Targeted Hyaluronan Degradation Enhanced Tumor Growth Inhibition in Gastrointestinal Cancer Models.

Area of Science:

• Oncology
• Biotechnology
• Immunology

Background:

• Solid tumors feature dense, hyaluronan (HA)-rich stroma hindering drug delivery and immune cell infiltration.
• Systemic hyaluronidase delivery alone shows limited efficacy in tumor growth inhibition.
• Targeted degradation of tumor stroma is crucial for effective cancer therapy.

Purpose of the Study:

• To develop and evaluate antibody-enzyme (AbEn) molecules for targeted hyaluronan degradation.
• To assess the efficacy of AbEn molecules in overcoming stromal barriers in solid tumors.
• To investigate the synergistic effects of AbEn-mediated HA depletion with other cancer therapies.

Main Methods:

• Fusion of antibodies with recombinant human hyaluronidase (HYAL) to create AbEn molecules.
• Characterization of AbEn stability, antigen-binding, and enzymatic activity.
• Evaluation of AbEn efficacy in preclinical cancer models, including colorectal, pancreatic, and breast cancer models.

Main Results:

• AbEn molecules exhibited stability and prolonged serum half-life (132 h).
• Trispecific antibody TAVO423 demonstrated superior intratumoral HA depletion and tumor growth inhibition (TGI) in colorectal cancer models compared to untargeted HYAL.
• Combinations of TAVO423 with 5-fluorouracil, anti-PD-L1, T-cell engagers, and antibody-drug conjugates showed enhanced TGI (49-67%).
• TAVO423 improved TGI in pancreatic cancer models and reversed immune exclusion in breast cancer models by increasing CD8+ TILs, synergizing with PD-1 blockade.

Conclusions:

• The modular AbEn platform enables targeted HA degradation in stromal HA-rich solid tumors.
• AbEn molecules represent a promising strategy to overcome physical barriers and enhance therapeutic efficacy.
• Targeted HA degradation has broad potential for improving treatment outcomes in various solid tumors.