AGX101: A TM4SF1-Directed Antibody-Drug Conjugate for the Treatment of Solid Cancers

AGX101 is a TM4SF1-directed antibody-drug conjugate.

This image represents the drug.

In blue is the antibody, which provides targeting to tumors. The antibody finds the protein TM4SF1, which is predominantly located in tumors, and binds to it.

In yellow is the conjugated drug payload, which endows the antibody with efficacy. AGX101’s payload is toxic to dividing cells, and is intended to kill cells in the tumor.

TM4SF1 has several features that make it attractive as a cancer target. It is expressed in two parts of the tumor, the tumor vasculature and the tumor cells. In the tumor vessels, TM4SF1 enables angiogenesis, the process by which tumors grow their blood supply. In tumor cells, TM4SF1 enables invasion and metastasis. Angiogenesis, invasion, and metastasis are hallmarks of cancer that are substantially responsible for its lethality.

AGX101 is selective for tumors

TM4SF1 antibodies are highly selective for tumors. The bar chart shows data from clinical radioimaging with a TM4SF1-directed antibody, published in 1997.

The tumor stands out strongly compared to other organs.

As a result of this excellent tumor homing, most AGX101 effects are expected to be on-tumor.

Figure 1. Whole body and organ dosimetry for 10 breast cancer patients treated with 131 I-ChL6. Tumor dosimentry for the 7 patients with superficial tumors. The cross bar represents the mean for lung, liver  or tumors

Data source: PMID: 917228

AGX101 attacks both the tumor vasculature and the tumor cells.

AGX101’s effect against the tumor vasculature is illustrated in the below mouse model. A surrogate drug for AGX101, identical except that the antibody targets mouse TM4SF1 rather than human TM4SF1, kills the small blood vessels of the tumor and the large vessels (artery and vein) that feed and drain the tumor. This deprives the tumor of its supply of nutrients and oxygen, and leads to a necrotic death of cells in the middle of the tumor. The tumor can be repeatedly treated in this way until it has shrunk to minimal size.

Control treatment

Drug treatment

AGX101’s effect against tumor cells has also been tested in mouse models. Below, a human glioblastoma cell line was implanted in a mouse, and treatment with AGX101 effectively shrank the tumor.

A third mechanism of action, also demonstrated in mouse models, is the activation of immunity against the tumor.

These three mechanisms of action offer potential for robust efficacy against solid cancers.