Research and development of antibody-drug conjugates targeting the stroma of pancreatic cancer

A new strategy to breach the "castle wall" of cancer: Taking on intractable pancreatic cancer with the bystander effect

One hallmark of intractable cancers such as pancreatic cancer and cholangiocarcinoma (bile duct cancer) is the reactive proliferation of cancer-associated fibroblasts (CAFs) in the region outside the cancer cells known as the "stroma"—these sometimes outnumber the cancer cells themselves. In these cancers, CAFs can be seen proliferating in a pattern that surrounds the cancer cell nests. CAFs are cells with a high capacity to produce extracellular matrix components such as collagen, and the deposition of this extracellular matrix induces fibrosis of the stroma. It is known that hardening of the cancer tissue due to fibrosis activates cancer cells and increases their proliferative and invasive potential. Furthermore, fibrosis and hardening of cancer tissue are known to induce vascular collapse within tumors and the creation of an ischemic microenvironment, reducing drug delivery efficiency and forming an immunosuppressive tumor microenvironment.

In the past, attempts were made to develop therapies that suppress CAF proliferation or kill CAFs, but neither clinical trials nor clinical studies have succeeded; the strategy of killing or suppressing CAFs is said to be in need of a rethink. We aim to move away from conventional thinking and develop a novel therapy to efficiently deliver anticancer drugs to pancreatic cancer cells: using antibody-drug conjugates (ADCs) that target a CAF marker molecule that we have independently identified.

In 2019, we identified Meflin, a glycosylphosphatidylinositol (GPI)-anchored molecule with leucine-rich repeats in its extracellular domain, as the most CAF-specific membrane molecular marker. We conducted assessments using genetically modified mice, spontaneous cancer mouse models, and human pathological tissue specimens. The assessments have demonstrated that Meflin-positive CAFs accumulate with high sensitivity around cancer cells, that Meflin is also expressed in CAFs at metastatic sites, and that it shows higher mRNA expression levels compared with other CAF membrane marker molecules. We have confirmed that Meflin is a molecule specifically expressed in CAFs across many cancer types accompanied by stromal fibrotic reactions, including cholangiocarcinoma, colorectal cancer, lung cancer, breast cancer, urothelial carcinoma, and renal cancer, in addition to pancreatic cancer. Although Meflin is also expressed in stromal cells of normal tissue, its expression level there has been confirmed to be extremely low compared with CAFs.

We have obtained a large number of anti-Meflin monoclonal antibodies and have produced ADCs (hereinafter referred to as anti-Meflin ADCs) by conjugating these antibodies to payloads via linkers. We have found that anti-Meflin ADCs show marked antitumor effects in multiple tumor-bearing mouse models.

The expected mechanism of action of the anti-Meflin ADC is the "bystander effect": after the ADC is taken into CAF cells, the payload released from the ADC by proteolytic enzymes is expelled extracellularly by drug exporters, and that payload then kills neighboring cancer cells. We used cell culture experiments to confirm that CAFs are not killed in this process.

Based on these findings, we aim to verify the superiority of anti-Meflin ADC therapy over existing cytotoxic anticancer drugs and the detailed pharmacological mechanism of the bystander effect, conduct safety studies using GMP-grade ADCs, and initiate a Phase I clinical trial in patients with unresectable advanced pancreatic cancer.

Meflin-positive CAFs have been confirmed to be present in virtually all cancers accompanied by stromal fibrotic reactions. Furthermore, unlike cancer cells, which acquire treatment resistance or accumulate genetic mutations progressively and/or under the selective pressure of anticancer therapy, the phenotype of CAFs is known to be stable. We hope that in the future, anti-Meflin ADCs will be broadly applied to these many types of cancer, as well as to cancers that have acquired resistance to other treatments.