Flexible, stable: Against cancer

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  • Published: Nov 1, 2018
  • Author: David Bradley
  • Channels: NMR Knowledge Base
thumbnail image: Flexible, stable: Against cancer

Therapeutic link

Antibody–Drug Conjugates with Pyrrole-Based KSP Inhibitors as the Payload Class Linking therapeutically active molecules to specific antibodies can help to pilot them to their designated targets and minimize side effects—especially when treating tumors. In the journal Angewandte Chemie, scientists have now described novel conjugates made from antibodies and a kinesin spindle protein inhibitor. Wiley-VCH

Various techniques have been used in studies that show how linking therapeutically active molecules to specific antibodies can help them target disease sites, specifically in cancer, and so minimize side effects.

Hans Georg Lerchen, Beatrix Stelte-Ludwig, Sarah Johannes, Yolanda Cancho-Grande, Christoph Mahlert, Simone Greven, Carsten Terjung of Bayer AG R&D Pharmaceuticals in Wuppertal, Sven Wittrock, Annette Sommer, and Sandra Berndt of Bayer AG R&D Pharmaceuticals Berlin, Nils Griebenow Bayer AG Animal Health, Lead Discovery Monheim, Germany, and Anne-Sophie Rebstock Bayer AG Crop Science Lyon, in France, describe details in the journal Angewandte Chemie. The multi-centre Bayer team has developed novel conjugates made from antibodies and a kinesin spindle protein inhibitor. They explain that by changing the linker between the two components they can tune the anticancer activity of this cytostatic drug, pointing out that it is effective against a broad range of cancers but not without side effects.

Cancer chemotherapy conjugates

Chemotherapy against cancer is infamously potent in the sense that it can lead to complete remission in many cases but comes with some very unpleasant side effects. Cytostatic drugs in particular interfere with the regulation mechanisms of all cells in the body, leading to a range of side effects including hair loss, nausea, and immune system depression, which in turn makes the patient more susceptible to infection. This is a critical problem in the post-operative context and in the face of the rise of antibiotic resistance among many common and debilitating strains of bacteria. Pharmaceutical scientists always hope to develop treatments that minimize side effects and one common approach is to find the means to introduce the cytostatic drug directly into the tumour cells prior to the toxic, anticancer, effects being enabled in the compound.

One of the ways to achieve targeted and timed drug delivery is to attach the small drug molecule to an antibody protein to make a bulky conjugate. The bridge between the two, known as a linker, must hold the conjugate together for as long as it remains circulating in the blood until it reaches its target. Given that the antibody has been chosen so that it binds specifically and selectively to antigen binding sites on the targeted tumour cells this seems likely to be a successful approach. Docking of the antibody triggers uptake of the conjugate into the cancer cells. Once inside, the drug is released as tumour cell enzymes attempt to break down the "invader". Once released it has its lethal cytostatic effect on the tumour cell. Healthy cells by and large are not even touched by the conjugate and so never succumb to the drug, in theory.

Targeting tumours

The number of cytostatic drugs that have been successfully incorporated into such antibody conjugates has so far been rather limited. Lerchen and his colleagues, however, have now tried this with a cytotoxin that uses a different mechanism than classic cytostatic drugs for attacking the cell cycle. It is a novel pyrrole-based kinesin spindle protein (KSP) inhibitor. KSP plays a key role in centrosome separation during cell division. Blocking this step causes a strong antitumour effect. The team explains that even a very low dose of this inhibitor compound can be highly effective against numerous types of cancer cell in the laboratory and potentially in the clinic. They simply use a different antibody to target different types of tumour.

The researchers have now demonstrated that they could connect the inhibitor at a variety of attachment points using stable linkers to the antibody and so avoid premature splitting that might allow the drug to reach and harm healthy cells. By changing the linkers they can tune activity to specific clinical needs. Moreover, inhibitors that cannot be expelled from the tumour cells accumulate within, which lengthens the time they remain active against the cancer. Laboratory tests have already demonstrated great efficacy against various tumour models. Animal testing has shown complete

Related Links

Angew Chem Int Edn Engl 2018, online: "Antibody–Drug Conjugates with Pyrrole-Based KSP Inhibitors as the Payload Class "

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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