Switchable antibodies for cancer treatment

Antibodies have been used for decades, in particular in the treatment of numerous serious diseases. As recently as May 2021, the US Food and Drug Administration approved the hundredth antibody drug for clinical use.

Tailor-made antibodies are currently a great hope in the treatment of tumours. They specifically identify tumour cells and use them to recruit defence cells of the immune system that are able to detect and destroy tumour cells. These immune cells carry so-called Fc-gamma receptors on their surface that they use to identify therapeutic antibodies that are bound to the tumour cells. “However, this receptor-mediated interaction can also lead to unwanted side effects of the antibody's active ingredient and trigger an unwanted immune reaction in healthy tissue,” explains Professor Harald Kolmar of the Applied Biochemistry working group at the Department of Chemistry, Technical University of Darmstadt. “The aim of our work was to find a way to temporarily block the immune stabilisation of the antibody and only activate it directly on the tumour. This novel technology is based on the targeted blockage of the antibody with a protein that sits on the antibody like a lid, which prevents it from interacting with the immune cells. Enzymes produced by the tumour cells can then cleave the protein lid and reactivate the antibody.”

Above all, the principle should be suitable for general use and for use, in the same way, on most therapeutic antibodies in cancer treatment. In order to illustrate that this is possible, PhD student Adrian Elter applied the concept to two different therapeutic antibodies, that are approved for the treatment of breast cancer and leukaemia, respectively. “Using immune cells from blood donors, we were able to demonstrate that in both cases, the antibody is only activated after cleavage by the enzymes associated with the tumour, which means that a controllable drug with potentially reduced side effects is a possibility,” Elter summarises the results of his doctoral thesis.

The results of the strategic cooperation between the Technical University of Darmstadt and Merck have been published in the journal “Frontiers in Immunology”.

The idea for the project goes back to the “Merck Innovation Cup”, for which students from all over the world are invited to a summer camp at Merck and develop their own ideas for a complete innovative project plan under the guidance of experienced Merck researchers.

“We are delighted with the success of the ideas developed at the Merck Innovation Cup, which we have already been able to validate with great success several times in cooperation with Professor Kolmar of the TU Darmstadt,” says Ulrich Betz, Vice President Innovation at Merck.

WG Applied Biochemistry/sip