# SIGLEC6 binder design brief

**Modality:** Depleting mAb or ADC. Afucosylated human IgG1 (enhanced ADCC/FcγRIIIa) for mast-cell depletion; internalizing receptor → ADC-compatible (MMAE or PBD payload).

**Target epitope:** Ig-V domain (28–123). Two options:
- **Functional-site epitope** — sialic-acid-binding Arg cluster (R122, R100, R109–114): blocks ligand engagement + enables depletion. Well-conserved (low ESM entropy).
- **Non-competitive epitope** — acidic face E28/E37/E84/D73/D82: pure depletion without ligand competition; useful if ligand-blocking causes on-target toxicity.

**Paratope strategy:** CDR-H3 anchored on the Arg cluster (electrostatic complementarity — acidic CDR residues); CDR-H2/L3 framing the exposed β-sheet face. Target KD < 5 nM for efficient depletion.

**Selectivity:** MUST counter-screen vs SIGLEC5 (closest paralog) and SIGLEC11; the Arg cluster is Siglec-conserved, so specificity comes from the surrounding loops. Confirm no binding to SIGLEC6 on placental trophoblast (expression site — safety).

**Developability:** epitope clean (1 N-glyc, 2 oxidation-prone) — no reformatting needed.

**Differentiation:** no clinical/pipeline EoE agent depletes mast cells; fully orthogonal to dupilumab and anti-IL-33/IL-13.