There are approximately 6,000 membrane proteins within the human proteome, and a substantial portion of them remains unexplored as potential targets for cancer diagnosis and treatment. Monoclonal antibodies play a pivotal role in identifying cell surface targets in tumors and find utility both as therapeutic agents and in diagnostic validation. Notably, among protein drug targets, 60% are membrane proteins, encompassing diverse categories such as GPCRs, ion channels, receptors, membrane-associated enzymes, solute carriers, and transporters.

Despite the considerable promise of antibodies in targeting membrane proteins for cancer diagnosis and treatment, several challenges persist. These include difficulties in accessing epitopes, which is reflected in the limited number of approved biologics for such targets. Additionally, progress in the development of transmembrane proteins as therapeutic agents is hindered by ongoing issues such as limited expression, in vitro insolubility, unstable purification processes, and the complexities of maintaining their native conformation.

GenScript proposes the use of mRNA as a viable antigen format for antibody development targeting these membrane proteins. The following cases provide insight into our experiences with this approach, showcasing its potential in addressing the current obstacles in this field.

mRNA as Novel Immunization Strategy for Membrane Protein Targets

Immunogen format Weaknesses Strengths Recommended index
mRNA Instability of mRNA, mRNA delivery Direct translation of mRNA in the cytoplasm, spontaneous protein PTM in mammalian cells, natural conformation, no need for adjuvant ★★★★★
DNA low expression level since DNA must cross the nuclear membrane for transcription, high cost for DNA immunization
Protein High technical limitation of full length GPCRs expression and purification in vitro High immunogenicity ★★
Peptide Only recognize linear epitopes, not conformational epitopes, epitope omission Low synthesis cost ★★★★
VLP Non-specific antibody generation, little difference between positive and negative screening Higher abundance of target antigen compared with overexpressed cells ★★★
Overexpressed cell line Low immunogenicity due to the very low percentage of GPCR of interest on the entire membrane ★★
Nanodisc Low success rate of GPCRs assembly with MSPs and phospholipid to form Nanodisc Similar to natural cell membrane structure ★★★



Case Study

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