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Immunoconjugates for Cancer Imaging and Therapy
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Immunoconjugates for Cancer Imaging and Therapy

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 50743

Special Issue Editors

Dr. João P. C. Tomé

E-Mail Website
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

E-Mail Website
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

E-Mail Website
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

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Keywords

  • antibody
  • drug
  • antigen
  • tumor
  • imaging
  • therapy
  • immunoconjugates

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Published Papers (7 papers)

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Research

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16 pages, 10081 KiB  
Article
[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://doi.org/10.3390/molecules26061568 - 12 Mar 2021
Cited by 14 | Viewed by 3205
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 [...] Read more.
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 (SUVmean) 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 SUVmean changes were negatively correlated with [89Zr]-pertuzumab SUVmean (r = −0.5887, p = 0.0030). The baseline [18F]-FDG SUVmean was negatively correlated with initial [89Zr]-pertuzumab SUVmean (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  
Article
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://doi.org/10.3390/molecules26010004 - 22 Dec 2020
Cited by 29 | Viewed by 5566
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 [...] Read more.
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  
Article
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://doi.org/10.3390/molecules25245976 - 17 Dec 2020
Cited by 24 | Viewed by 4520
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 [...] Read more.
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  
Article
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://doi.org/10.3390/molecules25184302 - 19 Sep 2020
Cited by 23 | Viewed by 4194
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 [...] Read more.
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  
Article
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://doi.org/10.3390/molecules25102315 - 15 May 2020
Cited by 7 | Viewed by 4812
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 [...] Read more.
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 (t1/2 ~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  
Review
Antibody–Drug Conjugates for Cancer Therapy
by Umbreen Hafeez, Sagun Parakh, Hui K. Gan and Andrew M. Scott
Molecules 2020, 25(20), 4764; https://doi.org/10.3390/molecules25204764 - 16 Oct 2020
Cited by 263 | Viewed by 24038
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 [...] Read more.
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  
Review
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://doi.org/10.3390/molecules25204621 - 11 Oct 2020
Cited by 9 | Viewed by 3377
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 [...] Read more.
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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