Low-level whole-brain radiation enhances theranostic potential of single-domain antibody fragments for human epidermal growth factor receptor type 2 (HER2)-positive brain metastases.

Abstract

Background

Single-domain antibody fragments (aka VHH, ~ 13 kDa) are promising delivery systems for brain tumor theranostics; however, achieving efficient delivery of VHH to intracranial lesions remains challenging due to the tumor-brain barrier. Here, we evaluate low-dose whole-brain irradiation as a strategy to increase the delivery of an anti- human epidermal growth factor receptor type 2 (HER2) VHH to breast cancer-derived intracranial tumors in mice.

Methods

Mice with intracranial HER2-positive BT474BrM3 tumors received 10-Gy fractionated cranial irradiation and were evaluated by noninvasive imaging. Anti-HER2 VHH 5F7 was labeled with 18F, administered intravenously to irradiated mice and controls, and PET/CT imaging was conducted periodically after irradiation. Tumor uptake of 18F-labeled 5F7 in irradiated and control mice was compared by PET/CT image analysis and correlated with tumor volumes. In addition, longitudinal dynamic contrast-enhanced MRI (DCE-MRI) was conducted to visualize and quantify the potential effects of radiation on tumor perfusion and permeability.

Results

Increased 18F-labeled 5F7 intracranial tumor uptake was observed with PET in mice receiving cranial irradiation, with maximum tumor accumulation seen approximately 12 days post initial radiation treatment. No radiation-induced changes in HER2 expression were detected by Western blot, flow cytometry, or on tissue sections. DCE-MRI imaging demonstrated transiently increased tumor perfusion and permeability after irradiation, consistent with the higher tumor uptake of 18F-labeled anti-HER2 5F7 in irradiated mice.

Conclusion

Low-level brain irradiation induces dynamic changes in tumor vasculature that increase the intracranial tumor delivery of an anti-HER2 VHH, which could facilitate the use of radiolabeled VHH to detect, monitor, and treat HER2-expressing brain metastases.

Department

Description

Provenance

Citation

Published Version (Please cite this version)

10.1093/noajnl/vdac135

Publication Info

Procissi, Daniele, Stephen A Jannetti, Markella Zannikou, Zhengyuan Zhou, Darryl McDougald, Deepak Kanojia, Hui Zhang, Kirsten Burdett, et al. (2022). Low-level whole-brain radiation enhances theranostic potential of single-domain antibody fragments for human epidermal growth factor receptor type 2 (HER2)-positive brain metastases. Neuro-oncology advances, 4(1). p. vdac135. 10.1093/noajnl/vdac135 Retrieved from https://hdl.handle.net/10161/25980.

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Scholars@Duke

Vaidyanathan

Ganesan Vaidyanathan

Professor Emeritus in Radiology

Dr. Vaidyanathan is a professor in the Department of Radiology.  He is a member of the Nuclear Medicine track of the Medical Physics Graduate Program.  His research involves development of radiopharmaceuticals especially for oncologic applications.  Some of the projects he is involved in are given below.

I.          New methods of radiohalogenating antibodies and its variants 

a) Development of newer residualizing agents for the radiohalogenation of internalizing monoclonal antibodies.

b)  Development of fluorine-18 labeled residualizing agents for labeling nanobodies.

c) Pre-targeting approach via bioorthogonal chemistry for in vivo labeling of antibodies and nanobodies with 18F and 211At.

d)  Methods to label antibodies pre-conjugated with a prosthetic group of the tin precursor of residualizing agents.

e) Multimodal prosthetic groups for labeling antibodies and peptides with multiple radioisotopes.

II.         MIBG Analogs for PET imaging

Radioiodinated MIBG is used in the diagnosis of the pathophysiology of the heart as well as neuroendocrine tumors such as neuroblastoma (NB).  Design and development of newer fluorine-18 labeled MIBG analogues useful in the PET imaging of NB as well as that of myocardial diseases.

III. Noninvasive Imaging of Alkylguanine-DNA alkyltransferase (AGT) 

AGT is a DNA repair protein and is primarily responsible for drug resistance in alkylator chemotherapy. An inverse correlation has been established between the tumor AGT content and the therapeutic outcome. The amount of AGT varies from tumor to tumor and within a group of patients of similar cancer. Thus, it is important to quantify tumor AGT of individual patients before administering alkylator chemotherapy. Our goal is to develop radiolabeled agents with which AGT can be quantified in a noninvasive manner by PET or SPECT imaging. 

IV. PSMA targeting for prostate cancer therapy 

Development of At-211 labeled urea-based inhibitor of Prostate-specific membrane antigen.

Zalutsky

Michael Rod Zalutsky

Jonathan Spicehandler, M.D. Distinguished Professor of Neuro Oncology, in the School of Medicine

The overall objective of our laboratory is the development of novel radioactive compounds for improving the diagnosis and treatment of cancer. This work primarily involves radiohalo-genation of biomolecules via site-specific approaches, generally via demetallation reactions. Radionuclides utilized for imaging include I-123, I-124 and F-18, the later two being of particular interest because they can be used for the quantification of biochemical and physiological processes in the living human through positron emission tomography. For therapy, astatine-211 decays by the emission of alpha-particles, a type of radiation considerably more cytotoxic that the beta-particles used in conventional endoradiotherapy. The range of At-211 alpha particles is only a few cell diameters, offering the possibility of extremely focal irradiation of malignant cells while leaving neighboring cells intact. Highlights of recent work include: a)
development of reagents for protein and peptide radioiodination that decrease deiodination in vivo by up to 100-fold, b) demonstration that At-211 labeled monoclonal antibodies are effective in the treatment of a rat model of neoplastic meningitis, c) synthesis of a thymidine analogue labeled with At-211 and the demonstration that this molecule is taken up in cellular DNA with highly cytotoxicity even at levels of only one atom bound per cell and d) development of
radiohalobenzylguanidines which are specifically cytotoxic for human neuroblastoma cells.


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