Flexible, Stable, and Potent Against Cancer

  • ChemPubSoc Europe Logo
  • Author: Angewandte Chemie International Edition
  • Published Date: 30 October 2018
  • Source / Publisher: Angewandte Chemie International Edition/Wiley-VCH
  • Copyright: Wiley-VCH Verlag GmbH & Co. KGaA
thumbnail image: Flexible, Stable, and Potent Against Cancer

New Payload Class in Antibody–Drug Conjugates

Linking therapeutically active molecules to specific antibodies can help to pilot them to their designated targets and minimize side effects—especially when treating tumors. Hans-Georg Lerchen, Bayer AG R&D Pharmaceuticals, Wuppertal, Germany, and colleagues have described novel conjugates made from antibodies and a kinesin spindle protein inhibitor. Changing the linker between the two components allows for tuning the activity of this cytostatic drug, which is effective against a broad range of cancers.

Medications need to be highly effective, but relatively free of side effects. This is particularly important in cancer treatment, because cytostatic drugs interfere with the regulation mechanisms of all cells in the body, causing symptoms like impairment of immune defenses, hair loss, and nausea. Treatments, therefore, aim to introduce cytostatic drugs directly into tumor cells before triggering their toxic effect.

One of the ways to achieve this is to attach such small drug molecules to an antibody, creating a conjugate. The bridging component, called the linker, must hold the conjugate together for as long as it circulates in the blood. The antibody binds specifically to binding sites (antigens) that are especially numerous on the surfaces of targeted tumor cells. The docking of the antibody triggers uptake of the conjugate inside the cancer cells. There, the drug is released by enzymes to carry out its destructive task specifically on the cancer cell. Healthy cells remain largely unharmed.

Kinesin Spindle Protein Inhibitor

The number of cytostatic drugs that have been successfully incorporated into such antibody conjugates has been limited so far. The team has found 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 antitumor effect. Even very low doses of the inhibitor were highly effective against a broad range of cancer cell lines. The researchers have demonstrated that this technique can be used to make highly active antibody conjugates. The use of different antibodies allows them to target a variety of tumor types.

The team was able to connect the inhibitor to the antibody at a variety of attachment points using stable linkers, thereby hindering premature splitting. Only inside the tumor cells are the conjugates metabolized by enzymes, releasing the inhibitor. Changing the linker allows for the controlled variation of the resulting inhibitor molecules, so that their activity can be tailored to specific requirements. Inhibitors that cannot be expelled from the cells accumulate in the tumor cells, lengthening their active period. Inhibitors that can be expelled may enter neighboring tumor cells, which is especially useful in the treatment of tumors that contain a heterogenic pattern of antibody binding sites.

The new conjugates are highly effective in vitro and were shown to be effective in tumor models for various indications in vivo. In experiments with mice, they led to complete remission of a human bladder tumor model—with minimal side effects.


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