Bispecific antibody targeting cathepsin G peptide kills leukemia cells while sparing normal bone marrow | Research

The takeaway

A novel T cell-engaging bispecific antibody targeting cathepsin G leader sequence peptide CG1 on HLA-A2 killed primary AML cells in vitro and in vivo while showing no activity against normal bone marrow.

Kills AML, spares marrow
Bispecific antibody targeting a cathepsin G peptide-HLA complex selectively destroys leukemia while showing no activity against normal bone marrow

What the researchers found

CG1/A2xCD3 showed high binding affinity to CG1/HLA-A2, potent killing of HLA-A2+ primary AML and cell lines in vitro and in vivo, tumor- and antibody-dependent T cell activation and cytokine secretion, and no activity against normal bone marrow.

Why it matters

AML has limited treatment options and high relapse rates. Targeting peptide-HLA complexes with bispecific antibodies offers a precision approach that can distinguish leukemia from normal blood cells, potentially reducing treatment toxicity.

How the study worked

Antibody engineering, binding affinity assays, in vitro cytotoxicity against primary AML and cell lines, in vivo xenograft models, T cell activation/cytokine assays, and normal bone marrow safety testing.

What this study cannot tell us

Restricted to HLA-A2+ patients (~40-50% of populations). Single peptide target. Preclinical data only. Safety in humans not established. Potential for on-target off-tumor toxicity needs evaluation.

How to read the evidence

Rigorous preclinical study with in vitro primary AML data, in vivo xenografts, and normal tissue safety testing. Strong proof of concept for clinical development.

When this study was published

Published in 2025.

The bigger picture

TCR-mimic antibodies represent a new frontier in cancer immunotherapy, accessing intracellular antigens presented on HLA molecules—targets invisible to conventional antibodies. This approach could be applied to other cancers with overexpressed intracellular proteins.

Questions still open

Will CG1/A2xCD3 advance to clinical trials for AML?
Can this approach be extended to other HLA types for broader patient coverage?
How does this compare to existing AML immunotherapies like BiTEs and CAR-T?

Common questions

How does this antibody find and kill leukemia cells?

The antibody recognizes a specific peptide from cathepsin G protein that is displayed on the surface of leukemia cells via HLA-A2 molecules. It then grabs a nearby T cell (immune cell) and brings it close to the leukemia cell, triggering the T cell to kill the cancer cell. Normal bone marrow cells show much lower levels of this peptide, so they are spared.

Why target a peptide instead of the whole protein?

Cathepsin G is inside the cell where antibodies cannot reach it. However, cells naturally break down internal proteins into peptides and display them on their surface via HLA molecules. By targeting this displayed peptide, the antibody effectively reaches an intracellular target—a major advantage for cancer immunotherapy.

Read the original research

Immunotherapy targeting a leader sequence cathepsin G-derived peptide.

Leukemia, 39(4), 888-898

View on PubMed ↗Publisher’s paper ↗

Citation

Shi, Chunhua; Tian, Ze; Yan, Jun; Zhang, Mao; Sukhumalchandra, Pariya; Chang, Edward; Yang, Guojun; You, Junping; Cui, Meng; Shi, Qing; Kerros, Celine; Philips, Anne; Qiao, Na; Torikai, Hiroki; Patchametla, Sathvik; Sergeeva, Anna; St John, Lisa; He, Helen; Wiederschain, Dmitri; Lee, Benjamin H; Paulus, Geraldine L C; Zha, Dongxing; Molldrem, Jeffrey; Alatrash, Gheath. (2025). Immunotherapy targeting a leader sequence cathepsin G-derived peptide.. Leukemia, 39(4), 888-898. https://doi.org/10.1038/s41375-025-02520-x