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Immunoconjugates for Cancer Imaging and Therapy

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Chemical Biology".

Deadline for manuscript submissions: closed (31 July 2021) | Viewed by 39224

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Special Issue Editors

Dr. João P. C. Tomé

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Guest Editor

Centro de Química Estrutural, Institute of Molecular Science and Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal
Interests: (photo)active (hybrid)materials; porphyrins; phthalocyanines; photomedicine; photoinduced energy; electron-transfer materials; optical (chemo)sensors; (photo)catalysis
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Jason S. Lewis

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Guest Editor

Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
Interests: development of radiopharmaceuticals for targeted diagnosis and treatment of cancer

Dr. Patricia Pereira

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Guest Editor

Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA
Interests: glycoconjugates; immunoconjugates; anti-cancer agents; PET imaging; photodynamic therapy; radiation therapy

Special Issue Information

Dear Colleagues,

Monoclonal antibodies (mAbs), with a high affinity for cancer cell surface antigens, are the most attractive biomolecules as diagnostics and therapeutics in oncology. Since the development of hybridoma technology, in 1975, several antibodies have been developed against either validated or novel tumor antigens overexpressed or selectively expressed on cancer cells.
Antibodies conjugated with drugs incorporate the high affinity/specificity of the mAb with the cytotoxicity of the drug and therefore selectively destroy tumor cells. On the other hand, optical- and radionuclide-labeled antibodies generate images with an intensity proportional to the amount of antibody-targeted tumor-antigen, allowing disease diagnosis and staging, and detection of tumor recurrence.
The present Special Issue on “Immunoconjugates for Cancer Imaging and Therapy” welcomes articles reporting original discoveries and reviews in the context of antibody–drug conjugates and optical- and radionuclide-labeled antibodies to be used as therapeutics and diagnostics in oncology.

Prof. Dr. João Paulo C. Tomé
Prof. Jason S. Lewis
Dr. Patricia Pereira
Guest Editors

Manuscript Submission Information

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Keywords

antibody
drug
antigen
tumor
imaging
therapy
immunoconjugates

Published Papers (7 papers)

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Research

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16 pages, 10081 KiB

Open AccessArticle

[⁸⁹Zr]-Pertuzumab PET Imaging Reveals Paclitaxel Treatment Efficacy Is Positively Correlated with HER2 Expression in Human Breast Cancer Xenograft Mouse Models

by Yun Lu, Meng Li, Adriana V. F. Massicano, Patrick N. Song, Ameer Mansur, Katherine A. Heinzman, Benjamin M. Larimer, Suzanne E. Lapi and Anna G. Sorace

Molecules 2021, 26(6), 1568; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26061568 - 12 Mar 2021

Cited by 9 | Viewed by 2462

Abstract

Paclitaxel (PTX) treatment efficacy varies in breast cancer, yet the underlying mechanism for variable response remains unclear. This study evaluates whether human epidermal growth factor receptor 2 (HER2) expression level utilizing advanced molecular positron emission tomography (PET) imaging is correlated with PTX treatment efficacy in preclinical mouse models of HER2+ breast cancer. HER2 positive (BT474, MDA-MB-361), or HER2 negative (MDA-MB-231) breast cancer cells were subcutaneously injected into athymic nude mice and PTX (15 mg/kg) was administrated. In vivo HER2 expression was quantified through [⁸⁹Zr]-pertuzumab PET/CT imaging. PTX treatment response was quantified by [¹⁸F]-fluorodeoxyglucose ([¹⁸F]-FDG) PET/CT imaging. Spearman’s correlation, Kendall’s tau, Kolmogorov–Smirnov test, and ANOVA were used for statistical analysis. [⁸⁹Zr]-pertuzumab mean standard uptake values (SUV_mean) of BT474 tumors were 4.9 ± 1.5, MDA-MB-361 tumors were 1.4 ± 0.2, and MDA-MB-231 (HER2−) tumors were 1.1 ± 0.4. [¹⁸F]-FDG SUV_mean changes were negatively correlated with [⁸⁹Zr]-pertuzumab SUV_mean (r = −0.5887, p = 0.0030). The baseline [¹⁸F]-FDG SUV_mean was negatively correlated with initial [⁸⁹Zr]-pertuzumab SUV_mean (r = −0.6852, p = 0.0002). This study shows PTX treatment efficacy is positively correlated with HER2 expression level in human breast cancer mouse models. Molecular imaging provides a non-invasive approach to quantify biological interactions, which will help in identifying chemotherapy responders and potentially enhance clinical decision-making. Full article

(This article belongs to the Special Issue Immunoconjugates for Cancer Imaging and Therapy)

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14 pages, 1318 KiB

Open AccessFeature PaperArticle

Glypican-3-Targeted Alpha Particle Therapy for Hepatocellular Carcinoma

by Meghan M. Bell, Nicholas T. Gutsche, A. Paden King, Kwamena E. Baidoo, Olivia J. Kelada, Peter L. Choyke and Freddy E. Escorcia

Molecules 2021, 26(1), 4; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26010004 - 22 Dec 2020

Cited by 18 | Viewed by 4356

Abstract

Glypican-3 (GPC3) is expressed in 75% of hepatocellular carcinoma (HCC), but not normal liver, making it a promising HCC therapeutic target. GC33 is a full-length humanized monoclonal IgG1 specific to GPC3 that can localize to HCC in vivo. GC33 alone failed to demonstrate therapeutic efficacy when evaluated in patients with HCC; however, we posit that cytotoxic functionalization of the antibody with therapeutic radionuclides, may be warranted. Alpha particles, which are emitted by radioisotopes such as Actinium-225 (Ac-225) exhibit high linear energy transfer and short pathlength that, when targeted to tumors, can effectively kill cancer and limit bystander cytotoxicity. Macropa, an 18-member heterocyclic crown ether, can stably chelate Ac-225 at room temperature. Here, we synthesized and evaluated the efficacy of [²²⁵Ac]Ac–Macropa–GC33 in mice engrafted with the GPC3-expressing human liver cancer cell line HepG2. Following a pilot dose-finding study, mice (n = 10 per group) were treated with (1) PBS, (2) mass-equivalent unmodified GC33, (3) 18.5 kBq [²²⁵Ac]Ac–Macropa–IgG1 (isotype control), (4) 9.25 kBq [²²⁵Ac]Ac–Macropa–GC33, and (5) 18.5 kBq [²²⁵Ac]Ac–Macropa–GC33. While significant toxicity was observed in all groups receiving radioconjugates, the 9.25 kBq [²²⁵Ac]Ac–Macropa–GC33 group demonstrated a modest survival advantage compared to PBS (p = 0.0012) and 18.5 kBq [²²⁵Ac]Ac–IgG1 (p = 0.0412). Hematological analysis demonstrated a marked, rapid reduction in white blood cells in all radioconjugate-treated groups compared to the PBS and unmodified GC33 control groups. Our studies highlight a significant disadvantage of using directly-labeled biomolecules with long blood circulation times for TAT. Strategies to mitigate such treatment toxicity include dose fractionation, pretargeting, and using smaller targeting ligands. Full article

(This article belongs to the Special Issue Immunoconjugates for Cancer Imaging and Therapy)

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18 pages, 7561 KiB

Open AccessArticle

Quantification of Trastuzumab–HER2 Engagement In Vitro and In Vivo

by Alena Rudkouskaya, Jason T. Smith, Xavier Intes and Margarida Barroso

Molecules 2020, 25(24), 5976; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25245976 - 17 Dec 2020

Cited by 17 | Viewed by 3441

Abstract

Human EGF Receptor 2 (HER2) is an important oncogene driving aggressive metastatic growth in up to 20% of breast cancer tumors. At the same time, it presents a target for passive immunotherapy such as trastuzumab (TZM). Although TZM has been widely used clinically since 1998, not all eligible patients benefit from this therapy due to primary and acquired drug resistance as well as potentially lack of drug exposure. Hence, it is critical to directly quantify TZM–HER2 binding dynamics, also known as cellular target engagement, in undisturbed tumor environments in live, intact tumor xenograft models. Herein, we report the direct measurement of TZM–HER2 binding in HER2-positive human breast cancer cells and tumor xenografts using fluorescence lifetime Forster Resonance Energy Transfer (FLI-FRET) via near-infrared (NIR) microscopy (FLIM-FRET) as well as macroscopy (MFLI-FRET) approaches. By sensing the reduction of fluorescence lifetime of donor-labeled TZM in the presence of acceptor-labeled TZM, we successfully quantified the fraction of HER2-bound and internalized TZM immunoconjugate both in cell culture and tumor xenografts in live animals. Ex vivo immunohistological analysis of tumors confirmed the binding and internalization of TZM–HER2 complex in breast cancer cells. Thus, FLI-FRET imaging presents a powerful analytical tool to monitor and quantify cellular target engagement and subsequent intracellular drug delivery in live HER2-positive tumor xenografts. Full article

(This article belongs to the Special Issue Immunoconjugates for Cancer Imaging and Therapy)

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13 pages, 1986 KiB

Open AccessArticle

UCNP-based Photoluminescent Nanomedicines for Targeted Imaging and Theranostics of Cancer

by Evgenii L. Guryev, Anita S. Smyshlyaeva, Natalia Y. Shilyagina, Evgeniya A. Sokolova, Samah Shanwar, Alexey B. Kostyuk, Alexander V. Lyubeshkin, Alexey A. Schulga, Elena V. Konovalova, Quan Lin, Indrajit Roy, Irina V. Balalaeva, Sergey M. Deyev and Andrei V. Zvyagin

Molecules 2020, 25(18), 4302; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25184302 - 19 Sep 2020

Cited by 20 | Viewed by 3229

Abstract

Theranostic approach is currently among the fastest growing trends in cancer treatment. It implies the creation of multifunctional agents for simultaneous precise diagnosis and targeted impact on tumor cells. A new type of theranostic complexes was created based on NaYF₄: Yb,Tm upconversion nanoparticles coated with polyethylene glycol and functionalized with the HER2-specific recombinant targeted toxin DARPin-LoPE. The obtained agents bind to HER2-overexpressing human breast adenocarcinoma cells and demonstrate selective cytotoxicity against this type of cancer cells. Using fluorescent human breast adenocarcinoma xenograft models, the possibility of intravital visualization of the UCNP-based complexes biodistribution and accumulation in tumor was demonstrated. Full article

(This article belongs to the Special Issue Immunoconjugates for Cancer Imaging and Therapy)

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13 pages, 1780 KiB

Open AccessFeature PaperArticle

⁸⁹Zr-Labeled AR20.5: A MUC1-Targeting ImmunoPET Probe

by Kimberly Fung, Delphine Vivier, Outi Keinänen, Elaheh Khozeimeh Sarbisheh, Eric W. Price and Brian M. Zeglis

Molecules 2020, 25(10), 2315; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25102315 - 15 May 2020

Cited by 6 | Viewed by 3888

Abstract

High expression levels of the tumor-associated antigen MUC1 have been correlated with tumor aggressiveness, poor response to therapy, and poor survival in several tumor types, including breast, pancreatic, and epithelial ovarian cancer. Herein, we report the synthesis, characterization, and in vivo evaluation of a novel radioimmunoconjugate for the immuno-positron emission tomography (immunoPET) imaging of MUC1 expression based on the AR20.5 antibody. To this end, we modified AR20.5 with the chelator desferrioxamine (DFO) and labeled it with the positron-emitting radiometal zirconium-89 (t_1/2 ~3.3 d) to produce [⁸⁹Zr]Zr-DFO-AR20.5. In subsequent in vivo experiments in athymic nude mice bearing subcutaneous MUC1-expressing ovarian cancer xenografts, [⁸⁹Zr]Zr-DFO-AR20.5 clearly delineated tumor tissue, producing a tumoral activity concentration of 19.1 ± 6.4 percent injected dose per gram (%ID/g) at 120 h post-injection and a tumor-to-muscle activity concentration ratio of 42.4 ± 10.6 at the same time point. Additional PET imaging experiments in mice bearing orthotopic MUC1-expressing ovarian cancer xenografts likewise demonstrated that [⁸⁹Zr]Zr-DFO-AR20.5 enables the visualization of tumor tissue—including metastatic lesions—with promising tumor-to-background contrast. Full article

(This article belongs to the Special Issue Immunoconjugates for Cancer Imaging and Therapy)

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Review

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33 pages, 2021 KiB

Open AccessReview

Antibody–Drug Conjugates for Cancer Therapy

by Umbreen Hafeez, Sagun Parakh, Hui K. Gan and Andrew M. Scott

Molecules 2020, 25(20), 4764; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25204764 - 16 Oct 2020

Cited by 172 | Viewed by 18419

Abstract

Antibody–drug conjugates (ADCs) are novel drugs that exploit the specificity of a monoclonal antibody (mAb) to reach target antigens expressed on cancer cells for the delivery of a potent cytotoxic payload. ADCs provide a unique opportunity to deliver drugs to tumor cells while minimizing toxicity to normal tissue, achieving wider therapeutic windows and enhanced pharmacokinetic/pharmacodynamic properties. To date, nine ADCs have been approved by the FDA and more than 80 ADCs are under clinical development worldwide. In this paper, we provide an overview of the biology and chemistry of each component of ADC design. We briefly discuss the clinical experience with approved ADCs and the various pathways involved in ADC resistance. We conclude with perspectives about the future development of the next generations of ADCs, including the role of molecular imaging in drug development. Full article

(This article belongs to the Special Issue Immunoconjugates for Cancer Imaging and Therapy)

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12 pages, 1253 KiB

Open AccessFeature PaperReview

Antibody-Targeted Imaging of Gastric Cancer

by Komal Mandleywala, Shayla Shmuel, Patricia M. R. Pereira and Jason S. Lewis

Molecules 2020, 25(20), 4621; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25204621 - 11 Oct 2020

Cited by 7 | Viewed by 2550

Abstract

The specificity of antibodies for antigens overexpressed or uniquely expressed in tumor cells makes them ideal candidates in the development of bioconjugates for tumor imaging. Molecular imaging can aid clinicians in the diagnosis of gastric tumors and in selecting patients for therapies targeting receptors with a heterogeneous intratumoral or intertumoral expression. Antibodies labeled with an imaging radiometal can be used to detect primary tumors and metastases using whole-body positron emission tomography (PET) or single photon emission computed tomography (SPECT), both during diagnosis and monitoring disease response. Conjugated with fluorescent dyes, antibodies can image tumors by targeted optical imaging. This review provides an overview of the most recent advances in the use of antibodies labeled with radiometals or conjugated with fluorescent dyes for gastric cancer imaging. Full article

(This article belongs to the Special Issue Immunoconjugates for Cancer Imaging and Therapy)

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