Elsevier

Nuclear Medicine and Biology

Volumes 108–109, May–June 2022, Pages 33-43
Nuclear Medicine and Biology

Radiation dosimetry and efficacy of an 89Zr/225Ac-labeled humanized anti-MUC5AC antibody

https://doi.org/10.1016/j.nucmedbio.2022.02.003Get rights and content
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Abstract

Introduction

Theranostic applications are currently difficult to achieve owing to the limited evaluation of suitable chelators for therapeutic nuclides, such as 225Ac and 227Th. With a focus on targeted α therapy and theranostics using human IgG as a drug-delivery system (i.e., combining highly cytotoxic α-particle emitter radiation with efficient tumor targeting), we developed a recombinant humanized Nd2 (hNd2) as an anti-MUC5AC antibody since MUC5AC is highly expressed in patients with pancreatic cancer. Therefore, we aimed to evaluate the performance of 89Zr- (for diagnosis) and 225Ac- (for therapy) labeling of these antibodies using well-controlled radioisotope (RI)-labeling technology in pancreatic cancer mouse models.

Methods

89Zr-labeled hNd2 (NMK89) and 225Ac-labeled hNd2 (NMT25) were manufactured by chemical conjugation using affinity peptides. A binding assay and the evaluation of plasma stability were performed in vitro to confirm the properties of NMK89 and NMT25. In vivo, we evaluated biodistribution, positron emission tomography (PET)/computed tomography (CT) imaging, antitumor effects, and toxicity. Moreover, the exposure dose in humans was estimated based on the biodistribution evaluation in normal mice.

Results

NMK89 and NMT25 showed binding specificity to MUC5AC and stability with radiochemical purity ≥90% in mice and human plasma following incubation for 168 h. NMK89 showed high accumulation in tumors and low non-specific accumulation in normal tissues. The antitumor effect of NMT25 was dose-dependent and significantly suppressed tumor growth in the NMT25 treatment groups compared with the control group (p < 0.05). NMK89 and NMT25 showed similar pharmacokinetics and biodistribution characteristics. Additionally, the human estimated exposure dose of NMK89 and NMT25 was confirmed, and the effective dose of NMK89 and NMT25 was 0.33 mSv/MBq and 177.5 mSv/MBq, respectively.

Conclusion

NMK89 showed specific accumulation in the MUC5AC-expressing tumors, while NMT25 showed strong antitumor effects. These results suggest NMK89 and NMT25 as promising theranostic agents for pancreatic cancer.

Abbreviations

ATCC
American Type Culture Collection
BUN
blood urea nitrogen
CCAP
chemical conjugation by affinity peptide
CK
creatine kinase
CT
computed tomography
DFO
deferoxamine
FBS
fetal bovine serum
ICR
Institute of Cancer Research
LDAC
low-dose cytarabine
mCRPC
metastatic castration-resistant prostate cancer
NHS
N-hydroxysuccinimide
PBS
phosphate-buffered saline
PET
positron emission tomography
RBE
relative biological effectiveness
RCP
radiochemical purity
SPECT
single-photon emission computed tomography

Keywords

89Zr
225Ac
MUC5AC
Pancreatic cancer
Targeted α therapy
Theranostics

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