Increasing Tumor Penetration with Heavy Chain Antibody Drug Conjugates

ADCs are traditionally made with IgG scaffolds and have many benefits, including long half-lives, specific antigen binding, stability, immune interactions, and cellular toxicity. IgGs are about 150 KDa in size, which can affect their ability to penetrate solid tumors. The Binding-site barrier effect explains the limitation for solid tumor penetration due to slow diffusion across the tumor, due to IgG size and ADC hydrophobicity (due to drug conjugation), and tight binding to their target antigen. We developed a HER2-targeting heavy chain antibody (hcAb), which is a fusion of a HER2-targeting nanobody and IgG Fc. This design creates a smaller (75 KDa) and more hydrophilic antibody scaffold that can assist in faster diffusion across solid tumors. Traditional drug conjugation techniques are successful in creating heavy-chain Antibody-Drug Conjugates (hcADCs) and allow for direct comparison of toxicity and penetration in cell and organoid studies with traditional IgG-based ADCs.