Format

Send to

Choose Destination
Mol Cancer Ther. 2020 Jan;19(1):157-167. doi: 10.1158/1535-7163.MCT-18-1302. Epub 2019 Oct 9.

Precision Chemoradiotherapy for HER2 Tumors Using Antibody Conjugates of an Auristatin Derivative with Reduced Cell Permeability.

Author information

1
Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California.
2
Department of Pathology, University of California San Diego, La Jolla, California.
3
Division of Hematology and Oncology, Department of Medicine, University of California San Diego, La Jolla, California.
4
University of California San Diego, Moores Cancer Center, La Jolla, California.
5
Division of Surgical Oncology, Department of Surgery, University of California San Diego, La Jolla, California.
6
Department of Pharmacology, University of California San Diego, La Jolla, California.
7
Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California. sjadvani@ucsd.edu.
#
Contributed equally

Abstract

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 with MMAE. In murine xenograft models, MMAF anti-HER2 antibody conjugates had less drug accumulated in the normal tissue surrounding tumors compared with 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.

PMID:
31597712
PMCID:
PMC6946877
[Available on 2020-07-01]
DOI:
10.1158/1535-7163.MCT-18-1302
Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center