CD70-targeted platform for diagnosing and treating multiple myeloma

Background CD70, overexpressed in multiple myeloma (MM), is a promising target for theranostics. This study developed a CD70-targeted theranostic pair: the immuno-positron emission tomography tracer [ 89 Zr]Zr-DFO-ABDB6 and the therapeutic agent [ 177 Lu]Lu-DOTA-ABDB6, aiming to combine imaging and radiotherapy for MM. Methods CD70 expression was confirmed in patients with MM samples (positivity rate, 66.7%) and RPMI-8226 xenografts. The nanobody derivative ABDB6 was conjugated to DFO or DOTA and radiolabeled with 89 Zr or 177 Lu. Pharmacokinetics, biodistribution, and toxicity were evaluated in NCG and nude mice. Therapeutic efficacy was assessed in RPMI-8226 tumor-bearing mice via tumor volume measurement and survival analysis. Results [ 89 Zr]Zr-DFO-ABDB6 showed high tumor uptake (7.81±0.79% ID/g at 72 hours) and tumor-to-muscle ratios up to 10.63±5.71 in an MM model. [ 177 Lu]Lu-DOTA-ABDB6 treatment at a therapeutic dose of 40–80 µCi suppressed tumor growth and extended median survival to 61–69 days (vs 35–36 days in the control group). [ 177 Lu]Lu-DOTA-ABDB6 treatment at higher doses (300–600 µCi) caused transient hematotoxicity and organ stress, which resolved by 28 days. Tumor relapse occurred after single-dose treatment, indicating the need for regimen optimization. Conclusions The CD70-targeted theranostic pair allows precise imaging and effective radiotherapy in MM models. Low-dose [ 177 Lu]Lu-DOTA-ABDB6 treatment (40–80 µCi) is safe and effective, supporting clinical translation. Future studies should explore repeated dosing or the use of alpha-emitters (eg, 225 Ac) to improve durability. [ 89 Zr]Zr-DFO-ABDB6/[ 177 Lu]Lu-DOTA-ABDB6 theranostic pair provides a novel management strategy for CD70-positive MMs.