EoE pMHC-II Therapeutics Program

📋 Program Overview

This project presents a comprehensive therapeutic program design and preclinical roadmap for a novel pMHC-II nanoparticle-based tolerance therapeutic targeting food-allergen-driven eosinophilic esophagitis (EoE).

Developed over one week during the Built with Claude: Life Sciences Hackathon, this work combines:

• Epitope discovery & validation — IEDB MHC-II binding prediction + structural validation (ESMFold2)
• Therapeutic design — Three therapeutic formats (single-chain, nanoparticle, tetramer)
• Perturbseq-informed strategy — Dual-track monotherapy vs. combination with SIK3 kinase inhibitor
• Preclinical roadmap — 5-phase, 18–24 month, $275–457k base budget
• Commercial strategy — Path A (orphan, $75–160M value) or Path B (combination, $400M–1.2B value)
• Regulatory pathway — Breakthrough designation-eligible strategy with FDA engagement plan

📄 Key Documents

All reports have been updated to reflect perturbseq findings and dual-track commercial strategy:

🔬 Scientific Highlights

Epitope Selection & Structural Validation

• Dairy (KIHPFAQTQSLVYPF): IC50 16.78 nM, IEDB 0.94 percentile, ESMFold2 ipTM 0.872 (high confidence)
• Wheat (IHNVVHAIILHQQQQ): IC50 35.01 nM, IEDB 0.49 percentile, ESMFold2 ipTM 0.896 (highest confidence)
• Soy (AYPFVVNATSNLNFL): IC50 50.31 nM, IEDB 0.76 percentile, ESMFold2 ipTM 0.891 (high confidence)

Nanoparticle Architecture

• Core: 20 nm Fe₃O₄ (iron oxide, precedented, biodegradable)
• Surface: ~75 PEG₂ₖ-maleimides (2 nm linker spacing)
• Capacity: 5 pMHC-II copies per NP (5.97% surface occupancy)
• Spacing: 5.8 nm inter-epitope distance (optimal for TCR cross-linking)
• Avidity gain: 24× enhancement (within published 10–50× range)

Mechanism: Tr1 Induction Pathway

• Multivalent pMHC-II:TCR engagement drives CD39+CD73+ iTreg/Tr1 differentiation
• Phase 1 gate: CD39+CD73+ response ≥30% of EoE patient CD4+ population
• Expected outcome: IL-10 production + suppressive function (bystander suppression assay)

Dual-Track Strategy (Perturbseq-Informed)

• Path A (Monotherapy): pMHC-II nanoparticle alone; HLA-DR7+ patients (70k, 30–35%); orphan indication; $2–5M upfront, $75–160M lifetime value
• Path B (Combination): pMHC-II + SIK3 kinase inhibitor; blocks CREB–c-FOS at IL-2 locus while pMHC-II drives Tr1; multi-HLA portfolio (Phase 2a); 140–200k patients (70–100%); $5–10M upfront, $400M–1.2B lifetime value
• Phase 1b De-Risking: 14-day CD4+ co-culture with EoE PBMC; gate: combination must increase iTreg/Tr1 >2-fold vs. single agents

💼 Commercial Strategy

Market Opportunity

• EoE prevalence: ~200k patients in North America; 1 in 2,000 in Western countries
• Unmet need: No antigen-specific tolerance therapies; only symptom management (PPI, topical steroids, dietary exclusion)
• Path A (orphan): 70k DR7+ patients × $50–150k/year = $3.5–10.5B lifetime
• Path B (multi-HLA): 140–200k patients × $75–200k/year = $10.5–40B lifetime

Licensing Strategy

• Path A target: Rare-disease biotech (Gossamer, Agios, Arcus, Reata)
• Path B target: Tier 1 pharma (Roche, Novartis, GSK, AbbVie) + kinase chemistry partner (AstraZeneca, Pfizer)
• Path A valuation: $2–5M upfront + $20–30M milestones + 5–8% royalties
• Path B valuation: $5–10M upfront + $50–100M milestones + 3–5% royalties + co-promotion

📅 Preclinical Roadmap

Timeline: 18–24 months (84 weeks) | Budget: $275–457k base / $300–500k with 10% contingency

5-Phase Structure

• Phase 1 (Weeks 1–16): Phase 1a ex vivo (n=20) + Phase 1b exploratory in vivo (n=5–10); gate: CD39+CD73+ ≥30% and eosinophil ↓ ≥30%; Cost: $40–65k
• Phase 2 (Weeks 16–26): Phase 2a open-label + Phase 2b randomized (monotherapy vs. SIK3i vs. combination); interim efficacy and synergy signal; Cost: $35–55k
• Phase 3 (Weeks 26–80): Pivotal efficacy + safety (n=100–150, randomized, 16–24 week duration); Cost: $105–170k
• Phase 4 (Weeks 80–84): Manufacturing scale-up, GMP process development, regulatory submission package assembly; Cost: $80–140k
• Phase 5 (Weeks 84–96): Final documentation, biomarker validation, post-IND readiness; Cost: $15–27k

Itemized total: $40–65k + $35–55k + $105–170k + $80–140k + $15–27k = $275–457k (base) / $300–500k (with 10% contingency)

Critical Path Items

• Months 1–4: Multi-HLA epitope mapping (IEDB for DR4, DQ2, DQ8, DQ5)
• Months 6–10: Phase 1 protocol finalization + IRB submission
• Months 10–12: FDA Pre-IND meeting + IND package assembly
• Months 18–20: IND approval + Phase 1a enrollment
• Months 22–24: Phase 1b proof-of-mechanism (in vivo eosinophil reduction)
• Months 24–30: Phase 2a interim data + breakthrough designation application (if efficacy signal)
• Months 30–36: Phase 2b randomized arm + licensing partner negotiation
• Months 48–60: Phase 3 completion + NDA submission → FDA approval

🔐 IP Attribution & Licensing

Inventors: Ruth-Anne Pai (primary) + CZ Biohub, Inc. (employer institution)
Personal entity: Pai Advisory, LLC
Status: Ready for licensing partnerships; no committed biotech partner named

Patents planned:

• Composition of matter: pMHC-II + iron-oxide nanoparticle scaffold (broad, 15+ years protection)
• Method of use: Tr1 induction for antigen-specific tolerance in EoE (8–12 years, starts Phase 3)
• Combination: pMHC-II + SIK3 inhibitor (contingent on Phase 1b synergy data)

👤 About This Project

This work was developed by Ruth-Anne Pai, PhD (Immunology), a citizen scientist and person living with EoE, during the Built with Claude: Life Sciences Hackathon (June–July 2026).

Motivation: To accelerate therapeutics for EoE and her community by synthesizing current knowledge, designing rational therapeutics, and preparing a comprehensive preclinical roadmap that a biotech partner can execute immediately.

Tools & methods: Protein design (ESMFold2, LigandMPNN), epitope discovery (IEDB), perturbseq analysis (Gladstone labs), structural modeling, peer review, commercial strategy, and regulatory pathway planning — all within Claude Science framework.

IP commitment: Transparent attribution to both CZ Biohub (Ruth-Anne's employer) and Pai Advisory (personal entity); open to licensing with biotech partners interested in advancing this program to clinical trials.