A Structure-Guided, Conformation-Specific Antibody-Drug Conjugate for AML Immunotherapy

Acute myeloid leukemia (AML) is an aggressive blood cancer that remains extremely difficult to treat. Even the most advanced therapies attack both leukemia cells and healthy blood-forming cells, leading to severe side effects and poor long-term outcomes. This happens because existing treatments cannot distinguish between cancerous and normal cells when they share the same surface proteins. Traditionally, cancer therapies look for the presence or absence of proteins on tumor cells. However, proteins are dynamic molecules that can shift and adopt multiple structural shapes, much like a lock that changes its position. Recognizing and targeting these structural changes could reveal completely new ways to distinguish malignant from healthy cells. Our research group at UCSF developed a method called structural surfaceomics to study these subtle shape differences directly on the cell surface using advanced biochemical tools. Using this approach, we discovered that one specific protein, integrin beta 2, adopts an open, active shape that appears uniquely on AML cells but is absent on normal blood stem and progenitor cells. This finding was unexpected because integrin beta 2 exists on many cell types, our lab’s work revealed that only its active shape defines leukemia cells. We engineered antibodies that can recognize and bind specifically to this active shape, creating a new type of therapy called conformation-specific targeting. By linking these specialized antibodies to cytotoxic drug molecules, we can form antibody–drug conjugates (ADCs) that precisely deliver their payload only to cells displaying the active conformation of the protein, minimizing harm to normal tissues and preserving bone marrow function.
This represents the first strategy in AML to exploit a protein's shape rather than its mere presence for targeted therapy. If successful, this approach could lead to safer and more effective treatment options that selectively eliminate leukemic cells, reduce toxicities associated with standard chemotherapy, and improve both survival and quality of life for patients. Beyond AML, our work introduces a generalizable framework for shape-based drug targeting, opening a new frontier for precision cancer therapies that leverage protein dynamics to achieve unprecedented selectivity across multiple malignancies driven by aberrant protein conformational changes.