Maximizing therapeutic potential and safety: Exploring multi/dual-payload antibody conjugates as cancer theranostics

Tumor heterogeneity greatly contributes to the failure of traditional cancer treatments. This leads to tumor relapse, recurrence, and ultimately metastasis, presenting serious clinical challenges. In recent decades, advances in antibody-based immunotherapy have emerged as promising new pillars to combat cancers. Although single payload antibody drug conjugates (ADCs) have resulted in drastic improvements in patient outcomes compared with unconjugated antibodies, multiple de novo and acquired resistance mechanisms inherent with cancer cells have left patients with less than desired outcomes. Newer studies are exploring the use of dual and multiple payload ADCs to enhance effectiveness. These payloads include chemotherapeutic and/or radiotherapeutic agents. The approaches leverage the synergistic effects of the different payloads alongside the immunotherapeutic properties of the antibody carriers. This review presents a comprehensive overview of dual-payload monoclonal antibody conjugates for cancer therapy and diagnosis (theranostics). Additionally, it explores the use of various imageable radiometals that are conjugated to the ADCs for imaging/diagnosis. It discusses the role of radioisotope decay schemes (such as alpha emission, beta emission, or Auger electron emission) along with factors such as linker type and chelator, as well as drug-to-antibody ratio (DAR), which are aimed at enhancing the synergistic effects between the therapeutic payloads while ensuring safety. Because none of these dual-payload ADCs have reached the clinic, this review employs a predictive method to estimate human equivalent dose (HED), maximum tolerable dose (MTD), and radiotoxicity in humans based on preclinical data. Additionally, it discusses the combinatorial behavior of two cytotoxic payloads linked to a monoclonal antibody.