The activated conformation of integrin β₇ is a novel multiple myeloma-specific target for CAR T cell therapy

Area of Science:

• Immunology
• Oncology
• Cell Biology

Background:

• Cancer-specific cell-surface antigens are key targets for immunotherapy.
• Integrins, cell surface receptors, are potential targets, but identifying specific conformations is challenging.

Purpose of the Study:

• To identify and characterize a specific therapeutic target for multiple myeloma (MM) using monoclonal antibodies (mAbs).
• To evaluate the potential of targeting a specific integrin conformation for MM immunotherapy.

Main Methods:

• Screened over 10,000 anti-MM mAb clones to identify MMG49.
• Characterized MMG49 binding to integrin β7 in different conformations.
• Developed and tested MMG49-derived chimeric antigen receptor (CAR) T cells in vitro.

Main Results:

• MMG49 specifically recognizes a subset of integrin β7 molecules in their active conformation.
• The MMG49 epitope is exposed only in the active integrin β7 conformation, not in resting states.
• MMG49 CAR T cells demonstrated anti-MM activity without affecting normal hematopoietic cells.

Conclusions:

• The active conformation of integrin β7 is a viable and specific target for multiple myeloma immunotherapy.
• MMG49 CAR T cell therapy presents a promising strategy for treating MM with high specificity.