CD74-Targeted Cathepsin-Inhibitor Antibody-Drug Conjugate Triggers Apoptosis in DLBCL

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• CD74 and Cathepsin L (CTSL) are overexpressed in diffuse large B-cell lymphoma (DLBCL) compared to normal tissues.
• High expression of CD74 and CTSL correlates with reduced overall survival in DLBCL patients, identifying a high-risk subgroup.
• Cathepsins are implicated in cancer progression, invasion, and metastasis, and are upregulated in DLBCL.

Purpose of the Study:

• To investigate the coordinated overexpression of CD74 and CTSL in DLBCL.
• To propose dual targeting of CD74 and CTSL using antibody-drug conjugates (ADCs) for improved DLBCL treatment.
• To develop and evaluate a novel cathepsin inhibitor-based ADC for DLBCL therapy.

Main Methods:

• Transcriptomic analysis of public datasets (TCGA, GTEx) to assess CD74 and CTSL expression in DLBCL.
• Kaplan-Meier analysis to correlate gene expression with overall survival.
• Development of a modified cathepsin inhibitor (M-GB) for antibody conjugation, forming an M-GB-ADC, and in vitro evaluation of its efficacy and specificity.

Main Results:

• Significant overexpression and strong correlation between CD74 and CTSL expression in DLBCL.
• Elevated CD74/CTSL levels associated with poor overall survival in DLBCL.
• A novel M-GB-ADC demonstrated high specificity for CD74-expressing lymphoma cells, inducing selective cell death with minimal toxicity to non-target cells.

Conclusions:

• Coordinated overexpression of CD74 and CTSL defines a high-risk DLBCL subgroup.
• Targeting CD74 and CTSL simultaneously via ADCs is a promising strategy for relapsed/refractory DLBCL.
• The developed M-GB-ADC represents a potential targeted therapy overcoming resistance and improving outcomes in DLBCL.