Transmembrane proteins effector monoclonal antibodies

 

Transmembrane proteins are probably the most complex and challenging antigens to target with monoclonal antibodies. Indeed, despite their strong presence in the animal kingdom and their implications in many cellular mechanisms, they remain very difficult to access due to intrinsic properties.

Membrane receptors family

Among the membrane receptors, we can mention the:

·      G protein-coupled receptors (GPCRs),

·      Ion channels,

·      Transporters,

·      Proteins of the viral envelope,

·      Receptor tyrosine kinases (RTKs),

·      Immunoglobulin superfamily (IgSF).

 


Challenges of transmembrane antigens

Membrane receptors present the following challenges:

  • Low exposure of epitopic regions,
  • Structurally complex antigens with many loops, multiple areas of interaction with the ligand and highly dependent on the direct environment since transmembrane proteins are embedded in the lipid bilayer of membranes,
  • Low immunogenicity when injected into animals,
  • Traditionally low expressed, and toxic when over-expressed
  • Highly conserved throughout the animal kingdom.

 


Technical solutions for monoclonal antibody generation against membrane targets

 

Several companies have developed expensive CHO and HEK cell lines expressing different GPCRs, but generating many non-specific monoclonal antibodies and causing major problems during the screening phase.

 

SYnAbs has developed its own vector SYnDNA allowing the expression of a GPCR on a rat or mouse cell lines (SYnCell) for both DNA immunization and whole-cell autologous immunization in rat-LOU (SYnAbs proprietary species) and mice species. The application of such technologies have lead to the generation of the anti-CD2 rat monoclonal Siplizumab (MEDI-507), licensed to MedImmune.

 

In parallel, SYnAbs has developed proprietary technologies to specifically modify residues on peptide sequences involved in ligand interaction. Success on this particular approach have been proven for the generation of mouse therapeutic anti-GPCR.