Zr-89 Immuno-PET Targeting Ectopic ATP Synthase Enables In-Vivo Imaging of Tumor Angiogenesis

Park, Bok-Nam; Kim, Ga-Hee; Ko, Seung-A; Shin, Ga-Hee; Lee, Su Jin; An, Young‐Sil; Yoon, Joon-Kee

doi:10.3390/ijms20163928

Cited by 6 publications

(6 citation statements)

References 25 publications

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“…The whole antibody was a superior tracer probably due to larger size (preventing renal clearance), longer systemic retention, and better protein stability in vivo as compared to the smaller formats. Our results agree with similar studies where smaller formats were not necessarily better in tumor targeting and accumulation than full antibodies. − We think that the the enzymatically generated Fab′2 fragment suffers from reduced stability in vitro and in vivo, which could be improved using mammalian expression and therefore needs further investigation. High renal uptake and retention of 89 Zr-conjugated Fc-less short antibody formats could be avoided by using renal radio-protectants.…”

Section: Resultssupporting

confidence: 89%

Pharmacokinetics and Biodistribution of ⁸⁹Zr-Miltuximab and Its Antibody Fragments as Glypican-1 Targeting Immuno-PET Agents in Glioblastoma

et al. 2023

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Glioblastoma (GBM) is the most aggressive form of primary brain cancer, accounting for about 85% of all primary central nervous system (CNS) tumors. With standard treatment strategies like surgery, radiation, and chemotherapy, the median survival time of patients with GBM is only 12−15 months from diagnosis. The poor prognosis of GBM is due to a very high tumor recurrence rate following initial treatment, indicating a dire need for improved diagnostic and therapeutic alternatives for this disease. Antibody-based immunotheranostics holds great promise in treating GBM, combining the theranostic applications of radioisotopes and target-specificity of antibodies. In this study, we developed and validated antibody-based positron emission tomography (PET) tracers targeting the heparan sulfate proteoglycan, glypican-1 (GPC-1), for noninvasive detection of disease using diagnostic molecular imaging. GPC-1 is overexpressed in multiple solid tumor types, including GBM, and is a promising biomarker for novel immunotheranostics. Here, we investigate zirconium-89 ( 89 Zr)-conjugated Miltuximab (a clinical stage anti-GPC-1 monoclonal antibody developed by GlyTherix, Ltd.) and engineered fragments for their potential as immuno-PET tracers to detect GPC-1 positive GBM tumors in preclinical models. We explore the effects of molecular size, avidity, and Fc-domain on the pharmacokinetics and biodistribution in vivo, by comparing in parallel the full-length antibody (Miltuximab), Fab′2, Fab, and single-chain variable fragment (scFv) formats. High radiolabeling efficiency (>95%) was demonstrated by all the formats and the stability postradiolabeling was higher for larger constructs of Miltuximab and the Fab. Receptor-mediated internalization of all 89 Zr-labeled formats was observed in a human GBM cell line in vitro, while full-length Miltuximab demonstrated the highest tumor retention (5.7 ± 0.94% ID/g, day-9 postinjection (p.i.)) and overall better tumor-to-background ratios than the smaller Fc-less formats. Results from in vivo PET image quantification and ex vivo scintillation counting were highly correlated. Altogether, 89 Zr-DFO-Miltuximab appears to be an effective immuno-PET imaging agent for detecting GPC-1 positive tumors such as GBM and the current results support utility of the Fc containing whole mAb format over smaller antibody fragments for this target.

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Section: Resultssupporting

confidence: 89%

Pharmacokinetics and Biodistribution of ⁸⁹Zr-Miltuximab and Its Antibody Fragments as Glypican-1 Targeting Immuno-PET Agents in Glioblastoma

et al. 2023

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“…Therefore, ATPS could serve as a novel target for anti-angiogenic cancer therapies. As previously demonstrated, the anti-ATPS mAb used in this study can target tumor vasculature and cancer cells [ 9 ]. In this study, 177 Lu-DOTA-ATPS mAb showed a significant inhibitory effect on MKN-45 gastric cancers.…”

Section: Discussionmentioning

confidence: 86%

“…Radioiodine ( 131 I)-labeled anti-ATPS antibody effectively suppressed the tumor growth by 2.5-fold in a gastric cancer model [ 8 ]. Anti-ATPS antibodies labeled with Zirconium-89 ( 89 Zr) demonstrated significantly higher targeting specificity for MDA-MB-231 tumors with abundant ectopic ATPS expression compared to PC-3 tumors with low expression [ 9 ]. Given its role in tumor angiogenesis, ectopic ATPS emerges as a novel target for developing effective anti-angiogenic therapies.…”

Section: Introductionmentioning

confidence: 99%

177Lu Anti-Angiogenic Radioimmunotherapy Targeting ATP Synthase in Gastric Cancer Model

Park,

An,

Kim

et al. 2024

Antibodies

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This study investigated a novel radioimmunotherapy strategy for targeting tumor angiogenesis. We developed a radiopharmaceutical complex by labeling an anti-adenosine triphosphate synthase (ATPS) monoclonal antibody (mAb) with the radioisotope 177Lu using DOTA as a chelating agent. 177Lu-DOTA-ATPS mAb demonstrated high labeling efficiency (99.0%) and stability in serum. MKN-45 cancer cells exhibited the highest cellular uptake, which could be specifically blocked by unlabeled ATPS mAb. In mice, 177Lu-DOTA-ATPS mAb accumulated significantly in tumors, with a tumor uptake of 16.0 ± 1.5%ID/g on day 7. 177Lu-DOTA-ATPS mAb treatment significantly reduced the viability of MKN-45 cells in a dose-dependent manner. In a xenograft tumor model, this radioimmunotherapy strategy led to substantial tumor growth inhibition (82.8%). Furthermore, combining 177Lu-DOTA-ATPS mAb with sunitinib, an anti-angiogenic drug, enhanced the therapeutic efficacy of sunitinib in the mouse model. Our study successfully developed 177Lu-DOTA-ATPS mAb, a radioimmunotherapy agent targeting tumor blood vessels. This approach demonstrates significant promise for inhibiting tumor growth, both as a single therapy and in combination with other anti-cancer drugs.

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“… 37 , 38 Moreover, MAS is able to modulate the astrocyte inflammatory response, which is related to the initiation of glioma. 39 , 40 …”

Section: Atp Synthase Is Required For Malignant Tumor Growthmentioning

confidence: 99%

Defueling the cancer: ATP synthase as an emerging target in cancer therapy

Wang

Qian

2021

Molecular Therapy - Oncolytics

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Reprogramming of cellular metabolism is a hallmark of cancer. Mitochondrial ATP synthase (MAS) produces most of the ATP that drives the cell. High expression of the MAS-composing proteins is found during cancer and is linked to a poor prognosis in glioblastoma, ovarian cancer, prostate cancer, breast cancer, and clear cell renal cell carcinoma. Cell surface-expressed ATP synthase, translocated from mitochondrion to cell membrane, involves the angiogenesis, tumorigenesis, and metastasis of cancer. ATP synthase has therefore been considered a therapeutic target. We review recent various ATP synthase inhibitors that suppress tumor growth and are being tested for the clinic.

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Zr-89 Immuno-PET Targeting Ectopic ATP Synthase Enables In-Vivo Imaging of Tumor Angiogenesis

Cited by 6 publications

References 25 publications

Pharmacokinetics and Biodistribution of ⁸⁹Zr-Miltuximab and Its Antibody Fragments as Glypican-1 Targeting Immuno-PET Agents in Glioblastoma

Pharmacokinetics and Biodistribution of ⁸⁹Zr-Miltuximab and Its Antibody Fragments as Glypican-1 Targeting Immuno-PET Agents in Glioblastoma

177Lu Anti-Angiogenic Radioimmunotherapy Targeting ATP Synthase in Gastric Cancer Model

Defueling the cancer: ATP synthase as an emerging target in cancer therapy

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Zr-89 Immuno-PET Targeting Ectopic ATP Synthase Enables In-Vivo Imaging of Tumor Angiogenesis

Cited by 6 publications

References 25 publications

Pharmacokinetics and Biodistribution of 89Zr-Miltuximab and Its Antibody Fragments as Glypican-1 Targeting Immuno-PET Agents in Glioblastoma

Pharmacokinetics and Biodistribution of 89Zr-Miltuximab and Its Antibody Fragments as Glypican-1 Targeting Immuno-PET Agents in Glioblastoma

177Lu Anti-Angiogenic Radioimmunotherapy Targeting ATP Synthase in Gastric Cancer Model

Defueling the cancer: ATP synthase as an emerging target in cancer therapy

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Product

Resources

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Pharmacokinetics and Biodistribution of ⁸⁹Zr-Miltuximab and Its Antibody Fragments as Glypican-1 Targeting Immuno-PET Agents in Glioblastoma

Pharmacokinetics and Biodistribution of ⁸⁹Zr-Miltuximab and Its Antibody Fragments as Glypican-1 Targeting Immuno-PET Agents in Glioblastoma