A study presented at the 50th Annual Meeting of the American Society for Clinical Oncology (ASCO) being held May 30 – June 3, 2014 in Chicago, Ill, describes the results of a phase I clinical trial of the investigational agent DMOT4039A (also known as RG7600; Genentech/Roche) against pancreatic and ovarian cancers. In this early clinical trial with the goal of identifying possible risks and defining likely dosages, the drug was well tolerated and in some patients showed initial evidence of anti-cancer activity.

According to data from the American Cancer Society, pancreatic cancer accounts for about 3% of all cancers in the U.S., and accounts for about 7% of cancer deaths. The ACS data further shows that about 46,420 people (23,530 men and 22,890 women) will be diagnosed with pancreatic cancer and about 39,590 people (20,170 men and 19,420 women) are expected to die as a result of the disease. [1]

Ovarian cancer risk
Ovarian cancer ranks fifth in cancer deaths among women, accounting for more deaths than any other cancer of the female reproductive system. A woman’s risk of getting ovarian cancer during her lifetime is about 1 in 73. Her lifetime chance of dying from ovarian cancer is about 1 in 100. [2]

Lonza
ADC Bio
MabPlex
 

Ovarian cancer mainly develops in older women. About half of the women who are diagnosed with ovarian cancer are 63 years or older. The disease is more common in white women than African-American women. The ACS expected that in 2014 about 21,980 women will receive a new diagnosis of ovarian cancer and an estimated 14,270 women will die from the disease.[2]

Colin Weekes
Colin Weekes

New drug candidate
The investigational drug DMOT4039A* is a combination of a chemotherapeutic agent with an antibody, technically called an antibody-drug conjugate or ADC. Just as cells of the immune system use antibodies to recognize pathogens, researchers in this study designed antibodies to recognize a protein over-expressed by these cancer cells. In this case, the protein is mesothelin. The engineered antibodies attach to mesothelin on the cells, and bring along their chemotherapeutic cargo directly to the mesothelin-rich cancer cells.[3]

“The deal is that the cell has to express the protein. The more it’s expressed only on cancer cells, the more targeted the therapy becomes,” explained Colin Weekes, MD, PhD, (Photo) CU Cancer Center investigator and assistant professor in the Division of Oncology at the CU School of Medicine.

From T-DM1 to Kadcyla
A similar antibody-drug conjugate approach is used by the breast cancer agent T-DM1 (Trastuzumab emtansine, Kadcyla®, Genentech/Roche), which attaches chemotherapy to an antibody that seeks the HER2 protein in HER2+ breast cancers.

The current phase I clinical trial, sponsored by the agent’s manufacturer, Genentech, was carried out at the University of Colorado Cancer Center, in the Netherlands, and at three Mayo Clinic locations in Scottsdale, Arizona, Jacksonville, Florida, and Rochester Minnesota. The study enrolled 71 patients, with no dose-limiting toxicities seen at maximum study dosage.[4]

Does it make sense?
“For tumors that overexpress a specific protein ADCs may make sense,” Weekes says. “But for other tumors with specific genetic abnormality that doesn’t result in overexpression of a protein, it won’t make sense.” Weekes further explained that the creation of antibody-drug conjugates requires technically sophisticated procedures to create “linker constructs” between drug and antibody. “You can’t just put any drug on these things,” Weekes says.

But in tumors that overexpress certain proteins, or perhaps in tumors that can be made to overexpress certain proteins, the strategy of targeting cancers with antibody-drug conjugates remains promising. The agent DMOT4039A is now being evaluated for further human clinical trials.


* DMOT4039A  (also known as RG-7600) is an Antibody-drug Conjugate in which a humanized IgG1 anti-MSLN monoclonal antibody is conjugated to the cytotoxic agent monomethyl auristatin E (MMAE) via a protease-cleavable peptide linker.