ADAPT, a novel scaffold protein-based probe for radionuclide imaging of molecular targets that are expressed in disseminated cancers

Javad Garousi, Sarah Lindbo, Johan Nilvebrant, Mikael Astrand, Jos Buijs, Mattias Sandström, Hadis Honarvar, Anna Orlova, Vladimir Tolmachev, Sophia Hober

Research output: Contribution to journalArticlepeer-review

27 Citations (Scopus)

Abstract

Small engineered scaffold proteins have attracted attention as probes for radionuclide-based molecular imaging. One class of these imaging probes, termed ABD-Derived Affinity Proteins (ADAPT), has been created using the albumin-binding domain (ABD) of streptococcal protein G as a stable protein scaffold. In this study, we report the development of a clinical lead probe termed ADAPT6 that binds HER2, an oncoprotein overexpressed in many breast cancers that serves as a theranostic biomarker for several approved targeting therapies. Surface-exposed amino acids of ABD were randomized to create a combinatorial library enabling selection of high-affinity binders to various proteins. Furthermore, ABD was engineered to enable rapid purification, to eradicate its binding to albumin, and to enable rapid blood clearance. Incorporation of a unique cysteine allowed site-specific conjugation to a maleimido derivative of a DOTA chelator, enabling radionuclide labeling, 111In for SPECT imaging and 68Ga for PET imaging. Pharmacologic studies in mice demonstrated that the fully engineered molecule 111In/68Ga-DOTA- (HE)3-ADAPT6 was specifically bound and taken up by HER2- expressing tumors, with a high tumor-to-normal tissue ratio in xenograft models of human cancer. Unbound tracer underwent rapid renal clearance followed by high renal reabsorption. HER2- expressing xenografts were visualized by gamma-camera or PET at 1 hour after infusion. PET experiments demonstrated feasibility for discrimination of xenografts with high or low HER2 expression. Our results offer a preclinical proof of concept for the use of ADAPT probes for noninvasive in vivo imaging.

Original languageEnglish
Pages (from-to)4364-4371
Number of pages8
JournalCancer Research
Volume75
Issue number20
DOIs
Publication statusPublished - 15 Oct 2015
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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