Taking it to the tumors

Algeta has been evaluating thepotential of alpha-particle emitting elements in the treatment ofcancer because there is evidence that they can cause double-strandDNA breaks that trigger cell death in tumors while having verylocalized effects due to the very short range of the alpha particle.Thorium-227 is one such alpha-particle emitting element that Algetais investigating, and the company's working theory is that bylinking thorium-227 to cancer-targeting molecules, such as monoclonalantibodies, they can develop a pipeline of TTCs to effectively takedown tumors.

Nanobodies are antibody-derivedtherapeutic proteins containing the unique structural and functionalproperties of naturally occurring heavy-chain antibodies. TheNanobody technology was originally developed following the discoverythat camels and llamas possess fully functional antibodies that lacklight chains.

"The goal is to establish if aNanobody-Thorium 227 conjugate can be generated and whether theresulting conjugate can target a specific population of tumor cellsand induce death in those cells," says Andreas Menrad, chiefscientific officer of Ablynx. "We believe that the specificcharacteristics of the Nanobodies—small size, very stable andhaving potential for tumor-specific formatting—could make themideal to deliver thorium-227 to the tumor. We believe that theNanobodies' specific nature will provide advantages over othertechnologies. Following this initial phase, a broader collaborationcould be established."

This is the fifth TTC program to bepublicly disclosed by Algeta so far, and the Norwegian company isoptimistic about the potential of such conjugates.

"Alpha-emitters do not need to beinternalized to exert their clinical effect as they pass through thetumor cell wall and cause irreparable double-stranded DNA breaks incells. This mechanism also suggests that targeted alpha emitterswould not necessarily be affected by mutation and resistancemechanisms," explains Thomas Ramdahl, executive vice president andchief technology officer of Algeta. But he adds, "To reach thetumor cells, however, Thorium-227 needs to be linked to targetingmolecules, such as monoclonal antibodies or Nanobodies as in thiscollaboration with Ablynx. Algeta has another TTC collaborationunderway with Sanofi on an undisclosed target, and other TTC programsfocused on HER2 for breast cancer, PDGFR for anti-angiogenesis andhematological 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 andconjugation technologies, as well as to its alpha-emitterthorium-227. Both companies will contribute resources toward thecollaboration, which is expected to last for as long as a yearinitially with the option for extension thereafter. No further termshave been disclosed.

Although he didn't note when talksbetween the two companies began, Menrad did tell ddn thatAblynx initiated discussions, "and Algeta was very receptive to theidea of a collaboration. This agreement was finalized very rapidly,which indicates the enthusiasm on both sides."

Algeta has already made significantprogress on alpha-emitting pharmaceuticals, with its leadalpha-pharmaceutical, radium-223 dichloride (radium-223), having beenthe subject of a filing with European drug regulators in December2012. Algeta made the filing for the treatment of advanced prostatecancer that has metastasized to the bones. Menrad notes, however,that "Radium-223 is different from thorium-227 in that it does notneed to be linked to a targeting molecule to reach the tumor cells,as it self-targets to areas of high bone metabolism caused by thetumor by virtue of its chemical similarity to calcium."

For its part, Ablynx has some 25programs in the pipeline and seven Nanobodies that have actuallyreached clinical development stage. Ablynx has ongoing researchcollaborations and significant partnerships with various big-namepharmaceutical companies, including Boehringer Ingelheim, Merck KGaA,Novartis and Merck & Co.