Development of [89Zr]Zr-DFO-hu3F8 and [225Ac]Ac-DOTA-hu3F8 Theranostic Pairs Targeting GD2 in Neuroblastomas

Relapsed and refractory high-risk neuroblastoma (NBL)
patients
have limited treatment options and a poor prognosis, highlighting
the urgent need for novel targeted therapies. This study evaluates
the GD2-targeting PET imaging agent [89Zr]Zr-DFO-hu3F8
and the radioimmunotherapy agent [225Ac]Ac-DOTA-hu3F8 in
NBL animal models. The GD2 overexpressing IMR32 tumor was assessed
by using [89Zr]Zr-DFO-hu3F8 PET imaging to confirm targeting
efficacy. The safety and therapeutic efficacy of [225Ac]Ac-DOTA-hu3F8
were evaluated in GD2-positive NBL xenografts. ImmunoPET revealed
the high and sustained uptake of [89Zr]Zr-DFO-hu3F8 in
IMR32 tumors compared to the [89Zr]Zr-DFO-IgG control group. In vitro biodistribution analysis showed that a tumor uptake
was 58.47 ± 3.64%ID/g at 168 h post-injection. A single dose
of [225Ac]Ac-DOTA-hu3F8 treatment significantly suppressed
tumor growth, with most tumors (4/5) achieving complete remission
at medium and high doses (11.1 and 18.5 kBq). Overall, our findings
demonstrate that alpha-targeted therapy based on hu3F8 holds significant
potential as a promising curative treatment strategy for NBL.