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17 pages, 1643 KiB

Open AccessArticle

IL3RA-Targeting Antibody–Drug Conjugate BAY-943 with a Kinesin Spindle Protein Inhibitor Payload Shows Efficacy in Preclinical Models of Hematologic Malignancies

by Dennis Kirchhoff, Beatrix Stelte-Ludwig, Hans-Georg Lerchen, Antje Margret Wengner, Oliver von Ahsen, Pascale Buchmann, Stephan Märsch, Christoph Mahlert, Simone Greven, Lisa Dietz, Michael Erkelenz, Ruprecht Zierz, Sandra Johanssen, Dominik Mumberg and Anette Sommer

Cancers 2020, 12(11), 3464; https://doi.org/10.3390/cancers12113464 - 20 Nov 2020

Cited by 12 | Viewed by 4698

Abstract

IL3RA (CD123) is the alpha subunit of the interleukin 3 (IL-3) receptor, which regulates the proliferation, survival, and differentiation of hematopoietic cells. IL3RA is frequently expressed in acute myeloid leukemia (AML) and classical Hodgkin lymphoma (HL), presenting an opportunity to treat AML and [...] Read more.

IL3RA (CD123) is the alpha subunit of the interleukin 3 (IL-3) receptor, which regulates the proliferation, survival, and differentiation of hematopoietic cells. IL3RA is frequently expressed in acute myeloid leukemia (AML) and classical Hodgkin lymphoma (HL), presenting an opportunity to treat AML and HL with an IL3RA-directed antibody–drug conjugate (ADC). Here, we describe BAY-943 (IL3RA-ADC), a novel IL3RA-targeting ADC consisting of a humanized anti-IL3RA antibody conjugated to a potent proprietary kinesin spindle protein inhibitor (KSPi). In vitro, IL3RA-ADC showed potent and selective antiproliferative efficacy in a panel of IL3RA-expressing AML and HL cell lines. In vivo, IL3RA-ADC improved survival and reduced tumor burden in IL3RA-positive human AML cell line-derived (MOLM-13 and MV-4-11) as well as in patient-derived xenograft (PDX) models (AM7577 and AML11655) in mice. Furthermore, IL3RA-ADC induced complete tumor remission in 12 out of 13 mice in an IL3RA-positive HL cell line-derived xenograft model (HDLM-2). IL3RA-ADC was well-tolerated and showed no signs of thrombocytopenia, neutropenia, or liver toxicity in rats, or in cynomolgus monkeys when dosed up to 20 mg/kg. Overall, the preclinical results support the further development of BAY-943 as an innovative approach for the treatment of IL3RA-positive hematologic malignancies. Full article

(This article belongs to the Special Issue Therapeutic Monoclonal Antibodies and Antibody Products, Their Optimization and Drug Design in Cancers)

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14 pages, 3202 KiB

Open AccessArticle

An Antibody Specific for the Dog Leukocyte Antigen DR (DLA-DR) and Its Novel Methotrexate Conjugate Inhibit the Growth of Canine B Cell Lymphoma

by Marta Lisowska, Magdalena Milczarek, Jarosław Ciekot, Justyna Kutkowska, Wojciech Hildebrand, Andrzej Rapak and Arkadiusz Miazek

Cancers 2019, 11(10), 1438; https://doi.org/10.3390/cancers11101438 - 26 Sep 2019

Cited by 10 | Viewed by 4050

Abstract

Canine B-cell lymphoma (CBL) is an incurable, spontaneous lymphoid malignancy constituting an accurate animal model for testing novel therapeutic strategies in human medicine. Resources of available species-specific therapeutic monoclonal antibodies (mAbs) targeting CBL are scarce. The aim of the present study was to [...] Read more.

Canine B-cell lymphoma (CBL) is an incurable, spontaneous lymphoid malignancy constituting an accurate animal model for testing novel therapeutic strategies in human medicine. Resources of available species-specific therapeutic monoclonal antibodies (mAbs) targeting CBL are scarce. The aim of the present study was to evaluate the therapeutic potential of mAb B5, specific for the dog leukocyte antigen DR (DLA-DR) and its antibody-drug conjugate with methotrexate (B5-MTX). B5 induced caspase-dependent apoptosis of DLA-DR-expressing canine B cell lymphoma/CLBL1 and CLB70 leukemia lines, but not the GL-1 line not expressing DLA-DR. The cytotoxicity of B5-MTX to sensitive cells was further potentiated by a payload of MTX, but without any substantial off-target effects. The infusion of B5 and B5-MTX in a murine model of disseminated, advanced canine lymphoma, mediated >80% and >90% improvement in survival, respectively, and was well tolerated by the animals. Interestingly, the concentrations of soluble DLA-DR (sDLA-DR) antigens present in the blood serum of tumor-bearing mice were found proportional to the tumor burden. On this basis, sDLA-DR levels were evaluated as a potential biomarker using samples from canine lymphoma patients. In summary, the action of B5 and B5-MTX holds promise for further development as an alternative/complementary option for the diagnosis and treatment of canine lymphoma. Full article

(This article belongs to the Special Issue Therapeutic Monoclonal Antibodies and Antibody Products, Their Optimization and Drug Design in Cancers)

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19 pages, 10348 KiB

Open AccessArticle

Incorporation of a Hydrophilic Spacer Reduces Hepatic Uptake of HER2-Targeting Affibody–DM1 Drug Conjugates

by Haozhong Ding, Mohamed Altai, Sara S. Rinne, Anzhelika Vorobyeva, Vladimir Tolmachev, Torbjörn Gräslund and Anna Orlova

Cancers 2019, 11(8), 1168; https://doi.org/10.3390/cancers11081168 - 14 Aug 2019

Cited by 15 | Viewed by 4221

Abstract

Affibody molecules are small affinity-engineered scaffold proteins which can be engineered to bind to desired targets. The therapeutic potential of using an affibody molecule targeting HER2, fused to an albumin-binding domain (ABD) and conjugated with the cytotoxic maytansine derivate MC-DM1 (AffiDC), has been [...] Read more.

Affibody molecules are small affinity-engineered scaffold proteins which can be engineered to bind to desired targets. The therapeutic potential of using an affibody molecule targeting HER2, fused to an albumin-binding domain (ABD) and conjugated with the cytotoxic maytansine derivate MC-DM1 (AffiDC), has been validated. Biodistribution studies in mice revealed an elevated hepatic uptake of the AffiDC, but histopathological examination of livers showed no major signs of toxicity. However, previous clinical experience with antibody drug conjugates have revealed a moderate- to high-grade hepatotoxicity in treated patients, which merits efforts to also minimize hepatic uptake of the AffiDCs. In this study, the aim was to reduce the hepatic uptake of AffiDCs and optimize their in vivo targeting properties. We have investigated if incorporation of hydrophilic glutamate-based spacers adjacent to MC-DM1 in the AffiDC, (Z_HER2:2891)₂–ABD–MC-DM1, would counteract the hydrophobic nature of MC-DM1 and, hence, reduce hepatic uptake. Two new AffiDCs including either a triglutamate–spacer–, (Z_HER2:2891)₂–ABD–E₃–MC-DM1, or a hexaglutamate–spacer–, (Z_HER2:2891)₂–ABD–E₆–MC-DM1 next to the site of MC-DM1 conjugation were designed. We radiolabeled the hydrophilized AffiDCs and compared them, both in vitro and in vivo, with the previously investigated (Z_HER2:2891)₂–ABD–MC-DM1 drug conjugate containing no glutamate spacer. All three AffiDCs demonstrated specific binding to HER2 and comparable in vitro cytotoxicity. A comparative biodistribution study of the three radiolabeled AffiDCs showed that the addition of glutamates reduced drug accumulation in the liver while preserving the tumor uptake. These results confirmed the relation between DM1 hydrophobicity and liver accumulation. We believe that the drug development approach described here may also be useful for other affinity protein-based drug conjugates to further improve their in vivo properties and facilitate their clinical translatability. Full article

(This article belongs to the Special Issue Therapeutic Monoclonal Antibodies and Antibody Products, Their Optimization and Drug Design in Cancers)

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22 pages, 1915 KiB

Open AccessArticle

Synthesis and Enhanced Cellular Uptake In Vitro of Anti-HER2 Multifunctional Gold Nanoparticles

by Esteban Cruz and Veysel Kayser

Cancers 2019, 11(6), 870; https://doi.org/10.3390/cancers11060870 - 21 Jun 2019

Cited by 40 | Viewed by 8498

Abstract

Nanoparticle carriers offer the possibility of enhanced delivery of therapeutic payloads in tumor tissues due to tumor-selective accumulation through the enhanced permeability and retention effect (EPR). Gold nanoparticles (AuNP), in particular, possess highly appealing features for development as nanomedicines, such as biocompatibility, tunable [...] Read more.

Nanoparticle carriers offer the possibility of enhanced delivery of therapeutic payloads in tumor tissues due to tumor-selective accumulation through the enhanced permeability and retention effect (EPR). Gold nanoparticles (AuNP), in particular, possess highly appealing features for development as nanomedicines, such as biocompatibility, tunable optical properties and a remarkable ease of surface functionalization. Taking advantage of the latter, several strategies have been designed to increase treatment specificity of gold nanocarriers by attaching monoclonal antibodies on the surface, as a way to promote selective interactions with the targeted cells—an approach referred to as active-targeting. Here, we describe the synthesis of spherical gold nanoparticles surface-functionalized with an anti-HER2 antibody-drug conjugate (ADC) as an active targeting agent that carries a cytotoxic payload. In addition, we enhanced the intracellular delivery properties of the carrier by attaching a cell penetrating peptide to the active-targeted nanoparticles. We demonstrate that the antibody retains high receptor-affinity after the structural modifications performed for drug-conjugation and nanoparticle attachment. Furthermore, we show that antibody attachment increases cellular uptake in HER2 amplified cell lines selectively, and incorporation of the cell penetrating peptide leads to a further increase in cellular internalization. Nanoparticle-bound antibody-drug conjugates retain high antimitotic potency, which could contribute to a higher therapeutic index in high EPR tumors. Full article

(This article belongs to the Special Issue Therapeutic Monoclonal Antibodies and Antibody Products, Their Optimization and Drug Design in Cancers)

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13 pages, 3788 KiB

Open AccessArticle

An Fc-Optimized CD133 Antibody for Induction of Natural Killer Cell Reactivity Against Colorectal Cancer

by Bastian J. Schmied, Fabian Riegg, Latifa Zekri, Ludger Grosse-Hovest, Hans-Jörg Bühring, Gundram Jung and Helmut R. Salih

Cancers 2019, 11(6), 789; https://doi.org/10.3390/cancers11060789 - 7 Jun 2019

Cited by 13 | Viewed by 4620

Abstract

The introduction of monoclonal antibodies (mAbs) has largely improved treatment options for cancer patients. The ability of antitumor mAbs to elicit antibody-dependent cellular cytotoxicity (ADCC) contributes to a large extent to their therapeutic efficacy. Many efforts accordingly aim to improve this important function [...] Read more.

The introduction of monoclonal antibodies (mAbs) has largely improved treatment options for cancer patients. The ability of antitumor mAbs to elicit antibody-dependent cellular cytotoxicity (ADCC) contributes to a large extent to their therapeutic efficacy. Many efforts accordingly aim to improve this important function by engineering mAbs with Fc parts that display enhanced affinity to the Fc receptor CD16 expressed, e.g., on natural killer (NK) cells. Here we characterized the CD133 mAb 293C3-SDIE that contains an engineered Fc part modified by the amino acid exchanges S239D/I332E—that reportedly increase the affinity to CD16—with regard to its ability to induce NK reactivity against colorectal cancer (CRC). 293C3-SDIE was found to be a stable protein with favorable binding characteristics achieving saturating binding to CRC cells at concentrations of approximately 1 µg/mL. While not directly affecting CRC cell growth and viability, 293C3-SDIE potently induced NK cell activation, degranulation, secretion of Interferon-γ, as well as ADCC resulting in potent lysis of CRC cell lines. Based on the preclinical characterization presented in this study and the available data indicating that CD133 is broadly expressed in CRC and represents a negative prognostic marker, we conclude that 293C3-SDIE constitutes a promising therapeutic agent for the treatment of CRC and thus warrants clinical evaluation. Full article

(This article belongs to the Special Issue Therapeutic Monoclonal Antibodies and Antibody Products, Their Optimization and Drug Design in Cancers)

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16 pages, 3826 KiB

Open AccessArticle

Differential Effects of Ang-2/VEGF-A Inhibiting Antibodies in Combination with Radio- or Chemotherapy in Glioma

by Gergely Solecki, Matthias Osswald, Daniel Weber, Malte Glock, Miriam Ratliff, Hans-Joachim Müller, Oliver Krieter, Yvonne Kienast, Wolfgang Wick and Frank Winkler

Cancers 2019, 11(3), 314; https://doi.org/10.3390/cancers11030314 - 6 Mar 2019

Cited by 10 | Viewed by 5387

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

(This article belongs to the Special Issue Therapeutic Monoclonal Antibodies and Antibody Products, Their Optimization and Drug Design in Cancers)

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12 pages, 1881 KiB

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

by Maria Silvia Cona, Mara Lecchi, Sara Cresta, Silvia Damian, Michele Del Vecchio, Andrea Necchi, Marta Maria Poggi, Daniele Raggi, Giovanni Randon, Raffaele Ratta, Diego Signorelli, Claudio Vernieri, Filippo de Braud, Paolo Verderio and Massimo Di Nicola

Cancers 2019, 11(2), 223; https://doi.org/10.3390/cancers11020223 - 14 Feb 2019

Cited by 19 | Viewed by 4281

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

(This article belongs to the Special Issue Therapeutic Monoclonal Antibodies and Antibody Products, Their Optimization and Drug Design in Cancers)

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13 pages, 5078 KiB

Open AccessCommunication

The Risks and Benefits of Immune Checkpoint Blockade in Anti-AChR Antibody-Seropositive Non-Small Cell Lung Cancer Patients

by Koichi Saruwatari, Ryo Sato, Shunya Nakane, Shinya Sakata, Koutaro Takamatsu, Takayuki Jodai, Remi Mito, Yuko Horio, Sho Saeki, Yusuke Tomita and Takuro Sakagami

Cancers 2019, 11(2), 140; https://doi.org/10.3390/cancers11020140 - 24 Jan 2019

Cited by 21 | Viewed by 5160

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

(This article belongs to the Special Issue Therapeutic Monoclonal Antibodies and Antibody Products, Their Optimization and Drug Design in Cancers)

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12 pages, 1548 KiB

Open AccessArticle

Influence of Vitamin D in Advanced Non-Small Cell Lung Cancer Patients Treated with Nivolumab

by Jessica Cusato, Carlo Genova, Cristina Tomasello, Paolo Carrega, Selene Ottonello, Gabriella Pietra, Maria Cristina Mingari, Irene Cossu, Erika Rijavec, Anna Leggieri, Giovanni Di Perri, Maria Giovanna Dal Bello, Simona Coco, Simona Boccardo, Guido Ferlazzo, Francesco Grossi and Antonio D’Avolio

Cancers 2019, 11(1), 125; https://doi.org/10.3390/cancers11010125 - 21 Jan 2019

Cited by 13 | Viewed by 5438

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

(This article belongs to the Special Issue Therapeutic Monoclonal Antibodies and Antibody Products, Their Optimization and Drug Design in Cancers)

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Review

Jump to: Research

17 pages, 636 KiB

Open AccessReview

The Changing Paradigm for the Treatment of HER2-Positive Breast Cancer

by Aena Patel, Nisha Unni and Yan Peng

Cancers 2020, 12(8), 2081; https://doi.org/10.3390/cancers12082081 - 28 Jul 2020

Cited by 76 | Viewed by 11482

Abstract

For decades, HER2-positive breast cancer was associated with poor outcomes and higher mortality rates than other breast cancer subtypes. However, the advent of Trastuzumab (Herceptin) has significantly changed the treatment paradigm of patients afflicted with HER2-positive breast cancer. The discovery of newer HER2-targeted [...] Read more.

For decades, HER2-positive breast cancer was associated with poor outcomes and higher mortality rates than other breast cancer subtypes. However, the advent of Trastuzumab (Herceptin) has significantly changed the treatment paradigm of patients afflicted with HER2-positive breast cancer. The discovery of newer HER2-targeted therapies, such as Pertuzumab (Perjeta), has further added to the armamentarium of treating HER2-positive breast cancers. This review highlights recent advancements in the treatment of HER2-positive diseases, including the newer HER2-targeted therapies and immunotherapies in clinical trials, which have paved (and will further update) the way for clinical practice, and become part of the standard of care in the neoadjuvant, adjuvant or metastatic setting. Full article

(This article belongs to the Special Issue Therapeutic Monoclonal Antibodies and Antibody Products, Their Optimization and Drug Design in Cancers)

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15 pages, 303 KiB

Open AccessReview

Structure and Optimization of Checkpoint Inhibitors

by Sarah L. Picardo, Jeffrey Doi and Aaron R. Hansen

Cancers 2020, 12(1), 38; https://doi.org/10.3390/cancers12010038 - 21 Dec 2019

Cited by 41 | Viewed by 5901

Abstract

With the advent of checkpoint inhibitor treatment for various cancer types, the optimization of drug selection, pharmacokinetics and biomarker assays is an urgent and as yet unresolved dilemma for clinicians, pharmaceutical companies and researchers. Drugs which inhibit cytotoxic T-lymphocyte associated protein-4 (CTLA-4), such [...] Read more.

With the advent of checkpoint inhibitor treatment for various cancer types, the optimization of drug selection, pharmacokinetics and biomarker assays is an urgent and as yet unresolved dilemma for clinicians, pharmaceutical companies and researchers. Drugs which inhibit cytotoxic T-lymphocyte associated protein-4 (CTLA-4), such as ipilimumab and tremelimumab, programmed cell death protein-1 (PD-1), such as nivolumab and pembrolizumab, and programmed cell death ligand-1 (PD-L1), such as atezolizumab, durvalumab and avelumab, each appear to have varying pharmacokinetics and clinical activity in different cancer types. Each drug differs in terms of dosing, which becomes an issue when drug comparisons are attempted. Here, we examine the various checkpoint inhibitors currently used and in development. We discuss the antibodies and their protein targets, their pharmacokinetics as measured in various tumor types, and their binding affinities to their respective antigens. We also examine the various dosing regimens for these drugs and how they differ. Finally, we examine new developments and methods to optimize delivery and efficacy in the field of checkpoint inhibitors, including non-fucosylation, prodrug formations, bispecific antibodies, and newer small molecule and peptide checkpoint inhibitors. Full article

(This article belongs to the Special Issue Therapeutic Monoclonal Antibodies and Antibody Products, Their Optimization and Drug Design in Cancers)

24 pages, 659 KiB

Open AccessFeature PaperReview

Therapeutic Monoclonal Antibodies and Antibody Products: Current Practices and Development in Multiple Myeloma

by Francesca Bonello, Roberto Mina, Mario Boccadoro and Francesca Gay

Cancers 2020, 12(1), 15; https://doi.org/10.3390/cancers12010015 - 19 Dec 2019

Cited by 35 | Viewed by 6765

Abstract

Immunotherapy is the latest innovation for the treatment of multiple myeloma (MM). Monoclonal antibodies (mAbs) entered the clinical practice and are under evaluation in clinical trials. MAbs can target highly selective and specific antigens on the cell surface of MM cells causing cell [...] Read more.

Immunotherapy is the latest innovation for the treatment of multiple myeloma (MM). Monoclonal antibodies (mAbs) entered the clinical practice and are under evaluation in clinical trials. MAbs can target highly selective and specific antigens on the cell surface of MM cells causing cell death (CD38 and CS1), convey specific cytotoxic drugs (antibody-drug conjugates), remove the breaks of the immune system (programmed death 1 (PD-1) and PD-ligand 1/2 (L1/L2) axis), or boost it against myeloma cells (bi-specific mAbs and T cell engagers). Two mAbs have been approved for the treatment of MM: the anti-CD38 daratumumab for newly-diagnosed and relapsed/refractory patients and the anti-CS1 elotuzumab in the relapse setting. These compounds are under investigation in clinical trials to explore their synergy with other anti-MM regimens, both in the front-line and relapse settings. Other antibodies targeting various antigens are under evaluation. B cell maturation antigens (BCMAs), selectively expressed on plasma cells, emerged as a promising target and several compounds targeting it have been developed. Encouraging results have been reported with antibody drug conjugates (e.g., GSK2857916) and bispecific T cell engagers (BiTEs^®), including AMG420, which re-directs T cell-mediated cytotoxicity against MM cells. Here, we present an overview on mAbs currently approved for the treatment of MM and promising compounds under investigation. Full article

(This article belongs to the Special Issue Therapeutic Monoclonal Antibodies and Antibody Products, Their Optimization and Drug Design in Cancers)

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21 pages, 1579 KiB

Open AccessReview

Targeting Negative and Positive Immune Checkpoints with Monoclonal Antibodies in Therapy of Cancer

by Katsiaryna Marhelava, Zofia Pilch, Malgorzata Bajor, Agnieszka Graczyk-Jarzynka and Radoslaw Zagozdzon

Cancers 2019, 11(11), 1756; https://doi.org/10.3390/cancers11111756 - 8 Nov 2019

Cited by 102 | Viewed by 8437

Abstract

The immune checkpoints are regulatory molecules that maintain immune homeostasis in physiological conditions. By sending T cells a series of co-stimulatory or co-inhibitory signals via receptors, immune checkpoints can both protect healthy tissues from adaptive immune response and activate lymphocytes to remove pathogens [...] Read more.

The immune checkpoints are regulatory molecules that maintain immune homeostasis in physiological conditions. By sending T cells a series of co-stimulatory or co-inhibitory signals via receptors, immune checkpoints can both protect healthy tissues from adaptive immune response and activate lymphocytes to remove pathogens effectively. However, due to their mode of action, suppressive immune checkpoints may serve as unwanted protection for cancer cells. To restore the functioning of the immune system and make the patient’s immune cells able to recognize and destroy tumors, monoclonal antibodies are broadly used in cancer immunotherapy to block the suppressive or to stimulate the positive immune checkpoints. In this review, we aim to present the current state of application of monoclonal antibodies in clinics, used either as single agents or in a combined treatment. We discuss the limitations of these therapies and possible problem-solving with combined treatment approaches involving both non-biological and biological agents. We also highlight the most promising strategies based on the use of monoclonal or bispecific antibodies targeted on immune checkpoints other than currently implemented in clinics. Full article

(This article belongs to the Special Issue Therapeutic Monoclonal Antibodies and Antibody Products, Their Optimization and Drug Design in Cancers)

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33 pages, 886 KiB

Open AccessReview

Monoclonal Antibodies in Dermatooncology—State of the Art and Future Perspectives

by Malgorzata Bobrowicz, Radoslaw Zagozdzon, Joanna Domagala, Roberta Vasconcelos-Berg, Emmanuella Guenova and Magdalena Winiarska

Cancers 2019, 11(10), 1420; https://doi.org/10.3390/cancers11101420 - 24 Sep 2019

Cited by 9 | Viewed by 4939

Abstract

Monoclonal antibodies (mAbs) targeting specific proteins are currently the most popular form of immunotherapy used in the treatment of cancer and other non-malignant diseases. Since the first approval of anti-CD20 mAb rituximab in 1997 for the treatment of B-cell malignancies, the market is [...] Read more.

Monoclonal antibodies (mAbs) targeting specific proteins are currently the most popular form of immunotherapy used in the treatment of cancer and other non-malignant diseases. Since the first approval of anti-CD20 mAb rituximab in 1997 for the treatment of B-cell malignancies, the market is continuously booming and the clinically used mAbs have undergone a remarkable evolution. Novel molecular targets are constantly emerging and the development of genetic engineering have facilitated the introduction of modified mAbs with improved safety and increased capabilities to activate the effector mechanisms of the immune system. Next to their remarkable success in hematooncology, mAbs have also an already established role in the treatment of solid malignancies. The recent development of mAbs targeting the immune checkpoints has opened new avenues for the use of this form of immunotherapy, also in the immune-rich milieu of the skin. In this review we aim at presenting a comprehensive view of mAbs’ application in the modern treatment of skin cancer. We present the characteristics and efficacy of mAbs currently used in dermatooncology and summarize the recent clinical trials in the field. We discuss the side effects and strategies for their managing. Full article

(This article belongs to the Special Issue Therapeutic Monoclonal Antibodies and Antibody Products, Their Optimization and Drug Design in Cancers)

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16 pages, 4253 KiB

Open AccessReview

Tumor Neovascularization and Developments in Therapeutics

by Yuki Katayama, Junji Uchino, Yusuke Chihara, Nobuyo Tamiya, Yoshiko Kaneko, Tadaaki Yamada and Koichi Takayama

Cancers 2019, 11(3), 316; https://doi.org/10.3390/cancers11030316 - 6 Mar 2019

Cited by 98 | Viewed by 7430

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

(This article belongs to the Special Issue Therapeutic Monoclonal Antibodies and Antibody Products, Their Optimization and Drug Design in Cancers)

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14 pages, 2369 KiB

Open AccessReview

Targeting the Tetraspanins with Monoclonal Antibodies in Oncology: Focus on Tspan8/Co-029

by Mathilde Bonnet, Aurélie Maisonial-Besset, Yingying Zhu, Tiffany Witkowski, Gwenaëlle Roche, Claude Boucheix, Céline Greco and Françoise Degoul

Cancers 2019, 11(2), 179; https://doi.org/10.3390/cancers11020179 - 3 Feb 2019

Cited by 25 | Viewed by 4571

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

(This article belongs to the Special Issue Therapeutic Monoclonal Antibodies and Antibody Products, Their Optimization and Drug Design in Cancers)

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