The Rise of ADCs and Their Current Challenges
The recent surge in antibody-drug conjugates (ADC) approvals by the FDA, now totalling eleven, showcases their potential in targeted therapeutics. The majority of these ADCs are produced through cysteine-selective bioconjugation. However, there’s a prevalent challenge with many of these ADCs – they use maleimide functionalized linkers known for their instability. This instability leads to the drug detaching in circulation, resulting in increased off-target toxicity and decreased efficacy. While various alternatives have been explored, many lack adequate in vivo evaluations.
A Breakthrough in Conjugation Techniques
In this study, the researchers introduce a phosphonamidate-based hydrophilic conjugation handle. By exploiting the compact structure of ethynylphosphonamidates, they’ve designed a cysteine-selective conjugation method that incorporates hydrophilic O-substituents directly. This approach enhances the water solubility and conjugation efficiency of traditionally hydrophobic linker-payloads, such as Val-Cit-PAB-MMAE, found in five marketed ADCs. Using PEG12 and PEG24 as hydrophilic substituents, they were able to create the first ADCs with eight MMAE payloads per antibody, which offers a higher drug-to-antibody ratio (DAR) of 8, without compromising the pharmacokinetic profiles.
Impressive In Vivo Results and Future Potential
These newly developed ADCs displayed enhanced in vitro and in vivo efficacy, with DAR 8 versions outperforming their DAR 4 counterparts. The DAR 8 ADC showed superior in vivo efficacy, suggesting the introduced hydrophilicity effectively offsets the hydrophobicity of the eight VC-PAB-MMAE units. Moreover, ADCs linked with longer PEG showed slower clearance from blood, comparable to lower modified Adcetris. Ultimately, this novel PEG-substituted phosphonamidate conjugation approach provides an efficient method for creating highly efficacious DAR 8 ADCs using hydrophobic payloads and native antibodies without affecting their pharmacokinetic profile. This breakthrough offers the potential to develop even more potent ADCs, marking a significant step towards improved therapeutic outcomes.
Ochtrop, Philipp, Jahzerah, Jahaziel , et al,. “Compact hydrophilic electrophiles enable highly efficacious high DAR ADCs with excellent in vivo PK profile” Chemical Science (2023). DOI https://doi.org/10.1039/D2SC05678J
Philipp Ochtrop, Jahaziel Jahzerah, Paul Machui, Isabelle Mai, Dominik Schumacher, Jonas Helma, Marc-André Kasper, and Christian P. R. Hackenberger.