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Development of [89Zr]Zr-DFO-hu3F8 and [225Ac]Ac-DOTA-hu3F8 Theranostic Pairs Targeting GD2 in Neuroblastomas
Lingling Zheng1, Xu Yang1, Jun Liu1
1Department of Nuclear Medicine, Beijing Friendship Hospital Affiliated to Capital Medical University, Beijing 100050, China.
Abstract:
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.
Insights
Targeted alpha therapy using hu3F8 shows promise for neuroblastoma (NBL). A GD2-targeting agent ([89Zr]Zr-DFO-hu3F8) confirmed tumor uptake, while [225Ac]Ac-DOTA-hu3F8 induced complete remission in NBL models.
Area of Science:
- Oncology
- Nuclear Medicine
- Immunotherapy
Background:
- High-risk neuroblastoma (NBL) presents limited therapeutic options and poor prognosis.
- There is an urgent need for novel targeted therapies for relapsed and refractory NBL.
- GD2 is a validated target for NBL therapy.
Purpose of the Study:
- To evaluate the GD2-targeting PET imaging agent [89Zr]Zr-DFO-hu3F8 for NBL imaging.
- To assess the safety and therapeutic efficacy of the alpha-immunotherapy agent [225Ac]Ac-DOTA-hu3F8 in NBL models.
Main Methods:
- GD2-positive IMR32 NBL xenografts were used in animal models.
- [89Zr]Zr-DFO-hu3F8 PET imaging assessed targeting efficacy and tumor uptake.
- [225Ac]Ac-DOTA-hu3F8 was administered as a single dose to evaluate therapeutic effects.
Main Results:
- ImmunoPET demonstrated high and sustained uptake of [89Zr]Zr-DFO-hu3F8 in IMR32 tumors.
- In vitro biodistribution showed tumor uptake of 58.47 ± 3.64%ID/g at 168 h.
- A single dose of [225Ac]Ac-DOTA-hu3F8 led to significant tumor growth suppression and complete remission in 4/5 tumors at higher doses.
Conclusions:
- GD2-targeting immunoPET ([89Zr]Zr-DFO-hu3F8) is effective for NBL imaging.
- Alpha-targeted immunotherapy ([225Ac]Ac-DOTA-hu3F8) demonstrates significant therapeutic potential for NBL.
- Hu3F8-based alpha-targeted therapy offers a promising curative strategy for neuroblastoma.
