Ablynx' signature product is the Nanobody®, which is based on the heavy chain antibodies produced by members of the camel family. It is the smallest antibody unit that has full functional binding ability, according to Willem van de Velde, Ph.D., a scientist team leader, and for this reason is of great interest in the area of antibody engineering.
One of the notable achievements of the Ablynx program has been the fast tracking of Nanobodies directed against cancer target CXCR4, Dr. van de Velde said. This cell surface molecule plays a role in immune signaling and its overexpression has been correlated with poor response in various types of cancer.
Several years ago Ablynx developed a number of formatted, functional Nanobodies, including potent antagonists of CXCR4. One of these, ALX-0651, has moved through clinical testing in non-Hodgkin lymphoma and multiple myeloma, and an IND filing with the FDA is expected during the course of 2011.
Dr. van de Velde reported that Nanobodies have many advantages over conventional monoclonal antibodies, including the fact that the molecules are more physically stable and characterized by a lower propensity for aggregation.
Using Aggresolve™ software designed by Lonza, Dr. van de Velde and his colleagues were able to select the amino acid sequences for the Nanobodies that showed the least chance of misfolding and forming aggregates. The program can suggest sequence changes to reduce aggregation and stabilize engineered proteins. It can be used to either engineer sequences de novo or correct an already generated framework.
Nanobodies have other auspicious properties including resistance to pH extremes, high temperatures, and proteases. This is not surprising given the fact that they are much smaller than traditional antibody molecules. Because of their small size, manufacturing costs are also reportedly less, typically one-third the cost of conventional antibody production.
When Dr. van de Velde and his co-workers tested a number of antibodies, they found a range of production over six orders of magnitude. Pichia is clearly preferable to E. coli as a host, in that a typical Pichia production run yields greater than 95% pure Nanobody.
Considering the overall process, Dr. van de Velde argued that Nanobodies offer a considerable range of advantages over other antibody options. “Host creation is less time consuming, growth of cell lines uses no animal products, Nanobodies are secreted and there is no viral clearance required, and, finally, Nanobodies show long-term stability and are homogeneous and simple molecules.”