A Novel Antibody Drug Conjugate Against Pancreatic Cancer

Known as the "king of cancer," pancreatic cancer is still one of the most deadly fmalignant tumors in humans. It is usually asymptomatic in its early stages, and most patients are already in the advanced stage at the time of diagnosis. Only about 10% of patients are still alive in five years after diagnosis. Not only traditional chemotherapy and radiotherapy helpless for pancreatic cancer, but also immunotherapy, which has revolutionized the treatment of many other types of cancer, is ineffective against pancreatic cancer to a large extent.

On November 3, a team of scientists from Boston Children's Hospital reported a new progress in the treatment of pancreatic cancer in Advanced Science. Their preclinical studies have shown that using a highly selective and potent antibody-drug conjugate (ADC) can significantly and lastingly regress the tumors in mice.

Why pancreatic cancer is so difficult to treat? On the one hand, pancreatic tumors are poorly vascularized, so it is difficult to deliver drugs to the tumor, on the other hand, unlike other cancers, pancreatic tumor cells are encased in a "protective layer" composed of stromal cells and their secreted intercellular matrix.

"It is difficult to get drugs into these tumors, we have developed a new therapy (chemo-immunotherapy agent) that can selectively identify and penetrate pancreatic tumors better than other therapies." explained Dr. Marsha Moses , the leader of this new research.

To be specific, Dr. Moses' team has developed an antibody-drug conjugates targeting ICAM1. ADC is a new type of targeted drugs consisting of "monoclonal antibodies, cytotoxic drugs, and linkers that connect the two." Because antibodies are targeted (recognizing the surface antigens of cancer cells), they can selectively "transport" cytotoxic molecules directly to tumor cells, performing anticancer functions without affecting healthy cells.

Dr. Peng Guo, who participated in the study, explained: “The size of ADC is similar to the size of a single antibody. Due to small diameter, these drugs are able to penetrate the 'protective layer' and reach pancreatic cancer cells better than other innovative therapies, such as T-cell immunotherapy and nano-drugs.”

Differential overexpression of ICAM1 in human pancreatic cancer tissues and cells (Source: Advanced Science)

Using ICAM1 as a target for an anti-pancreatic ADC was the team's choice after screening dozens of different proteins on the surface of the tumor. ICAM1 (CD54), a transmembrane glycoprotein of the immunoglobulin superfamily, is abnormally overexpressed in a variety of cancers, such as pancreatic cancer, triple-negative breast cancer, melanoma, and thyroid cancer, and is often associated with aggressive phenotypes and poor prognosis. In pancreatic cancer, KRAS (G12D) mutation directly induces the expression of ICAM1 on pancreatic acinar cells. KRAS (G12D) mutation is the most common oncogenic mutation occurring in 70%-95% of pancreatic cancer patients.

DM1-ICAM1 antibody-drug conjugates (Source: Advanced Science)

In this study, the scientists first tested four candidate ADCs in two human pancreatic cancer cell lines and normal pancreatic cells. The results showed that the ADC conjugated by the ICAM1 antibody and the cytotoxic drug DM1 (mertansine, which is clinically used to treat HER2-positive breast cancer) is superior to other ADCs. The DM1-ICAM1 antibody combination has no harm to non-cancerous pancreatic cells that do not express ICAM-1.

Then, the research team randomly grouped the mice carrying pancreatic tumors and each group would be treated with one of the four therapies : 1) DM1-ICAM1 antibody-drug conjugates, 2) DM1 conjugated a non-targeting antibody, 3) gemcitabine (a first-line chemotherapy drug for pancreatic cancer), and 4) PBS.

Using DM1-ICAM1 antibody-drug conjugates to selectively eliminate pancreatic cancer cells (Source: Advanced Science)

The results of the study showed that compared with other groups, even with only two injections, the mice treated with the DM1-ICAM1 antibody-drug conjugates drug showed a significant reduction in tumors, and this anti-tumor effect persisted during the 14-day study period.

DM1-ICAM1 antibody-drug conjugates inhibits metastasis (Source: Advanced Science)

DM1-ICAM1 antibody-drug conjugates therapy also effectively inhibited the metastasis of multiple organs (including lung, liver, spleen, etc.). In addition, the toxicity of DM1-ICAM1 antibody-drug conjugates was not observed.

Using non-invasive MRI to evaluate the expression of ICAM1 in pancreatic cancer tumors (Source: Advanced Science)

It is worth mentioning that Dr. Jing Huang, who participated in this study, designed an MRI-based molecular tumor imaging technology to support ICAM1 ADC therapy. This technique can confirm the presence of ICAM1 on the tumor surface without invasive biopsy. This may help predict treatment effects and monitor changes in efficacy.

Dr. Moses said: “Although other ADCs have been tested in pancreatic cancer, none of them have shown sufficient efficacy in the clinic, and they can cause off-target toxicity. Our approach is expected to achieve greater precision through specific targeting and effective monitoring.” It is learned that the research team will carry out further research in the future, hoping to promote this innovative therapy into the clinical development stage.

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Reference:
[1] Jing Huang et al. A Rationally Designed ICAM1 Antibody Drug Conjugate for Pancreatic Cancer. Advanced Science(2020)
[2] Precision chemo-immunotherapy for pancreatic cancer? (Resource：Children's Hospital Boston)