In vitro evaluation of anti-HIV radioimmunoconjugates labeled with astatine-211, thorium-227 and actinium-225

IF 3 4区医学 Q1 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING

Nuclear medicine and biology Pub Date : 2026-03-01 Epub Date: 2026-01-23 DOI:10.1016/j.nucmedbio.2026.109602

Anne-Sophie Kuhlmann , Donald K. Hamlin , Yawen Li , Xinyi Wang , Lily Li , Chris Orvig , Hans-Peter Kiem , Brenda M. Sandmaier , D. Scott Wilbur , Seth Pincus , Robert D. Harrington

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Abstract

We conducted an in vitro investigation of the selective cytotoxicity of alpha-emitting radioimmunoconjugates (α-RICs) directed against cells expressing HIV envelope (Env) proteins. It is well known that monoclonal antibody (mAb)-targeted α-emitting radionuclides can effectively kill antigen-expressing cells; however, the expected low-level expression of HIV antigens on latently infected cells poses an obstacle to all anti-HIV immune-based treatments, including α-RICs. This investigation tested the cytotoxicity of the HIV envelope antigen-binding mAbs, PGT126 (binding gp120) and 7B2 (binding gp41), conjugated with labeling chelators that bind the α-emitters astatine-211 (²¹¹At), actinium-225 (²²⁵Ac) or thorium-227 (²²⁷Th).

Methods

High specific activity (SA) preparations of the α-RICs were made to increase the proportion of mAb conjugates carrying the α-emitting isotope. RIC cytolytic activity was evaluated against a cell line stably expressing the HIV envelope.

Results

²¹¹At-labeled mAb conjugates did not demonstrate specific cell killing, while the longer lived radiometal α-RICs, ²²⁷Th and ²²⁵Ac, efficiently and specifically killed HIV envelope expressing cells.

Conclusions

Potential explanations for these differential effects include the longer half-lives of ²²⁵Ac and ²²⁷Th compared to ²¹¹At and differences in the decay properties of radiometals compared to radiohalogens. These encouraging in vitro results suggest that in vivo evaluations of α-RIC in depleting the HIV harboring cells are warranted.

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以砹-211、钍-227和锕-225标记的抗hiv放射免疫偶联物的体外评价

我们在体外研究了α-放射免疫偶联物（α-RICs）对表达HIV包膜（Env）蛋白的细胞的选择性细胞毒性。众所周知，单克隆抗体（mAb）靶向α-放射核素能有效杀伤表达抗原的细胞；然而，预期的HIV抗原在潜伏感染细胞上的低水平表达对所有抗HIV免疫治疗（包括α-RICs）构成了障碍。本研究检测了HIV包膜抗原结合单克隆抗体PGT126（结合gp120）和7B2（结合gp41）的细胞毒性，它们与α-发射体astatin -211 （211At）、act锕-225 （225Ac）或钍-227（227）结合。方法采用高比活（SA）法制备α- ric，提高单抗偶联物携带α-发射同位素的比例。在稳定表达HIV包膜的细胞系上评估RIC的细胞溶解活性。结果211at标记的mAb偶联物没有特异性杀伤细胞，而寿命较长的放射性金属α-RICs， 227和225Ac能够有效特异性杀伤表达HIV包膜的细胞。结论对这些差异效应的可能解释包括225Ac和227的半衰期比211At长，以及放射性金属与放射性卤素的衰变特性不同。这些令人鼓舞的体外结果表明，α-RIC在体内消耗HIV窝藏细胞的评估是有根据的。

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来源期刊

Nuclear medicine and biology 医学-核医学

CiteScore

6.00

自引率

9.70%

发文量

479

审稿时长

51 days

期刊介绍： Nuclear Medicine and Biology publishes original research addressing all aspects of radiopharmaceutical science: synthesis, in vitro and ex vivo studies, in vivo biodistribution by dissection or imaging, radiopharmacology, radiopharmacy, and translational clinical studies of new targeted radiotracers. The importance of the target to an unmet clinical need should be the first consideration. If the synthesis of a new radiopharmaceutical is submitted without in vitro or in vivo data, then the uniqueness of the chemistry must be emphasized. These multidisciplinary studies should validate the mechanism of localization whether the probe is based on binding to a receptor, enzyme, tumor antigen, or another well-defined target. The studies should be aimed at evaluating how the chemical and radiopharmaceutical properties affect pharmacokinetics, pharmacodynamics, or therapeutic efficacy. Ideally, the study would address the sensitivity of the probe to changes in disease or treatment, although studies validating mechanism alone are acceptable. Radiopharmacy practice, addressing the issues of preparation, automation, quality control, dispensing, and regulations applicable to qualification and administration of radiopharmaceuticals to humans, is an important aspect of the developmental process, but only if the study has a significant impact on the field. Contributions on the subject of therapeutic radiopharmaceuticals also are appropriate provided that the specificity of labeled compound localization and therapeutic effect have been addressed.