{
  "version": 3,
  "created_at": "2026-07-07T22:38:55.709Z",
  "task_summary": "Phase 3: computational protein-therapeutic design for validated EoE leads",
  "agents": [],
  "phases": [
    {
      "name": "Plan",
      "delegations": [
        {
          "steps": [
            {
              "title": "Lead roster lock & target-structure preparation",
              "description": "Fix the Phase-3 design roster from the Phase-2 revised dossier: SIGLEC6 (lead, depleting mAb/ADC), IL1RL1/ST2 (blocking mAb), CCL26 (neutralizing mAb / CCR3 axis) as protein-design leads; ALOX15 routed to a separate small-molecule note (intracellular); MSLN parked pending surface-expression validation. Prepare clean AlphaFold structures (already fetched, v6) plus any experimental PDB complexes (SIGLEC6-sialoglycan, IL-33/ST2 = 4KC3-class, CCL26/CCR3) via RCSB. Deliverable: roster_lock.csv + a structure inventory table + a 2-panel figure showing each lead's domain architecture with the targetable region highlighted. Save structures as Mol*-viewable artifacts."
            },
            {
              "title": "PPI / binding-interface analysis",
              "description": "For each lead, characterize the native binding interface computationally: for receptors (SIGLEC6, IL1RL1) map ligand-contacting residues from experimental complexes or AF2-multimer-style docking of the AF monomers; for CCL26 map the CCR3-engagement surface. Use freesasa/biotite for buried-surface-area, per-residue contact maps, and hotspot identification. Deliverable: interface_analysis.png (per-target contact map + hotspot residues), interface_residues.csv (epitope residue lists with BSA), and a written interface summary. CPU-feasible."
            },
            {
              "title": "Benchmark existing-therapeutic binding modes",
              "description": "Map where clinical/pipeline agents bind relative to our proposed epitopes to quantify differentiation: astegolimab/tozorakimab (anti-ST2/IL-33) footprint vs our IL1RL1 epitope; dupilumab (IL-4Rα, indirect) vs the whole roster; cendakimab (anti-IL-13) context. Pull reported epitope/structure data where available. Deliverable: differentiation_map.csv + a figure overlaying competitor epitopes on target surfaces, making the 'upstream/orthogonal to dupilumab' argument structural rather than narrative."
            },
            {
              "title": "ESM-family epitope conservation & developability scan",
              "description": "Run ESM-2 (650M if memory permits, else 8M) across each target's epitope region: per-residue masked-LM conservation, variant-effect scoring to flag mutation-tolerant vs constrained epitope positions (escape risk), and embedding-based liability screen. Separately scan candidate antigen sequences for developability motifs (N-glycosylation, deamidation NG/NS, isomerization DG, unpaired Cys, aggregation-prone stretches). Deliverable: esm_epitope_analysis.png (conservation/variant-effect track along epitope), developability_liabilities.csv. CPU-feasible."
            },
            {
              "title": "Antibody / binder design specifications",
              "description": "Author concrete paratope/binder design briefs per lead: framework choice (humanized IgG1 afucosylated for SIGLEC6 ADCC; IgG1 or decoy for IL1RL1; neutralizing IgG for CCL26), CDR targeting of the mapped epitope hotspots, format (mAb vs ADC vs bispecific), and payload/effector strategy. CONDITIONAL GPU step: if a remote host is added, run de novo binder backbone generation (RFdiffusion/BindCraft) against the SIGLEC6 Ig-V epitope; otherwise deliver specification-only. Deliverable: design_briefs/ per-target markdown + binder_design_targets.csv (+ designed backbones if GPU)."
            },
            {
              "title": "Designed-binder structure validation (conditional GPU)",
              "description": "CONDITIONAL on GPU availability: refold designed binder–target complexes with ESMFold2-Fast or Chai-1, score interface quality (predicted DockQ/ipTM, pAE at interface), and rank designs. Without GPU, substitute a validation-protocol specification documenting the exact refold/scoring pipeline and acceptance thresholds to run once compute is available. Deliverable: binder_validation.csv + complex structure artifacts (Mol*-viewable), or the protocol spec."
            },
            {
              "title": "pMHC / TCR antigen-presentation analysis",
              "description": "Exploit the Phase-2 IFN-γ→epithelial HLA class I induction finding: quantify the epithelial antigen-presentation program (HLA-A/B/C, B2M, TAP1/2, immunoproteasome PSMB8/9) across cell types and endotypes from the single-cell + bulk data; run MHC class I binding prediction (netMHCpan-style, CPU) on candidate EoE-associated antigen sources to nominate presented peptides relevant to a pMHC/TCR-directed approach. Deliverable: antigen_presentation.png + pmhc_candidates.csv. Framed as exploratory given no EoE-specific antigen ground truth."
            },
            {
              "title": "Immunogenicity & developability screen of candidates",
              "description": "Screen candidate binder/antigen sequences for clinical liabilities: MHC-II binding (T-cell epitope / anti-drug-antibody risk) prediction, humanness scoring, and aggregation/PTM liabilities consolidated from Step 4. Rank leads by combined developability. Deliverable: immunogenicity_screen.csv + a developability heatmap figure across leads."
            },
            {
              "title": "Companion-diagnostic assay specification",
              "description": "Translate the Phase-2 stratification into assay specs: per lead target, define the patient-selection biomarker (SIGLEC6+ mast fraction by IHC/flow; soluble ST2 ELISA; tissue/serum eotaxin-3), the endotype it enriches (from cross-cohort addressable fractions), and a proposed cutoff rationale. Deliverable: companion_dx_specs.csv + a figure pairing each therapeutic modality with its selection assay and addressable patient fraction."
            },
            {
              "title": "Consolidate Phase-3 design package & report",
              "description": "Integrate all Phase-3 outputs into a design package: revised_design_dossier.csv (per lead: epitope, modality, differentiation, developability, companion Dx, GPU-design status), eoe_phase3_report.md (methods, results, caveats, what needs GPU/wet-lab), and a phase3_summary.png dashboard. Explicitly document which deliverables are specification-only pending compute/wet-lab, so the hand-off state is unambiguous. Save all as artifacts."
            }
          ]
        }
      ],
      "id": "phase-0"
    }
  ],
  "desired_outputs": [
    "Per-target PPI/interface dossier (SIGLEC6, IL1RL1/ST2, CCL26) with defined binding epitopes",
    "ESM-family epitope conservation + variant-effect + developability analysis",
    "Antibody/binder design specifications (paratope brief; de novo backbones if GPU available)",
    "Designed-binder structure validation (conditional on GPU)",
    "pMHC/TCR antigen-presentation analysis for the epithelial HLA axis",
    "Immunogenicity + developability screen for candidate binders",
    "Companion-diagnostic assay specification per lead target",
    "Consolidated Phase-3 protein-design package + report"
  ],
  "feasibility": {
    "rationale": "Analytical backbone (interface/PPI analysis, ESM-family sequence work, epitope mapping, developability, pMHC prediction, assay specs) is CPU-feasible on the 8 GB local host and builds directly on Phase-2 outputs and fetched AlphaFold structures. Two steps — de novo binder design and designed-complex structure validation — require GPU; list_compute is currently empty, so these are marked conditional and will need a remote host added (Customize → Compute) or will fall back to specification-only deliverables.",
    "confidence": "medium"
  }
}