Galectin-3 binding protein (Gal-3BP) is a glycoproteinthat isoverexpressed and secreted by several cancers and has been implicatedas a marker of both tumor progression and poor prognosis in melanoma,non-small cell lung cancer, head and neck squamous cell carcinoma,and breast cancer. The expression of Gal-3BP by a variety of neoplasmsmakes it an enticing target for both diagnostics and therapeutics,including immuno-positron emission tomography (immunoPET) probes andantibody-drug conjugates (ADCs). Herein, we report the development, in vitro characterization, and in vivo evaluationof a pair of Gal-3BP-targeting radioimmunoconjugates for Zr-89-immunoPET. A humanized anti-Gal-3BP antibody, 1959, and its correspondingADC, 1959-sss/DM4 (DM4 = ravtansine), were modified with desferrioxamine(DFO) to yield DFO-1959 and DFO-1959-sss/DM4 immunoconjugates bearing1-2 DFO/monoclonal antibody. Both DFO-modified immunoconjugatesretained their affinity for Gal-3BP in enzyme-linked immunosorbentassay experiments. The chelator-bearing antibodies were radiolabeledwith zirconium-89 (t (1/2) & AP; 3.3 d)to produce radioimmunoconjugates [Zr-89]-Zr-DFO-1959and [Zr-89]-Zr-DFO-1959-sss/DM4 with high specificactivity (>444 MBq/mg, >12 mCi/mg) and stability (>80% intactafter168 h in human serum at 37 & DEG;C). In mice bearing subcutaneousGal-3BP-secreting A375-MA1 xenografts, [Zr-89]-Zr-DFO-1959clearly delineated tumor tissue, reaching a maximum tumoral activityconcentration (54.8 & PLUSMN; 15.8%ID/g) and tumor-to-background contrast(tumor-to-blood = 8.0 & PLUSMN; 4.6) at 120 h post-injection. The administrationof [Zr-89]-Zr-DFO-1959 to mice bearing subcutaneous Gal-3BP-expressingmelanoma patient-derived xenografts produced similarly promising results.[Zr-89]-Zr-DFO-1959 and [Zr-89]-Zr-DFO-1959-sss/DM4exhibited nearly identical pharmacokinetic profiles in the mice bearingA375-MA1 tumors, though the latter produced higher uptake in the spleenand kidneys. Both [Zr-89]-Zr-DFO-1959 and [Zr-89]-Zr-DFO-1959-sss/DM4effectively visualized Gal-3BP-secreting tumors in murine models ofmelanoma. These results suggest that both probes could play a rolein the clinical imaging of Gal-3BP-expressing malignancies, particularlyas companion theranostics for the identification of patients likelyto respond to Gal-3BP-targeted therapeutics such as 1959-sss/DM4.
Visualizing Galectin-3 Binding Protein Expression with ImmunoPET
Ippoliti R.;
2023-01-01
Abstract
Galectin-3 binding protein (Gal-3BP) is a glycoproteinthat isoverexpressed and secreted by several cancers and has been implicatedas a marker of both tumor progression and poor prognosis in melanoma,non-small cell lung cancer, head and neck squamous cell carcinoma,and breast cancer. The expression of Gal-3BP by a variety of neoplasmsmakes it an enticing target for both diagnostics and therapeutics,including immuno-positron emission tomography (immunoPET) probes andantibody-drug conjugates (ADCs). Herein, we report the development, in vitro characterization, and in vivo evaluationof a pair of Gal-3BP-targeting radioimmunoconjugates for Zr-89-immunoPET. A humanized anti-Gal-3BP antibody, 1959, and its correspondingADC, 1959-sss/DM4 (DM4 = ravtansine), were modified with desferrioxamine(DFO) to yield DFO-1959 and DFO-1959-sss/DM4 immunoconjugates bearing1-2 DFO/monoclonal antibody. Both DFO-modified immunoconjugatesretained their affinity for Gal-3BP in enzyme-linked immunosorbentassay experiments. The chelator-bearing antibodies were radiolabeledwith zirconium-89 (t (1/2) & AP; 3.3 d)to produce radioimmunoconjugates [Zr-89]-Zr-DFO-1959and [Zr-89]-Zr-DFO-1959-sss/DM4 with high specificactivity (>444 MBq/mg, >12 mCi/mg) and stability (>80% intactafter168 h in human serum at 37 & DEG;C). In mice bearing subcutaneousGal-3BP-secreting A375-MA1 xenografts, [Zr-89]-Zr-DFO-1959clearly delineated tumor tissue, reaching a maximum tumoral activityconcentration (54.8 & PLUSMN; 15.8%ID/g) and tumor-to-background contrast(tumor-to-blood = 8.0 & PLUSMN; 4.6) at 120 h post-injection. The administrationof [Zr-89]-Zr-DFO-1959 to mice bearing subcutaneous Gal-3BP-expressingmelanoma patient-derived xenografts produced similarly promising results.[Zr-89]-Zr-DFO-1959 and [Zr-89]-Zr-DFO-1959-sss/DM4exhibited nearly identical pharmacokinetic profiles in the mice bearingA375-MA1 tumors, though the latter produced higher uptake in the spleenand kidneys. Both [Zr-89]-Zr-DFO-1959 and [Zr-89]-Zr-DFO-1959-sss/DM4effectively visualized Gal-3BP-secreting tumors in murine models ofmelanoma. These results suggest that both probes could play a rolein the clinical imaging of Gal-3BP-expressing malignancies, particularlyas companion theranostics for the identification of patients likelyto respond to Gal-3BP-targeted therapeutics such as 1959-sss/DM4.Pubblicazioni consigliate
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.