RT Journal Article
SR Electronic
T1 IL13Rα2-Targeting Antibodies for Immuno-PET in Solid Malignancies
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 605
OP 611
DO 10.2967/jnumed.124.268762
VO 66
IS 4
A1 Gajecki, Leah
A1 Lebedeva, Irina V.
A1 Liao, Yu-Rou
A1 Ambriz, Daisy
A1 Carter, Lukas M.
A1 Kumpf, Melina
A1 Lovibond, Samantha
A1 Hachey, Justin S.
A1 Graham, Maya S.
A1 Postow, Michael
A1 Lewis, Jason S.
A1 Andrew, David P.
A1 Baca, Manuel
A1 Schöder, Heiko
A1 Larson, Steven M.
A1 Veach, Darren R.
A1 Krebs, Simone
YR 2025
UL http://jnm.snmjournals.org/content/66/4/605.abstract
AB Interleukin-13 receptor α-2 (IL13Rα2) is a cell surface receptor frequently expressed in solid malignancies, such as glioblastoma and melanoma, with limited expression in healthy tissue, rendering it an ideal target for noninvasive and specific tumor delineation. In this study, we report the development of 5 novel IL13Rα2-targeted human monoclonal antibodies (mAbs) KLG-1–5; in subsequent in vitro and in vivo studies after radiolabeling with 89Zr, we evaluate their performance to identify a lead candidate. Methods: Five novel human anti-IL13Rα2 mAbs KLG-1–5 were developed and in vitro binding properties and target specificity assessed. In vivo 89Zr-immuno-PET using KLG-1–5 was conducted in a subcutaneous U-87 MG glioblastoma mouse model, and a mass dose titration study was conducted with lead candidate KLG-3. Ex vivo biodistribution results were used to derive prospective dosimetry of 177Lu-labeled KLG-3. Targeting with KLG-3 was also verified in an A-375 melanoma model using the optimized conditions determined in the U-87 MG xenograft model. Results: In vitro studies confirmed target specificity and pico- to low nanomolar binding affinity. Immuno-PET studies with KLG-1–5 in U-87 MG xenografts demonstrated continuously increasing tumoral uptake with maximal uptake at 144 h after tracer injection, clearance of the unbound tracer from the blood pool, and little uptake in any other normal tissues, leading to high-contrast images. KLG-3 provided the highest tumoral uptake and tumor–to–normal tissue ratios and was chosen as the lead candidate, and further dose optimization with this antibody led to tumoral uptake of 97 ± 6 maximum percent of injected dose per gram at 144 h after tracer injection. Ex vivo biodistribution-derived prospective dosimetry for 177Lu-labeled KLG-3 predicted a favorable therapeutic index, encouraging the development of IL13Rα2-targeted radioimmunotherapy. Of note, KLG-3 performed similarly well in a melanoma model, emphasizing the versatility of this antibody. Conclusion: Lead candidate anti-IL13Rα2 mAb KLG-3 validated highly specific target binding in human glioblastoma and melanoma models, resulting in high-contrast PET images with minimal accumulation in off-target healthy tissues. Prospective dosimetry of its 177Lu-labeled counterpart suggested therapeutic efficacy at relatively low injected activities, supporting further pursuit of KLG-3 in future translational radioimmunotherapy applications.