# IL1RL1/ST2 binder design brief

**Modality:** Blocking human IgG1 mAb (astegolimab-class), or engineered soluble ST2 decoy. Effector-silent Fc (LALA) — mechanism is IL-33 signal blockade, not cell killing.

**Target epitope:** IL-33 binding interface, 1781 Ų across Ig1–Ig2–Ig3 (experimental, from 4KC3). Hotspots: **Tyr119, Phe245, Leu308, Lys22, Arg38, Tyr132, Gln39**.
- Focus CDRs on the **Ig2 hotspot cluster (Tyr119, Tyr132, Thr135, Asp137)** + **Ig3 (Phe245, Leu308, Leu311)** — the highest-BSA contiguous patch.
- AVOID the N-glycosylated sub-regions (8 sites in epitope) — steer paratope to the glyco-free hotspot core.

**Paratope strategy:** large epitope favors a conventional Fab (broad CDR footprint) over a small scaffold; CDR-H3 over the aromatic Tyr119/Phe245 hotspots (aromatic stacking), CDR-L1/L2 engaging the Lys22/Arg38 charged rim.

**Differentiation (structural):** clinical anti-IL-33 antibodies (tozorakimab/itepekimab) target the LIGAND — only 9/25 tozorakimab-epitope residues touch the ST2 site. Receptor-side blockade is IL-33-isoform/oxidation-independent and complements ligand antibodies.

**Companion biomarker:** soluble ST2 (sST2) from the same gene — patient selection ELISA.