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Cancers
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Monoclonal Antibodies: Applications in Diagnosis and Immunotherapy of Cancer
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Monoclonal Antibodies: Applications in Diagnosis and Immunotherapy of Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Causes, Screening and Diagnosis".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 26410

Special Issue Editors

Prof. Kar Muthumani

E-Mail Website
Guest Editor
1. Vaccine & Immunotherapy Center, The Wistar Institute, Philadelphia, PA 19104, USA
2. GeneOne Life Science Inc., Fort Washington, PA 19034, USA
Interests: development of prophylactic and therapeutic synthetic vaccines to offer broad; rapid; and sustained protection against pathogen and cancer targets
Special Issues, Collections and Topics in MDPI journals
Dr. Kenneth E. Ugen

E-Mail Website
Guest Editor
University of South Florida, Morsani College of Medicine, Department of Molecular Medicine, Tampa, USA
Interests: Research focuses on applied and translational immunology with the goal of developing and characterizing novel gene-based vaccines and therapies against infectious agents and cancer
Dr. Alagarsamy Srinivasan

E-Mail Website
Guest Editor
Formerly Associated with Thomas Jefferson University & Center for Prostate Disease Research, Uniformed Services University, Bethesda, MD 20814, USA
Interests: liquid biopsy; tumor antigens; autoantibodies; multi-omics; prognostic biomarkers; diagnostic biomarkers; cancer vaccines; immunotherapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The high specificity exhibited by monoclonal antibodies (mAbs) towards their target antigens is the basis for the consideration of mAbs as therapeutic agents. This has been an active area of investigation for more than thirty years. Currently, mAbs are being used to treat cancers, autoimmune, and several other diseases. The number of monoclonal antibodies available has been on the rise in the past five years according to the FDA and ongoing clinical trials. The use of mAbs for therapeutic purposes has its origins in the studies conducted with serum containing polyclonal antibodies and used to treat infectious diseases including diphtheria in the late 19th century. Similar approaches were also extended to human cancer through inoculation of several species of animals with variable success rates. Advances made in the latter half of the 20th century in several areas of science contributed greatly to our understanding of the cells and immune system. The birth of molecular biology extended the studies at the molecular and mechanistic levels. Molecular biology related to mAbs resulted in the discovery of hybridoma technology (Kohler and Milstein, 1975), for the production of specific antibodies, and helped the field enormously. Further, recombinant DNA technology provided tools for the generation of engineered mAbs.

On the therapeutic front, mAbs are pursued by the pharma industry to the extent that around 645 mAbs were undergoing clinical trials as of 2018. Interestingly, one third is directed towards cancer therapy. This is partly due to the technological revolution that has helped shorten the traditional development process of mAbs. Besides native antibodies, modified antibodies, in the form of chimeric, humanized, and antibody fragments (Fab, scFv and single domain), are in the pipeline.

The goal of this Special Issue, entitled “Monoclonal Antibodies: Applications in Diagnosis and Immunotherapy of Cancer”, is to provide the latest information on topics relevant to the design, development, and therapeutic uses of mAbs. These include:

  • development and optimization of mAbs using novel platforms;
  • engineering of antibody fragments (Fab, scFv and single domain) and their uses in therapy;
  • bispecific antibodies;
  • mAbs-drug conjugates (radioactive particles, chemotherapy drugs and cell toxins);
  • mAbs in diagnostic applications;
  • mAbs in imaging and radiotherapy;
  • combinatorial use of mAbs;
  • gene and viral based delivery of mAbs for therapy;
  • chimeric antigen receptor (CAR);
  • Fc fusion proteins as therapeutic agents.

As outlined above, the Special Issue proposes to cover a wide range of topics. For this reason, we are welcoming reviews, research articles, and perspectives on the subject. We hope to provide readers with information on the current state of the field as well as areas for future research.  

Prof. Kar Muthumani
Dr. Kenneth E. Ugen
Prof. Alagarsamy Srinivasan
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (5 papers)

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Research

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12 pages, 3374 KiB  
Article
Mouse Preclinical Cancer Immunotherapy Modeling Involving Anti-PD-1 Therapies Reveals the Need to Use Mouse Reagents to Mirror Clinical Paradigms
by Arta M. Monjazeb, Ziming Wang, Logan V. Vick, Cordelia Dunai, Christine Minnar, Lam T. Khuat and William J. Murphy
Cancers 2021, 13(4), 729; https://doi.org/10.3390/cancers13040729 - 10 Feb 2021
Cited by 2 | Viewed by 3568
Abstract
Immune checkpoint inhibition (ICI) has emerged as one of the most powerful tools to reverse cancer induced immune suppression. Monoclonal antibodies (mAbs) targeting programmed cell death 1/programmed cell death ligand 1(PD-1/PD-L1) are FDA-approved and their clinical use is rapidly expanding. As opposed to [...] Read more.
Immune checkpoint inhibition (ICI) has emerged as one of the most powerful tools to reverse cancer induced immune suppression. Monoclonal antibodies (mAbs) targeting programmed cell death 1/programmed cell death ligand 1(PD-1/PD-L1) are FDA-approved and their clinical use is rapidly expanding. As opposed to the clinical paradigm, which can result in significant responses and toxicities, it has been difficult to reproduce these effects preclinically using mouse models. In large part, this is due to models, which employ rapidly growing ex vivo cultured transplantable tumor cell lines engrafted into young naïve inbred laboratory mice. However, another issue concerns the use and repeated application of xenogeneic reagents in mice (i.e., rat or hamster mAbs directed against mouse antigens at variance with clinical use of human or humanized mAbs). Building on our previous studies demonstrating that repeated administration of commonly used xenogeneic anti-PD-1 mAbs derived from both rat and hamster can induce fatal hypersensitivity in some tumor-bearing mice, we sought to compare these result with the effects of a mouse anti-mouse PD-1 mAb. Application of a murine anti-mouse PD-1 (clone: MuDX400) did not result in lethal anaphylaxis in the 4T1 tumor model. It also displayed superior antitumor effects in this and other tumor models, as it did not induce neutralizing antibody responses against the anti-PD-1 mAb, such as were observed when using xenogeneic anti-PD1 mAbs. These results demonstrate that more accurate preclinical modeling necessitates the use of mouse reagents mirroring the clinical scenario to ascertain long-term effects or toxicities, while avoiding xenogeneic responses, which do not occur clinically. Furthermore, these studies suggest a direct mechanism, whereby preclinical murine studies have often failed to recapitulate the clinical efficacy and toxicity of single agent checkpoint inhibition. Full article
(This article belongs to the Special Issue Monoclonal Antibodies: Applications in Diagnosis and Immunotherapy of Cancer)
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16 pages, 7743 KiB  
Article
89Zr-Labeled Domain II-Specific scFv-Fc ImmunoPET Probe for Imaging Epidermal Growth Factor Receptor In Vivo
by Elahe Alizadeh, Khan Behlol Ayaz Ahmed, Viswas Raja Solomon, Vijay Gaja, Wendy Bernhard, Amal Makhlouf, Carolina Gonzalez, Kris Barreto, Angel Casaco, C. Ronald Geyer and Humphrey Fonge
Cancers 2021, 13(3), 560; https://doi.org/10.3390/cancers13030560 - 01 Feb 2021
Cited by 5 | Viewed by 2810
Abstract
Epidermal growth factor receptor I (EGFR) is overexpressed in many cancers. The extracellular domain of EGFR has four binding epitopes (domains I- IV). All clinically approved anti-EGFR antibodies bind to domain III. Imaging agents that bind to domains other than domain III of [...] Read more.
Epidermal growth factor receptor I (EGFR) is overexpressed in many cancers. The extracellular domain of EGFR has four binding epitopes (domains I- IV). All clinically approved anti-EGFR antibodies bind to domain III. Imaging agents that bind to domains other than domain III of EGFR are needed for accurate quantification of EGFR, patient selection for anti-EGFR therapeutics and monitoring of response to therapies. We recently developed a domain II-specific antibody fragment 8709. In this study, we have evaluated the in vitro and in vivo properties of 89Zr-8709-scFv-Fc (105 kDa). We conjugated 8709-scFv-Fc with the deferoxamine (DFO) chelator and radiolabeled the DFO-8970-scFv with 89Zr. We evaluated the binding of 89Zr-DFO-8709-scFv-Fc in EGFR positive and negative cell lines DLD-1, MDA-MB-231 and MDA-MB-435, respectively, and in mouse xenograft models. Simultaneously, we have compared the binding of 89Zr-8709-scFv-Fc with 111In-nimotuzumab, a domain III anti-EGFR antibody. DFO-8709-scFv-Fc displayed similar cell binding specificity as 8709-scFv-Fc. Saturation cell binding assay and immunoreactive fraction showed that radiolabeling did not alter the binding of 8709-scFv-Fc. Biodistribution and microPET showed good uptake of 89Zr-8709-scFv-Fc in xenografts after 120 h post injection (p.i). and was domain-specific to EGFR domain II. 89Zr-8709-scFv-Fc did not compete for binding in vitro and in vivo with a known domain III binder nimotuzumab. The results show that 89Zr-8709-scFv-Fc is specific to domain II of EGFR making it favorable for quantification of EGFR in vivo, hence, patient selection and monitoring of response to treatment with anti-EGFR antibodies. Full article
(This article belongs to the Special Issue Monoclonal Antibodies: Applications in Diagnosis and Immunotherapy of Cancer)
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18 pages, 3318 KiB  
Article
Nimotuzumab Site-Specifically Labeled with 89Zr and 225Ac Using SpyTag/SpyCatcher for PET Imaging and Alpha Particle Radioimmunotherapy of Epidermal Growth Factor Receptor Positive Cancers
by Viswas Raja Solomon, Kris Barreto, Wendy Bernhard, Elahe Alizadeh, Patrick Causey, Randy Perron, Denise Gendron, Md. Kausar Alam, Adriana Carr, C. Ronald Geyer and Humphrey Fonge
Cancers 2020, 12(11), 3449; https://doi.org/10.3390/cancers12113449 - 20 Nov 2020
Cited by 10 | Viewed by 3554
Abstract
To develop imaging and therapeutic agents, antibodies are often conjugated randomly to a chelator/radioisotope or drug using a primary amine (NH2) of lysine or sulfhydryl (SH) of cysteine. Random conjugation to NH2 or SH groups can require extreme conditions and [...] Read more.
To develop imaging and therapeutic agents, antibodies are often conjugated randomly to a chelator/radioisotope or drug using a primary amine (NH2) of lysine or sulfhydryl (SH) of cysteine. Random conjugation to NH2 or SH groups can require extreme conditions and may affect target recognition/binding and must therefore be tested. In the present study, nimotuzumab was site-specifically labeled using ∆N-SpyCatcher/SpyTag with different chelators and radiometals. Nimotuzumab is a well-tolerated anti-EGFR antibody with low skin toxicities. First, ΔN-SpyCatcher was reduced using tris(2-carboxyethyl)phosphine (TCEP), which was followed by desferoxamine-maleimide (DFO-mal) conjugation to yield a reactive ΔN-SpyCatcher-DFO. The ΔN-SpyCatcher-DFO was reacted with nimotuzumab-SpyTag to obtain stable nimotuzumab-SpyTag-∆N-SpyCatcher-DFO. Radiolabeling was performed with 89Zr, and the conjugate was used for the in vivo microPET imaging of EGFR-positive MDA-MB-468 xenografts. Similarly, ∆N-SpyCatcher was conjugated to an eighteen-membered macrocyclic chelator macropa-maleimide and used to radiolabel nimotuzumab-SpyTag with actinium-225 (225Ac) for in vivo radiotherapy studies. All constructs were characterized using biolayer interferometry, flow cytometry, radioligand binding assays, HPLC, and bioanalyzer. MicroPET/CT imaging showed a good tumor uptake of 89Zr-nimotuzumab-SpyTag-∆N-SpyCatcher with 6.0 ± 0.6%IA/cc (n = 3) at 48 h post injection. The EC50 of 225Ac-nimotuzumab-SpyTag-∆N-SpyCatcher and 225Ac-control-IgG-SpyTag-∆N-SpyCatcher against an EGFR-positive cell-line (MDA-MB-468) was 3.7 ± 3.3 Bq/mL (0.04 ± 0.03 nM) and 18.5 ± 4.4 Bq/mL (0.2 ± 0.04 nM), respectively. In mice bearing MDA-MB-468 EGFR-positive xenografts, 225Ac-nimotuzumab-SpyTag-∆N-SpyCatcher significantly (p = 0.0017) prolonged the survival of mice (64 days) compared to 225Ac-control IgG (28.5 days), nimotuzumab (28.5 days), or PBS-treated mice (30 days). The results showed that the conjugation and labeling using SpyTag/∆N-SpyCatcher to nimotuzumab did not significantly (p > 0.05) alter the receptor binding of nimotuzumab compared with a non-specific conjugation approach. 225Ac-nimotuzumab-SpyTag-∆N-SpyCatcher was effective in vitro and in an EGFR-positive triple negative breast cancer xenograft model. Full article
(This article belongs to the Special Issue Monoclonal Antibodies: Applications in Diagnosis and Immunotherapy of Cancer)
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Review

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13 pages, 778 KiB  
Review
Engineering Anti-Tumor Monoclonal Antibodies and Fc Receptors to Enhance ADCC by Human NK Cells
by Kate J. Dixon, Jianming Wu and Bruce Walcheck
Cancers 2021, 13(2), 312; https://doi.org/10.3390/cancers13020312 - 16 Jan 2021
Cited by 43 | Viewed by 9555
Abstract
Tumor-targeting monoclonal antibodies (mAbs) are the most widely used and characterized immunotherapy for hematologic and solid tumors. The significance of this therapy is their direct and indirect effects on tumor cells, facilitated by the antibody’s antigen-binding fragment (Fab) and fragment crystallizable region (Fc [...] Read more.
Tumor-targeting monoclonal antibodies (mAbs) are the most widely used and characterized immunotherapy for hematologic and solid tumors. The significance of this therapy is their direct and indirect effects on tumor cells, facilitated by the antibody’s antigen-binding fragment (Fab) and fragment crystallizable region (Fc region), respectively. The Fab can modulate the function of cell surface markers on tumor cells in an agonistic or antagonistic manner, whereas the Fc region can be recognized by an Fc receptor (FcR) on leukocytes through which various effector functions, including antibody-dependent cell-mediated cytotoxicity (ADCC), can be elicited. This process is a key cytolytic mechanism of natural killer (NK) cells. These innate lymphocytes in the human body recognize tumor-bound antibodies exclusively by the IgG Fc receptor CD16A (FcγRIIIA). Two allelic versions of CD16A bind IgG with either lower or higher affinity. Cancer patients homozygous for the higher affinity allele of CD16A have been reported to respond significantly better to mAb therapies for various malignancies. These studies revealed that mAb therapy efficacy positively correlates with higher affinity binding to CD16A. Approaches to enhance tumor antigen targeting by NK cells by modifying the Fc portion of antibodies or the FcR on NK cells are the focus of this review. Full article
(This article belongs to the Special Issue Monoclonal Antibodies: Applications in Diagnosis and Immunotherapy of Cancer)
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12 pages, 1450 KiB  
Review
Monoclonal Antibody-Based Immunotherapy and Its Role in the Development of Cardiac Toxicity
by Mohit Kumar, Chellappagounder Thangavel, Richard C. Becker and Sakthivel Sadayappan
Cancers 2021, 13(1), 86; https://doi.org/10.3390/cancers13010086 - 30 Dec 2020
Cited by 14 | Viewed by 5946
Abstract
Immunotherapy is one of the most effective therapeutic options for cancer patients. Five specific classes of immunotherapies, which includes cell-based chimeric antigenic receptor T-cells, checkpoint inhibitors, cancer vaccines, antibody-based targeted therapies, and oncolytic viruses. Immunotherapies can improve survival rates among cancer patients. At [...] Read more.
Immunotherapy is one of the most effective therapeutic options for cancer patients. Five specific classes of immunotherapies, which includes cell-based chimeric antigenic receptor T-cells, checkpoint inhibitors, cancer vaccines, antibody-based targeted therapies, and oncolytic viruses. Immunotherapies can improve survival rates among cancer patients. At the same time, however, they can cause inflammation and promote adverse cardiac immune modulation and cardiac failure among some cancer patients as late as five to ten years following immunotherapy. In this review, we discuss cardiotoxicity associated with immunotherapy. We also propose using human-induced pluripotent stem cell-derived cardiomyocytes/ cardiac-stromal progenitor cells and cardiac organoid cultures as innovative experimental model systems to (1) mimic clinical treatment, resulting in reproducible data, and (2) promote the identification of immunotherapy-induced biomarkers of both early and late cardiotoxicity. Finally, we introduce the integration of omics-derived high-volume data and cardiac biology as a pathway toward the discovery of new and efficient non-toxic immunotherapy. Full article
(This article belongs to the Special Issue Monoclonal Antibodies: Applications in Diagnosis and Immunotherapy of Cancer)
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