Targeting Minimal Residual Disease in Multiple Myeloma: The Promise of AMG 424 Bispecific Antibody

Multiple myeloma (MM), a common blood cancer with a global incidence exceeding 62,000 cases in 2012, remains challenging to treat, particularly for patients who experience relapses after standard treatments. There is an urgent need for new treatments that can eradicate minimal residual disease (MRD), which is harder to detect and takes longer to manifest. Bispecific T cell engager (BiTE) molecules, which rally T cells to attack cancer cells, have shown promise in treating blood cancers and could be key in reducing MRD.

CD38, a protein found on the surface of various immune cells and plasma cells, is overexpressed in MM cells and serves as a validated target for therapy. AMG 424 is a newly developed humanized bispecific antibody designed to target CD38 and CD3, with the aim of enhancing T cell engagement with MM cells. This antibody features an XmAb Fc domain that is capable of interacting with nonhuman primate (NHP) CD3 and CD38, a feature that was critical in its selection process due to its balanced affinity for both targets.

In a series of laboratory tests, eight different bispecific molecules with varying affinities for CD3 and CD38 were evaluated for their ability to induce T cell-dependent cytotoxicity (TDCC) against cancer cells, deplete B cells, and trigger cytokine release. AMG 424 was chosen for its optimal performance in these assays, particularly its robust TDCC activity against cancer cells with low CD38 expression and its reduced cytokine release compared to other molecules with higher CD3 affinity.

Further in vivo studies in mice bearing human T cells and an orthotopic xenograft model showed that AMG 424 could significantly inhibit tumor growth and extend survival. In NHPs, the antibody was able to deplete peripheral CD38-expressing cells, demonstrating its pharmacodynamic effect. Additionally, AMG 424's activity was found to be largely unaffected when combined with current standard treatments, suggesting its potential for use in combination therapies.

The findings indicate that AMG 424 has the potential to be a novel therapeutic agent for MM, capable of targeting cancer cells through T cell-mediated lysis and offering a new approach to eliminating MRD. Its ability to clear target cells in vitro and in vivo, along with its compatibility with existing treatments, supports the need for further research into its use as a standalone treatment or in combination with current therapies.