The design of ADCs, in theory, allows the agent to have a better efficacy to toxicity ratio than, for example, chemotherapy. “You can selectively deliver high doses of a toxic payload to the cancer cell while sparing the normal cells,” explained Aditya Bardia, MD, MPH, medical oncologist at Massachusetts General Hospital, Boston, Massachusetts, during an interview with Cancer Therapy Advisor.

However, unlike some targeted therapies that have the option of being orally administered, ADCs must be administered intravenously. “That could be a disadvantage from a patient perspective,” said Dr Bardia, who was also not involved in the study.

In the current study, researchers first confirmed the expression levels for the target antigen, finding it to be highly expressed on several solid tumors, including gastric, pancreatic, bladder, breast, and colon cancers, as well as some hematologic lymphomas, such as multiple myeloma and diffuse large B-cell lymphoma (DLBCL).

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In particular though, CD205 was highly expressed on pancreatic, bladder, and triple-negative breast cancers, with only low levels of expression on normal tissues, leading to further study of these 3 cancer types in mouse models.

A xenograft mouse model of pancreatic cancer with high expression of CD205 was treated with MEN1309/OBT076 and antitumor activity was seen, with half of the mice having complete regressions of the tumor.

In contrast, no antitumor activity was seen in a xenograft model of pancreatic cancer that had no CD205 expression. In a patient-derived xenograft model of pancreatic cancer with heterogeneous CD205 expression, exposure to MEN1309/OBT076 led to a more modest outcome: 1 of 6 mice had a complete response and 1 of 6 mice had a partial response.

In mouse models of bladder cancer and triple-negative breast cancer, MEN1309/OBT076 also showed antitumor activity.

And this antitumor activity in mouse models was observed independent of antigen expression levels, which Dr Bardia found “a bit surprising.” He speculated that this could be the result of a bystander effect, meaning that the agent could impact healthy cells that don’t express that antigen.

“While it’s good to have some bystander effect, a lot of bystander effect could also result in additional toxicity with this agent,” he said. For instance, given that the cytotoxic agent is DM4, the agent could lead to peripheral neuropathy in patients, he said.

Overall, if this agent is to be successful in pancreatic cancer, it will need to be able to penetrate the tumor stroma, which functions as a shield against anticancer drugs and is one reason why drug development for pancreatic cancer has had such limited success. “The best therapy in the world is not going to work if it doesn’t get to the cancer itself,” said Dr Smaglo.

Disclosures: Several study authors reported a working relationship with Menarini Group, the sponsor of the trial, or Oxford Biotherapeutics, a codeveloper of MEN1309/OBT076. For a full list of disclosures, please refer to the original paper.

References

  1. Merlino G, Fiascarelli A, Bigioni M, et al. MEN1309/OBT076, a first-in-class antibody-drug conjugate targeting CD205 in solid tumors. Mol Cancer Ther. 2019;18(9):1533-1543.
  2. O’Reilly EM, Oh DY, Dhani N, et al. Durvalumab with or without tremelimumab for patients with metastatic pancreatic ductal adenocarcinoma: a phase 2 randomized clinical trial [published online July 19, 2019]. JAMA Oncol. doi: 10.1001/jamaoncol.2019.1588