Presenting a talk on Ablynx’ Nanobodies®, a class of antibody-derived therapeutic proteins based on single-domain antibody fragments, Hilde Revets, Ph.D., senior research fellow, acknowledged that GPCR targets have been difficult to hit with monoclonal antibodies given certain intrinsic characteristics of both GPCRs and mAbs.
Nanobody therapeutic proteins are based on the smallest functional fragment (termed VHH) of naturally occurring heavy-chain antibodies. As Dr. Revets described, “the cloned and isolated VHH domain is a stable polypeptide harboring the full antigen-binding capacity of the original heavy-chain antibody. As a result of this small size and particular three-dimensional structure, Nanobodies have the potential to access uncommon epitopes on targets, as well as cavities within molecular targets hidden or shielded from the much larger conventional antibodies.”
Dr. Revets presented work on Ablynx’ oncology candidate targeting the CXCR4 GPCR, noting that the candidate is “unlikely to have the same side-effect profile” of other similar candidates being pursued in the marketplace. Nanobodies are thus not associated with the attrition rates common for small molecule drugs, given “technological and biophysical advantages that enable them to outperform conventional antibodies” in specific metrics.
“Our technology has allowed us to quickly move forward with a number of programs in cardiovascular disease, CNS, inflammation, musculoskeletal disorders, and oncology.” Currently, there are three Nanobodies in Phase II, two in Phase I, and this year, the company intends to bring three other programs to Phase I.
Aside from a seemingly robust R&D platform, Nanobodies are also permitting Ablynx to pursue different formulations. “Nanobodies are more resistant to extremes of pH and temperature and to attack by proteases than are mAbs. Nanobodies are also characterized by solubility, so we can formulate them at high concentrations.
“These characteristics together confer the possibility of alternative modes of delivery, such as pulmonary delivery via nebulizer, and we believe the technology is robust enough also to consider oral or topical applications,” Dr. Revets said. She also reported that Nanobodies can be produced at commercial efficiency in prokaryotic systems like E. coli, as well as in eukaryotic yeast expression systems, to reduce costs as well as time lines to the clinic.
As for all drug discovery and development efforts, the basics—which, again, for GPCRs can be particularly confounding—are essential. “There is no one general strategy to follow for GPCRs,” Dr. Revets asserted. “These receptors can vary widely in their activity, so it is crucial to have solid selection tools, screening assays, biological readout, and in vivo proof-of-concept models.”