Special Issue "Therapeutic Monoclonal Antibodies and Antibody Products, Their Optimization and Drug Design in Cancers"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: 31 July 2019

Special Issue Editor

Guest Editor
Assoc. Prof. Dr. Veysel Kayser

School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
Website | E-Mail
Interests: Monoclonal antibodies; biosimilars; biobetters; bispecifics; protein aggregation; biotherapeutics; influenza; rabies; vaccines and vaccinology

Special Issue Information

Dear Colleagues,

Various forms of antibody products, in particular full-size monoclonal antibodies (mAbs), have been dominating the biologics market as a result of their specificity and selectivity. They are also the mainstay for the development of next-generation biologics and biobetters for a number of disorders, including cancer. Currently, there are more than 70 approved antibody therapeutics on the market, but hundreds more are in clinical trials at various stages. Perhaps not surprisingly, a considerable number of these medications have been developed for the treatment of different types of cancers.

Because of the recent expirations of patent protections and changes in the regulatory framework around the world, biosimilars of widely used biologics, including mAbs, have slowly started to appear; nevertheless, we are yet to see a global impact of biosimilars. Notwithstanding the biosimilar development, a great deal of effort is being made to develop the next generation of mAbs. These comprise different forms of antibody products including, but not limited to, bispecific or multispecific mAbs, hyperglycosylated mAbs, antibody–drug-conjugates (ADC), single-domain antibodies (nanobodies), and antibody-based nanoparticles. The majority of these new developments transpired to address concerns of structural stability of antibodies, commonly observed formulation issues, strategies to prevent protein degradation especially due to aggregation or to enhance antibodies’ efficacy and specificity.

Trail-and-error methods still dominate the overall drug development and are commonly applied in different phases of the development of biologics, including antibody therapeutics. Rational drug development is only possible by the development of novel experimental and computational methods and by elucidating interactions at the molecular level. Most of the drug candidates comprising the next-generation biologics and antibody products would benefit from additional optimization. With the advance of experimental and computational methods, we can further optimize antibodies as never before.

In this Special Issue, we will collate a number of studies showcasing the current state of play as well as recent developments in mAb therapeutics and other antibody products used in cancer, their optimization using experimental and computational approaches, new developments in bi- and multi-specifics, ADC, nanobodies, and antibody-based nanoparticle arenas.

Assoc. Prof. Veysel Kayser
Guest Editor

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 papers will be 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 monthly 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 1800 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.

Keywords

  • Monoclonal Antibodies (mAbs)
  • Antibody Medicines
  • Antibody–Drug Conjugates (ADC)
  • Bispecific Antibodies
  • Next-generation Biologics
  • Single-domain Antibodies (Nanobodies)
  • Antibody Optimization

Published Papers (6 papers)

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Research

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Open AccessArticle Differential Effects of Ang-2/VEGF-A Inhibiting Antibodies in Combination with Radio- or Chemotherapy in Glioma
Cancers 2019, 11(3), 314; https://doi.org/10.3390/cancers11030314
Received: 31 December 2018 / Revised: 28 February 2019 / Accepted: 28 February 2019 / Published: 6 March 2019
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Abstract
Antiangiogenic strategies have not shown striking antitumor activities in the majority of glioma patients so far. It is unclear which antiangiogenic combination regimen with standard therapy is most effective. Therefore, we compared anti-VEGF-A, anti-Ang2, and bispecific anti-Ang-2/VEGF-A antibody treatments, alone and in combination [...] Read more.
Antiangiogenic strategies have not shown striking antitumor activities in the majority of glioma patients so far. It is unclear which antiangiogenic combination regimen with standard therapy is most effective. Therefore, we compared anti-VEGF-A, anti-Ang2, and bispecific anti-Ang-2/VEGF-A antibody treatments, alone and in combination with radio- or temozolomide (TMZ) chemotherapy, in a malignant glioma model using multiparameter two-photon in vivo microscopy in mice. We demonstrate that anti-Ang-2/VEGF-A lead to the strongest vascular changes, including vascular normalization, both as monotherapy and when combined with chemotherapy. The latter was accompanied by the most effective chemotherapy-induced death of cancer cells and diminished tumor growth. This was most probably due to a better tumor distribution of the drug, decreased tumor cell motility, and decreased formation of resistance-associated tumor microtubes. Remarkably, all these parameters where reverted when radiotherapy was chosen as combination partner for anti-Ang-2/VEGF-A. In contrast, the best combination partner for radiotherapy was anti-VEGF-A. In conclusion, while TMZ chemotherapy benefits most from combination with anti-Ang-2/VEGF-A, radiotherapy does from anti-VEGF-A. The findings imply that uninformed combination regimens of antiangiogenic and cytotoxic therapies should be avoided. Full article
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Open AccessArticle Combination of Baseline LDH, Performance Status and Age as Integrated Algorithm to Identify Solid Tumor Patients with Higher Probability of Response to Anti PD-1 and PD-L1 Monoclonal Antibodies
Cancers 2019, 11(2), 223; https://doi.org/10.3390/cancers11020223
Received: 12 December 2018 / Revised: 19 January 2019 / Accepted: 12 February 2019 / Published: 14 February 2019
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Abstract
Predictive biomarkers of response to immune-checkpoint inhibitors (ICIs) are an urgent clinical need. The aim of this study is to identify manageable parameters to use in clinical practice to select patients with higher probability of response to ICIs. Two-hundred-and-seventy-one consecutive metastatic solid tumor [...] Read more.
Predictive biomarkers of response to immune-checkpoint inhibitors (ICIs) are an urgent clinical need. The aim of this study is to identify manageable parameters to use in clinical practice to select patients with higher probability of response to ICIs. Two-hundred-and-seventy-one consecutive metastatic solid tumor patients, treated from 2013 until 2017 with anti- Programmed death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) ICIs, were evaluated for baseline lactate dehydrogenase (LDH) serum level, performance status (PS), age, neutrophil-lymphocyte ratio, type of immunotherapy, number of metastatic sites, histology, and sex. A training and validation set were used to build and test models, respectively. The variables’ effects were assessed through odds ratio estimates (OR) and area under the receive operating characteristic curves (AUC), from univariate and multivariate logistic regression models. A final multivariate model with LDH, age and PS showed significant ORs and an AUC of 0.771. Results were statistically validated and used to devise an Excel algorithm to calculate the patient’s response probabilities. We implemented an interactive Excel algorithm based on three variables (baseline LDH serum level, age and PS) which is able to provide a higher performance in response prediction to ICIs compared with LDH alone. This tool could be used in a real-life setting to identify ICIs in responding patients. Full article
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Open AccessCommunication The Risks and Benefits of Immune Checkpoint Blockade in Anti-AChR Antibody-Seropositive Non-Small Cell Lung Cancer Patients
Cancers 2019, 11(2), 140; https://doi.org/10.3390/cancers11020140
Received: 30 December 2018 / Revised: 18 January 2019 / Accepted: 21 January 2019 / Published: 24 January 2019
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Abstract
Background: Anti-programmed cell death 1 (PD-1) monoclonal antibodies (Abs) unleash an immune response to cancer. However, a disruption of the immune checkpoint function by blocking PD-1/PD-ligand 1(PD-L1) signaling may trigger myasthenia gravis (MG) as a life-threatening immune-related adverse event. MG is a neuromuscular [...] Read more.
Background: Anti-programmed cell death 1 (PD-1) monoclonal antibodies (Abs) unleash an immune response to cancer. However, a disruption of the immune checkpoint function by blocking PD-1/PD-ligand 1(PD-L1) signaling may trigger myasthenia gravis (MG) as a life-threatening immune-related adverse event. MG is a neuromuscular disease and is closely associated with being positive for anti-acetylcholine receptor (anti-AChR) Abs, which are high specific and diagnostic Abs for MG. Methods: A 72-year-old man was diagnosed with chemotherapy-refractory lung squamous cell carcinoma and nivolumab was selected as the third-line regimen. We describe the first report of an anti-AChR Ab-seropositive lung cancer patient achieving a durable complete response (CR) to an anti-PD-1 antibody therapy. To further explore this case, we performed multiplex immunofluorescence analysis on a pretreatment tumor. Results: The patient achieved a durable CR without developing MG. However, the levels of anti-AChR Abs were elevated during two years of anti-PD-1 antibody therapy. The tumor of the subclinical MG patient had high PD-L1 expression and an infiltrated–inflamed tumor immune microenvironment. Conclusions: This study suggests that immune checkpoint inhibitors can be safely used and provide the benefits for advanced cancer patients with immunologically ‘hot’ tumor even if anti-AChR Abs are positive. Although careful monitoring clinical manifestation in consultation with neurologist is needed, immune checkpoint inhibitors should be considered as a treatment option for asymptomatic anti-AChR Ab-seropositive cancer patients. Full article
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Open AccessArticle Influence of Vitamin D in Advanced Non-Small Cell Lung Cancer Patients Treated with Nivolumab
Cancers 2019, 11(1), 125; https://doi.org/10.3390/cancers11010125
Received: 11 December 2018 / Revised: 12 January 2019 / Accepted: 16 January 2019 / Published: 21 January 2019
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Abstract
Nivolumab is one of the most commonly used monoclonal antibodies for advanced non-small cell lung cancer treatment, to the extent that the presence of its anti-antibody is considered a negative prognostic factor. Vitamin D (VD) modulates expression of the genes involved in drug [...] Read more.
Nivolumab is one of the most commonly used monoclonal antibodies for advanced non-small cell lung cancer treatment, to the extent that the presence of its anti-antibody is considered a negative prognostic factor. Vitamin D (VD) modulates expression of the genes involved in drug metabolism and elimination. Immune system regulation and immunodeficiency is frequent in non-small cell lung cancer patients. To date, no data have been reported about the relationship between nivolumab and VD. The aim of this study was to quantify plasma 25-hydroxyVD (25-VD) and 1,25-VD, nivolumab, and its anti-antibody before starting treatment (baseline) and at 15, 45 and 60 days of therapy. VD-pathway-associated gene single nucleotide polymorphisms (SNPs) were also evaluated. Molecules were quantified through enzyme-linked immunosorbent assay, and SNPs through real-time PCR. Forty-five patients were enrolled. Median nivolumab concentrations were 12.5 μg/mL, 22.3 μg/mL and 27.1 μg/mL at 15, 45 and 60 days respectively. No anti-nivolumab antibodies were found. Correlations were observed between nivolumab concentrations and 25-VD levels. Nivolumab concentrations were affected by VD-pathway-related gene SNPs. VDBP AC/CC genotype and baseline 25-VD < 10 ng/mL predicted a nivolumab concentration cut-off value of <18.7 μg/mL at 15 days, which was associated with tumor progression. This is the first study showing VD marker predictors of nivolumab concentrations in a real-life context of non-small cell lung cancer treatment. Full article
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Review

Jump to: Research

Open AccessReview Tumor Neovascularization and Developments in Therapeutics
Cancers 2019, 11(3), 316; https://doi.org/10.3390/cancers11030316
Received: 28 December 2018 / Revised: 28 February 2019 / Accepted: 4 March 2019 / Published: 6 March 2019
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Abstract
Tumors undergo fast neovascularization to support the rapid proliferation of cancer cells. Vasculature in tumors, unlike that in wound healing, is immature and affects the tumor microenvironment, resulting in hypoxia, acidosis, glucose starvation, immune cell infiltration, and decreased activity, all of which promote [...] Read more.
Tumors undergo fast neovascularization to support the rapid proliferation of cancer cells. Vasculature in tumors, unlike that in wound healing, is immature and affects the tumor microenvironment, resulting in hypoxia, acidosis, glucose starvation, immune cell infiltration, and decreased activity, all of which promote cancer progression, metastasis, and drug resistance. This innate defect of tumor vasculature can however represent a useful therapeutic target. Angiogenesis inhibitors targeting tumor vascular endothelial cells important for angiogenesis have attracted attention as cancer therapy agents that utilize features of the tumor microenvironment. While angiogenesis inhibitors have the advantage of targeting neovascularization factors common to all cancer types, some limitations to their deployment have emerged. Further understanding of the mechanism of tumor angiogenesis may contribute to the development of new antiangiogenic therapeutic approaches to control tumor invasion and metastasis. This review discusses the mechanism of tumor angiogenesis as well as angiogenesis inhibition therapy with antiangiogenic agents. Full article
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Open AccessReview Targeting the Tetraspanins with Monoclonal Antibodies in Oncology: Focus on Tspan8/Co-029
Cancers 2019, 11(2), 179; https://doi.org/10.3390/cancers11020179
Received: 19 December 2018 / Revised: 28 January 2019 / Accepted: 30 January 2019 / Published: 3 February 2019
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Abstract
Tetraspanins are exposed at the surface of cellular membranes, which allows for the fixation of cognate antibodies. Developing specific antibodies in conjunction with genetic data would largely contribute to deciphering their biological behavior. In this short review, we summarize the main functions of [...] Read more.
Tetraspanins are exposed at the surface of cellular membranes, which allows for the fixation of cognate antibodies. Developing specific antibodies in conjunction with genetic data would largely contribute to deciphering their biological behavior. In this short review, we summarize the main functions of Tspan8/Co-029 and its role in the biology of tumor cells. Based on data collected from recently reported studies, the possibilities of using antibodies to target Tspan8 in immunotherapy or radioimmunotherapy approaches are also discussed. Full article
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