Abstract
HER3-binding affibody molecules are a promising format for visualization of HER3 expression. Cobalt-55, a positron-emitting isotope, with a half-life of 17.5 h, allows for next-day imaging. We investigated the influence of the charge of the radiocobalt–chelator complex on the biodistribution of anti-HER3 affibody molecule (HE)3-ZHER3 and compared the best radiocobalt-labeled variant with a recently optimized gallium-labeled variant. Affibody conjugates (HE)3-ZHER3-X (X = NOTA, NODAGA, DOTA, DOTAGA) were labeled with [57Co]Co (surrogate for 55Co). Affinity measurements, binding specificity and cellular processing were studied in two HER3-expressing cancer cell lines. Biodistribution was studied 3 and 24 h post-injection (pi) in mice with HER3-expressing BxPC-3 xenografts and compared to [68Ga]Ga-(HE)3-ZHER3-NODAGA. Micro-single-photon emission tomography/computed tomography (microSPECT/CT) and micro-positron emission tomography/computed tomography (microPET/CT) imaging was performed 3 and 24 h pi. Stably labeled conjugates bound to HER3 with subnanomolar affinity. [57Co]Co-(HE)3-ZHER3-DOTA had the best tumor retention and a significantly lower concentration in blood than other conjugates, leading to superior tumor-to-blood and tumor-to-liver ratios 24 h pi. Compared to [68Ga]Ga-(HE)3-ZHER3-NODAGA 3 h pi, [57Co]Co-(HE)3-ZHER3-DOTA provided superior imaging contrast in liver 24 h pi. Concluding, the composition and charge of the [57Co]Co–chelator complex influenced the uptake in tumors and normal tissue. [57Co]Co-(HE)3-ZHER3-DOTA provided the best imaging properties among the cobalt-labeled conjugates. Delayed imaging of HER3 expression with [57Co]Co-(HE)3-ZHER3-DOTA improved imaging contrast compared to early-time-point imaging with [68Ga]Ga-(HE)3-ZHER3-NODAGA.
Highlights
Upregulation of the human epidermal growth factor receptor type 3 (HER3) is associated with the progression of several solid cancers, such as prostate, breast, pancreatic or colorectal cancer [1,2,3]
Tumor uptake of [57Co]Co-(HE)3-ZHER3-DOTAGA was below 1% ID/g, the lowest among the tested conjugates
Uptake in tumors and HER3-expressing organs and kidneys could be visualized clearly, and images resembled the results from the biodistribution studies
Summary
Upregulation of the human epidermal growth factor receptor type 3 (HER3) is associated with the progression of several solid cancers, such as prostate, breast, pancreatic or colorectal cancer [1,2,3]. Co-expression of HER3 is, considered a cause for the development of therapy resistance, which has, for instance, been documented for the tyrosine kinase inhibitors (TKIs) lapatinib and gefitinib, targeting epidermal growth factor receptor (EGFR) and HER2 [6,7,8]. Inhibition of HER3-mediated signaling might have potential to overcome therapy resistance [4,9] and monitoring of HER3 expression could, aid strategic decision making for cancer therapy. A major drawback of radiolabeled antibodies for imaging is the long residence time in blood and their hepatobiliary elimination pathway
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