Molecular Partners’ current beliefs and expectations. These statements involve risks and uncertainties that could cause actual results to differ materially from those reflected in such statements. Some of the key factors that could cause actual results to differ from Molecular Partners’ expectations include, but are not limited to, those set forth in under the heading “Risk Factors” in Molecular Partners’ Annual Report on Form 20-F for the year ended December 31, 2024 and other filings Molecular Partners makes with the SEC from time to time. These documents are available on the Investors page of Molecular Partners’ website at www.molecularpartners.com. In addition, this presentation contains information relating to interim data as of the relevant data cutoff date, results of which may differ from topline results that may be obtained in the future. Molecular Partners’ audited consolidated financial statements at and for the year ended December 31, 2025 are not yet available. As a result, the financial information described in this presentation is preliminary and unaudited, represents management’s estimate as of the date hereof and is subject to completion of the Company’s financial closing procedures for the fourth quarter and fiscal year ended December 31, 2025. This preliminary financial information may materially differ from the actual results that will be reflected in the Company’s audited consolidated financial statements when such financial statements are completed and publicly disclosed. The Company’s independent registered public accounting firm has not conducted an audit or review of, and does not express an opinion or any other form of assurance with respect to, the Company’s preliminary results. Any forward-looking statements speak only as of the date of this presentation and are based on information available to Molecular Partners as of the date of this release, and Molecular Partners assumes no obligation to, and does not intend to, update any forward-looking statements, whether as a result of new information, future events or otherwise. 2
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3 Extending the Boundaries of Targeted Cancer Therapies DARPin Designed Ankyrin Repeat Protein Target Our Pipeline • Differentiated Assets with focus in Oncology • MP0712 / Targeted radiotherapy and MP0533 / next-gen immune cell engagers • Early clinical readouts for patient value across indications with high unmet need Our Company • Clinical-stage biotech company, founded 2004 • Operations & listing in Switzerland (SIX, 2014) and US (Nasdaq, 2021) • Financed (USD ~116 M / CHF ~93 M*) to capture upcoming value inflection points Our Capabilities • DARPin therapeutics: new class of drugs, clinically-validated, proprietary platforms • Strong team to execute up to clinical POC • Global partnerships to access technology & capabilities (Orano Med) *Unaudited financials as of December 31, 2025. POC, proof of concept.
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4 Continued Innovation in DARPin Discovery, Therapeutic Designs EITHER-OR Differentiated Candidates Tailored to Patient NeedsDARPin Drug Design Process Computational Designs Display Technologies Deep Data Mining Radio-DARPin therapeutics Conditional, logic-gated Switch-DARPin candidates Multispecific DARPin candidates Targeted DARPin Therapeutics ✓ Highly precise tumor targeting ✓ Tumor-localized activity ✓ Low uptake in healthy tissues Proprietary DARPin Libraries ➢ Powered by >20 years of clinical learnings ➢ Designed for low immunogenicity A C T T target HLE
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5 r/r AML and AML/MDS CD33 x CD123 x CD70 x CD3 Advanced Solid Tumors FAP x CD40 Ovarian Cancer 212Pb x MSLN SCLC & NECs 212Pb x DLL3 Our Pipeline – Differentiated Therapeutics for Patient Value RESEARCH PRE-CLINICAL PHASE 1 PHASE 2 PHASE 3 CANDIDATEPLATFORM MP0712 MP0726 Undisclosed Programs (Solid Tumors) MP0533 MP0317 HSCT cKit x CD16a x CD47 Co-development* CD3 x CD2 x MSLN x EpCAM *The co-development agreement with Orano Med includes up to 10 targeted radiotherapy programs, including MP0712 and MP0726. AML, acute myeloid leukemia; DLL3, Delta-like ligand 3; HSCT, hematopoietic stem cell transplant; MDS, myelodysplastic syndrome; MSLN, mesothelin; NEC, neuroendocrine cancer; r/r, relapsed/refractory; SCLC, small cell lung cancer. Co-development* MP0621 (Switch-DARPin) Switch-DARPin T Cell Engager Radio-DARPin Therapy (RDT) Next-Gen Immune Cell Engagers Radio - C Radio - D Radio - E Radio - F
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Radio-DARPins ➢ Ideal vectors for precise delivery of potent radio-isotopes ➢ Potential to unlock broad target space across solid tumor indications
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DARPin: IDEAL VECTOR FOR RADIOPHARMACEUTICALS • Proven selective targeting • High affinity, tumor retention • Broad target space • Small size Radio-DARPins for Next-Gen Targeted Alpha Therapy ALPHA-EMITTING THERAPEUTIC ISOTOPE • Proven clinical efficacy • High energy deposition LINKER & CHELATOR SURFACE ENGINEERING • Enabled by high stability • Reduce kidney accumulation HALF-LIFE EXTENDER • Tailored systemic exposure • Promote tumor uptake HLE 7
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Global Partnership to Develop 212Pb Radio-DARPin Therapeutics Combining DARPin versatility with the power of 212Pb for next-gen Targeted Alpha Therapy 8 4 Radio-DARPin programs 50:50 cost and share split 4 MP-owned programs 2 MP-owned programs with opt-in option for OM for 50:50 cost:share split Pipeline of ten 212Pb radiotherapy products 212Pb x DLL3 212Pb x MSLN TEXAS, US: Preclinical development GMP supply for early clinical phases INDIANA, US: Industrial scale manufacturing Global shipping hub ATLab US FRANCE: 212Pb starting material ATLab Europe SWITZERLAND: Preclinical assessment DARPin engine, fast & high throughput World class technologies & capabilities combined MOLECULAR PARTNERS PIONEERS of DARPin THERAPEUTICS ORANO MED PIONEERS of TARGETED ALPHA THERAPY FULL VALUE CHAIN PARTNERSHIP 1 2 3 4 5 6 7 8 9 10 212PbDARPin MP0726 MP0712
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Our Scientific Advisory Board to Accelerate Development of Targeted Radiotherapeutics Ken Herrmann, M.D. Chair James Cook Member Jason Lewis, Ph.D. Member Michael Morris Member ➢ Chaired by Prof. Ken Herrmann, M.D., globally renowned expert in the field of nuclear medicine ➢ Other Board members bring significant clinical and industry expertise, supporting transition from early clinical validation to strategic development 9
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MP0712 Targeted Radiotherapy for Lung Cancer ➢ Specific tumor uptake reported in initial human images ➢ Phase 1/2a in US open, early data in 2026
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MP0712: Why DLL3-Targeting Radiotherapy for SCLC T Cell Engagers • Tarlatamab approved • 40% RR • 9.7 months DoR • Substantial side effects Antibody-Drug Conjugates • Phase 1/2 • 70% RR • Risk of chemo-resistance • Manageable side effects Radiotherapy (MP0712) • Phase 0/1 • SCLC highly radio-sensitive • Manageable side effects • Combinable with other MoAs 11DoR, duration of response; MoA, mode of action; RR, response rate; SCLC, small cell lung cancer. DLL3 212Pb
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MP0712: Potent Efficacy at Clinically-Relevant Dose in Mice 0 10 20 30 40 50 60 70 80 0 500 1000 1500 2000 Days since cell injection Tumor Volume (mm3) average ± SEM MP0712 (4x10µCi) MP0712 (8x5µCi) Negative control (4x10µCi) Buffer Steiner et al, TRP 2024 Croset et al, EANM 2024 Lizak et al, SNMMI 2024 12 High Tumor Accumulation (Tumor > Kidney) Reduction of Established Tumors Mice xenografted i.v. with NCI-H82. Dose: 10 µCi of 212Pb at 0.01 mg/kg of DLL3 DARPin. Efficacy study in NCI-H82 s.c. model / MP0712 and negative control injected 4 x 10 μCi at 0.01 mg/kg or 8 x 5 μCi at 0.01mg/kg every 1; 10 μCi = 370 kBq Blood Bladder Small intestine Colon Spleen Kidneys Liver Lung Heart Tail NCI-H82 0 20 40 60 80 100 %ID/g 4 h 24 h 12 22 26 57 0 10 20 30 40 50 60 70 80 0 500 1000 1500 2000 Days since cell injection Tumor Volume (mm3) average ± SEM MP0712 (4x10µCi) MP0712 (8x5µCi) Negative control (4x10µCi) Buffer 0 10 20 30 40 50 60 70 80 0 500 1000 1500 2000 Days since cell injection Tumor Volume (mm3) average ± SEM MP0712 (4x10µCi) MP0712 (8x5µCi) Negative control (4x10µCi) Buffer 0 10 20 30 40 50 60 70 80 0 500 1000 1500 2000 Days since cell injection Tumor Volume (mm3) average ± SEM MP0712 (4x10µCi) MP0712 (8x5µCi) Negative control (4x10µCi) Buffer 0 10 20 30 40 50 60 70 80 0 500 1000 1500 2000 Days since cell injection Tumor Volume (mm3) average ± SEM MP0712 (4x10µCi) MP0712 (8x5µCi) Negative control (4x10µCi) Buffer
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Targeting DLL3: Why do we see High Tumor Uptake, Despite the low Copy Number Croset et al, EANM 2024 Lizak et al, SNMMI 2024 NCI-H82 i.v. model: 212Pb-DOTAM-DARPin - single injection - dose: 10 µCi (0.01 mg/kg). SCLC, small cell lunc cancer. NCI-H82 tumors 0 200 400 600 800 ABC value Low DLL3 Density on Tumor Cells (of <1000 receptors/cell) High Tumor Accumulation (MP0712: Tumor > Kidney) ? 13 Blood Kidneys NCI-H82 0 20 40 60 80 100 1 22 57 23 12 26 %ID/g 4 h 24 h NCI-H82 tumors
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0 10 20 30 0 2000 40000 80000 Hours Fluorescence (MFI) DARPin-AF488 Non-binding control MP0712-DLL3 DARPin is Rapidly Internalized and Accumulates Intracellularly in DLL3-expressing Cells in vitro 14 Spike DARPin + wash DAPI DARPin EEA1 Surface-bound DLL3-DARPin is rapidly internalized into SHP-77 human SCLC cells* Internalized DLL3-DARPin shows significant co-localization to the endosomal compartment in hDLL3-HEK cells** DLL3-DARPin accumulates in hDLL3-HEK cells over time (beyond the bound fraction at saturation)* * Internalization of DARPins labelled with anti-DARPin Fab-Alexa 488 conjugate ** Immunofluorescence co-staining of anti-DARPin antibody, an early endosomal marker (EEA1) and cell nucleus marker (DAPI) after (3 h incubation) MFI, Mean Fluorescence Intensity. Continuous DARPin presence (reloading) maximum surface binding (spike & wash)
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Hypothesis: Free Surface DLL3 is Continually Replenished for Binding and Internalization of MP0712 MP0712 – format selection: Optimized half-life and DARPin binder to exploit internalization & replenishment of DLL3 for radio-payload accumulation in SCLC cells Created with BioRender 15SCLC, small cell lung cancer.
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MP0712 Development Pathway 1. Imaging 2. Treatment MP0712 203Pb 212Pb MP0712 SCLC patient SCLC patient MP0712 binding to tumor cells MP0712-induced tumor cell death tumor tumor Solid tumor cells Dying tumor cells 16 SPECT Re-imaging Phase 1/2a Study: Named Patient Access Program: ➢ Imaging and dosimetry with 203Pb ➢ Option for treatment with 212Pb Request from NuMeRI, Pretoria, South Africa* ➢ Safety of 212Pb ➢ Efficacy signals ➢ Includes an imaging and dosimetry step with 203Pb NuMeRI, Nuclear Medicine Research Infrastructure; SCLC, small cell lung cancer; SPECT, single-photon emission computed tomography.
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SPECT/CT Imaging of 203Pb-MP0712 in SCLC: A Case Example from a Named Patient Access Program in South Africa 17 Patient characteristics • 69-year-old male (smoker) • Small cell neuroendocrine carcinoma of the lung • Stage III at referral, primary tumor located at superior mediastinum Treatment history • Radiotherapy and chemotherapy Dosing & Result • 5.1 mCi of 203Pb-MP0712 • Stage IV by MP0712 - SPECT with 4 liver mets Patient imaged as part of a Named Patient Access Program at NuMeRI, Pretoria, South Africa. Example of patient case series presented with courtesy of Prof. Dr. M. Sathekge. Full data are planned to be presented by the NuMeRI team at the Theranostics World Congress (TWC) 2026. 116 h post injection4 h post injection 24 h post injection Primary lesion Liver mets ➢ Initial high blood pool, followed by specific uptake in primary and metastatic lesions over time, and limited accumulation in healthy organs in line with MP0712 MoA MP0712
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Phase 2 studies MP0712 Phase 1/2a Study for SCLC and other NECs • First-in-Human, US multicenter, Phase 1/2a study of MP0712 monotherapy • Patients with small cell lung cancer (SCLC) and other neuro-endocrine cancers (NECs) – Every patient will be imaged (203Pb) before treatment (212Pb) – Patient pre-selection on DLL3 expression: not planned for SCLC and LC NEC of lung, foreseen for epNEC Registration study 2L+ SCLC patients IO, immuno-oncology; LC NEC, large cell neuroendocrine cancer; PoC, proof-of-concept; RP2D, recommended phase 2 dose. 18 Phase 1: Dose Escalation Main objectives: safety, RP2D N=15–39 patients SCLC and lung LC NEC; N=9-39 patients epNEC 203Pb- MP0712 Imaging / dosimetry (SPECT) 75 MBq n=3* 105 MBq n=3-12* 150 MBq n=3-12* RP2D 200 MBq n=6-12* Phase 2a: Dose Expansion and PoC Main objectives: efficacy signals, confirm safety and RP2D N=30 patients SCLC and NEC 212Pb-MP0712 (treatment): * Evaluable patients (Bayesian Logistic Regression Model guided dose escalation) **epNEC to start at a dose level previously tested in SCLC or LC NEC of lung at which a first signal of pharmacological activity is detected. RP2D for epNEC is anticipated to be same as RP2D for SCLC/LC NEC of lung. Dose Y** n=6-12* Dose X** n=3-12* … Registration in patients with other NECs 1–2L combination with IO SCLC
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2 MP0712 Conclusions & Outlook MP0712: 212Pb x DLL3 Radio-DARPin therapeutic candidate for SCLC • Strong pre-clinical data with attractive BioD, efficacy & safety profile • High tumor uptake leveraging rapid internalization & replenishment of DLL3 • Initial human images* show specific uptake in primary & metastatic tumor lesions supporting intended MoA Outlook • Full 203Pb-MP0712 compassionate care imaging & dosimetry data at TWC in January 2026 • MP0712 Phase 1 open in US, first patient first dose expected in Q1’26 • Initial data from Phase 1 in 2026 *Patient case from Named Patient Access / Compassionate care in South Africa, imaged with 203Pb-MP0712. BioD, biodistribution; HLE, half-life extension; SCLC, small cell lung cancer; TWC, Theranostics World Congress. 19
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MP0726 Targeted Radiotherapy for Ovarian Cancer ➢ Targeting membrane-bound MSLN ➢ Progressing to FIH imaging
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212Pb x MSLN Targeted Radio-DARPin for Ovarian Cancer (OC) Combining distinctive DARPin features with the power of 212Pb for next-gen targeted alpha therapy OC: high medical need and marginal progress • > 50% patients die within 5 years post-diagnosis (diagnosis often in late stage) • Poor treatment options: ~80% recurrence rate post 1L chemo, limited 2L options (FRɑ-targeted Tx relevant for only 40% patients) MSLN: a promising target for OC as 1st indication • Highly expressed in OC (>80% prevalence), expression maintained in metastases • Shed MSLN detected in serum of OC patients, might limit efficacy of MSLN- targeted therapies1,2,3,4 (e.g., CAR T/NK, ADC, TCE in development) RDT x MSLN: targeted delivery of alpha radiation with 212Pb • MSLN DARPin targets membrane-proximal epitope (and not shed MSLN) • 212Pb payload: high energy alpha emissions in short time frame • Potential for combinations with immunotherapy (incl. next-gen TCEs) 1. Awuah et al. 2016; 2. Zhang et al. 2011; 3. Smith et al. 2024 (ASCO poster); 4. Pastan et al. 2024. ADC, anti-drug conjugate; CAR T, chimeric antigen receptor T cell; FRɑ, folate receptor alpha; MSLN, mesothelin; NK, natural killer cell; OC, ovarian cancer; TCE, T cell engager; Tx, treatment. 21 Product composition αMSLN DARPin 212Pb HLE Tumor cell Shed MSLN Membrane-proximal epitope Full-length MSLN cleavage +
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MP0726: 212Pb x MSLN Radio-DARPin for Ovarian Cancer Wullschleger S, et al., AACR 2025. OVCAR-8 Cell binding competition assay (100nM DARPin with increasing concentration of shed MSLN). Mice xenografted s.c. with hMSLN-MC38 (Biocytogen). Dose: 10 µCi of 212Pb at 0.01 mg/kg of MSLN DARPin. FIH, first in human. Outlook: Progressing MP0726 to FIH imaging Tumor cell shed MSLN Membrane-proximal epitope Full-length MSLN “Distal” DARPin “Proximal” DARPin Binding maintained in presence of shed MSLN Binding inhibited in presence of shed MSLN Blood Small intestine Colon Kidneys Liver Lung Heart Tail hMSLN-MC38 0 20 40 60 6.5 1.7 1.5 7.8 7.3 2.6 1.8 1.0 32.2 25.8 3.4 1.6 8.1 7.0 10.1 6.5 4.2 16.9 Proximal MSLN DARPin-1 x HLE %ID/g 4h 24h Favorable biodistribution in hMSLN-MC38 tumor model Cell binding maintained despite shed MSLN 10-1 101 102 103 104 0 20 40 60 80 100 OVCAR-8 Cell binding competition assay 100nM DARPin with increasing concentration of shed MSLN shed MSLN [nM] Normalized binding (%) 0 Proximal DARPin Distal DARPin 22
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23 Outlook & Conclusions – Radio-DARPin Therapeutics Radio-DARPin Therapeutics Vector Isotope Target & Disease Patient Need MP0712 MP0726 Ongoing projects Nominate 1–2 for FIH imaging mid 2026 MSLN x 212Pb Ovarian Cancer DLL3 x 212Pb SCLC & NECs Overcome low target density on tumor cell Selectivity for membrane-bound antigen Radio C Radio D Radio E Radio F Overcome low target density on tumor cell Exquisitely low kidney uptake Address high homology to receptors on healthy tissues … Next projects Preparation of building blocks for research focus in 2027 Targets A+B Targets A+C Targets B+C Target E FIH, first in human; NEC, neuroendocrine cancer; SCLC, small cell lung cancer. Multi-specifics to address tumor heterogeneity Multi-specifics to address tumor heterogeneity
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Outlook
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Outlook and Upcoming Milestones in 2026 Switch-DARPin • Progress MP0726 towards FIH imaging • Nomination of new RDT programs mid 2026 • First-in-Human Phase 1 study open in US, first patient dosing imminent • Full imaging and dosimetry data from South Africa presentation at TWC in January 2026 • Initial safety data from Phase 1 anticipated in H1 2026, initial activity in H2 2026 Cash USD ~116 M (CHF ~93 M*, incl. short-term time deposits) ensures funding until 2028 *Unaudited financials as per December 31, 2025. FIH, first in human; TWC, Theranostics World Conference. MP0533 MP0712 • Conclusion of dose escalation, update in H1 2026 • Investigator-initiated combo trials under discussion Radio-DARPin Therapy (RDT) • Lead candidate selection in H1 2026, update at AACR 2026 25 MP0317 • Phase 2 combo study started in France, now dosing patients
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Twenty Years of Pioneering DARPin Therapeutics for Patients Thank You Our Team, Summer 2025
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MP0317 A FAP-localized CD40 agonist for local immune cell activation and TME modulation ➢ Phase 2 combo IIT ongoing in advanced biliary tract cancer TUMOR CELLTUMOR CELL IMMUNE CELLIMMUNE CELL
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28 MP0317: Unlocking CD40 Activity Through Local Activation • FAP is a validated tumor target overexpressed in at least 28 different cancer types and its expression is not downregulated during disease progression • MP0317 is designed to bind tumor-localized FAP and induce CD40-mediated activation of immune cells in the tumor, thereby overcoming systemic toxicity and allowing a wider therapeutic dosing range Solution: MP0317 – FAP-dependent tumor-localized CD40 activation Problem: Toxicity of CD40 antibodies has so far limited their activity • CD40 agonists can activate B cells, DCs and MΦ to enhance the efficacy of IO drugs, especially in “cold tumors” • Systemic activation of CD40 via mAbs has been hampered by significant toxicities, therefore limiting their potential of reaching a therapeutically active dose DC, dendritic cell; FAP, fibroblast activation protein; HSA, human serum albumin; MΦ, macrophage; mAb, monoclonal antibody; IO: immuno-oncology.
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29 MP0317 Leads to Remodeling of Tumor Microenvironment Tumor biopsy of a patient with GIST in Cohort 5b (Q1W); biopsy location: peritoneum. DC, dendritic cell; FAP, fibroblast activation protein; GIST, gastrointestinal stromal tumor. PRIOR TO TREATMENT CYCLE 2 DAY 8 High DC infiltration in FAP- positive tumor area in presence of MP0317 29 DC infiltration MP0317 Gomez-Roca et al, SITC 2023 poster presentation Summary of MP0317 Phase 1 Study • 46 patients treated in 9 cohorts • Favorable safety profile across all tested dose cohorts up to highest planned dose (10 mg/kg) • Clinical evidence of tumor- localized CD40 pathway and immune cell activation, leading to tumor microenvironment remodeling
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30 MP0317 Phase 2 Combo Study in Advanced Biliary Tract Cancer Study Objective (NCT07036380) • Investigator-initiated, randomized, multicenter study to assess the clinical benefit (safety and efficacy) of MP0317 combined with standard of care (SoC) in 1st line advanced biliary tract cancer (cholangiocarcinoma) Background • Why Cholangiocarcioma: high FAP expression, immune suppressive TME • Hypothesis: MP0317 to enable SOC via TME remodeling • SoC benchmark (durvalumab (anti-PD-L1), plus gemcitabine/cisplatin): 12-month PFS rate ~24%, median OS 12.8 months1 Outlook & Objective • Increase duration of response (12-month PFS rate ~36%) • Open label study & interim analysis by YE 2027 N=50 N=25 MP0317 + SoC SoC MP0317 given Q3W, 5 cycle. SoC given Q3W for 8 cycles, followed by Durvalumab only for maintenance every 4 weeks until progression. Simon two-stage design; futility analysis n=20. 1Do-Youn Oh et al, NEJM Evid 2022;1(8); DOI: 10.1056/EVIDoa2200015 (TOPAZ-1 study). PFS, progression-free survival; OS, overall survival; TME, tumor microenvironment; YE, year-end. Patient Randomization Study design MP0317 Ph2 Study RecruitingPh2 Study Recruiting
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31 31 MP0533 Tetra-specific, Mutation-agnostic T-cell Engager for AML ➢ Phase 1/2a ongoing and validating dose level ➢ Decisional data in H1 2026 to inform next steps AML CELLAML CELL T CELLT CELL
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32 MP0533: A Tetra-specific TCE for Consolidation Therapy in AML CD33 x CD123 x CD70 • Broadest coverage of AML heterogeneity (3 antigens) addressing poly-clonality • Selectivity for AML vs healthy cells CD33 x CD123 x CD70 • Broadest coverage of AML heterogeneity (3 antigens) addressing poly-clonality • Selectivity for AML vs healthy cells Anti-CD3 • T cell engager (TCE) • Mutation agnostic AML killing mechanism Anti-CD3 • T cell engager (TCE) • Mutation agnostic AML killing mechanism Half-life Extension • 2 x HSA DARPins • ~2-day half-life Half-life Extension • 2 x HSA DARPins • ~2-day half-life AML heterogeneity enables clones to evade SoC MP0533 eradicates all escaping AML cells DARPin, designed ankyrin repeat protein; HSA, human serum albumin; SoC, standard of care; TCE, T cell engager.
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33 CR, complete response; CRh/CRi, CR with partial/incomplete hematologic recovery; DR, dose regimen; ELN, European LeukemiaNet; MDS, myelodysplastic syndrome; MLFS, morphologic leukemia-free state. Encouraging Clinical Responses in Patients with Low Disease Burden Intermediate densification (DR 8) 3 responders (of 8 patients), manageable safety high low Further Densification (DR 9*) 1 responder (of 7 patients), manageable safety *DR 9 Included pre-treatment with obinutuzumab Bories et al. ASH 2025 Poster Presentation Data cut-off: 01 Sept 2025 DR 8 1 2 3 4 5 6 7 8 9 10 11 Months 4 5 6 7 8 9 10 11 DR 9 1 2 3 Months Response (ELN 2022) NR CR CRi CRh MLFS CR CRCRh CRh
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34 Mutation-agnostic AML-cell Killing in Patients high low Further Densification (DR 9*) 1 responder (of 7 patients), manageable safety DR 9 1 2 3 4 5 6 7 8 9 10 11 Months Response (ELN 2022) NR CR CRi CRh MLFS CR *DR 9 Included pre-treatment with obinutuzumab Bories et al. ASH 2025 Poster Presentation Data cut-off: 01 Sept 2025 BMA, bone marrow aspirate; CR, complete response; CRh/CRi, CR with partial/incomplete hematologic recovery; DR, dose regimen; ELN, European LeukemiaNet; MDS, myelodysplastic syndrome; MLFS, morphologic leukemia-free state.
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35 Planned Segments for MP0533 Development – IIT R/R AML – relapse Oligoblastic (<20% blasts) Front-line AML – suboptimal response Oligoblastic (<20% blasts) “Fast to market” • Company-sponsored • INTERCEPT “Maximize market value (of combo)” • Company-sponsored • ADAPT, HOVON Aza, azacitidine; IIT, investigator-initiated trial; RR, response rate; R/R, relapsed/refractory; Ven, venetoclax.
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36 36 Switch-DARPin Platform Next-generation T cell engagers
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37 Binding to TAAs releases CD3 Switch-DARPin CD3 DARPin masked by 2-in-1 Switch in absence of TAAs OFF ON Immune cell-mediated killing CD3 Switch-DARPin for Next-Gen TCEs with Enhanced Function Tackling current limitations of TCEs in solid tumors Healthy Cell T-Cell CD3 CD2 MSLN No immune cell engagement ➢ TCE is silent and inactive in circulation ➢ TCE is activated to kill the tumor cell ➢ TCE is co-stimulated (no exhaustion) TAA, tumor associated antigen; TCE, T cell engager. Next update on CD3 Switch TCE at AACR 2026 EpCAM (TAA2) α-CD3 (Mask) MSLN CD3 CD2 MSLN (TAA1) Killing TumorT Cell --------
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38 MSLN x EpCAM x CD2 x CD3 Switch-DARPin Enables “AND- ate” for Preferential Killing of Double vs Single TAA Expressing Cells 0.00001 0.0001 0.001 0.01 0.1 1 10 100 1000 -20 0 20 40 60 80 100 120 140 160 Target cell killing [Switch DARPin] (nM) Cytotoxicity (LDH) [%] EpCAM; epithelial cellular adhesion molecule; MSLN, mesothelin. EpCAM+ MSLN+ EpCAM+ MSLN+ Bianchi et al, AACR 2025 0.00001 0.0001 0.001 0.01 0.1 1 10 100 1000 0 20 40 60 80 100 T-cell Activation [Switch DARPin] (nM) CD25+ [%] CD8 Tcells CHO-MSLN/EpCAM CHO-EpCAM CHO-MSLN PanT only, no target cells -MSLN -EpCAM/CD3 Mask -CD3 -CD2
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39 CD3 Switch-DARPin with CD2 Co-Stimulation Induces Tumor Regression **** 40 45 50 55 60 65 70 0 200 400 600 800 1000 1200 Day after tumor cells injection Tumor volume (mm3) PBS CD2/CD3 Switch CD2/CD3 RandomizationPBMC Daily Treatment Antitumor activity in OVCAR-3 xenograft model NS Blood Blood Safety of CD2/CD3 Switch: in vivo cytokine release TNF, tumor necrosis factor; IL-6, interleukin-6; PBS, phosphate buffered saline; PBMCs, peripheral blood mononuclear cells. • Masking of CD3 allows the safe use of strong CD3 and co-stimulation binders in one molecule • Also confirmed in human whole blood cytokine release assay Robinson et al, SITC 2024 Bianchi et al, AACR 2025 0 20 40 60 80 IL-6 [pg/mL] LLOQ ✱✱✱✱ 0 2 5 0 5 0 0 7 5 0 1 0 0 0 TNF-alpha [pg/mL] LLOQ ✱✱✱✱ Serum cytokines in blood taken at 2 h post first injection were analyzed using MSD U-plex system.
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40 CD2 Co-stimulation Enables Sustained T Cell Function Higher cytotoxic activitySuperior T cell proliferation profile CD3 Switch CD3 Switch w/ Co-stimulator Round 1 Round 2 Round 3 Round 4 1000 10000 100000 CD8 T cell counts (cells/well) 0.001nM 0.1nM 10nM 0 10 20 30 40 50 % Killing (AUC reduction vs co-cultures only) Repetitive exposure - CD2/CD3 Repetitive exposure - CD3 Freshly stimulated - CD2/CD3 Freshly stimulated - CD3 After 3 rounds, T cells were co-cultured with labeled Caov-3 cells and DARPins for 48h in an IncuCyte to measure killing. CD2 CD3 CD2 CD3 CD2 CD3 CD2 CD3 CD2 CD3 CD3 only CD3 / CD2 Switch Round 1 Round 2 Round 3 Round 4 Cytotoxicity (IncuCyte) Setup of repetitive T cell stimulation assay: Bianchi et al, SITC 2025
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41 Fc-Switch-DARPin Supports Q2W–Q3W Dosing Schedule in Clinic Parameter Fc MW (kDa) 115 Mouse Cmax (nM) 76.5 Mouse HL (h) ~50–80h Scaled human HL (weeks) 2–3(1) (1) Scaling based on known HL of human IgG Fc in mice, which is of 1-2 days (as experimentally measured for the Fc) vs 21 days in human PK characteristics of Switch-DARPin in female wild-type BALB/c mice following single i.v. bolus injection of 1 mg/kg. Results represent two groups with n=3 mice per time point (mean, SD). Concentrations were measured by sandwich ELISA. PK, pharmacokinetics; MW, molecular weight; HLE, half-life extension. DARPin exposure in mice (1 mg/kg) -MSLN -EpCAM/CD3 Mask -CD3 -CD2 Fc HLE Bianchi et al, SITC 2025