Nanobodies for voltage-gated ion channels

GHENT, Belgium—Ablynx, a biopharmaceutical company engagedin the discovery and development of Nanobodies, a novel class of therapeuticproteins based on single-domain antibody fragments, announced last month thatit will partner with Merck & Co. Inc., through an unnamed subsidiary, todevelop and commercialize Nanobody candidates directed toward a voltage-gatedion channel, with the option to develop and commercialize a Nanobody to asecond target. Merck is known as MSD outside the United States and Canada.

Under the terms of the agreement, Merck gains exclusiveglobal rights to Nanobodies against the selected target, with an option forsimilar rights to a second target. Upon signing, Merck will pay Ablynx an $8.4million upfront payment and a $2.5 million fee for research funding. Inaddition, Ablynx will be eligible to receive up to $578 million in research,regulatory and commercial milestone payments associated with the progress ofmultiple candidates as well as tiered royalties on any products derived fromthe collaboration. Ablynx will be responsible for the discovery of Nanobodycandidates and Merck will be responsible for the research, development,manufacturing and commercialization of any Nanobody product resulting from thecollaboration.

Dr. Edwin Moses, chairman and CEO of Ablynx, notes that todate, monoclonal antibodies have demonstrated little success in ion channelapplications. The agreement with Merck reflects the potential power of theNanobody platform, he states.

"Due to the formatting flexibility of Nanobodies, we areable to combine antibody-like selectivity and multi-specificity in onemolecule, making them ideal candidates for ion channel modulators," he says.

Ablynx has already demonstrated modulation of ion channelactivity in electrophysiology assays and has identified functional Nanobodiesagainst both voltage-gated and ligand-gated ion channels. The company currentlyhas seven Nanobody programs at the clinical development stage. Nanobodies canbe generated to have either an agonistic (enhancing) or antagonistic (blocking)effect. The Ablynx platform provides the ability to design modular drugs basedon Nanobody building blocks combined with each other, with other proteindomains or with other molecules or drugs. These can combine more than onefunction in the final drug format.

Ablynx has combined Nanobodies in a wide range of formats,including unique multivalent (multiple Nanobodies with identical binding sitesfor the same antigen), biparatopic (two Nanobodies binding two differentepitopes on the same antigen), bispecific (Nanobodies binding to two differentantigens) and bifunctional molecules. These formats are easy to construct andthe modular proteins can often be expressed at high levels in bacteria oryeast, Ablynx states. As a result of this formatting flexibility, the range oftherapeutic applications for Nanobodies appears to be beyond that possible forconventional antibodies and antibody fragments such as blocking ion channels.

To block ion channels, a number of Nanobodies can be linkedtogether (e.g., trimeric structure =multispecific) and the nature of Nanobodies allows for selectivity (i.e., like conventional antibodies, Nanobodies are highlyselective toward a certain target; this is in contrast with small molecules,which are generally less specific when blocking a certain target and often haveunwanted side effects).

The importance of ion channels is underlined by theirinvolvement in a wide range of conditions including neurological disorders,hypertension, diabetes, cancer and arrhythmia. They represent highly valuabletherapeutic targets that are currently modulated by a range of small moleculedrugs. According to Ablynx's count, in 2011 the top 20 best-selling ion channeldrugs rang up sales of almost $14 billion. These include Lyrica and Norvasc(Pfizer), Lamictal (epilepsy) and Exforge (Novartis), an Ablynx spokespersonnotes, while adding that as of today there are no approved antibody-based drugsthat target ion channels.

Ablynx is pursuing Nanobody therapies for a range of serioushuman diseases, including inflammation, hematology, oncology and pulmonarydisease, and has about 25 programs in its pipeline. The company has ongoingresearch collaborations and significant partnerships with major pharmaceuticalcompanies, including Boehringer Ingelheim, Merck Serono and Novartis.