Taking it to the tumors
GHENT, BelgiumóLooking to deliver therapeutics right to tumors, Ablynx and Oslo, Norway-based Algeta ASA recently entered into a research collaborationóthe first between the two companiesóto evaluate a novel targeted thorium conjugate (TTC) based on combining Algeta's proprietary thorium-227 alpha- pharmaceutical payload with Nanobodies generated using Ablynx's proprietary technology platform.
Algeta has been evaluating the potential of alpha-particle emitting elements in the treatment of cancer because there is evidence that they can cause double-strand DNA breaks that trigger cell death in tumors while having very localized effects due to the very short range of the alpha particle. Thorium-227 is one such alpha-particle emitting element that Algeta is investigating, and the company's working theory is that by linking thorium-227 to cancer- targeting molecules, such as monoclonal antibodies, they can develop a pipeline of TTCs to effectively take down tumors.
Nanobodies are antibody-derived therapeutic proteins containing the unique structural and functional properties of naturally occurring heavy- chain antibodies. The Nanobody technology was originally developed following the discovery that camels and llamas possess fully functional antibodies that lack light chains.
"The goal is to establish if a Nanobody-Thorium 227 conjugate can be generated and whether the resulting conjugate can target a specific population of tumor cells and induce death in those cells," says Andreas Menrad, chief scientific officer of Ablynx. "We believe that the specific characteristics of the Nanobodiesósmall size, very stable and having potential for tumor-specific formattingócould make them ideal to deliver thorium-227 to the tumor. We believe that the Nanobodies' specific nature will provide advantages over other technologies. Following this initial phase, a broader collaboration could be established."
This is the fifth TTC program to be publicly disclosed by Algeta so far, and the Norwegian company is optimistic about the potential of such conjugates.
"Alpha-emitters do not need to be internalized to exert their clinical effect as they pass through the tumor cell wall and cause irreparable double-stranded DNA breaks in cells. This mechanism also suggests that targeted alpha emitters would not necessarily be affected by mutation and resistance mechanisms," explains Thomas Ramdahl, executive vice president and chief technology officer of Algeta. But he adds, "To reach the tumor cells, however, Thorium-227 needs to be linked to targeting molecules, such as monoclonal antibodies or Nanobodies as in this collaboration with Ablynx. Algeta has another TTC collaboration underway with Sanofi on an undisclosed target, and other TTC programs focused on HER2 for breast cancer, PDGFR for anti-angiogenesis and hematological cancers."
Under the terms of the collaboration, Ablynx will provide access to novel Nanobodies against a specific, undisclosed target, and Algeta will provide access to chelation and conjugation technologies, as well as to its alpha-emitter thorium-227. Both companies will contribute resources toward the collaboration, which is expected to last for as long as a year initially with the option for extension thereafter. No further terms have been disclosed.
Although he didn't note when talks between the two companies began, Menrad did tell ddn that Ablynx initiated discussions, "and Algeta was very receptive to the idea of a collaboration. This agreement was finalized very rapidly, which indicates the enthusiasm on both sides."
Algeta has already made significant progress on alpha-emitting pharmaceuticals, with its lead alpha-pharmaceutical, radium-223 dichloride (radium-223), having been the subject of a filing with European drug regulators in December 2012. Algeta made the filing for the treatment of advanced prostate cancer that has metastasized to the bones. Menrad notes, however, that "Radium-223 is different from thorium-227 in that it does not need to be linked to a targeting molecule to reach the tumor cells, as it self-targets to areas of high bone metabolism caused by the tumor by virtue of its chemical similarity to calcium."
For its part, Ablynx has some 25 programs in the pipeline and seven Nanobodies that have actually reached clinical development stage. Ablynx has ongoing research collaborations and significant partnerships with various big-name pharmaceutical companies, including Boehringer Ingelheim, Merck KGaA, Novartis and Merck & Co.