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Nanobodies for voltage-gated ion channels
GHENT, BelgiumóAblynx, a biopharmaceutical company engaged in the discovery and development of Nanobodies, a novel class of therapeutic proteins based on single-domain antibody fragments, announced last month that it will partner with Merck & Co. Inc., through an unnamed subsidiary, to develop and commercialize Nanobody candidates directed toward a voltage-gated ion channel, with the option to develop and commercialize a Nanobody to a second target. Merck is known as MSD outside the United States and Canada.
Under the terms of the agreement, Merck gains exclusive global rights to Nanobodies against the selected target, with an option for similar rights to a second target. Upon signing, Merck will pay Ablynx an $8.4 million upfront payment and a $2.5 million fee for research funding. In addition, Ablynx will be eligible to receive up to $578 million in research, regulatory and commercial milestone payments associated with the progress of multiple candidates as well as tiered royalties on any products derived from the collaboration. Ablynx will be responsible for the discovery of Nanobody candidates and Merck will be responsible for the research, development, manufacturing and commercialization of any Nanobody product resulting from the collaboration.
Dr. Edwin Moses, chairman and CEO of Ablynx, notes that to date, monoclonal antibodies have demonstrated little success in ion channel applications. The agreement with Merck reflects the potential power of the Nanobody platform, he states.
"Due to the formatting flexibility of Nanobodies, we are able to combine antibody-like selectivity and multi-specificity in one molecule, making them ideal candidates for ion channel modulators," he says.
Ablynx has already demonstrated modulation of ion channel activity in electrophysiology assays and has identified functional Nanobodies against both voltage-gated and ligand-gated ion channels. The company currently has seven Nanobody programs at the clinical development stage. Nanobodies can be generated to have either an agonistic (enhancing) or antagonistic (blocking) effect. The Ablynx platform provides the ability to design modular drugs based on Nanobody building blocks combined with each other, with other protein domains or with other molecules or drugs. These can combine more than one function in the final drug format.
Ablynx has combined Nanobodies in a wide range of formats, including unique multivalent (multiple Nanobodies with identical binding sites for the same antigen), biparatopic (two Nanobodies binding two different epitopes on the same antigen), bispecific (Nanobodies binding to two different antigens) and bifunctional molecules. These formats are easy to construct and the modular proteins can often be expressed at high levels in bacteria or yeast, Ablynx states. As a result of this formatting flexibility, the range of therapeutic applications for Nanobodies appears to be beyond that possible for conventional antibodies and antibody fragments such as blocking ion channels.
To block ion channels, a number of Nanobodies can be linked together (e.g., trimeric structure = multispecific) and the nature of Nanobodies allows for selectivity (i.e., like conventional antibodies, Nanobodies are highly selective toward a certain target; this is in contrast with small molecules, which are generally less specific when blocking a certain target and often have unwanted side effects).
The importance of ion channels is underlined by their involvement in a wide range of conditions including neurological disorders, hypertension, diabetes, cancer and arrhythmia. They represent highly valuable therapeutic targets that are currently modulated by a range of small molecule drugs. According to Ablynx's count, in 2011 the top 20 best-selling ion channel drugs rang up sales of almost $14 billion. These include Lyrica and Norvasc (Pfizer), Lamictal (epilepsy) and Exforge (Novartis), an Ablynx spokesperson notes, while adding that as of today there are no approved antibody-based drugs that target ion channels.
Ablynx is pursuing Nanobody therapies for a range of serious human diseases, including inflammation, hematology, oncology and pulmonary disease, and has about 25 programs in its pipeline. The company has ongoing research collaborations and significant partnerships with major pharmaceutical companies, including Boehringer Ingelheim, Merck Serono and Novartis.