A Gentler, More Effective Cancer Treatment?

During cancer treatment with classical chemotherapy severe side effects can occur. To reduce these, the FMP collaborates with the Munich-based company Tubulis to develop a new generation of antibody-drug conjugates (ADCs). The strength of ADCs lies in the combination of the antibody’s targeting accuracy with which it captures the tumor cell and the high potency of the conjugated drug that is able to efficiently kill the targeted cell. To achieve this, the antibody recognizes specific surface proteins on cancer cells and enters the tumor cell directly with the drug. This allows the transport of highly potent cytotoxins directly into the cancer cells, while sparing healthy cells and organs.

To effectively kill the targeted cancer cells, each antibody must deliver as many active ingredients as possible into the cell. Therefore, one of the goals of developing new antibody-drug conjugates is to increase the number of drugs per antibody. However, a challenge related to this is that commonly used highly potent drugs that are well suited for antibody-drug conjugates are often molecules with large hydrophobic (water-repellent) structures. These structures, which are poorly soluble in aqueous systems, can lead to aggregation of the antibody-drug conjugates in the blood (i.e., sticking together) wich leads to rapid clearance from the circulation and thus a loss of efficacy, as the ADC cannot reache its target – the cancer tumor – anymore.

In our current publication, we present a chemical solution for linking the very hydrophobic drug structures to the antibody while incorporating a hydrophilic (i.e., water-loving) "floatation aid" based on polyethylene glycol (PEG) chains. In this way, the conjugates are more water-soluble and will circulate longer in the body to reach the tumor and efficiently kill its cells.

With help from Dr. Barth van Rossum, we designed the front cover for the publication, which includes a cartoon illustrating the advantages of our new technology that enables the construction of ADCs with up to 8 drugs per antibody. The cartoon shows a water slide named "PK-Slide” (i.e., pharmacokinetics slide), which represents the path through the bloodstream in the human body that the ADCs must overcome to reach the tumor. Thanks to the hydrophilic PEG chains, represented here by the swim rings, our ADCs slide smoothly into the tumor that sits in the water basin. The conjugates without swim rings, which get stuck on the slide and do not reach the pool, represent ADCs with inappropriate hydrophobic structures that aggregate in the body and thus show low efficiency in tumor targeting.

In the future, this new technology will help to construct and develop new ADCs that enable efficient and more tolerable cancer therapy.

Author German Text: Philipp Ochtrop, Translation Michel Otayek

Philipp Ochtrop was a Postdoc in Christian Hackenberger’s research unit at the FMP and is now a senior scientist in the FMP and LMU spin-off Tubulis GmbH.

Publication:
Compact hydrophilic electrophiles enable highly efficacious high DAR ADCs with excellent in vivo PK profile. P. Ochtrop, J. Jahzerah, P. Machui, I. Mai, D. Schumacher, J. Helma, M.-A. Kasper, C.P.R. Hackenberger. Chemical Science 2023, DOI: 10.1039/D2SC05678J