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Manuscripts

# Two manuscripts, from design to evidence

A design-and-roadmap paper on antigen-specific pMHC-II nanoparticle therapeutics for EoE, and a target-and-binder brief on the CCL26 / POSTN effector axis. Both are computationally grounded and openly documented, with structures and data available to download.

Manuscript 1

## Rational design of multivalent nanoparticle–pMHC-II immunotherapies for food-allergen tolerance in eosinophilic esophagitis

Ruth-Anne Pai, PhD (lead author, EoE patient-researcher) · with Claude AI computational support

Rather than broadly suppressing the immune system, this design re-educates the specific food-reactive T-cell clones that drive EoE. Three food triggers (dairy, wheat, soy) converge on a single HLA-DRB1*07:01 backbone with a swappable peptide cassette — folded, groove-validated, and displayed multivalently on an iron-oxide nanoparticle to induce IL-10–secreting regulatory (Tr1) T cells.

9
constructs (3 formats × 3 foods)
0.87–0.90
ipTM across pMHC-II complexes
15/15
peptide residues seated in-groove
24×
avidity gain at 5 pMHC / nanoparticle
Design space. Three formats (soluble single-chain → anergy; nanoparticle → Tr1 tolerance; tetramer → clone depletion) across dairy, wheat, and soy. All nine share one backbone; only the 15-mer peptide cassette changes. Lead epitopes: dairy FAQTQSLVY (17 nM), wheat HNVVHAIIL (35 nM), soy FVVNATSNL (50 nM), all HLA-DR7-restricted.
Epitope discovery & validation. Affinity ranking, IEDB stringency, and the ~92-fold context dependency that favored the dairy precursor form. The dairy epitope is tetramer-validated; wheat and soy are computational priors flagged for Phase-1 functional validation.
Nanoparticle architecture. A 20 nm Fe₃O₄ core, ~75 PEG-maleimide linkers, 5 pMHC copies at 5.8 nm spacing — tuned for TCR cross-linking and Tr1 priming, with a 3/5/8-copy valency-optimization ladder.

### Structural models

Three pMHC-II:peptide complexes were co-folded (ESMFold2-Fast, GPU) and inspected for canonical groove geometry. Download the atomic coordinates below — `.pdb` files open in PyMOL, ChimeraX, or any Mol* viewer.

Complex | Peptide (15-mer) | ipTM | Structure
--- | --- | --- | ---
Dairy pMHC-II | `KIHPFAQTQSLVYPF` | 0.872 | dairy_pmhc.pdb
Wheat pMHC-II | `IHNVVHAIILHQQQQ` | 0.896 | wheat_pmhc.pdb
Soy pMHC-II | `AYPFVVNATSNLNFL` | 0.891 | soy_pmhc.pdb

### Preclinical roadmap

A five-phase, 18–24 month path to IND submission — human ex-vivo validation, murine proof-of-concept, GLP toxicology and biodistribution, GMP manufacturing, and regulatory filing — each with explicit go / no-go decision gates.

### Downloads

Manuscript (.docx) Supplemental (.docx) Construct sequences (.fasta) Construct specs (.csv) Epitope table (.csv) Full deliverables index (.md)
Manuscript 2

## Effector-specific blockade of the CCL26 (eotaxin-3) & POSTN axis in EoE

CCL26 and POSTN emerged from the omics target scan as high-evidence, no-trial biology — the eosinophil-recruitment axis downstream of Th2 inflammation. This brief lays out the binder-design strategy: a neutralizing anti-CCL26 antibody (or CCR3 antagonist) and a POSTN-interface binder, with ESM-guided escape-risk analysis steering the paratope.

CCL26 (eotaxin-3) binder. A designed binder (orange) occludes the CCR3-engagement surface of the mature chemokine (epitope in blue) — neutralizing the dominant EoE eosinophil chemoattractant.
POSTN (periostin) binder. A helical binder engaging the POSTN interface — targeting the matricellular protein that amplifies eosinophil adhesion and tissue remodeling in EoE.

### Design rationale

### Two routes for CCL26

A neutralizing anti-CCL26 IgG1 must occlude the N-loop / 40s-loop docking surface to block CCR3 site-1 engagement — a high-affinity (KD < 1 nM) requirement for the small, 71-aa antigen. Alternatively, a small-molecule CCR3 antagonist targets the invariant receptor and captures the other eotaxins (CCL11/CCL24) on the same axis for a broader anti-eosinophil effect.

### ESM-guided escape hardening

The sole ESM escape-risk position in the CCL26 epitope (H39) sits inside the N-loop docking surface — so the design co-engages the disulfide-rigid, conserved 40s loop rather than relying on H39. For the IL1RL1 interface, CDRs are steered toward conserved aromatic hotspots (Y119 / F245) and away from the escape-prone rim.

### Why it differentiates

Effector-specific eosinophil-recruitment blockade — narrower and more targeted than dupilumab's broad Th2 blockade, and universal across EoE endotypes (Phase-2 addressable in ~99% of patients).

### Structure downloads

CCL26 lead complex (.pdb) CCL26 target (.pdb) POSTN lead complex (.pdb)