Targeting of bowel tissue by fully human antibodies cross-reactive with human and mouse GPA33 antigen

Monoclonal antibodies are indispensable therapeutic agents for various diseases, including cancer, autoimmune disorders, and infectious diseases. Glycoprotein A33 (GPA33), a cell surface antigen highly expressed in colorectal cancer, provides a compelling therapeutic target; however, the species-specificity of anti-GPA33 antibodies has limited their utility in preclinical models, thus inhibiting their development. Here, we generated and characterized fully human, cross-reactive anti-GPA33 antibodies using phage-display technology with transchromosomic antibody-producing animals. The resulting single-chain variable fragment and single-chain variable fragment crystallizable antibodies exhibited high specificity and affinity for both human and mouse GPA33. In vivo imaging confirmed their targeted retention in mouse intestine, indicating their potential for developing targeted therapeutic approaches. The ability of these antibodies to recognize both human and murine GPA33 enhances their applicability in preclinical models, improving their translation from experimental to clinical applications. These results highlight the feasibility of developing cross-reactive, fully human antibodies and support the advancement of GPA33-targeted diagnostic approaches and the exploration of novel therapeutic strategies for relevant gastrointestinal diseases.