# CCL26 (eotaxin-3) binder design brief

**Modality:** Two routes — (a) neutralizing anti-CCL26 IgG1, or (b) small-molecule CCR3 antagonist (preferred if epitope proves too small for a durable mAb).

**Target epitope:** CCR3-engagement surface on the mature chemokine (24–94):
- **Site-2 (N-terminus, T24–K31)** — flexible, drives receptor activation.
- **N-loop (33–45) + 40s loop** — site-1 docking. Disulfide-constrained (C33–C57, C34–C73) → rigid, good epitope but small.

**Paratope strategy:** neutralizing mAb must occlude the N-loop/40s-loop docking surface to prevent CCR3 site-1 engagement. Given the small (71-aa) antigen and single dominant surface, a high-affinity mAb (KD < 1 nM) is needed to outcompete CCR3.

**Alternative — CCR3 antagonist:** the receptor is a GPCR with small-molecule tractability; CCR3 blockade also captures the other eotaxins (CCL11/CCL24) driving the same axis — broader anti-eosinophil effect. Recommend evaluating both in parallel.

**Escape-risk caveat:** the sole ESM escape-risk position in the CCL26 epitope (H39, entropy 2.34) falls INSIDE the N-loop docking surface recommended above — a paratope anchored there carries some variant-escape risk. Mitigate by co-engaging the disulfide-rigid 40s loop (conserved) rather than relying on H39, or favor the CCR3-antagonist route (targets the invariant receptor). For IL1RL1, note 6/18 escape-risk positions are also interface residues — steer CDRs toward the conserved aromatic hotspots (Y119/F245, low entropy) and away from the escape-prone rim.

**Differentiation:** effector-specific eosinophil-recruitment blockade; narrower and more targeted than dupilumab's broad Th2 blockade; universal across endotypes (Phase-2 addressable ~99%).