Fc-Engineered Anti-FAP Antibodies Enhance NK Cell-Mediated ADCC and Remodel the Immunosuppressive Tumor Microenvironment

The protocol demonstrates exceptional rigor through its phased, de-risking approach. The inclusion of a Phase 1 in silico validation with explicit GO/NO-GO criteria (e.g., ≥4-fold predicted ADCC improvement, therapeutic index ≥10:1) is a sophisticated and cost-effective strategy that prioritizes mechanistic feasibility before committing to expensive in vivo studies.

The hypothesis demonstrates strong theoretical coherence by directly transposing a validated paradigm from immuno-oncology: the Fc-engineering of antibodies to deplete immunosuppressive populations via ADCC, as established with anti-CTLA-4 and anti-4-1BB antibodies, onto the clinically relevant target of FAP+ CAFs. This is a logical and well-supported extension of the state of the art.

The proposal correctly identifies a genuine biological barrier: the low baseline ADCC against stromal cells due to inhibitory signals (e.g., HLA-E) and the physical density of the ECM. Targeting CAFs via Fc-engineering is a logical extension of existing checkpoint and anti-angiogenic strategies, and the S239D/I332E mutation is a well-validated Fc enhancement approach.

Cible hautement validee cliniquement : FAP est une cible stromale bien etablie avec des anticorps (FAP-IL2v, RO6874281) deja en essais cliniques par Roche, ce qui valide l'accessibilite de la cible et reduit le risque de developpement technique.

Mécanisme clairement articulé avec une chaîne causale testable (Fc-engineering → ADCC → déplétion CAF → remodelage TME), ce qui facilite la rédaction d'un narratif scientifique convaincant pour les évaluateurs.