Biodistribution of 211At labeled HER-2 binding affibody molecules in mice

Abstract

Abstract. The size of affibody molecules makes them suitable as targeting agents for targeted radiotherapy with the ·-emitter 211 At, since their biokinetic properties match the short physical half-live of 211 At. In this study, the potential for this approach was investigated in vivo. Two different HER-2 binding affibody molecules were radiolabeled with 211 At using both the linker PAB (N-succinimidyl-para-astatobenzoate) and a decaborate-based linker, and the biodistribution in tumorbearing nude mice was investigated. The influence of L-lysine and Na-thiocyanate on the 211 At uptake in normal tissues was also studied. Based on the biokinetic information obtained, the absorbed dose was calculated for different organs. Compared with a previous biodistribution with 125 I, the 211 At biodistribution using the PAB linker showed higher uptake in lungs, stomach, thyroid and salivary glands, indicating release of free 211 At. When the decaborate-based linker was used, the uptake in those organs was decreased, but instead, high uptake in kidneys and liver was found. The uptake, when using the PAB linker, could be significantly reduced in some organs by the use of L-lysine and/or Na-thiocyanate. In conclusion, affibody molecules have suitable blood-kinetics for targeted radionuclide therapy with 211 At. However, the labeling chemistry affects the distribution in normal organs to a high degree and needs to be improved to allow clinical use.

Small-Animal PET Imaging of Human Epidermal Growth Factor Receptor Type 2 Expression with Site-Specific 18F-Labeled Protein Scaffold Molecules

“…Many other radiohalogens ( 125 I, 76/77/82 Br, and 211 At) and radiometals ( 99m Tc, 111/114m In, 90 Y, 177 Lu, and 68 Ga) have been used to label Affibody molecules (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). Our data are generally consistent with the findings reported in these published studies.…”

“…Over the last decade, noninvasive molecular imaging of HER2 expression with various imaging modalities has been extensively studied; these modalities include radionuclide imaging with PET and SPECT (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15), MRI (16), and optical imaging (17,18). PET imaging of HER2 (HER2 PET) is particularly useful because of its high sensitivity, high spatial resolution, strong quantification ability, and great potential for translation to clinical applications.…”

“…Recently, molecules that were derived from one of the IgG-binding domains of staphylococcal protein A (Affibody molecules) have received a lot of attention (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)19). Affibody molecules are composed of a relatively small engineered protein scaffold with 58 amino acid residues and a 3-helix-bundle scaffold structure.…”

Reagents for Astatination of Biomolecules. 6. An Intact Antibody Conjugated with a Maleimido-closo-Decaborate(2-) Reagent via Sulfhydryl Groups Had Considerably Higher Kidney Concentrations than the Same Antibody Conjugated with an Isothiocyanato-closo-Decaborate(2-) Reagent via Lysine Amines

“…Therefore, our first study was a comparison of the often used 211 At-labeling reagent, N-succinimidyl meta -[ 211 At]astatobenzoate, [ 211 At] 2b 20, 21 with a maleimido- closo -decaborate(2-) derivative, 4 , that had been prepared for conjugation with sulfhydryl groups on Fab́ 5 and engineered mAb fragments containing a cysteine residue. 22 That study demonstrated that higher in vivo stability was obtained, but more importantly, 211 At-labeling yields were much higher and the labeling process was much simpler when using the closo -decaborate(2-) mAb conjugate, 5a , than obtained in the two-step conjugation procedure required for use of [ 211 At] 2b . 4 In a subsequent study in mice directly comparing 211 At-labeled anti-CD45 mAb (30F11 conjugated with 4 ) and 213 Bi-labeled anti-CD45 mAb (30F11 conjugated with CHX-A”-DTPA), it was noted that tissue distributions and therapeutic outcomes were similar.…”

64Cu-Labeled Affibody Molecules for Imaging of HER2 Expressing Tumors

“…It has been demonstrated as a molecular target for therapeutic intervention, a prognostic indicator of patient survival, and as a predictive marker of response to antineoplastic therapy [6–8]. Numerous radionuclides including 18 F [9–11], 99m Tc [12–15], 111 In [16–19], 90 Y [20], 177 Lu [20, 21], 68 Ga [22], 125 I [14, 23–25], 76/77/82 Br [26], and 211 At [27] have been used to label the anti-HER2 Affibody molecules for tumor imaging or radiotherapy. These studies have clearly demonstrated that Affibody molecules are a promising new class of cancer targeting ligands and worthy of further investigation for developing probes for different tumor targets.…”