MFSD2A is a structurally complex lipid transporter that can modulate the permeability of the blood-brain barrier, allowing for the transport of drug therapeutics across this interface. Researchers at Harvard and Stanford Universities are studying this protein with the goal of modulating its function and allowing the passage of drugs through the blood-brain barrier. With the goal of obtaining an anti-MFSD2A antibody, the research teams approached Integral Molecular with this extremely challenging drug target.
Integral Molecular applied its MPS Antibody Discovery platform to isolate an anti-MFSD2A antibody. This platform is specially tailored to isolate antibodies against multipass membrane proteins. MFSD2A has a complex structure with 12 transmembrane domains. To generate a robust immune response in animals, Integral Molecular’s team incorporated MFSD2A into Lipoparticles (i.e. specialized virus-like particles) as a source of high-concentration, native antigen. These were used to immunize chickens to garner a robust immune response, as well as for phage panning to obtain antibodies that bound to the target.
Integral Molecular’s MPS platform successfully isolated antibodies against the complex MFSD2A transporter and provided valuable reagents to study the structure and function of this target. The research groups of Gu and Feng used the antibody scFv fragment as a tool to obtain a cryo-EM map of MFSD2A, the first for a eukaryotic lipid transporter within the MFS superfamily, providing them a better understanding of MFSD2A’s structure.The scFVs that were discovered enabled a functional study of MFSD2A and how it allows lipids to enter and exit through the transporter. Further functional and structural studies revealed pathologies associated with different mutations as well as insights into potential therapeutic applications. The antibody isolated using Integral Molecular’s MPS platform is featured in the article “Structure and mechanism of blood–brain-barrier lipid transporter MFSD2A” in the journal Nature (Feng et al., 2021).
Figure 9 (extended data) – The MFSD2A antibody fragment (scFv) bound to its target and enabled the first ever structural visualization of this complex 12-TM membrane protein.