AXL

Class

Conditionally active biologic (CAB) AXL-targeted antibody-drug conjugate (mecbotamab vedotin)

Pathway

Conditionally (pH-dependent) binds AXL receptor tyrosine kinase, delivering cytotoxic payload selectively in tumor microenvironment

AXL is a receptor tyrosine kinase belonging to the TAM family (Tyro3, Axl, Mer), normally activated by the ligand GAS6 to regulate processes such as cell survival, tissue clearance of dying cells, and immune regulation. In cancer, AXL is frequently overexpressed and contributes to tumor cell survival, invasion, epithelial-to-mesenchymal transition, and resistance to other therapies, including many targeted agents and chemotherapies. This has made AXL an attractive target for two distinct strategies: small-molecule kinase inhibitors that block its intracellular signaling, and antibody-based approaches that exploit AXL as a surface marker to deliver cytotoxic drugs directly to tumor cells. The conditionally active biologic (CAB) antibody-drug conjugate approach described here uses an antibody engineered to bind AXL preferentially under the altered pH conditions found in tumor tissue, rather than in normal, healthy tissue where AXL is also expressed. This conditional binding is intended to concentrate cytotoxic payload delivery within tumors while sparing normal AXL-expressing cells, addressing a key limitation of earlier AXL-directed antibodies. Together, these approaches target AXL-driven cancers and settings where AXL upregulation contributes to resistance against other therapies.