Mesothelin-directed protein-drug conjugates for mesothelin-low solid tumor therapy

Area of Science:

• Oncology
• Molecular Biology
• Drug Development

Background:

• Mesothelin (MSLN) is a therapeutic target for cancers, but its shedding into soluble MSLN (sMSLN) limits treatment efficacy.
• Existing MSLN-targeted therapies face challenges due to MSLN shedding and tumor penetration.

Purpose of the Study:

• To develop novel MSLN-targeting agents with improved efficacy and tumor penetration.
• To evaluate the therapeutic potential of DARPin-drug conjugates (DARPin-DCs) in preclinical cancer models.

Main Methods:

• Identified a MSLN-targeting DARPin (M7) binding to the C-terminal region.
• Developed two auristatin-based DARPin-DCs: M7A-DC and M7GA-DC.
• Assessed internalization, cytotoxicity, bystander killing, tumor spheroid penetration, and in vivo efficacy in pancreatic cancer models.

Main Results:

• M7A-DC and M7GA-DC effectively targeted MSLN-positive cells, releasing cytotoxic payloads (MMAE) and inducing bystander killing.
• DARPin-DCs demonstrated superior tumor spheroid penetration and cytotoxicity compared to antibody-drug conjugates (ADCs).
• M7GA-DC showed enhanced tumor control and survival benefits in pancreatic cancer models, including those with low MSLN expression.
• Combination with PD-1 blockade promoted anti-tumor immunity and long-term memory.

Conclusions:

• DARPin-DCs represent a promising therapeutic strategy for MSLN-expressing solid tumors.
• These conjugates overcome limitations of traditional ADCs, offering improved tumor penetration and efficacy.
• Combination therapy with immunotherapy holds significant translational potential for treating refractory cancers like pancreatic cancer.