Development of conformation-selective antibodies targeting human SLC15A4

Area of Science:

• Immunology
• Molecular Biology
• Biochemistry

Background:

• Solute carrier family 15 member 4 (SLC15A4) is an endolysosomal transporter vital for Toll-like receptor (TLR) 7/8/9 immune signaling.
• SLC15A4 forms a complex with the adaptor TASL in a conformation-dependent manner, influencing immune responses.
• Targeting SLC15A4 holds therapeutic potential for infections, cancers, and autoimmune disorders, but developing specific antibodies is challenging.

Purpose of the Study:

• To identify and characterize conformation-selective antibodies against human SLC15A4 (hSLC15A4).
• To investigate the functional impact of these antibodies on hSLC15A4 conformation and TASL binding.
• To explore the potential of these antibodies as therapeutic agents and research tools.

Main Methods:

• Systematic screening and validation of antibody clones targeting hSLC15A4.
• Characterization of antibody binding to distinct hSLC15A4 conformational states.
• Assessment of antibody effects on TASL binding and TLR pathway modulation.

Main Results:

• Identification of two conformation-selective antibodies, clones 107 and 235, targeting the endolysosomal lumen of hSLC15A4.
• Clone 107 binds to a TASL binding-incompetent, luminal-open state of hSLC15A4.
• Clone 235 stabilizes a TASL binding-competent, cytoplasmic-open state of hSLC15A4.

Conclusions:

• The study successfully generated antibodies recognizing distinct conformations of hSLC15A4.
• These antibodies can differentially modulate hSLC15A4 conformation and TASL interaction.
• The developed antibodies represent valuable tools for advancing research and developing targeted therapies for immune-related diseases.