Radionuclide Therapy of HER2-Positive Microxenografts Using a 177Lu-Labeled HER2-Specific Affibody Molecule

Abstract

A radiolabeled anti-HER2 Affibody molecule (Z HER2:342 ) targets HER2-expressing xenografts with high selectivity and gives good imaging contrast. However, the small size (f7 kDa) results in rapid glomerular filtration and high renal accumulation of radiometals, thus excluding targeted therapy. Here, we report that reversible binding to albumin efficiently reduces the renal excretion and uptake, enabling radiometal-based nuclide therapy.

Pre-clinical evaluation of [111In]-benzyl-DOTA-ZHER2:342, a potential agent for imaging of HER2 expression in malignant tumors

“…The NAP-5 size exclusion columns were from Amersham Biosciences (Uppsala, Sweden). The 111 In-benzyl-DTPA-Z HER2:342 conjugate for the comparative biodistribution experiment was prepared according to the procedure described by Tolmachev et al (26).…”

“…The conjugation of isothiocyanate-benzyl-DOTA to the Affibody molecule Z HER2:342 was performed similarly to the method described by Tolmachev et al (26), using a calculated chelator-to-protein molar ratio of 1:1, 2:1 or 3:1. Briefly, 500 μg of Z HER2:342 was mixed with freshly prepared solution of isothiocyanatebenzyl-DOTA in 0.07 M sodium borate buffer, pH 9.2.…”

“…Though 123 I possesses excellent imaging and dosimetric properties, indirect radioiodination requires well-trained personnel, and the short half-life of 123 I complicates the logistics. To facilitate clinical implementation of the Z HER2:342 Affibody molecule, we developed a procedure for 111 In labeling of Z HER2:342 conjugated with benzyl-DTPA via a thiourea bond (26). The use of benzyl-DTPA as a chelator ensured facile labeling permitting kit formulation and provided a tumor-to-blood ratio of 94 in SKOV-3 xenografts 4 h pi.…”

Stabilization of a β-hairpin in monomeric Alzheimer's amyloid-β peptide inhibits amyloid formation

“…On this account, affibody ligands to monomeric A␤ have recently been selected (20). Affibody ligands represent one class of engineered affinity proteins with applications in biotechnology, biochemical assays, disease diagnosis, and therapy (21)(22)(23). They are based on the Z domain derived from staphylococcal protein A and selected by phage display from a combinatorial protein library in which 13 of the 58 amino acid residues are randomized.…”

Engineering and characterization of a bispecific HER2 × EGFR‐binding affibody molecule

“…Affibody molecules have been genetically fused to other proteins, e.g. ABD (albumin-binding domain) [36] or Fc fragment [37] or to another identical affibody molecule to increase the functional affinity (avidity) [38][39][40]. bs targeting has been achieved with an affibody-ABD fusion molecule, to allow binding to both the target protein and human serum albumin in order to obtain increased in vivo half-life [36] or to Fc to take advantage of Fc functions.…”