On Demand Bioorthogonal Switching of an Antibody-Conjugated SPECT Probe to a Cytotoxic Payload: from Imaging to Therapy

作者：Pragya Adhikari, Guangmin Li, MaryAnn Go, Danielle Mandikian, Hanine Rafidi, Carl Ng, Sagana Anifa, Kevin M. Johnson, Linda Bao, Hilda Hernandez Barry, Rebecca K. Rowntree, Nicholas J. Agard, Cong Wu, Kang-Jye Chou, Donglu Zhang, Katherine R. Kozak, Thomas H. Pillow, Gail D. Lewis Phillips, Shang‐Fan Yu, C. Andrew Boswell, Jack Sadowsky · 发表于：Journal of the American Chemical Society · 年份：2024 · DOI：10.1021/jacs.4c03529 · 被引用次数：19 · 研究领域：Monoclonal and Polyclonal Antibodies Research、HER2/EGFR in Cancer Research、Click Chemistry and Applications

Antibody-drug conjugates (ADCs) for the treatment of cancer aim to achieve selective delivery of a cytotoxic payload to tumor cells while sparing normal tissue. In vivo, multiple tumor-dependent and -independent processes act on ADCs and their released payloads to impact tumor-versus-normal delivery, often resulting in a poor therapeutic window. An ADC with a labeled payload would make synchronous correlations between distribution and tissue-specific pharmacological effects possible, empowering preclinical and clinical efforts to improve tumor-selective delivery; however, few methods to label small molecules without destroying their pharmacological activity exist. Herein, we present a bioorthogonal switch approach that allows a radiolabel attached to an ADC payload to be removed tracelessly at will. We exemplify this approach with a potent DNA-damaging agent, the pyrrolobenzodiazepine (PBD) dimer, delivered as an antibody conjugate targeted to lung tumor cells. The radiometal chelating group, DOTA, was attached via a novel trans -cyclooctene (TCO)-caged self-immolative para -aminobenzyl (PAB) linker to the PBD, stably attenuating payload activity and allowing tracking of biodistribution in tumor-bearing mice via SPECT-CT imaging (live) or gamma counting (post-mortem). Following TCO-PAB-DOTA reaction with tetrazines optimized for extra- and intracellular reactivity, the label was removed to reveal the unmodified PBD dimer capable of inducing potent tumor cell killing in vitro ...