# Point-by-Point Response to Round-2 Reviews (v2 → v3)

**Decision:** Minor revision (unanimous; all three reviewers moved up from Major). The editor named four blocking items and six recommended items. Below, each is answered. All changes were made in silico or by editing; no wet-lab work was required.

## Blocking items

**B-1 — GUCY2C EAC tumor-mRNA expression from the esca_tcga_pan_can_atlas_2018 cohort.**
Attempted; honestly scoped. The cBioPortal access available to us exposes mutation, copy-number, and clinical endpoints but **no per-sample mRNA-expression retrieval**, so we could not pull GUCY2C tumor mRNA from that cohort without fabricating values. We did not invent them. Instead we (a) sharpened the flag in Results R3 to name this as the single highest-priority follow-up query and (b) state explicitly that the treatment-arm rationale is provisional until GUCY2C EAC tumor expression is reported. This preserves candor over a manufactured result; the query should be run against a portal build with an mRNA endpoint (or the GDC) before external submission.

**B-2 — DKK1 systemic safety in a surveillance population.**
Done. A new Discussion paragraph addresses DKK1's canonical Wnt-dependent bone/skeletal biology, interprets the fibroblast-dominant GTEx pattern (a cell-culture artifact; low solid-tissue levels consistent with a stromal/paracrine source), and states why systemic neutralization in otherwise-well Barrett's patients faces a higher safety bar than late-stage DKN-01 dosing. Gate G5 now names skeletal/systemic toxicity explicitly.

**B-3 — Interface residue → UniProt mapping.**
Done. Computed directly from the complex PDBs: GUCY2C interface residues map to UniProt P25092 positions 153–402 (within ECD 24–430); DKK1 interface residues map to O94907 positions 187–208 (within CRD2 178–256) — confirming domain engagement. Added to Results R5, Methods, and new **Table S6** (full offset mapping).

**B-4 — Figure 4 in-figure confidence notation.**
Done. Each Figure 4 panel now carries the in-panel annotation "single-model Boltz-2 · not consensus-validated," and the legend states the depicted structure is the highest-confidence of five diffusion seeds, not an ensemble or orthogonal consensus.

## Recommended items (addressed now; non-blocking)

**R-6 — GUCY2C tumor_selectivity 5 → 4 inconsistency.** Resolved, and the recomputation revealed something we now report honestly rather than assert away: recalibrating GUCY2C selectivity from 5 to 4 (window pending, O-2) lowers its composite 13.00→12.00 and *does* change the lane ranking — CDH17 (12.38) overtakes it and its Monte-Carlo rank-1 frequency falls from 80.7% to ~0% (top-3 ~48%). We state in Results and Table S0 that GUCY2C's top-target status is contingent on the optimistic selectivity score (so O-2 is decisive for lead choice as well as safety) and now carry CDH17 as a credible backup treatment-lane target.

**R-7 — Figure 1b non-dedup caveat on the figure.** Done — added to the Figure 1b legend.

**R-9 — Binder-diversity metric defined.** Done. Length-penalized pairwise identity: max 21.4% (GUCY2C set), 32.9% (DKK1 set; top pair dkk1_bb2/bb3, both alanine-rich), means ≈15%. Reported in Results R5 and Table S5, with the most-similar pairs named numerically.

**R-10 — DKK1 fibroblast artifact contextualized.** Done — Table S4 footnote flags the cultured-fibroblast value as non-physiological and frames the likely stromal/paracrine DKK1 source as compatible with a neutralizing-trap strategy.

**R-5 (association-weight grid) and R-8 (benchmarked %Ala calibration):** acknowledged as recommended-before-journal-submission. For R-8 we downgraded "clean" language to an internal-threshold framing and cite the calibration references to add. For R-5 we note the ±50% Monte Carlo already spans association-weight parity-to-premium within its U(2.5,7.5) draw and that a formal grid is a documented next step. Neither is blocking for preprint posting per the editor's letter.

## Net effect
All four blocking items are resolved except B-1, which is honestly scoped as a tooling limitation rather than papered over. The manuscript's claim strengths remain matched to (or below) its evidence, and the one item we could not compute is flagged as the top priority follow-up rather than fabricated.