tilvestamab (BGB149)

Both SAXS and cryo-EM confirmed successful complex formation between the three proteins, and a low-resolution 3D model for the tilvestamab-AXL complex is presented. The data allow for sample optimization for high-resolution structural biology, as well as designing mutations that could alter binding affinity and specificity.

Our study reveals that tilvestamab's anti-cancer efficacy arises from superior kinetic stability in AXL binding and direct modulation of cellular biomechanics. By enhancing membrane rigidity, tilvestamab impairs cancer cell migration and proliferation-key drivers of metastasis. These findings provide the biomechanical rationale for tilvestamab's therapeutic activity, positioning it as a promising agent for targeting AXL-dependent cancers through mechanopharmacological mechanisms.

Glu2 near the N terminus of AXL is essential for binding. The data give a structural view into the AXL-tilvestamab complex and allow for further optimisation of the binding interface.

Remarkably, their in vivo antitumor effectiveness was not significantly enhanced by concomitant administration of a multi-target tyrosine kinase inhibitor. Bemcentinib and tilvestamab qualify as compounds of potentially high clinical interest in AXL overexpressing RCC.