Targeted Antibody Drugs Ineffective in Mesothelioma, Immuno-imaging Shows

Targeted Antibody Drugs Ineffective in Mesothelioma, Immuno-imaging Shows

Using immuno-imaging to assess whether a tumor is likely to react to therapies targeting mesothelin, which is over-expressed in certain cancers, researchers demonstrated that a cancer drug linked to a mesothelin antibody is not likely to be effective in mesothelioma.

The study, “Preclinical Efficacy of an Antibody-Drug Conjugate Targeting Mesothelin Correlates with Quantitative 89Zr-ImmunoPET,” was published in the journal Molecular Cancer Therapeutics.

Connecting a cancer drug to an antibody targeting a tumor surface molecule is a technique to improve treatment effectiveness. This approach may also lower side effects because other organs are spared the often-toxic treatment effects.

But these antibody-drug conjugates often bind molecules that are not necessary for the cancer. If that’s the case, it’s possible that a tumor will do away with such factors as it progresses or spreads. When this happens, therapies using antibody-drug conjugates lose their effect. As a result, there is a need to non-invasively and repeatedly monitor the presence of such molecules on the tumor during treatment.

Mesothelin is present on the surface of mesothelioma and other types of cancers, such as ovarian or pancreatic cancers, and researchers have developed an antibody-drug conjugate to be used in these tumors. The compound, called DMOT4039A, links the anti-cancer agent monomethyl auristatin E (MMAE) to an antibody targeting mesothelin. It is currently in early clinical trials for ovary and pancreatic cancers.

Researchers at California-based Genentech and the University of Groningen in the Netherlands evaluated if a method called immuno-PET could be used to see how much of the drug actually entered tumor cells, and if the uptake was linked to drug effect. The method uses a weakly radioactive tracer molecule that is bound to the same anti-mesothelin antibody used in DMOT4039A.

The research team studied mice carrying human mesothelioma, pancreatic, or ovarian tumors. Among these three, they noted that mesothelioma had the lowest amount of mesothelin. It also did not respond to treatment with DMOT4039A.

But even with the low expression levels of mesothelin at the surface of mesothelioma cells, the researchers expected to see a small affect from DMOT4039. But immuno-imaging showed that few or none of the antibodies bound to the protein, explaining the lack of treatment effect of DMOT4039A.

For some of the other tumors, however, the researchers observed reduced cancer growth following treatment with the agent. This was linked to higher uptake of the DMOT4039A drug as assessed through immuno-PET, suggesting that this methodology is useful in determining whether an antibody-drug conjugate will be effective in treating certain types of tumors.

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