Design and Therapeutic Rationale of Antibody-Peptide Conjugates: Insights from Maridebart Cafraglutide (AMG133) and Emerging Applications

Abstract Therapeutic peptides have become an important class of pharmaceuticals, driven in part by the clinical success of long-acting incretin therapies. Despite their potency and specificity, peptides are intrinsically limited by rapid proteolytic degradation and renal clearance, resulting in short plasma half-lives and frequent dosing. Antibody-peptide conjugates represent an emerging class of biotherapeutics that combine the long half-life and target specificity of monoclonal antibodies (mAbs) with the chemical tunability and pharmacological activity of peptides. Unlike fusion proteins, antibody-peptide conjugates decouple peptide synthesis from antibody expression, enabling incorporation of non-proteinogenic amino acids, cyclic structures, and other chemical features that enhance peptide stability, potency, and half-life. This review examines the biological rationale, molecular design principles, and enabling technologies underlying antibody-peptide conjugates development, using the GIPR antagonist/GLP-1R agonist conjugate maridebart cafraglutide (AMG133) as a central case study. We illustrate how antibody-peptide conjugates can integrate complementary mechanisms of action into a single molecular entity and achieve sustained exposure profiles that are difficult to realize with fusion-based approaches. The discussion is extended to antibody-peptide conjugates programs across metabolic disease, oncology, neurology, pain, ocular, and infectious disease, highlighting recurring design themes such as half-life extension, targeted delivery, receptor-mediated internalization, and synergistic activity. Collectively, antibody-peptide conjugates represent a biology-driven and strategically important therapeutic modality that bridges antibody engineering and peptide medicinal chemistry. When guided by strong mechanistic rationale, antibody-peptide conjugates offer a powerful solution for therapeutic challenges that cannot be adequately addressed by peptides or antibodies alone.