Hingorani and Doan et al. developed antibody-drug conjugates (ADCs) of HER2-targeting antibodies (trastuzumab or pertuzumab) and radiosensitizing auristatin derivatives (MMAE or MMAF). While free MMAF had little effect on tumor cells due to low cell permeability, ADCs containing MMAF selectively killed HER2-rich tumor cells in vitro and radiosensitized them with no off-target bystander toxicity. In vivo, MMAF-loaded ADCs accumulated in tumor tissue but not normal tissue, and in combination with focal ionizing radiation they enhanced tumor control and increased survival in mice bearing two types of HER2-expressing tumors.
The most successful therapeutic strategies for locally advanced cancers continue to combine decades old classical radiosensitizing chemotherapies with radiotherapy. Molecular targeted radiosensitizers offer the potential to improve the therapeutic ratio by increasing tumor specific kill while minimizing drug delivery and toxicity to surrounding normal tissue. Auristatins are a potent class of anti-tubulins that sensitize cells to ionizing radiation damage and are chemically amenable to antibody conjugation. To achieve tumor selective radiosensitization, we synthesized and tested anti-HER2 antibody drug conjugates of two auristatin derivatives with ionizing radiation. Monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF) were attached to the anti-HER2 antibodies trastuzumab and pertuzumab through a cleavable linker. While MMAE is cell permeable, MMAF has limited cell permeability as free drug resulting in diminished cytotoxicity and radiosensitization. However when attached to trastuzumab or pertuzumab, MMAF was as efficacious as MMAE in blocking HER2 expressing tumor cells in G2/M. Moreover, MMAF anti-HER2 conjugates selectively killed and radiosensitized HER2-rich tumor cells. Importantly when conjugated to targeting antibody, MMAF had the advantage of decreased bystander and off-target effects compared to MMAE. In murine xenograft models, MMAF anti-HER2 antibody conjugates had less drug accumulate in the normal tissue surrounding tumors compared to MMAE. Therapeutically, systemically injected MMAF anti-HER2 conjugates combined with focal ionizing radiation increased tumor control and improved survival of mice with HER2-rich tumor xenografts. In summary, our results demonstrate the potential of cell impermeable radiosensitizing warheads to improve the therapeutic ratio of radiotherapy by leveraging antibody drug conjugate technology.
Author Info: (1) Department of Radiation Medicine and Applied Sciences, University of California, San Diego. (2) Department of Radiation Medicine and Applied Sciences, University of California,
Author Info: (1) Department of Radiation Medicine and Applied Sciences, University of California, San Diego. (2) Department of Radiation Medicine and Applied Sciences, University of California, San Diego. (3) Department of Radiation Medicine and Applied Sciences, University of California, San Diego. (4) Department of Radiation Medicine and Applied Sciences, University of California, San Diego. (5) Department of Pathology, University of California, San Diego. (6) Department of Pathology, University of California, San Diego. (7) Department of Radiation Medicine and Applied Sciences, University of California, San Diego. (8) Moores Cancer Center, University of California, San Diego. (9) Moores Cancer Center, University of California, San Diego. (10) Department of Pharmacology, University of California, San Diego. (11) Department of Radiation Medicine and Applied Sciences, University of California, San Diego sjadvani@ucsd.edu.
