HEV-Targeted Antibody-Drug Conjugate Promotes Long-Term Cardiac Allograft Acceptance

Area of Science:

• Immunology
• Transplantation Biology
• Glycobiology

Background:

• Naive T cell entry into lymph nodes (LNs) is vital for heart transplant acceptance.
• High endothelial venules (HEVs) in LNs facilitate T cell entry via specific glycoproteins.
• CHST4 is crucial for forming the sulfated carbohydrate (6-sulfo sialyl Lewis X) on HEVs that binds L-selectin on T cells.

Purpose of the Study:

• To investigate the role of CHST4 in HEV function and heart transplant outcomes.
• To develop a novel antibody-drug conjugate (ADC) targeting the CHST4/HEV axis for targeted delivery of immunoregulatory drugs.
• To promote long-term cardiac transplant survival by enhancing regulatory T cell generation.

Main Methods:

• Utilized CHST4 knockout and inducible diphtheria toxin receptor mouse models to study HEV function in heart allograft transplantation.
• Assessed transplant outcomes in fully MHC-mismatched and single MHC class II-mismatched models.
• Developed a dual-payload ADC (rapamycin and tubastatin A) conjugated to an HEV-targeting antibody (MHA112) and tested its efficacy in murine models.

Main Results:

• CHST4 deficiency in HEVs impaired T cell entry into LNs, reduced regulatory T cell formation, and disrupted transplant acceptance.
• The HEV-targeted ADC significantly prolonged allograft survival and suppressed chronic rejection.
• The ADC enhanced regulatory T cell induction, reduced pro-inflammatory T cells, and decreased immune cell infiltration in allografts, using lower drug doses than free drugs.

Conclusions:

• CHST4 in HEVs plays a critical role in regulatory T cell generation and heart transplant acceptance.
• A CHST4-based, HEV-targeted ADC represents a promising therapeutic strategy for suppressing heart transplant rejection.