Affinity-optimized TROP2 antibodies support potent antitumor activity in antibody-drug conjugates

Area of Science:

• Oncology
• Immunology
• Drug Development

Background:

• Trophoblast cell surface antigen 2 (TROP2) is overexpressed in epithelial tumors, correlating with poor prognosis.
• Antibody-drug conjugates (ADCs) targeting TROP2 demonstrate clinical efficacy but face challenges with on-target, off-tumor toxicity due to normal tissue expression.
• There is a need for strategies to improve antitumor efficacy while mitigating toxicity in TROP2-targeted therapies.

Purpose of the Study:

• To identify and characterize novel anti-TROP2 monoclonal antibodies for therapeutic development.
• To engineer novel ADCs with optimized binding properties to enhance efficacy and reduce toxicity.
• To evaluate the therapeutic potential of novel anti-TROP2 ADCs in preclinical tumor models.

Main Methods:

• A novel fully human monoclonal antibody targeting a unique TROP2 conformational epitope with reduced binding affinity was identified using a phage library.
• The antibody was engineered into homogeneous ADCs with auristatin and/or duocarmycin payloads.
• Comparative studies were conducted against a surrogate of sacituzumab govitecan in TROP2-expressing tumor models.

Main Results:

• The novel anti-TROP2 ADCs exhibited significant antitumor activity in both mouse xenograft and syngeneic tumor models.
• Despite lower binding affinity, the novel antibody-drug conjugates demonstrated potent therapeutic efficacy.
• Epitope selection and affinity tuning were identified as key factors for enhancing therapeutic outcomes.

Conclusions:

• Novel anti-TROP2 ADCs represent a promising therapeutic strategy for cancer treatment, balancing efficacy and potential toxicity.
• Optimization of antibody binding characteristics is crucial for developing safer and more effective TROP2-targeted therapeutics.
• Further development of these optimized ADCs could lead to improved patient outcomes in TROP2-expressing cancers.