| July 2023 AI-Powered Precision Antibody Therapeutics |
| 2 Forward-looking Statements Certain statements in this presentation constitute "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, as amended. Words such as "may," "might," "will," "should," "believe," "expect," "anticipate," "estimate," "continue," "predict," "forecast," "project," "plan," "intend" or similar expressions, or statements regarding intent, belief, or current expectations, are forward-looking statements. These forward-looking statements are based upon current estimates. While iBio, Inc., a Delaware corporation (including its consolidated subsidiaries, “iBio,” the “Company,” “we,” “us” or “our”) believes these forward-looking statements are reasonable, undue reliance should not be placed on any such forward-looking statements, which are based on information available to us on the date of this presentation. These forward-looking statements are subject to various risks and uncertainties, many of which are difficult to predict that could cause actual results to differ materially from current expectations and assumptions from those set forth or implied by any forward-looking statements. Important factors that could cause actual results to differ materially from current expectations include, among others, the Company’s ability to obtain regulatory approvals for commercialization of its product candidates, or to comply with ongoing regulatory requirements, regulatory limitations relating to its ability to promote or commercialize its product candidates for specific indications, acceptance of its product candidates in the marketplace and the successful development, marketing or sale of products, its ability to attain license agreements, the continued maintenance and growth of its patent estate, its ability to establish and maintain collaborations, its ability to obtain or maintain the capital or grants necessary to fund its research and development activities, competition, its ability to retain its key employees or maintain its NYSE American listing, and the other factors discussed in the Company’s most recent Annual Report on Form 10-K and the Company’s subsequent filings with the SEC, including subsequent periodic reports on Forms 10-Q and 8-K. The information in this presentation is provided only as of today, and we undertake no obligation to update any forward-looking statements contained in this presentation on account of new information, future events, or otherwise, except as required by law. This presentation, and any oral statements made in connection with this presentation, shall not constitute an offer to sell, or the solicitation of an offer to buy, or a recommendation to purchase any equity, debt or other securities of the Company, nor, in connection with any securities offering by the Company, will there be any sale of these securities in any state or other jurisdiction in which such offer, solicitation or sale would be unlawful prior to the registration or qualification under the securities laws of such state or jurisdiction. |
| * U.S. Patent No. 11,545,238 iBio’s technology stack delivers precision antibodies designed to minimize downstream development risk through AI-guided epitope-steering and mAb optimization 3 Patented* epitope-steering AI-engine allows us to target specific regions of proteins Ab-optimizing StableHu™ technology coupled with mammalian display technology speeds up Lead Optimization; potentially minimizes downstream risks EXECUTIVE SUMMARY Team of experienced AI/ML scientists and drug hunters have the skills and capabilities to quickly advance antibodies from concept to in vivo POC Lead molecules comparable to “hard-to-engineer” antibodies licensed or acquired with upfronts ranging from $35-85M and total potential values >$500M at similar stages of development EngageTx™ optimized next gen CD3 T-cell engager antibody panel with reduced cytokine release, Non-Human Primate (NHP) cross-reactivity and reduced risk for immunogenicity |
| • Patented* epitope engineering • AI-engineered epitope maintains target structure 1 Epitope Engineering *U.S. Patent No. 11,545,238 (issued January 3, 2023) 4 Harnessing iBio’s Tech Stack: From Precision Antibody Identification and Optimization to Tailored Bispecifics Multiple validations with difficult targets and MoAs • Mammalian-display library enriched with functional antibodies • Human sequence and optimization faster than traditional methods 3 StableHu Antibody Optimizer • Human antibody diversity • Clinically validated frameworks • Benchmarked vs. competitive libraries 2 Proprietary Antibody Library • Diminished cytokine release • NHP cross-reactivity for advanced safety assessment ahead of clinical trials • Reduced immunogenicity risk 4 EngageTx CD3 Antibody Panel |
| Match Engineered Structure to Target Refined for Greater Stability Optimized for Water Solubility Unlocking High-Value Drug Targets: AI-Engineered Epitopes are Generalizable to a Broad Set of Complex Structural Drug Binding Sites Junctional Epitopes Complex Secondary Structures Membrane Proteins (e.g. GPCR) Loop Display 1 2 3 AI Epitope Engine 5 |
| Input Antibody StableHu AI-Engine Mammalian Display Output Antibody Template CDR Predict library of human CDR variants Single-cell screen mammalian display CDR library Optimized antibody with fully human CDRs Accelerate Success: StableHu Antibody Optimization & Mammalian Display Screening Propel Faster, Cost-Effective Antibody Development 6 |
| 7 EngageTx, a CD3-Based T-Cell Engager Panel, Addresses 3 Key Challenges: Cytokine Release, NHP Cross-Reactivity and Immunogenicity Risk Numerous tumor antigen arms Diverse CD3 engager arms 1 Sequence Diversity 2 Hu-Cyno Cross-Reactivity 3 Range of Cytokine Release Increased humanness and broad CD3 activity for optimized paring with tumor antigen arms Risk reduction via cyno monkey toxicity study compatibility Tailored cytokine release for expanded therapeutic window Release of cytokines TNFα, IFNγ, IL-2, (IL6) Increased cytotoxicity Reduced cytokine release Release of cytotoxic granules Granzyme, Perforin Cascade of immune activation Tumor cell death Activated T cell Tumor cell |
| 8 From Idea To Clinical Candidate: We Believe Our Discovery Platform Improves Probability of Success, Speed, and Developability AI-powered sequence optimization to improve performance AI-powered precision targeting of conformational & sub-dominant epitopes Epitope-specific antigens built to efficiently & selectively discover antibodies AI-generated naïve antibody library, free of sequence liabilities Optimized bi-specifics leveraging broad potency range, human-monkey cross-reactivity, & sequence diversity Optimized Leads evaluated & ranked in translational disease models Epitope Engineering Proprietary Human mAb Library StableHu Antibody Optimizer EngageTx Engineered Epitope Optimized mAb Lead Pool Getting it right from the outset Precision antibody targeting takes the lengthy trial and error out of mAb discovery and improves probability of success More speed, mitigated risk Reduced number of iterative optimization steps, lower immunogenicity risk and improved developability Enhanced bispecifics control Wide potency range with reduced cytokine release and NHP cross-reactivity to strengthen preclinical safety assessment |
| Capitalizing on AI: We Believe Our Platform Powers a Focused, Capital Efficient Business Plan 9 AI Discovery Platform • Partner existing molecules or discovery projects against new targets • Potential for upfront, milestone payments and/or royalties Strategic Partnerships • Advancing a select few “fast followers” • Potential licensing and asset sales for other molecules Proprietary Pipeline • Exclusive licensing for non-core therapeutic areas to 3rd parties (vaccines, etc.) • Potential for upfront technology access fee and milestones plus royalties for multiple targets Third Party Collaboration |
| PROGRAMS EARLY DISCOVERY LATE DISCOVERY LEAD OPTIMIZATION IND-ENABLING CLINICAL Oncology IBIO-101 Endostatin E4 Trop-2 x CD3* MUC16 Target 5 EGFRvIII CCR8 Target 8 Autoimmune PD-1 10 Catalyzing Innovation: Technology Stack Spurs Rapid Pipeline Growth and Maturation in Cancer Immunotherapies Immuno-Oncology Immuno-Oncology Immuno-Oncology Immuno-Oncology Solid Tumors Immuno-Oncology Immuno-Oncology Autoimmune Diseases Solid Tumors *Developed with Engage Tx bispecific platform |
| * Acquisition / Merger + License or collaboration 11 Market-Tested Potential: Competitor Early-Stage Deals Signal Promising Opportunities for Our Pipeline FEB 2021 Pre-2019 2020 2021 2022 CCR8 Gilead / Jounce+ : $85M upfront, $35M equity investment, $685M milestones SEP 2020 PD-1 agonist Merck / Pandion*: Acquired for $1.85B SEP 2018 Roche / Tusk Therapeutics*: $81M upfront, $677M milestones IBIO-101 (CD25) JUN & DEC 2021 CCR8 Fibrogen / HiFiBio+ : $25M option fee, $35M option exercise, $1.1B milestones SEP 2022 EGFRvIII Seagen / LAVA Therapeutics+ : $50M upfront, $650M milestones AUG 2022 PD-1 agonist Gilead / Mirobio*: Acquired for $405M MAY 2022 EGFRvIII Taiho / Cullinan Oncology+ : $275M upfront, $130M milestones OCT 2022 CD3 Gilead / MacroGenics+ : $60M upfront, $1.7B milestones JUL 2021 CD3 Eli Lilly / Merus+ : $40M cash upfront, $20M investment, $540M milestones JUL 2021 CD3 Amgen / Teneobio*: $900M upfront, $1.6B milestones 2023 CCR8 Coherus / Surface Oncology*: Acquired for $65M JUN 2023 JAN 2023 CD3 GSK / WuXi Biologics+ : $40M upfront, $1.46B milestones CCR8 Gilead / Jounce+ : $67M for remaining stake in CCR8 program JAN 2023 TROP-2 Gilead / Immunomedics*: Acquired for $21B SEP 2020 TROP-2 AstraZeneca / Daiichi+ : $1B upfront (some deferred), $5B milestones JUL 2020 APR 2023 EGFRvIII Pierre Fabre / Scorpion+ : $65M upfront, $553M milestones |
| Our Leadership Team Brings Drug Discovery and Development Experience 12 Martin Brenner, DVM, Ph.D. CEO & CSO Lisa Middlebrook CHRO Marc Banjak GC Felipe Duran CFO |
| 13 iBio Company Highlights • Ticker: IBIO (NYSE AMERICAN); ~16.8M shares outstanding as of 3/31/23 • Reduced cash burn after CDMO divestment • $9.8M of cash as of 3/31/23* Financial * includes restricted cash AI-driven discovery tech stack • Patented epitope-engineering technology • StableHu antibody optimizer coupled with mammalian display • EngageTx next generation bi-specific antibody platform Layered Business Model • Strategic partnerships • Proprietary pipeline • Exclusive platform licensing for specific disease areas outside of I/O Pipeline of difficult to find biologics • Pipeline of 10 preclinical programs of hard to drug targets • Targets in focus of major immuno-oncology (I/O) companies with significant deal flow • Promising early CMC development data for lead asset IBIO-101 |
| Preclinical Pipeline 14 |
| 15 IBIO-101 IL-2 Sparing Anti-CD25 |
| Recent Transactions & Milestones *Roche acquisition of Tusk Therapeutics com pleted for €70M upfront, acquiring worldwide rights to anti-CD25 program . Values converted to dollars as reported in public press releases **Data presented by Roche at AACR 2023 16 IBIO-101 for Regulatory T-Cell (Treg) Depletion Depletion of immunosuppressive Tregs via antibody dependent cellular cytotoxicity (ADCC), without disrupting activation of effector T-cells (Teffs) in the tumor microenvironment • Solid tumors • Hairy cell leukemia • Relapsed mult. myeloma • Lymphoma • Head & neck cancer *Roche / Tusk Therapeutics (Sep 2018) $81M upfront, $677M milestones • IL-2 sparing anti-CD25 antibodies enables depletion of Tregs without affecting Teffs • Fast-follower to Roche’s RG6292 clinical molecule Target Mechanism Potential Indications Differentiation / Opportunity PRECLINICAL TESTING IND CLINICAL TESTING CLINICAL PROOF OF CONCEPT **Roche RG6292 Ph1 Data (Apr 2023) Well-tolerated: manageable safety profile Confirmed MOA: Reduced intratumoral Tregs Efficacy: 29% stable disease (45% PD-L1 combo) |
| Data on file. Treg = Regulatory T Cells; Teff = Effector T Cells; ADCC = Antibody Dependent Cellular Cytotoxicity 17 IBIO-101 Reduces Tumor Growth in Preclinical Studies by Selectively Depleting Immunosuppressive Tregs without Affecting Cancer Killing Teffs Indiscriminate depletion of Treg + Teff TUMOR Teff 1 st gen CD25 mAbs depleted immuno-suppressive Treg and immuno-stimulatory Teff Limited efficacy 2 nd gen IBIO-101 selectively targets Tregs without blocking IL-2 signaling to Teffs Strong preclinical anti-tumor response IBIO Proliferation -101 Natural Killer Cell Preferential Treg depletion ADCC 1st Gen CD25 TUMOR IL-2 CD25 (IL-2Rα) JAK JAK Treg JAK JAK Teff JAK JAK Treg JAK JAK Teff IL-2 signaling Blocked IL-2 pathways IL-2 |
| RG6292 is Roche’s m onoclonal antibody that targets CD25 (IL-2Rα). IBIO-101 data on file. 18 IBIO-101 Selectively Depletes Tregs while preserving IL-2 signaling IBIO-101 potently binds recombinant CD25 which leads to Treg depletion while sparing Teffs 0.0001 0.001 0.01 0.1 1 10 100 0.0 0.5 1.0 1.5 2.0 2.5 Antibody Concentration (ug/mL) CD25 Protein Binding (higher and left is better) Negative control, EC50 = no binding IBIO-101, EC50= 16.4 ng/ml RG6292 (Roche), EC50= 24.7 ng/ml 0.1 1 10 100 1000 10000 100000 0 20000 40000 60000 Antibody Concentration (ng/ml) Treg Killing Reporter Assay (higher and left is better) Negative control, EC50 = no cell killing IBIO-101, EC50= 4.7 ng/ml RG6292, EC50 = 18.6 ng/ml 0.001 0.01 0.1 1 10 100 1000 0 20 40 60 80 100 120 IL-2 Concentration (ng/ml) % of IL-2 Signaling (higher and left is better) IL2, EC50= 0.11 ng/ml IBIO-101, EC50= 0.17 ng/ml RG6292, EC50 = 0.14 ng/ml 0.0001 0.001 0.01 0.1 1 10 100 0.0 0.5 1.0 1.5 2.0 2.5 Antibody Concentration (ug/mL) CD25 Protein Binding (higher and left is better) Negative control, EC50 = no binding IBIO-101, EC50= 16.4 ng/ml RG6292 (Roche), EC50= 24.7 ng/ml 0.001 0.01 0.1 1 10 100 1000 0 20 40 60 80 100 120 IL-2 Concentration (ng/ml) % of IL-2 Signaling (higher and left is better) IL2, EC50= 0.11 ng/ml IBIO-101, EC50= 0.17 ng/ml RG6292, EC50 = 0.14 ng/ml 0.1 1 10 100 1000 10000 100000 0 20000 40000 60000 Antibody Concentration (ng/ml) Treg Killing Reporter Assay (higher and left is better) Negative control, EC50 = no cell killing IBIO-101, EC50= 4.7 ng/ml RG6292, EC50 = 18.6 ng/ml 0.01 0.1 1 10 100 1000 10000 100000 0 20 40 60 80 100 Antibody Conentration (ng/ml) % Of T-cell Killing Treg killing, EC50= 7.09 ng/ml Activated CD4+ Teff killing, EC50= no activity Activated CD8+ Teff killing, EC50= no activity 0.01 0.1 1 10 100 1000 10000 100000 0 20 40 60 80 100 Antibody Conentration (ng/ml) % Of T-cell Killing Treg killing, EC50= 7.09 ng/ml Activated CD4+ Teff killing, EC50= no activity Activated CD8+ Teff killing, EC50= no activity |
| 19 IBIO-101 Increases in Teff/Treg Ratio in Preclinical Studies Inhibiting Tumor Growth Tumor growth inhibition correlates with T-eff/T-reg ratio Potently increases T-eff/T-reg ratio1 0 10 20 30 0 1000 2000 3000 4000 Days Tumor Volume (mm3 ) Negative Control IBIO-101, 0.1 mg/kg IBIO-101, 1.0 mg/kg RG6292 (Roche), 0.1 mg/kg RG6292 (Roche), 1 mg/kg * 0 10 20 30 0 1000 2000 3000 4000 Days Tumor Volume (mm3 ) Negative Control IBIO-101, 0.1 mg/kg IBIO-101, 1.0 mg/kg RG6292 (Roche), 0.1 mg/kg RG6292 (Roche), 1 mg/kg * hIgG1 Isotype RG6292 (Roche), 0.1 mg/kg RG6292 (Roche), 1.0mg/kg IBIO-101, 0.1 mg/kg IBIO-101, 1.0 mg/kg 0 50 100 150 200 250 Teff / Treg ratio (higher is better) * * * 1hCD25 anim al m odel - Data on file. * Significant vs * Significant vs Negative Control hIgG1 Isotype |
| 20 IBIO-101 in Combination With a Checkpoint Inhibitor Shows Greater Efficacy 0 10 20 30 0 1000 2000 3000 4000 Days Tumor Volume (mm3 ) Negative Control * Anti-PD1, 2.5 mg/kg IBIO-101, 1 mg/kg + anti-PD1, 2.5 mg/kg # IBIO-101, 1.0 mg/kg 0 10 20 30 0 1000 2000 3000 4000 Days Tumor Volume (mm3 ) Negative Control * Anti-PD1, 2.5 mg/kg IBIO-101, 1 mg/kg + anti-PD1, 2.5 mg/kg # IBIO-101, 1.0 mg/kg IBIO-101 + PD-1 Checkpoint Inhibitor In PreClinical Studies Enhances Tumor Suppression *hCD25 anim al m odel - Data on file. * Significant vs Negative Control # Significant vs Anti-PD-1 |
| 21 IBIO-101 is an Antibody With Favorable Characteristics for CMC Development • Identified manufacturing partner to produce IBIO-101 for Phase 1&2 clinical trials • Discovered suitable cell lines for manufacturing MCB • Established IBIO-101 CMC methodology for producing high yield, high purity, stable product under cGMP conditions Potential for Master Cell Bank (MCB) Development From 8 Promising Cell Lines Unoptimized Cell Lines Already Show Promising IBIO-101 Yields |
| 22 Anti-CCR8 High ADCC Anti-CCR8 for the Depletion of T-regulatory Cells |
| *Fibrogen/ HiFiBio: Fibrogenpurchased option to m ultiple program s in June 2021, then exercised the option for excl. license to CCR8 program in Dec. 2021. **Gilead / Jounce: Exclusive worldwide license to anti-CCR8 antibody. *** Coherus / Surface Oncology: acquisition, announced in June 2023, adds two clinical assets, including a phase 2 anti-IL-27 and a phase 1/2 anti-CCR8 for oncology. 23 CCR8 for Tumor-Infiltrating Treg Depletion Tumor-infiltrating Tregs highly express CCR8. iBio program targets depletion of highly immunosuppressive CCR8+ Tregs in tumor microenvironment via an ADCC mechanism. • Broadly applicable in solid tumors • Prospective combination therapy Target Mechanism Potential Indications Differentiation / Opportunity Recent Transactions & Milestones • Selective binding to CCR8 over its close homolog, CCR4 **Gilead / Jounce (Dec 2022): Original deal: $85M upfront, $35M equity investment, $685M milestones. 2023 Buyout : $67M for remaining rights. *Fibrogen / HiFiBio (Jun & Dec 2021): $25M option fee, $35M option exercise, $1.1B milestones PRECLINICAL TESTING IND CLINICAL TESTING CLINICAL PROOF OF CONCEPT ***Coherus / Surface (Jun 2023): Acquired for $65M |
| Zheng, et al. Cell 169.7 (2017): 1342-1356; Whiteside, et al. Im m unology 163(4) (2021): 512-520; Kidani, et al. PNAS 119(7) (2022): e2114282119 24 CCR8+ Treg Cells Are Tumor Infiltrating and Highly Immunosuppressive Depletion of CCR8+ Treg cells has potential to evoke potent tumor immunity • Systemic inflammation • Skin toxicity • Platelet depletion/aggregation Intratumor cytotoxic T-cell activation & tumor death Adverse events iBio CCR8 specific antibody CCR8 & CCR4 nonspecific antibody CCR4+ cells killed CCR4+ cells spared |
| Data on file 25 Afucosylated Anti-CCR8 Antibody Exhibits High Specificity, CCL1 Antagonism and CCR8-Specific Cell Killing High Specificity CCR8 Cell Binding 0.0001 0.001 0.01 0.1 1 10 0 2 4 6 8 10 hCCR8 overexpressed cells Ab. (nM) MFI hIgG1 isotype mIgG2A isotype Anti -hCCR4 - EC50 = NA Anti-mCCR8 - EC50 = NA SD-356253 - (iBio) - EC50 = 0.78 nM SD-692676 - (GS-1811) - EC50 = 0.43 nM 0.0001 0.001 0.01 0.1 1 10 0 10 20 30 40 50 hCCR4 overexpressed cells Ab. (nM) MFI hIgG1 isotype mIgG2A isotype Anti -hCCR4 - EC50 = 42.5 nM Anti-mCCR8 - EC50 = NA SD-356253 - (iBio)- EC50 = NA SD-692676 - (GS-1811)- EC50 = NA 0.000001 0.000010.00010.0010.01 0.1 1 10 0 10 20 30 40 CCR8 overexpressed cell Ab. (nM) % of cell killing hIgG1 hCCR4 - EC50 =NA SD-356253-(iBio) - EC50 = 0.004 nM SD-692676-(GS-1811) - EC50 = 0.002 nM PBMC-Induced CCR8 Cell Killing Potent binding to CCR8 overexpressing cells No binding to CCR4 overexpressing cells (Jounce/Gilead) (Jounce/Gilead) (Jounce/Gilead) Untreated CCL1 (7 nM) CCL1 (7 nM) + hIgG1 Iso. Ctl. Anti-hCCR8 (+)Ctl. SD-6926776-(GS-1811) Jounce/Gilead SD-356253 (iBio) CCR8-CCL1 Antagonism |
| 26 Unlocking the Power of Bi-Specific Antibodies with EngageTx, Our Versatile CD3 mAb Panel Wide Range of Affinities, NHP Cross Reactivity, High Developability |
| *Eli Lilly / Merus: FibrogenResearch collaboration using Merus’ proprietary platform to develop up to three CD3-engaging T-cell re-directing bispecific antibody therapies. ** GSK WuXi: License of WuXi’spreclininical CD3 bi-specific, plus 3 earlier stage programs ***Amgen / Teneobio: Teneobio was developing a heavy-chain only platform as well as its CD3 engager technology. TNB-585, the lead program, was in phase 1. + Gilead / MacroGenics: Gilead granted option to MGD024, a phase 1 CD3 bi-specific, plus collaboration on two additional research programs. 27 Next Generation Anti-CD3 T Cell Engagers T-cell-redirecting bispecific antibodies are a new therapeutic class that simultaneously targets CD3 on T cells and tumor antigens, inducing T cell mediated tumor cell killing • Broad solid tumor potential • Expands therapeutic options across programs Target Mechanism Potential Indications Differentiation / Opportunity Recent Transactions & Milestones • Range of T cell activation for diverse tumor antigens • Cyno-tox study compatibility • StableHu optimized sequence reduces downstream risks *Eli Lilly / Merus (July 2021): $40M upfront, $20M investment, $540M milestones, royalties PRECLINICAL TESTING IND CLINICAL TESTING CLINICAL PROOF OF CONCEPT ***Amgen / Teneobio (July 2021): $900M upfront, $1.6B downstream +Gilead / MacroGenics (Oct 2022): $60M upfront, $1.7B milestones, royalties **GSK / WuXi (Jan 2023): $40M upfront, $1.46B milestones, royalties |
| Data on file 28 Dual Approaches to a Diverse Panel of Anti-CD3 Antibodies Hu/Cyno CD3 & T Cell TCR CD3 Engineered Epitopes T Cell Template 1 Template 2 Structural-Epitope Immunization & Screening StableHu Optimizer AI Discovery Engine AI-Engineered Immunogens Epitope & T Cell Immunization Epitope & CD3 Screen 2 Template Antibodies Optimized Antibodies SCREEN Activation Binding 1 2 3 4 5 6 (-) Ctl ID |
| Data on file 29 Libraries and Screens Discover Hu-Cyno CD3 Cross-Reactive Antibodies Epitope-Steered Immunization 0 5 10 15 0 2 4 6 Human CD3 ELISA FoldChange / Background Cyno CD3 ELISA FoldChange / Background Immunized Library 1 100 200 Human T Cell Binding Fold Change / Background HIT 0 Human T Cell Binding Selected Hit Low Medium High StableHu Mammalian-Display Not Selected Library Screen: |
| Data on file 30 EngageTx is Selected for a Diversity of T Cell Binding and Activation EC50: 3 – 570 nM EC50: 2.5 – 70 nM Human T Cell Binding EC50 (nM) 0.1 1 10 100 0 20 40 60 80 Concentration (nM) IL-2 (pg/mL) Human T Cell Activation M80-H1-1 M80-H1-2 M80-H3-1 M80-L1-1 M80-L2-1 IgG1 Isotype (-) Ctl SP34 (+) Control 0.1 1 10 100 0 20 40 60 80 Concentration (nM) TNF-a (pg/mL) Human T Cell Activation M80-H1-1 M80-H1-2 M80-H3-1 M80-L1-1 M80-L2-1 IgG1 Isotype (-) Control SP34 (+) Control 0.1 1 10 100 0 20 40 60 80 Concentration (nM) IFN-g (pg/mL) Human T Cell Activation M80-H1-1 M80-H1-2 M80-H3-1 M80-H3-2 M80-L1-1 M80-L2-1 IgG1 Isotype (-) Control SP34 (+) Control CD69 T Cell Activation EC50 (nM) Hit Clones Hit Clones T Cell CD3 EC50 1 10 100 1000 Human T Cell Binding EC50 (nM) T Cell CD3 EC50 T Cell Assay: Ab Concentration (nM) IFN-γ (pg/mL) TNF-⍺ (pg/mL) IL-2 (pg/mL) ID 1 2 3 5 (-) Ctl 4 SP34 Gen1 benchmark SP34 Gen 1 benchmark Binding Activation Cytokines |
| 31 Anti-EGFRvIII High ADCC mAb Against Tumor-Specific EGFRvIII Cells |
| **Seagen / LAVA Therapeutics (Sep 2022): $50M upfront, $650M milestones ***Taiho / Cullinan Oncology (May 2022): $275M upfront, $130M milestones * Pierre Fabre / Scorpion: Scorpion licensed two preclinical-stage program s to Pierre Fabre which are targeted to specific EGFR m utations in lung cancer. **Seagentransaction with LAVA Therapeutics was an exclusive license to LAVA-1223 (EGFR program ), plus additional projects using Lava’s platform . ***Taiho transaction to acquire Cullinan Oncology’s subsidiary, Cullinan Pearl, which has worldwide rights outside of Japan to CLN-081/TAS6417 (EGFR m utant m Ab). 32 EGFRvIII for Glioblastoma and Other Cancers Binding a tumor-specific mutation of EGFR variant III with an afucosylated antibody for high ADCC. EGFRvIII is constantly “switched on” which can lead to the development of a range of different cancers. • Glioblastoma • Head & neck cancer • Non-small cell lung cancer Target Mechanism Potential Indications • Novel EGFRvIII high ADCC mechanism, potentially further reducing toxicity & expanding therapeutic window • Other enabling modalities: T Cell engager, ADC, CAR-T Differentiation / Opportunity Recent Transactions & Milestones PRECLINICAL TESTING IND CLINICAL TESTING CLINICAL PROOF OF CONCEPT *Pierre Fabre / Scorpion (Apr 2023): $65M upfront, $553M milestones |
| Skin toxicity No skin damage 33 iBio’s Anti-EGFRvIII mAbs Selectively Kill EGFRvIII-Positive Tumor Cells and Not EGFR1-Expressing Cells in Healthy Tissues iBio mAb binding specifically to EGFRvIII Tumor Size Reduction iBio mAb doesn’t bind to EGFR1 in skin Non-EGFRvIII specific mAb binds to EGFR1 in skin iBio mAb binding specifically to EGFRvIII Tumor Size Reduction Non EGFRvIII specific mAbskill cancer cells but can cause toxicity by binding to EGFR1 in skin cells iBio’s EGFRvIII-specific mAb exclusively kills cancer cells Data on file |
| 34 iBio’s EGFRvIII-Selective mAbs Kill Tumor Cells without Affecting Healthy Cells Negative control, EC50 = no binding Cetuximab, EC50 = 0.018 nM SD-233883, EC50 = 0.008 nM SD-710726, EC50 = 0.020 nM 0.0001 0.001 0.01 0.1 1 10 0 20 40 60 80 Antibody Concentration (nM) % Of Tumor Cell Killing (higher and left is better) Negative control, EC50 = no binding Cetuximab, EC50 = 0.018 nM SD-233883, EC50 = 0.008 nM SD-710726, EC50 = 0.020 nM iBio EGFRvIII mAbs bind recombinant EGFRvIII 0.001 0.01 0.1 1 10 100 0.0 0.5 1.0 1.5 2.0 Antibody Concentration (nM) Binding to Tumor Cells (higher and left is better) Negative control, EC50 = no binding Cetuximab, EC50 = 0.12 nM SD-233883, EC50 = 0.12 nM SD-710726, EC50 = 0.05 nM which leads to tumor cell killing 0.0001 0.001 0.01 0.1 1 10 0 20 40 60 80 Antibody Concentration (nM) % Healthy Cell Killing (lower is better) Negative control, EC50 = no binding Cetuximab, EC50 = 0.029 nM SD-233883, EC50 = no binding SD-710726, EC50 = no binding but not binding wild-type EGFR1 0.001 0.01 0.1 1 10 100 0.0 0.5 1.0 1.5 2.0 Antibody Concentration (nM) EGFR1 Protein Binding (lower is better) Negative control, EC50 = no binding Cetuximab, EC50 = 0.08 nM SD-233883, EC50 = no binding SD-710726, EC50 = no binding and thus not affecting healthy cells Data on file |
| 35 Anti-MUC16 Tumor Associated Epitope Non-Shed Epitope Anti-MUC16 Antibody |
| +Regeneron MUC16xCD3 (Sept 2022): Ph. 1 31% ORR Ph. 2 enrollment 36 MUC16 Potential for Ovarian and Other Cancers Bind a membrane-proximal MUC16 epitope Membrane-proximal binding avoids epitope elimination by tumors Bind a non-glycosylated epitope to avoid altered glycosylation on tumors • Ovarian • Uterine • Pancreatic Target Mechanism Potential Indications • MUC16 epitope avoids primary modes of tumor evasion • Enabling modalities: T Cell engager, ADC, CAR-T Differentiation / Opportunity Recent Transactions & Milestones PRECLINICAL TESTING IND CLINICAL TESTING CLINICAL PROOF OF CONCEPT ***Eureka – Juno/BMS (Jan 2016): CAR T Ph. 1 ongoing *2seventy – Regeneron (Jan 2022): CAR T 2023 IND planned **Genentech (Dec 2021): ADC Ph. 1: Favorable safety & efficacy *Regeneron, 2seventy name the target of their first solid tumor CAR-T, aim for 2023 IND ** Liu et al., An open-label phase I dose-escalation study of the safety and pharmacokinetics of DMUC4064A in patients with platinum-resistant ovarian cancer ***Eureka Therapeutics Announces Exclusive License Agreement between Memorial Sloan Kettering Cancer Center and Juno Therapeutics for Use of a Novel, Fully-Human MUC16 Binder in CAR T Cell Immunotherapy +Novel Regeneron Bispecific Antibodies Show Encouraging Anti-Tumor Activity in Two Advanced Solid Tumors |
| 37 MUC16 Is Overexpressed and Shed by Tumor Cells O-glycosylation N-glycosylation MUC16 epitope shedding Shedding eliminates the epitope and creates an antigen sink for most MUC16 antibodies Antibodies that bind the non-shed domain maintain activity N-terminal and tandem repeat (TR) domains that are shed Tumor associated epitope that is not shed Ovarian cancer cells |
| Weeks 1–2 Weeks 3–4 Week 5 38 Immunizations Were Steered to a MUC16 Epitope that Avoids Epitope Shedding Engineered Epitope Prime + MUC16 Cell Boost AI Discovery Engine MUC16 Engineered Epitope Structural-epitope Immunization & Screening Engineered Epitope ELISA Screen MUC16 OVCAR-3 MUC16high Cell Binding Screen higher cell binding MEM Nanoparticle MUC16 Expressing Cells MEM + Cells Hybridoma Screen Non-shed Aglycosylated Epitope |
| 39 Top Three Hit Clones Bind the Non-Glycosylated MUC16 Epitope Closest to the Membrane 1D7 8G4 21G6 Hits do not bind shed 230-mer Hits bind non-glycosylated non-shed 29-mer binding time O-glycosylation N-glycosylation N-terminal and tandem repeat (TR) domains that are shed Epitope KD = 8.0 nM KD = 5.4 nM KD = 14 nM Aglycosylated non-shed 29-mer Shed 230-mer Data on file |
| 40 Top MUC16 Clone 8G4 Binds OVCAR-3 Cells Comparable to Regeneron Benchmark Regeneron benchmark Clone ID: Secondary Only Unstained OVCAR-3 Cells 8G4 top clone higher cell binding Mode Normalized Data on file |
| 41 8G4 Clone Maintains OVCAR-3 Cell and MUC16 Epitope Binding in a Fully Human Framework 8G4 with fully human framework reduces immunogenicity risk Glycosylated MUC16 membrane-proximal epitope SPR: KD = 5.1 nM Iso. Ctl OVCAR-3 Cells Epitope binding Cell binding higher cell binding Data on file |
| 42 PD-1 Agonist Supports Restoration of Homeostasis for Inflammatory Diseases |
| 43 PD-1 Agonist to Alleviate Inflammatory Disease Selectively agonize PD-1 without antagonizing the natural PD-1:PD-L1 anti-inflammatory interaction • Rheumatoid arthritis • Broad application in treating inflammatory disease Target mechanism Potential indications Differentiation / opportunity Recent Transactions & Milestones • Potent PD-1 agonism vs. benchmarks with in vitro reporter and primary cell assays **Gilead / Mirobio (Aug 2022): Acquired for $405M *Merck / Pandion (Feb 2021): Acquired for $1.85B PRECLINICAL TESTING IND CLINICAL TESTING CLINICAL PROOF OF CONCEPT Eli Lilly (May 2023): Positive Ph 2a efficacy in RA patients • Merck / Pandion: At the time of acquisition, Pandion pipeline including an IL-2 fusion drug in phase 1a, as well as group of preclinical PD-1 agonists. ** Gilead / Mirobio: Mirobio pipeline at tim e of deal included a phase 1 BTLA (checkpoint) agonist as well as preclinical program s which included a PD-1 agonist. |
| PD-1 PD-L1 TCR MHC T-cell Antigen presenting cell 44 Antagonizing PD-1 with PD-L1 Blocking Worsens Autoimmunity and Systemic Inflammation Inflammatory Disease Tissue Healthy Tissue Increased & systemic inflammation No T-cell inhibition No T-cell inhibition Worsened Strong T-cell inhibition Weak T-cell inhibition Autoimmunity PD-1 Antagonist Antibody |
| 45 Agonizing PD-1 Without Blocking PD-L1 Restores Activated T-Cell Suppression Diseased Tissue Reduced inflammation Healthy Tissue Low-inflammation preserved PD-1 PD-L1 Strong TCR MHC T-cell inhibition T-cell Inflammatory Disease Tissue Healthy Tissue Weak T-cell inhibition Strong T-cell inhibition Strong T-cell inhibition Improved Autoimmunity Antigen presenting cell PD-1 Agonist Antibody |
| Benchmark Antibodies PD-1 Agonist Antibodies 46 In vitro PD-1 Agonism Equals or Surpasses Benchmarks and PD-L1 Ab ID EC50 (nM) SD-671823 0.88 SD-300670 0.31 SD-030629 0.36 SD-136366 0.28 SD-759028 0.52 SD-313018 (bispecific) 0.30 AnaptysBio APE12095 17.4 BMS/Celgene PD1AB6 0.76 IgG1 isotype control inactive 0.001 0.01 0.1 1 10 100 105 106 Concentration (nM) RLU PD-1 Agonism Reporter Assay 07 bivalent 0.001 0.01 0.1 1 10 100 105 106 Concentration (nM) RLU PD-1 Agonism Reporter Assay H01 bivalent 0.001 0.01 0.1 1 10 100 106 107 Concentration (nM) RLU D4-A7-7_201 EC50: 0.36 ± 0.11 nM D4_A7_7 IgG SD-671823 SD-300670 SD-030629 0.001 0.01 0.1 1 10 100 105 106 Concentration (nM) RLU PD-1 Agonism Reporter Assay 07 + H01 Tandem bispecific 0.001 0.01 0.1 1 10 100 105 106 Concentration (nM) RLU PD-1 Agonism Reporter Assay 07 Tandem tetravalent 0.001 0.01 0.1 1 10 100 105 106 Concentration (nM) RLU PD-1 Agonism Reporter Assay H01 Tandem tetravalent SD-136366 SD-759028 SD-313018 (bispecific) 0.001 0.01 0.1 1 10 100 105 106 Concentration (nM) RLU PD-1 Agonism Reporter Assay AnaptysBio APE12095 0.001 0.01 0.1 1 10 100 105 106 Concentration (nM) RLU PD-1 Agonism Reporter Assay BMS/Celgene PD1AB6 0.001 0.01 0.1 1 10 100 105 106 Concentration (nM) RLU PD-1 Agonism Reporter Assay IgG1 Isotype control AnaptysBio APE12095 BMS/Celgene PD1AB6 IgG1 isotype control Tetravalent Bivalent x x Data on file |
| Data on file 47 Primary T-Cell Suppression Equals or Surpasses Benchmarks and PD-L1 IL-2 at 24 hrs. % IL-2 Release Mean of 6 donors 0 100 200 Anti-HEL IgG1 Isotype Control CD69 at 72 hrs. CD69 MFI Mean of 6 donors 0 100 200 300 Anti-HEL IgG1 Isotype Control iBio Molecules Benchmark Molecules Natural Agonist |
