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Groundbreaking innovations by researchers at the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) provided the basis for the development of an antibody-drug conjugate (ADC) by the company Tubulis, which is now being used in a Phase I/IIa trial in tumour patients. Thanks to an innovative linker chemistry known as P5 technology, the active substance is delivered safely to its target and can also develop its effect over a long period of time. The beginning of a clinical trial just a few years after the discovery of the P5 technology is a major achievement that demonstrates the potential for applied research in an academic research institute.
To combat cancer, there is a need for active substances that specifically target cancerous cells and destroy them without damaging the surrounding healthy tissue or other bodily functions, as is often the case with conventional chemotherapies. So-called antibody-drug conjugates (ADCs) can specifically attack tumour cells by delivering toxic substances directly to the tumour, bypassing healthy cells. ADCs have been used for many years but tend to have only limited efficacy. This is mainly due to the fact that active substances may fall off beforehand and fail to reach the targeted tumour cell. A team led by Prof. Hackenberger at the FMP has addressed this problem and developed the novel P5 technology, one of the central components of the ADC developed by Tubulis. For nearly 20 years, Hackenberger has been researching chemical processes that can be used to specifically functionalise proteins and antibodies. With his team at the FMP, he discovered reactions that provide stable conjugates of active substances and antibodies with excellent solubility properties.
"The P5 technology can be used to produce highly stable, soluble antibody conjugates that are ideally suited as potential therapeutics," says Marc-André Kasper, who developed this reaction in his doctoral thesis at the FMP and is now head of chemical research at Tubulis. "The antibody on which the active substance sits acts as a kind of sniffer dog that finds the cancer cell." Another advantage of the new technology is its long-lasting effectiveness. Preclinical studies have shown complete, lasting regression of the tumour even after a single dose. Earlier ADCs, by contrast, often triggered undesirable side effects because the active substance fell off the antibody before it could reach the target cell.
"Our lab, and I in particular, are very proud that our technology, developed from basic research, has made an important contribution to an ADC candidate that is now being tested in cancer patients and could help fight their tumour disease effectively," said Prof. Hackenberger, head of the research group at the FMP that provided the basis for the P5 technology. "This technology offers great potential for the development of novel ADC product candidates, and I am excited by the progress the Tubulis team has made over the last few years toward this major milestone."
The company Tubulis, a joint spin-off of the FMP and the Ludwig-Maximilians-Universität (LMU) Munich, has proceeded to use the P5 technology to couple a Topoisomerase 1 agent with a specific antibody for ovarian cancer (ovarian cancer) and lung cancer. Both types of tumour are associated with a high mortality rate. The result is ADC TUB-040, which the company is now testing in a Phase I/IIa trial in cancer patients in the USA, Germany, Spain, and the United Kingdom.
In the near future, another ADC molecule (TUB-030) will also be tested in Phase I/IIa trials. Tubulis will also utilise the technology in further ADC product candidates and their partnerships while the FMP continues to research the technology and extend it to other areas of research.
Prof. Dr. Christian Hackenberger
Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)
Leibniz-Humboldt-Professur für Chemische Biologie, Humboldt-Universität zu Berlin
Phone +49 (0)30 / 94793 - 181
E-Mail hackenbe@fmp-berlin.de
Web fmp-berlin.de/hackenbe
Twitter: @PhosphorusFive
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P5 labeling technology as a molecular glue to construct antibody-drug-conjugates (ADCs) for clinical ...
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