ROR2

Class

Conditionally active biologic (CAB) ROR2-targeted antibody-drug conjugate (ozuriftamab vedotin, MMAE payload)

Pathway

Conditionally (pH-dependent) binds ROR2 receptor tyrosine kinase on tumor cells, sparing normal tissue

ROR2 is a receptor tyrosine kinase, a protein embedded in the cell membrane that relays chemical signals from outside a cell to its interior. During embryonic development, ROR2 participates in a signaling pathway called non-canonical Wnt signaling, which guides cell movement and tissue patterning. In healthy adults this pathway is largely quiet, but many tumors reactivate ROR2, using it to promote cell migration, invasion, and spread. This makes ROR2 an attractive marker for directing cancer therapy, provided it can be targeted without excessive harm to any normal tissue that retains low-level expression. The approach here is an antibody-drug conjugate: an antibody that recognizes ROR2 is chemically linked to a potent cytotoxic payload. The antibody is engineered to be a 'conditionally active biologic,' meaning it binds ROR2 preferentially under the more acidic conditions typical of the tumor microenvironment, while binding weakly at the near-neutral pH of normal tissue. This conditional binding is intended to concentrate the drug's cell-killing activity at the tumor while sparing normal cells that express ROR2 at lower levels. This mechanism is broadly relevant to solid tumors where ROR2 is overexpressed, offering a way to deliver cytotoxic chemotherapy selectively rather than systemically.