Mechanism of Action
Oncohist (recombinant human Histone H 1.3) is a novel biotherapeutic molecule for the treatment of tumours, in particular, haematologic malignancies. It is being jointly developed by Xenetic and our partner, SymbioTec GmbH. Extensive data has shown that histone H1 molecules attack the membrane of tumor cells selectively. They acheive this by recognising differences in membrane structure between tumor cells and their healthy counterparts. The phospholipid composition of cancer cell membranes is deregulated: phosphatidyl serine (PS) from the inside of the membrane bi-layer moves into the outer layer of the cell membrane. The extremely high affinity of PS and histone H1 for each other leads to the formation of PS-H1 aggregates and, in a second step, the formation of superaggregates which form channels in the membrane. These channels enable the uncontrolled mass exchange of cellular contents between the cell and the outside, leading to the rapid death of the cell (apoptosis followed by necrosis).
In addition, as a consequence of the cancer cell’s more general deregulation, core histones from the cell nucleus appear on the outside of the cell membrane, often as nucleosomes. Histone H1 applied from the outside leads to the formation of superaggregates and ruptures in the membranes.
Manufacturing
A complete manufacturing process for Oncohist, comprising a fermentation process in E. coli as well as a downstream purification process including analytics and quality control has been successfully established. A large-scale manufacturing process for the production of cGMP-grade material for clinical trials has been developed.
Preclinical Testing
The safety of Oncohist was effectively proven in several toxicology studies. Toxicokinetic studies demonstrate that Oncohist is widely distributed in the body, including bone marrow, and has a favourable half-life. Accumulation of Oncohist in any organ or tissue was not observed.
Clinical Testing
A pilot clinical study (phase IIa) with AML (Acute Myeloid Leukaemia) patients has been performed at the Saarland University Hospital at Homburg/Saar. The primary objective was demonstration of the safety of Oncohist. The data showed that Oncohist is well tolerated by patients and apparently safe. Proof of efficacy will be the objective of a subsequent Phase IIb study, however, encouragingly first signs of clinical effects were already seen among 22 patients, including:
- 3 partial remissions
- increase of thrombocytes and normalization of leukocytes
- stabilisation for several months in two patients
The clinical progression of Oncohist is continuing.
