BioWorld Today Correspondent

The intellectual property surrounding a certain class of cancer molecules has found a new home in Tube Pharmaceuticals GmbH, a Vienna-based start-up, which recently closed a seed funding round of €1 million (US$1.4 million).

Formed in February, Tube is commercializing a natural products platform that has as its foundation the discovery of tubulysin molecules over a decade ago at the Helmholtz Center for Infection Research (Helmholtz-Zentrum für Infektionsforschung) in Braunschweig, Germany. Those molecules, and their synthetic derivatives, can be covalently conjugated to a wide variety of carrier molecules, and thereby offer the potential to target many types of cells and tissues.

Gerhard Höfle and colleagues at the center first reported on tubulysins in 2000 as cytostatic compounds isolated from the culture broth of strains of Archangium gephyra and Angiococcus disciformis, both members of a Gram negative, soil-dwelling group of bacteria known as myxobacteria.

Tubulysins are tetrapeptidic in structure, three of whose four amino acid residues are unusual. Their name hints at their activity: The compounds bind to tubulin, the basic building block of microtubules, which play a structural role in the cell's cytoskeleton and a functional role in mitosis. Tubulysin binding causes microtubules to depolymerize, leading to break-up of the cytoskeleton. "And this drives the cell into apoptosis," Tube CEO Wolfgang Richter told BioWorld Today.

The compounds and their synthetic analogues are highly potent, with activity in the nanomolar and subnanomolar range. Their tubulin-binding site overlaps with that of vincristine, an antitumor molecule first approved in the 1960s.

"The mechanism of action is similar, but vincristine has severe side effects," Richter said.

Tubulysins are also highly toxic, but Tube, in its drug development efforts, is masking their effects by covalently attaching the molecules to a cyclodextrin polymer via a cleavable linker. They spontaneously form nanoparticles during the manufacturing process, Richter said.

It aims to exploit the enhanced permeability and retention (EPR) effect that is observed in solid tumors, whereby large macromolecular complexes are taken up more readily by tumor cells than by normal healthy cells. The phenomenon is thought to arise from the aberrant development of new blood vessels within the developing tumor.

"The tumor vasculature is usually very leaky," Richter said. "The targeting comes from the EPR effect."

Although it has selected a lead molecule, Tube is still 18 to 24 months from starting clinical trials and the company has yet to finalize an initial indication.

"The tubulysins are very potent against most cancer cell lines, so it's not clear yet. That has to be decided," Richter said.

In addition to the seed round, Tube is already pulling in cash from existing partners, and several more deals are in the offing.

Richter was only able to disclose one licensee, however, Endocyte Inc., of West Lafayette, Ind. The latter firm's preclinical breast cancer drug EC0531 consists of a tubulysin B molecule conjugated to folic acid.

The Tube program originally resided with Insert Therapeutics Inc., a Pasadena, Calif.-based majority-owned subsidiary of nanomedicine specialist Arrowhead Research Corp. Tube itself has gained rights to the cyclodextrin nanoparticle technology from the same source.