Targeting Leukemic Stem Cells: The Advancement of JNJ-63709178 in AML Therapy

Acute Myeloid Leukemia (AML) is a disease where the myeloid cells become cancerous, leading to an increase in abnormal white blood cells in the bone marrow and blood. Traditional treatments have not been successful in eradicating the disease due to their inability to completely remove leukemic stem cells (LSCs) from the bone marrow. A new approach to treating AML involves redirecting T-cells to target cancer cells.

CD123, a component of the interleukin-3 receptor, is found on the surface of AML cells and LSCs. A bispecific antibody, JNJ-63709178, has been developed to target these CD123+ cells. Utilizing Genmab's DuoBody technology, this antibody is designed to bind to both CD123 on cancer cells and CD3 on T-cells. As a humanized IgG4 bispecific antibody with a silenced Fc function, it can effectively recruit T-cells to attack tumor cells that express CD123.

In vitro studies have shown that JNJ-63709178 can effectively kill tumor cells (MOLM-13, OCI-AML5, and KG-1) with an EC50 range of 0.51-0.91 nM. Importantly, it does not affect CD123- cell lines, indicating a high level of specificity. The effectiveness of this antibody is also linked to the activation of T-cells and the release of cytokines such as TGF-β and TNF-α. Control antibodies lacking a functional arm did not induce cytotoxicity or T-cell activation.

In murine models of AML, JNJ-63709178 was able to suppress tumor growth and induce regression, correlating with T-cell infiltration and the expression of T-cell activation markers. Furthermore, the antibody was able to eliminate primary CD123+ cancer cells from AML patient blood samples without the need for additional T-cells.

Pharmacokinetic studies in cynomolgus monkeys suggest a dosing frequency of twice weekly for human trials. Currently, JNJ-63709178 is being evaluated in a Phase 1 clinical trial for relapsed and refractory AML patients. The study is registered at ClinicalTrials.gov with the ID: NCT02715011.

Several authors are affiliated with Janssen Pharmaceuticals R&D and have various disclosures including employment, stock options, and pending patents.